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Report of the National Cancer Institute
Cancer Prevention Program
Review Group

June 3, 1997
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TABLE OF CONTENTS:
  Executive Summary
  Recommendations
  Modifiable Risk Factors
  Animal Models and Extrapolation to Human Cancer Prevention
  Genetic Predispositions to Cancers and Detection of Precursor Lesions
  Chemoprevention Trials in Human Populations
  Behavioral Research and Behavioral Interventions Trials in Prevention
  Training of Health Professionals with Expertise in Prevention Research
  Organization and Infrastructure of the NCI Prevention Division

CHAPTERS:
  Introduction
  Goals of the National Cancer Program and the Role of Prevention
  Definition of Prevention
  Human Populations in Prevention Research
  NCI Cancer Prevention Program and Budget
  Intramural Component
  Organization and Infrastructure of the NCI Prevention Division
  Extramural Component
  Focus on the Division of Cancer Prevention and Control
  Inclusion of Prevention and Control Research within a Single Division
  Charge to the Review Group
  Process of the Review Group
  Modifiable Risk Factors
  Introduction
  The Need to Better Achieve Tobacco Avoidance
  Understanding the Basic Biology of Cancer and Diet and Nutrition
  Needed Diet/Nutrition and Cancer Research
  Physical Activity and Cancer Risk
  Alcohol Consumption and Cancer Risk
  Occupational and Environmental Carcinogens
  Infections Agents and Cancer Risk
  Recommendations
-Tobacco Exposure
-Diet and Nutrition
-Physical Activity
-Infectious Agents
  Animal Models and Extrapolation to Human Cancer Prevention
  Introduction
  Efficacy of Animal Models in Diet/Nutrition, Tobacco, Alcohol, and Physical
  Activity Studies
  Animal Models as Tools for the Evaluation of Potential Chemopreventive Agents
  Animal Models for Metabolism and Pharmacokinetic Studies
  Animal Models for Development and Validation of Intermediate Biomarkers
  Recommendations
  Genetic Predisposition to Cancer and Detection of Precursor Lesions
  Introduction
  Identification of High-Risk Populations
  Populations with a Hereditary Predisposition to Cancer
  Persons at Risk Due to Occupational or Environmental Exposures
  Persons with Premalignant Lesions
  Patients Successfully Treated with First Maliganacy
  Biomarkers as Predictors of Disease
  Current Status of Molecular Markers
  Feasibility
  Technology
  Funding Mechanisms
  Recommendations
  Chemoprevention Trials in Human Populations
  Introduction
  The Clinical Trials Process
  Preclinical Development and Selection of Candidate Agents for Human Trials
  Populations to be Studied in Chemoprevention Trials
  Methodological Considerations
  Cancer Prevention Trials Group
  Prevention Trials Committee for Biolgocial Studies
  Recommendations
  Behavioral Research and Behavioral Interventions Trials in Cancer Prevention
  Introduction
  Behavioral Interventions
  Components of a Behavioral Research Program in Prevention
-Epidemiology Foundations
-Expertise in Measurement and Evaluation
-Access to National Data on Key Behaviors
-Knowledge of Theories of Behavior
-Understanding of Behavior and Behavior Change
-Expertise in Cancer Risk Communication
-Strength in Intervention Design
-Expertise in Economics and Cost-effectiveness
-Mechanisms for Dissemination
  Trans-NCI and NIH Collaborations and Initiatives
  Specialized Training in Behavioral Science
  Intrastructure
  Recommendations
  Training of Health Professionals with Expertise in Prevention Research
  Introduction
  Intramural Training Program
  Extramural Fellowship Training Program
  Non-Federal Sources of Support
  Relevance of Training to Current Research
  Recommentations
  Training of Health Professionals with Expertise in Prevention Research
  Cancer Prevention Research Within NCI
  Organization of DCPC
  Create a Separate Prevention Division
  Strengthen the External Function of the Prevention Division
  Create a Separate Prevention Division
  Emphasize Behavioral Research
  Relocate the Community Clinical Oncology Program (CCOP)
  Improve Research Efforts in Diet/Nutrition, Tobacco, Alcohol, Physical Activity, and Infectious Agents
  Form a Chemoprevention and a Prevention Trials Group
  Increase the Role of the Prevention Division in Training
  Enhance Data Bases to Facilitate Cancer Prevention Research
  Interact with Other Federal and Nonfederal Agencies
  Recommendations

