Addressing Areas of Public Health Emphasis

Research on Tobacco and Tobacco-Related Cancers

The Opportunity

Lung cancer, the leading cause of cancer death, would be a rare disease in the absence of smoking. Smoking is the leading cause of cancers of the lung, mouth, larynx, esophagus, and bladder, and plays a role in cancers of the pancreas, cervix, and kidney. The devastating impact of tobacco use and tobacco smoke exposure on the incidence of cancer, heart disease, lung disease, stroke and other serious illnesses is both compelling and conclusive. Tobacco use causes more premature death (approximately 430,000 per year in the United States) than do all drugs of abuse combined. In 2002, about 170,000 people will die of cancer because of their use of tobacco products.

A major challenge in the fight against tobacco-related cancers is that addiction to nicotine drives the continued use of tobacco even when the user is fully aware of increased risk of disease and premature death. Some people will continue to smoke even as they undergo treatment for a life-threatening disease.

NCI's commitment to preventing, diagnosing, and treating tobacco-related cancers began more than 40 years ago and remains one of the Institute's highest priorities. To remain at the leading edge of this important area of research, NCI must devote additional resources to address the complex challenges of tobacco use. Research recommendations related to tobacco control made by NCI's Lung Cancer Progress Review Group echo many of the Institute's ongoing and planned research priorities, such as:

• Developing and expanding new approaches to the biology and treatment of nicotine addiction.
• Conducting basic biological research on the effects of tobacco exposures including the differential toxicity of various tobacco products.
• Continuing and evaluating current and planned population-based tobacco control efforts.
• Detecting and treating tobacco-related cancers and metastatic disease.

NCI also has a special concern for the health of former smokers who, despite quitting, now comprise about half of those diagnosed with lung cancer. The development and marketing of new tobacco products also is of great concern. Smokers may feel a false sense of security that they can significantly reduce their risk of disease by using these new products, when no data exists to suggest that they are in fact less harmful. Scientists must examine the toxicity of these products as well as evaluate whether or not "harm reduction" is a viable public health strategy. NCI's commitment to research on tobacco and tobacco related cancers is reflected in our investments both in basic biological research on the effects of tobacco exposures and in community-based studies of smoking prevention and cessation programs.

Progress in Pursuit of Our Goal

Defining Biological, Behavioral, and Social Bases of Tobacco Use and Addiction

NCI is advancing tobacco research to answer questions related to understanding why people - adults and youth - begin to use tobacco, become addicted, and have difficulty stopping use of tobacco products, and the genetic and environmental factors that influence tobacco use and addiction. Through a number of promising initiatives, NCI is advancing tobacco research to answer these questions.

Funding for Transdisciplinary Tobacco Use Research Centers (TTURCs), located within seven academic institutions, is approaching its fourth year of sponsorship by NCI, the National Institute on Drug Abuse (NIDA), and the Robert Wood Johnson Foundation. These centers are supporting a broad array of studies, including projects evaluating new models of nicotine addiction, the role of genetic and environmental factors in smoking initiation and persistence, methods for preventing tobacco use across cultures, and determinants of relapse. TTURC sponsored research continues to inform us.

• Certain genes regulating the activity of the neurotransmitter dopamine help determine which smokers are able to quit. Although these genes did not appear to influence the effectiveness of the medication bupropion, another gene involved in drug metabolism did predict therapeutic response to treatment. This research has implications for matching individual smokers to treatments that are effective, thereby potentially saving considerable frustration and cost for both patients and their healthcare providers.
• Older adolescence, peer smoking, cigarette availability, depression, delinquency, and alcohol use are factors that influence smoking progression in youth. Investigators also found that prenatal exposure to nicotine increases the likelihood that a smoker will progress to regular use. This information is being used to develop cessation programs for high-risk adolescents.
• Other research is revealing links between specific personality traits and early initiation of smoking. Teenagers with a combination of aggressive and depressive characteristics are at an elevated risk for cigarette smoking. Moreover, depressed adolescents who are highly receptive to tobacco advertising are also at higher risk. These findings lead researchers to believe that tailoring prevention and intervention efforts to encompass these factors could lead to a reduction in youth smoking.

NCI supports 50 research projects related to the prevention and cessation of tobacco use by children and youth. This wealth of cutting-edge research is beginning to yield insights into nicotine addiction and dependence. Studies reveal that adolescent smokers can experience withdrawal symptoms within one month of smoking initiation. A recently published study showed that not all tobacco dependence in youth is physiological, but that psychological determinants of dependence are equally significant. The authors of this study offered a theory whereby loss of autonomy signals onset of dependence. Loss of autonomy occurs when either the physical or psychological effects of nicotine present a barrier to quitting. Their work resulted in the "Hooked on Nicotine Checklist," a self-administered questionnaire that helps smokers identify ten warning signs of nicotine addiction. This measure offers a validated, theoretically based tool that measures dependence.

