"It was the unanimous and fundamental conclusion of the Tobacco Research Implementation Group that an unequivocal commitment
of the NCI to a comprehensive
but focused program of research on tobacco use can help to reverse
the epidemic of tobacco-related cancers."

Tobacco-related cancers exact an exorbitant toll on the Nation's public health. Tobacco use in the United States is responsible for over 450,000 total deaths and 170,000 cancer deaths every year. More than 30 percent of all cancer deaths are caused by tobacco. The magnitude and complexity of the public health problem created by tobacco use and its accompanying diseases heighten the importance of the National Cancer Institute's (NCI) tobacco-related research.

A constellation of scientific advances, public policy, and social and legal developments presents the scientific community with an unprecedented opportunity to expand research that can dramatically reduce the burden of death and disease caused by tobacco use. Seizing that opportunity, however, poses significant challenges for the NCI and the research and public health communities. In a field where every need seems pressing, it is imperative that we meet the challenge of identifying where tobacco-related research is most needed and how best to prioritize and achieve research objectives that will be financially responsible and have the greatest impact.

To accomplish this goal, the Director of the NCI created the Tobacco Research Implementation Group (TRIG), which includes more than two dozen leading scientists and experts from within the NCI, the National Institute on Drug Abuse (NIDA), and the Office of Behavioral and Social Sciences Research (Office of the Director), and from the extramural research community, as well as representatives of major NCI review and advisory committees. The TRIG was charged with establishing the NCI's tobacco-related cancer research priorities for the next 5 to 7 years.

The TRIG began by reviewing the extensive recommendations of four earlier advisory groups. Each of these earlier reports produced major recommendations for tobacco control research; however, no single previous report considered the entire spectrum of tobacco control research, from basic biological research to dissemination research. Furthermore, a number of the recommendations of these earlier review groups already had been partially or completely implemented. Therefore, in addition to reviewing these earlier reports, the TRIG analyzed NCI's current portfolio of tobacco research. Finally, the group sought input from representatives of other Federal agencies and private organizations around the Nation.

Through a consensus-building process, the TRIG identified and prioritized a core set of tobacco-related cancer research opportunities. Within this core set, nine unique, overarching research opportunities were identified as the highest priorities, requiring immediate implementation. These opportunities cover the range of tobacco control research from basic biological and basic biobehavioral research to clinical intervention, policy, epidemiology, surveillance research, and support for research infrastructure. The research priorities presented in this report also emphasize the unique opportunities and challenges of tobacco initiation, regular use, addiction, and cessation among youth and populations at disproportionate risk.

The TRIG emphasized that formation of strategic partnerships in the implementation of this research agenda is critical for success. The NCI must collaborate with partners in both the public and private sectors, such as NIDA, the Centers for Disease Control and Prevention, the American Cancer Society, and the Robert Wood Johnson Foundation.

This report includes two main components. A detailed Executive Summary is provided for readers who want an overview of the top recommendations. The full report, following the Executive Summary, provides a detailed background and rationale for the highest priorities and other important research recommendations. The considerable overlap between the Executive Summary and the report was crafted by design to meet the needs of different readers. The nine highest priorities are summarized below.

  1. Transdisciplinary Tobacco Research Centers should be created to study the initiation of tobacco use, prevention of tobacco use, addiction to tobacco, and/or treatment of tobacco addiction and tobacco-related cancers.

    Increasingly, tobacco control research must rely on transdisciplinary teams of experts in diverse areas, including, but not limited to, genetics, epidemiology, tobacco-induced carcinogenesis, medicine, health psychology and other behavioral/social sciences, policy, and marketing. Specialized, transdisciplinary tobacco research centers should embrace a range of disciplines and investigations, consolidate expertise, facilitate collaboration, and provide the foundation for major scientific advances as well as productive training programs that address the urgent need for producing the next generation of tobacco researchers. Within the broad spectrum of tobacco research, the levels of specialization would vary from center to center. All centers would focus on priority issues, where major gaps in knowledge (e.g., adolescent smoking) create important barriers to advancing the field. Such centers would provide unique opportunities for innovative approaches to research. The TRIG has made creation of these centers its top priority, envisioning them as part of a collaborative funding effort among NIH partners, especially the National Institute on Drug Abuse (NIDA), and private foundations. The centers are the most effective way to achieve the Institute's priorities in all areas of tobacco research. These centers should lead the Nation and the world in conducting tobacco research and in discovering new ways to combat tobacco use and its consequences. 