APPENDICES:
  Meetings of the Review Group and Acknowledgments
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Executive Summary

More than 2 million new cancer cases will be diagnosed in 1997. One in every four deaths in the United States--approximately 550,000 individuals per year--is the result of cancer. An overall increase of 18 percent in cancer incidence and an elevation in the mortality rate of about 7 percent occurred between 1971 and 1993 (Cancer at a Crossroads: A Report to Congress for the Nation. National Cancer Advisory Board, 1994) despite the "War on Cancer." However, recent statistics have shown an encouraging decrease in cancer mortality, suggesting that the battle against cancer may be taking a favorable turn. This reduction is probably the result of many factors, including enhanced early detection (e.g., increased use of mammography in the diagnosis of breast cancer), and earlier, more aggressive treatment of breast, colorectal, prostate and other cancers, although much room remains for improvement. Prevention efforts also have played an important role in the decrease in the proportion of Americans who smoke, especially adult males, and in reducing exposures to other known carcinogenic substances.

The Review Group on Cancer Prevention Research was appointed in 1996 by the National Cancer Institute (NCI) Director and the Chair of the NCI Board of Scientific Advisors. The Review Group was asked to consider how best to utilize the significant, albeit limited, resources and personnel of NCI in developing and sustaining a cancer prevention research program.

This review comes at an opportune time. There has been a growing appreciation of the role of prevention in controlling cancer. For example, the avoidance of cigarette smoking and of use of other tobacco products could reduce the incidence of lung cancer by 80 percent and significantly reduce the incidence of many other cancers (e.g., pancreas, kidney, head and neck). The adoption of diets that contain lower fat and increased fruits and vegetables could diminish the incidence of cancers of the colon and of other sites. And approximately 90 percent of skin cancers could be avoided through the adoption of various protective measures against the toxic rays of the sun.

The NCI Cancer Prevention Program Review Group strongly believes that prevention must be a principal component of the National Cancer Program if the cancer burden is to be reduced. A century-long experience with public health measures has shown that the prevention of disease is ultimately far more effective in reducing morbidity and mortality than is the treatment of already diagnosed disease. As such, it is apparent to the Review Group that over the next generation far greater reductions in cancer mortality will come from prevention than from the various treatments that are currently available or will be available in the coming years. In spite of this, a much smaller proportion of the NCI budget is committed to prevention than to various forms of treatment. Prevention must be well-represented in the programs of NCI, both intramurally and extramurally, and must have an appropriate budget. Furthermore, prevention, like all other elements of the National Cancer Program, must be founded upon excellent science, which originates from both the intramural and extramural research communities. It is through the application of excellent basic, clinical, and population-based research that effective preventive interventions can be mounted.

Because of its prime importance to the central objectives of the National Cancer Program, it is imperative that NCI's prevention efforts have outstanding leadership that will develop a creative, discovery-based, and assertive prevention research program and will utilize the strengths of both the intramural and extramural communities. Senior administrators of the prevention division also must work effectively with the NCI leadership in formulating this program.

The major responsibility for the NCI cancer prevention program lies within the Division of Cancer Prevention and Control (DCPC). Consequently, much of the activity of the Review Group centered on an analysis of this division's role in establishing the NCI cancer prevention agenda, providing the necessary leadership, representing the research interests of cancer prevention, and serving as effective spokespersons for the intramural and extramural research communities.

After receiving oral and written testimony and conducting interviews with intramural and extramural scientists, the Review Group perceived: a) the need for a better delineated, scientifically sound, long-term strategy for directing cancer prevention research into the next century; b) a need for additional outstanding scientists in leadership roles within DCPC; and c) the need for all other NCI divisions to focus greater attention on research toward the prevention of human cancers.

The Review Group briefly considered the appropriateness of including cancer prevention and control within a single organizational unit, as currently exists within DCPC. Because of a lack of sufficient data and the existence of another NCI review group which has the responsibility for evaluating cancer control efforts, the separation of these research functions was not considered further. Nevertheless, the Review Group believes that either the inclusion of cancer prevention and control within a single unit or the separation of these research functions would be compatible with pursuing the goals of NCI. In this report, the Review Group uses the phrase "prevention division" to describe an administrative unit that has the responsibility for directing and managing the NCI cancer prevention research agenda.