The Surgeon General's Report on Women and Smoking, released in 2001, highlights the need to build the science base on gender-specific outcomes related to smoking and to reduce health disparities among women. NCI, in partnership with the NIH Office of Research on Women's Health and the Department of Health and Human Services (DHHS) Office of Women's Health, the American Cancer Society, and other agencies and organizations will hold a conference focused on women, tobacco, and cancer. The conference will focus on research to better understand the cancer-related biological effect and behavioral factors related to tobacco use and /or exposure to environmental tobacco smoke.

Results from a recent study of prevalence and predictors of tobacco use among Asian Americans highlights the need for culturally tailored prevention, cessation, and treatment interventions. Investigators collected data on 1174 Chinese, Korean, Vietnamese, and Cambodian respondents in the Delaware Valley Region of the United States and found that 40.2 percent of respondents had a history of tobacco use and 29.6 percent were current users. Men were more likely than women to smoke, and there were significant differences among never smokers, current smokers, and ex-smokers by sex, ethnicity, educational attainment, and marital status. This study suggests the need to further examine subgroup differences among Asian American populations to develop more specific culturally tailored interventions.

Preventing Tobacco Use and Treating Addiction

NCI has a number of initiatives to prevent and treat nicotine addiction. Research supported through TTURCs, the State and Community Tobacco Control Intervention initiative, and many of the youth and tobacco research projects is producing important new insights and knowledge about the social, biobehavioral, and genetic factors that influence tobacco use and addiction. To complement these efforts, NCI and NIDA initiated a Working Group on Medication Development for Nicotine Addiction that explores ways to draw upon NIDA's expertise in addiction research as well as NCI's experience in drug development.

In 2002, NCI opened the doors to the Tobacco Intervention Research Clinic, a state-of-the-science center for tobacco use research by NCI scientists and collaborators, including those in the NCI and other NIH intramural programs. The clinic will be a resource for NIH scientists conducting a range of genetic, epidemiological, basic science, and behavioral research studies and could provide research-based tobacco cessation services to patients from the NIH community.

Disseminating Information Related to Tobacco Use and Addiction

Translating Research Into Improved Outcomes (TRIO) offers funding opportunities to current NCI-funded investigators to support critical dissemination of promising interventions in the field of tobacco use and other cancer control areas. NCI is also actively involved in a public-private collaborative effort to develop a National Blueprint for Disseminating and Implementing Evidenced-Based Clinical and Community Strategies to Promote Tobacco-Use Cessation. These guidelines identify effective cessation interventions and recommend application in clinics, healthcare systems, and communities to support tobacco users who want to quit smoking.

Preventing and Treating Tobacco-Related Cancers

The Lung Cancer Study, a pilot for the National Lung Cancer Screening Trial (NLST), began in 2000 to assess the feasibility of spiral computed tomography (CT or CAT) scan to detect early lung cancers. Healthy men and women aged 55 to 74, who are current or former smokers, are being recruited for NLST, which will be conducted at approximately 30 centers throughout the United States. As a vital effort to reduce the toll of lung cancer, the NLST will compare the spiral CT scan to a standard chest x-ray, both currently used to detect lung cancer at an early stage. The aim of the study is to show which test is better at reducing deaths from the disease.

NCI is funding preclinical and clinical studies to identify newer, more potent agents that may prevent cancers in former smokers. The preclinical studies focus on validating surrogate biomarkers for tobacco-related cancers in animal models under experimental protocols that mimic the high-risk smoker. These studies will identify and prioritize agents that prevent cancers in tobacco-susceptible organ systems.

The clinical research initiative is supporting four clinical trials evaluating the efficacy of chemopreventive agents in specified cohorts of former smokers. A variety of novel biomarkers as well as imaging modalities, such as the spiral CT scan, are being examined with regard to their potential utility in chemopreventive studies.

A recently developed mouse model for lung adenocarcinoma, a common human tumor associated with tobacco use, has helped scientists identify the specific pathway to tumor genesis. This information from the mouse may help to better predict treatment outcomes for patients with the same gene profile. Investigators with the Mouse Models of Human Cancer Consortium developed the model.

Understanding the Interplay Among Tobacco, Other Exposures, and Cancer

NCI is pursuing research opportunities to better understand the interplay among tobacco and other exposures such as alcohol and radon, and a person's cancer risk. This work involves resource intensive, longitudinal, screening and cohort studies that may involve genetic and biomarker components from tissue, blood, urine, sputum, and other body fluids.

Several studies within the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trials are specifically focusing on tobacco exposure and cancer. These studies are examining the relationship between tobacco and colon adenomas, a comparison of patients with emphysema, and a control group (persons without cancer or related symptoms) to identify genetic factors that may influence susceptibility to this condition. Another investigation will target current and former smokers to identify candidate genes thought to influence smoking.