  2. Basic biobehavioral research should be conducted to understand the sociocultural, psychological, physiological, and genetic factors that influence the initiation of tobacco use, progression to nicotine addiction, and smoking cessation among children, adolescents, and adults.

    Among the critical and fundamental unanswered questions facing researchers is why some people adopt or cease tobacco use, while others do not. Tobacco use results from a complex interplay of biological, behavioral, and environmental influences. Gaps in fundamental knowledge about tobacco adoption, maintenance, and cessation highlight the need for research to understand the interacting effects of these influences. Recent research breakthroughs in genetics now make it possible to examine the complex biological and behavioral foundations of tobacco use and nicotine addiction. For example, recent studies have identified genes that modify nicotine metabolism and the activity of neurochemicals that affect the reinforcing properties of nicotine. There also have been new findings concerning important biological differences in nicotine metabolism among individuals and ethnic groups. Research in this area may identify innate vulnerabilities to tobacco use and addiction in the context of sociocultural and psychological influences. Research to determine the critical thresholds for progression from occasional use of tobacco products to nicotine addiction would aid in identifying appropriate levels of intervention at different stages of tobacco use. In this effort, special attention must be given to the primary and interactive effects of developmental factors, psychological comorbid disorders, and tobacco product design and marketing influences. Research also is needed into the basic neurobiological processes and mechanisms related to nicotine addiction. Research in animals and cellular models would be needed since these processes and mechanisms would most likely entail cellular and molecular studies of the brain. This research will lead to improved treatments and intervention programs by increasing understanding of the biobehavioral underpinnings of tobacco use and nicotine dependence. This will help clinicians and public health providers better target prevention and treatment strategies. Much of the research in this area should be conducted in partnership with NIDA. 

  3. Research concerning the treatment of nicotine addiction should be conducted to find the best ways to tailor tobacco cessation interventions to specific sociocultural, psychological, physiological, and genetic subgroups.

    As new pharmacological treatment products become available, research is needed to evaluate and maximize their effectiveness in specific patient populations. Research also is needed to evaluate the relative effectiveness of behavioral modification approaches and pharmacological therapies, treatments that combine the two, and combinations of pharmacologic agents. These new combinations hold particular promise for increasing tobacco cessation rates. This research also will determine the effectiveness of these approaches for different subgroups of tobacco users, such as heavy smokers, pregnant women, African-Americans, and adolescents. It will help define optimal treatment for individuals with different psychological, physiological, or genetic profiles. Advances in genetics may offer many new and unexpected opportunities for the rational tailoring and matching of treatments to individuals based on genotype. The new digital electronic media also can be used, in combination with other strategies, to tailor programs based on information needs and preferences. Much of the research in this area should be conducted in partnership with NIDA. 

  4. Research should be conducted to improve community and state tobacco control programs and to increase the effectiveness of these programs for populations at disproportionate risk.

    Ultimately, promising interventions developed through research should be assessed at the community and state levels. Understanding societal influences on the decision to use tobacco is critical to reducing the tobacco-related disease burden. The need for useful research on the effectiveness of community and state interventions to reduce tobacco use has never been greater. New tobacco control programs are underway in almost every state, and major questions remain about the relative effectiveness of different components of these programs. Additionally, new validated measurement tools and systems to support this complex research are needed. Research in this area will provide a scientific basis for designing and implementing effective interventions, such as counter-advertising campaigns, and for improving a wide range of other programs that prevent the initiation of tobacco use and promote cessation. In developing these community and state tobacco control programs, special emphasis should be given to high-risk populations, especially low-income groups, where tobacco use is increasingly concentrated. The wide-ranging impact of state programs on large populations has been well documented, and further research can increase the effectiveness of these programs. 

  5. Research should be conducted to identify mechanisms for optimal dissemination of proven prevention and treatment interventions at the community and state levels.