The Review Group considered the focus of cancer control to be on persons with clinically overt cancers, while that of cancer prevention to be directed at apparently healthy populations, including those at high risk and/or those with detectable precancerous lesions. Nevertheless, prevention, which develops basic scientific principles and control, which applies these principles, must be linked in some fashion to provide a continuum from bench to population.

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Recommendations

The Review Group offers a number of specific recommendations about management and organizational structure and about research opportunities. The Review Group organized its deliberations and recommendations around the following topics, which appear as separate sections of this report: modifiable risk factors; animal models and extrapolation to human cancer prevention; genetic predispositions to cancers and detection of precursor lesions; chemoprevention trials in human populations; behavioral research and behavioral intervention trials in the cancer prevention program; training of health professionals with expertise in prevention research; and organization and infrastructure of the prevention division.

This report is submitted to the Board of Scientific Advisors and the National Cancer Advisory Board for its consideration. The recommendations are aimed at improving the health of Americans through a comprehensive cancer prevention research program.

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Modifiable Risk Factors

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Animal Models and Extrapolation to Human Cancer Prevention

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Genetic Predispositions to Cancers and Detection of Precursor Lesions

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Chemoprevention Trials in Human Populations

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Behavioral Research and Behavioral Interventions Trials in Prevention

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Training of Health Professionals with Expertise in Prevention Research

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Organization and Infrastructure of the NCI Prevention Division

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Introduction

More than 2 million new cancer cases will be diagnosed in 1997. One in every four deaths in the United States--approximately 550,000 individuals--is the result of cancer. The leading cause of deaths from cancer by far in both sexes is lung cancer, followed by cancers of the prostate, colon and rectum, and pancreas in men, and cancers of the breast, colon and rectum, ovary, and pancreas in women. Pancreatic and pulmonary cancers are particularly aggressive with little improvement in survival despite determined efforts over the past 30 years.

An overall increase of 18 percent in cancer incidence and an elevation in the mortality rate of about 7 percent occurred between 1971 and 1993 (Cancer at a Crossroads: A Report to Congress for the Nation. National Cancer Advisory Board, 1994) However, recent statistics have shown an encouraging decrease in cancer mortality, suggesting that the battle against cancer may be taking a favorable turn. This reduction is probably the result of many factors, including enhanced early detection (e.g., increased use of mammography in the diagnosis of breast cancer), and earlier, more aggressive treatment. Prevention efforts have also played an important role as evidenced by decreases in the proportion of Americans who still smoke. Progress has occurred in the treatment of breast, colorectal, and prostate cancers, although much room remains for improvement.

Goals of the National Cancer Program and the Role of Prevention

In the 1997/1998 budget request for the National Cancer Institute (NCI), The Nations's Investment in Cancer Research (1996), it is stated that the ultimate goal of the National Cancer Program is "to eradicate this disease once and for all" or at least to "reduce the burden of cancer, . . fewer deaths, fewer new cases." The success of the scientific discovery process during recent years has resulted in a substantial expansion of knowledge about how cancer arises and how changes in the genetic material of a cancer cell distinguish it from a normal cell. These and future insights should lead to discernible reductions in age-specific cancer incidence and mortality.

A growing appreciation has developed for the role of prevention in controlling cancer. Approximately 90 percent of the skin cancers expected to occur this year could have been avoided through the adoption of various protective measures against the toxic rays of the sun. The avoidance of cigarette smoking and of use of other tobacco products could reduce the incidence of lung cancer by 80 percent and significantly reduced the incidence of many other cancers (e.g., pancreas, kidney, head and neck). The adoption of diets that contain lower fat and increased fruits and vegetables could diminish the incidence of other cancers, for example, of the colon.

The NCI Cancer Prevention Program Review Group (hereafter referred to as the "Review Group") strongly believes that prevention must be a principal component of the National Cancer Program if the cancer burden is to be reduced. Prevention must be well-represented in the programs of NCI, both intramurally and extramurally, and must have an appropriate budget. Furthermore, prevention, like all other scientific elements of the National Cancer Program, must be founded upon excellent science, which originates from both the intramural and extramural research communities. It is through the application of excellent basic, clinical, and population-based research that effective preventive interventions can be mounted.

Because of its prime importance to the central objectives of the National Cancer Program, it is imperative that NCI's prevention efforts be championed by outstanding, widely respected leadership that will help in the development of a creative, discovery-based, and assertive prevention research program, and will use the strengths of the intramural and extramural communities in an effective manner. It is equally important that senior administrators of the prevention division have the respect of NCI leadership, and NCI's intramural and extramural research programs.