The Cohort Consortium, a group of investigators involved in separate prospective studies of large population groups, will expand their investigation beyond looking at breast and prostate cancer to identifying and studying tobacco-related cancers. These researchers will investigate a rare subtype of lung adenocarcinoma; lung cancer in young people, non-smokers, and families; and rarer tobacco-related tumors such as pancreas and nasal sinuses. Efforts are underway to collect tissue from a broader group of PLCO participants to allow high-throughput analysis of new markers of patients with specific cancers.

Additional relevant studies are yielding information on cancer risk related to the interplay among tobacco and other exposures:

• An interview study found a three-fold excess risk of esophageal cancer for those in the highest quartile of body mass. In addition to a predisposition of obese individuals to gastroesophageal reflux disease, an association was found with cigarette smoking, with little reduction in risk until 30 years after smoking cessation.
• A large case-control study of bladder cancer is ongoing in New England region of the United States and Spain to identify occupational bladder carcinogens and to evaluate cigarette smoking (black vs. blond tobacco in Spain) as well as phenacetin-containing analgesics, dietary factors, urination frequency, and pH. Genetic susceptibility markers will be evaluated in relation to bladder cancer risk as well as their interaction with environmental, occupational, and tobacco risk factors.

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The Plan - Research on Tobacco and Tobacco-Related Cancers

Understand the causes of tobacco use, addiction, and tobacco-related cancers and apply this knowledge to their prevention and treatment.

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International Activities

The World Health Organization (WHO) estimates that four million people die each year worldwide from tobacco-related illness, and if current trends continue, this figure will rise to about 10 million per year by 2030, with 70 percent of those deaths occurring in the developing world. There are approximately 1.25 billion smokers in the world with the majority of them (800 million) in developing countries. Examples of NCI support of global tobacco research include:

• Jointly sponsoring the Symposium on Tobacco-Related Cancers with the Japan Society for the Promotion of Science, in February 2002, to bring together international researchers to address molecular, epidemiology, behavioral, cancer control, and clinical aspects of these cancers.
• Co-hosting the Third International Conference on Smokeless Tobacco, September 2002, with the Centers for Disease Control and Prevention and the Sweden Centre for Tobacco Prevention.
• Providing $1.7 million over the next several years to extend and enhance the research interests of U.S. and collaborating foreign scientists and institutions to combat the growing incidence of tobacco-related illness in the developing world, through the International Tobacco and Health Research and Capacity Building program, led by the NIH Fogarty International Center.
• Initiating tobacco-related research activities as part of the prevention working group within the Ireland-Northern Ireland-NCI Consortium.
• Initiating a multi-institutional population based case-control study of lung cancer and smoking in Milan, Italy. This study of 4500 subjects investigates the genetics of nicotine addiction and lung cancer.

Public and Private Partnerships and Collaborations

In support of collaborative tobacco research efforts, NCI is:

• Supporting seven Transdisciplinary Tobacco Use Research Centers along with the National Institute on Drug Abuse (NIDA) and the Robert Wood Johnson (RWJ) Foundation to integrate tobacco-related research on genetic susceptibility, sociocultural factors, innovative treatments, and healthcare policy.
• Facilitating an NCI/NIDA Working Group on Medication Development for Nicotine Addiction to develop targeted new treatments.
• Partnering with 10 other public and private organizations to develop a "National Blueprint for Disseminating and Implementing Evidence-Based Clinical and Community Strategies to Promote Tobacco-Use Cessation."
• Organizing and sponsoring a Women, Tobacco, and Cancer Conference with the NIH Office of Research on Women's Health and DHHS Office of Women's Health, the American Cancer Society, the American Legacy Foundation, and others to identify and prioritize research strategies which will ultimately raise awareness and knowledge about the impact of smoking on women and adolescent girls.
• Sponsoring a National Tobacco Monitoring Research and Evaluation Workshop, in November 2002, along with the Centers for Disease Control and Prevention, RWJ, and American Legacy Foundation, to improve the utility of existing tobacco use surveillance systems.
• Participating in NOTURF (National Organization for Tobacco Use Research Funders), a consortium of research funding organizations in the United States and Canada dedicated to fostering communication and action around tobacco research.

Telephone-Based Intervention for Smoking Cessation

The use of telephone-based intervention for smoking cessation is a core component of behavioral interventions for smokers who want to quit. NCI provides this service through the CIS, providing accurate cancer information in English and Spanish to citizens in the United States, Puerto Rico, and the U.S. Virgin Islands and territories in Guam and Saipan, via a toll free number. NCI's Smoking Cessation Service serves smokers by:

• Assessing the caller's individual smoking behavior.
• Providing brief educational messages.
• Helping callers develop a personalized action plan for quitting.
• Reinforcing the information with written materials.