    As interventions for prevention and treatment are found to be effective in particular population groups, dissemination and diffusion trials are needed to evaluate the optimal methods for applying these approaches within entire health care systems and at the national, state, and community levels. There has been only modest attention to the challenging question of how to disseminate evidence-based tobacco control programs. Yet, there are exciting opportunities to adapt and disseminate proven interventions. For example, we know that few Americans (particularly the poor) currently have access to the most effective school-based prevention programs or to physician counseling and self-help cessation programs. There is a great need for a stronger science of dissemination and technology transfer and for research to evaluate polices and strategies that increase dissemination. Research also is needed to determine the types of system change needed to institutionalize tobacco control interventions. Effective dissemination of proven interventions will have a significant impact on tobacco use. 

  6. Research should be conducted to understand the impact of tobacco policies, including taxation and pricing, clean indoor air policies, marketing restrictions, youth access restrictions, and tobacco product and nicotine replacement regulation.

    Policy research can potentially influence some of the most wide-ranging interventions currently used in tobacco control. Public and private policies, such as those listed above, can reduce tobacco use among populations of entire states and nations. For example, policies that increase the price of tobacco, restrict its marketing, and limit where it can be used have resulted in a decrease in tobacco use. But numerous questions remain about the impact of other types of policies, such as youth access restrictions, as well as the relationship between policies and tobacco adoption, use, addiction, and cessation. For example, how do tobacco advertising and promotion interact with biobehavioral factors to increase youth susceptibility to tobacco use? How does product design, including amount of nicotine and mode of delivery, influence nicotine use and dependence among users? And what are the relative costs and benefits of mandating Medicaid coverage for nicotine addiction treatment? Additionally, opportunities exist to learn from effective foreign tobacco control policies, and the NCI is uniquely positioned to take the lead in research examining cross-national policy differences. International research could be especially useful in clarifying the impact of advertising restrictions on tobacco use. 

  7. Basic biological research should be conducted to identify and validate biomarkers of tobacco exposure and tobacco-induced cellular events as they relate to the different stages of carcinogenesis.

    Recent advances in defining the genetic and epigenetic basis of cancer will allow us to expand knowledge of the origins and processes of tobacco-induced cancers. This should lead to new ways to prevent, detect, diagnose, and treat cancer and discover why tobacco-related cancers are so difficult to cure. The focus of our recommendation is on biomarker development founded upon basic carcinogenesis research that will broaden the approach to risk assessment of people exposed to tobacco and allow for rational selection of biomarkers. These biomarkers include carcinogen-macromolecular adducts, assays to measure enzymes involved in critical cellular processes, methods to detect DNA damage and decreased DNA repair, RNA-based methods to identify changes in expression, genetic variations that increase vulnerability or resistance to cancer-causing chemicals, and metabolites of procarcinogens or cancer-causing agents. Basic research to explore mechanisms of tobacco-induced molecular damage at different stages of carcinogenesis will increase understanding of how tobacco carcinogens cause their deleterious effects and what the specific molecular changes and genetic targets are for these effects. More knowledge is required about how tobacco smoke carcinogens drive the stages of carcinogenesis, leading from early, preneoplastic events to tumor growth and metastasis, as well as how these carcinogens affect cancer susceptibility genes that have caretaker and gatekeeper functions within the cell. Research to understand these basic changes and to identify and validate biological markers is essential. The identification and validation of biomarkers, based upon new understandings of tobacco-induced carcinogenesis, will allow us to evaluate populations where we can directly assess human cancer risk using a wide range of biomarkers that represent different effects on the cell at the various stages of carcinogenesis. Ultimately, this knowledge will lead to more rational prevention methods and ways to identify who is at risk for the most aggressive cancers. Finally, basic biological research can make critically important contributions by examining tobacco-induced carcinogenesis in women and in former smokers. 

  8. Research should be conducted to understand genetic and environmental interactions in susceptibility to tobacco-related cancers in order to identify subgroups at risk.