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Definition of Prevention

As defined by the Review Group, cancer prevention research involves the development and evaluation of strategies for reducing cancer incidence. Such strategies could be aimed at preventing the initiation of the neoplastic process or at avoiding the progression to malignancy of already initiated cells. These efforts, which may be multidisciplinary and multifactorial, can involve a broad range of studies at the molecular, cellular, organismal and population levels.

Prevention is further classified as either primary or secondary. Primary prevention refers to the direct intervention of the malignant transformation process via the identification and characterization of factors that are involved. Secondary prevention refers to early detection, using approaches that may not actually prevent the initiation of cancer (e.g., colonoscopy, mammography) but may be aimed at the identification of cancerous and precancerous lesions at an early subclinical stage when cure may be possible. Screening may cut across both primary and secondary prevention since the populations to be tested may range from the healthy to those who are at high risk for a first or second malignancy. The Review Group has included early detection within its mandate, although it recognizes that several other subcommittees are reviewing related issues and making recommendations. This level of redundancy is appropriate.

The Review Group recognized an ambiguity in the definitions of cancer prevention and control and in some overlapping research areas. The Review Group believes that cancer control research should be focussed on the application at the population level of the fundamental principles that are developed through the prevention discovery process, while cancer prevention research is directed at the development of these general and specific principles in apparently healthy populations, including those at high risk and/or those with detectable precancerous lesions.

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Human Populations in Prevention Research

Although animal models are and will be used in basic cancer prevention research (chapter 3 considers the utility of various animal models), the results from these studies must ultimately be validated in humans. This validation will occur in populations that fall into the following four general categories: 1) healthy populations involved, for example, in diet/nutrition change, smoking cessation, or other lifestyle modification, or who are screened for cancer predisposition genes; 2) high risk populations in which a hereditary disposition exists or premalignant manifestations are already present, or those who are at high risk because of their successful treatment for a first malignancy; 3) high-risk populations because of chronic exposure to occupational or environmental chemicals or physical carcinogens, or to infectious agents implicated in the malignant process (e.g., HPV, HBV); and 4) the elderly population in which the risk for cancer is increased (e.g., for prostate cancer).

The validation process usually will require a clinical trial. A fundamental difference exists between human therapeutic and prevention trials. In a cancer therapeutic trial, the individual already has exhibited symptoms of the disease and may be in various stages of ill health. A greater tolerance for toxicity exists in the design of such a trial, so long as the potential benefit exceeds manageable toxicity. However, in a clinical prevention trial, where the individual participants are generally healthy and may not exhibit any symptoms of cancer, the guiding principle must be the absence of any significant toxicity from the intervention procedure, which may be conducted for a long duration. The conduct of human cancer prevention trials is discussed further in chapter five.

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NCI Cancer Prevention Program and Budget

At present, the research program in cancer prevention is conducted within the intramural components of NCI and through grants and contracts awarded to the extramural community. The Review Group found it difficult to estimate the total NCI budget for prevention because various definitions are used by different institute units. The Review Group's best estimate for the total NCI cancer prevention FY 1996 budget is about $400 million. To this figure could be added various components of physical, chemical and biological carcinogenesis, nutrition, observational epidemiology, and cancer control programs, which would increase the budget to approximately $740 million.

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Intramural Component

The preponderance of the cancer prevention budget is found within the Division of Cancer Prevention and Control (DCPC), approximately $188 million for FY 1996. This figure was reduced from a previous level of $200 million which included two research-based laboratories subsequently reassigned to other institute divisions. Of the $188 million in DCPC, $154 million is devoted to diet/nutrition and chemoprevention. Of the overall NCI budget, approximately 5 to 10 percent is for cancer prevention and control activities which include various clinical trials such as those conducted through the Community Clinical Oncology Program (CCOP).

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Extramural Component

The overall FY 1996 extramural budget (grants, cooperative agreement, and contracts) for cancer prevention, including primary prevention, early detection and diagnosis, and epidemiology, primarily is distributed through traditional grants and contracts; about 68 percent for grants and 32 percent for contracts. Of the total NCI extramural prevention budget, approximately 55 percent is the fiscal responsibility of DCPC. Thus, NCI has devoted a substantial budget for cancer prevention efforts with a significant amount designated for the extramural research community.

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Focus on the Division of Cancer Prevention and Control

As indicated above, a major responsibility for the NCI cancer prevention program lies within DCPC. Consequently, much of the activity of the Review Group centered on an analysis of this division's role in establishing the NCI cancer prevention agenda, providing the necessary leadership, representing the research interests of cancer prevention, and serving as an effective spokesperson for the intramural and extramural research communities.

After receiving oral and written testimony and conducting interviews with intramural and extramural scientists (see appendix A), the Review Group perceived: a) an apparent absence of a well-delineated, scientifically sound, long-term strategy for directing cancer prevention research into the next century; and b) a paucity of outstanding scientists in leadership roles within DCPC. These perceptions also focussed the Review Group's analysis of the cancer prevention research program on DCPC.

Because this report focuses on the cancer prevention agenda as directed by DCPC, a brief review of its current administrative structure is appropriate. A more detailed organizational chart for DCPC is presented as an appendix. The division includes three programs, Early Detection and Community Oncology, Cancer Prevention Research, and Cancer Control Research, plus the Biometry Branch and several smaller efforts.

The Early Detection and Community Oncology Program includes Early Detection, Community Oncology and Rehabilitation, and Preventive Oncology branches. The Cancer Prevention Research Program includes Cancer Prevention Studies, Chemoprevention, and Diet and Cancer branches. The Cancer Control Research Program includes Special Population Studies, Applied Research Cancer Statistics, Prevention and Control Extramural, and Public Health Applications branches.

The goals of the Biometry Branch are to a) plan and conduct investigations on cancer epidemiology, prevention, screening, diagnosis, treatment, and control by using mathematical and analytical statistical methods; b) develop biostatistical and epidemiologic methodology, and mathematical modeling of cancer prevention research areas; c) provide consultation in biostatistical and study design for DCPC staff and other NCI investigators; and d) supply expertise in statistics and biometry to program managers and other decision-makers.

Of all the branches within DCPC, only the Cancer Prevention Studies Branch and the Biometry Branch are classified as "intramural." All others are considered as serving the extramural community. However, as detailed in chapter 8, the Review Group was concerned about the appropriateness of this classification.

CCOP links community cancer practioners and primary care physicians with the clinical NCI Cooperative Groups and the NCI Cancer Centers, in order to increase the participation of patients in clinical cancer treatment, prevention and control trials. In addition, several Minority-Based CCOPs are active in enhancing the participation of minority populations in these clinical trials. The organizational positioning of the CCOP within DCPC appears to be a remnant of the past when the Cancer Centers Program also resided in this division.

Several mechanisms have been created to fulfill the mission of DCPC in cancer prevention. The Prevention Trials Decision Network is a system for selecting preventive agents that would be incorporated into large-scale clinical prevention trials. In particular, this group, which meets quarterly, prioritizes prospective large prevention trials and makes recommendations to the NCI Executive Committee.

DCPC also operates a major Cancer Registry which has proven to be of great value to intramural and extramural investigators with interests in cancer statistics. This annually updated database-the Surveillance, Epidemiology, and End Results (SEER) Program-provides a means for monitoring the contributions of individual, organizational, and societal factors to the cancer burden within the United States. The SEER Program, which was established in 1973, provides information on cancer incidence, survival and mortality obtained from 11 state and regional registries covering approximately 14 percent of the total U.S. population. In 1992, the SEER data base was expanded to increase the representation of U.S. Hispanic, Asian/Pacific Islander, and African American populations.

As newly reorganized under the leadership of the NCI Director, DCPC does not contain any programs or branches in which "bench" research is conducted. Previously however, two DCPC laboratories, the Laboratory of Nutritional and Molecular Regulation, and the Biomarkers and Prevention Research Branch, conducted bench science. These units have been transferred to the Division of Basic Sciences and the Division of Clinical Sciences, respectively.

As the Review Group assessed the administrative structure of DCPC, the need for change became obvious. Furthermore, the necessity for an enhanced role of the prevention division in training, and in providing additional databases that could be readily accessible by the community of cancer prevention researchers, became apparent. These recommendations are detailed in chapter 8 of this report.

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Inclusion of Prevention and Control Research within a Single Division

The Review Group briefly considered the necessity of including cancer prevention and control within a single organizational unit, as currently exists within DCPC. Because of a lack of sufficient data and the existence of another NCI review group which has the responsibility for evaluating cancer control efforts, the separation of these research functions was not considered further. The Review Group did conclude, however, that the inclusion of cancer prevention and control within a single unit or the separation of these research functions would not compromise the goals of NCI.