    Molecular and genetic epidemiology studies are needed to determine if tobacco-related cancer risks differ according to factors such as gender, race, and ethnicity and to discover the genetic and other biological factors responsible for these differences. Tobacco use provides an ideal model for the study of gene-environmental interactions. Continued study of interactions among multiple genes and between genetic and environmental factors is needed to increase understanding of why some individuals get cancer from smoking, but others are spared, and to develop methods for reducing risk of tobacco-related cancers. A better understanding of the independent and interacting effects of inherited susceptibilities and tobacco-exposure variables could elucidate risk profiles and the biological mechanisms involved in the development of cancer. This knowledge could lead to the development of tailored approaches to prevention and treatment of tobacco-related cancers. Highly targeted chemopreventive agents or cancer therapies could be developed for use by individuals with particular genotypes. It will be particularly important to study the effects of susceptibility to tobacco-related cancers in women who have been understudied in previous research and in former smokers who appear to be at continued risk for cancer development. Chemopreventive agents can also be used to treat former smokers, who remain at increased risk for lung cancer for years following cessation because of persistent carcinogen effects at the cellular and genetic levels. Finally, studies of youth and young adults (and especially cohort studies) may lead to a better understanding of the process of nicotine addiction as well as genetic and environmental factors that predispose individuals to this problem. 

  9. Research should be conducted on expanded surveillance systems to monitor tobacco use behaviors, the implementation and fidelity of tobacco-related interventions, and other factors that influence tobacco use.

    Surveillance research is critical to an effective, comprehensive tobacco control research program and is an integral and necessary component of a comprehensive research portfolio. Today, tobacco surveillance consists primarily of examining changes in tobacco use by analyzing questions added to national or state surveys and by estimating per capita tobacco consumption from federal or state excise tax receipts. While useful in highlighting changes in smoking behavior and prevalence, these data fall critically short of providing researchers, program evaluators, and policymakers with necessary information about why tobacco use changes occur (or fail to occur) and those factors that influence trends. A comprehensive and integrated program of surveillance research is needed to ensure consistency, frequency, and completeness of measurement. Information provided by such a system would facilitate efforts to understand biological, behavioral, and social influences that drive tobacco use among teenagers and adults. Also, as new, innovative interventions are developed and disseminated, surveillance mechanisms must monitor the implementation and quality of these interventions over time. By providing critical information needed to understand tobacco use behaviors and evaluate all aspects of tobacco control interventions in community settings, surveillance research facilitates a more comprehensive and effective tobacco research program at the state and national levels.

OTHER PRIORITY RESEARCH ISSUES

In addition to these highest priority tobacco research opportunities, the TRIG also made other recommendations. Research is needed concerning the influence of different tobacco products and alternative delivery devices/systems on initiation, nicotine addiction, and cessation of tobacco use. Investigation is also necessary to determine the optimal settings and mechanisms to deliver effective tobacco cessation treatments to culturally diverse and high-risk populations. Prevention research must focus upon development and evaluation of novel approaches for preventing tobacco use among youth at disproportionate risk.

CONCLUSION

The tobacco research opportunities identified by the Tobacco Research Implementation Group should be pursued through a variety of mechanisms. Most NCI-funded research must be supported through investigator-initiated research proposals. Every effort should be made to convey to the research community the NCI's interest in this broad range of tobacco control research, including training. In addition, several strategically chosen initiatives should use set-aside funds to catalyze research in selected high priority areas. The transdisciplinary centers could use a mechanism developed for Specialized Programs of Research Excellence (SPORE). Cofunding by NIDA and the Robert Wood Johnson Foundation would be desirable. Since the proposed community studies would be relatively large and complex, they would benefit from cofunding from other institutions and organizations. It may be useful to consider special mechanisms, such as the use of supplements to augment existing youth cohort studies. Wherever possible, strategic funding partnerships should be pursued to facilitate a coordinated, comprehensive attack on the tobacco problem.

The nine unique opportunities that are outlined in this report constitute the highest priorities for advancing the science of tobacco control. They are made with a thorough understanding of recent advances in this diverse field. A comprehensive approach to tobacco control research must include each of the activities described above. The aggressive pursuit of these nine research opportunities will significantly advance tobacco control research and maximize the potential for reducing tobacco use and tobacco-related diseases. As the new millennium approaches, the NCI should make the commitment to catalyze the research needed to turn the tide on the tobacco epidemic.