In regard to a definition of the scope of prevention versus control research, the Review Group does recommend that cancer control be focussed on persons with clinically-overt cancers although screening could also be included, while cancer prevention be directed at apparently healthy populations, including those at high risk and/or those with detectable precancerous lesions.

Charge to the Review Group

The Review Group on Cancer Prevention was appointed in 1996 by the NCI Director and the Chair of the NCI Board of Scientific Advisors. The Review Group was asked to consider how best to utilize the significant, albeit limited, resources and personnel of NCI in developing and sustaining a cancer prevention research program. Among the questions the Review Group was asked to consider are:


The Review Group also evaluated the existing intramural cancer prevention research program as well as other program components. Based on this evaluation, the Review Group offers a number of specific recommendations, some of which concern management and organizational structure, and some of which address avenues for research opportunity. In this report, the Review Group uses the phrase "prevention division" to describe a modified administrative unit that has the full responsibility for directing and managing the NCI cancer prevention research agenda.

The Review Group organized its deliberations around the following topics, which appear as separate sections of this report: modifiable risk factors; animal models and extrapolation to human cancer prevention; genetic predisposition to cancer and detection of precursor lesions; chemoprevention trials in human populations; behavioral research and behavioral intervention trials in the cancer prevention program; training of health professionals with expertise in prevention research; and organization and infrastructure of the prevention division.

Process of the Review Group

The Review Group met a number of times to accept oral testimony, review written communications, form subcommittees to address individual components of the charge, and review all recommendations of the subcommittees in order to build the consensus report. In addition, telephone conferences were conducted with subcommittee members. The formal meeting dates of the Review Group are included in appendix A, as are acknowledgments of those who assisted the committee in its deliberations by providing oral or written testimony.

This report is submitted to the Board of Scientific Advisors and the National Cancer Advisory Board for its consideration. The recommendations are aimed at improving the health of Americans through a comprehensive cancer prevention research program.

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MODIFABLE RISK FACTORS

Introduction

The cancer prevention research effort of the National Cancer Institute (NCI) should include a central focus on the identification and avoidance of exposures that may increase cancer risk, and the identification and enhancement of behaviors that may reduce cancer risk. Research on the impact of any such exposure or behavior on other important health outcomes (e.g., vascular diseases) is also critical to related public health recommendations and policy.

In terms of potential impact on cancer incidence and mortality, the highest priority risk, factor modifications concern reductions in exposure to tobacco products and changes in diet and nutrition. Very different research efforts appear to be needed in these two crucial areas. Cigarette smoking is the major known preventable cause of human cancer mortality and the epidemiological associations with cancer of the lung and cancer of various other organs are well characterized. However, a substantial commitment to the development of effective interventions for the prevention and cessation of tobacco use is needed, with emphasis on populations where the prevalence of tobacco use continues to be high. Additional research into the determinants of cigarette consumption among groups having high smoking prevalence and basic research into addiction mechanisms are needed to formulate improved behavioral and pharmacologic interventions.

In contrast, there are few diet and cancer relationships that can be regarded as reliably determined. International comparisons, time trend, and migrant studies suggest an important role for energy and macronutrient (i.e., fat, fat subtypes, protein, carbohydrate) consumption in determining the risk of several prominent cancers, and there is support for these associations from a considerable history of animal feeding trials. However, analytic epidemiologic studies (i.e., cohort and case-control studies) tend to suggest weak or null associations. It is not known whether the strong associations seen in aggregate studies are due to confounders, or whether the limitations of dietary self report invalidate the analytic studies, or both. There is a greater consistency of data from these same sources in support of a reduced risk of various cancers among persons having a high consumption of fruit and vegetables.

These associations are intriguing enough to properly impact dietary recommendations and to motivate the scrutiny of various substances found in fruits and vegetables in the search for cancer chemopreventive agents. However, even the reliability of the fruit and vegetable and cancer associations are reduced by measurement difficulties with self-reported diet, particularly since an adequate control of the confounding influences of macronutrient consumption is not currently possible. Evidently, to produce reliable epidemiologic information on diet/nutrition and cancer it will be necessary to strengthen study quality (e.g., by requiring the incorporating of appropriate dietary biomarkers in analytic epidemiologic studies). Methodologic research is also needed to clarify the potential of, and interplay among, aggregate studies, analytic studies, and human intervention trials, and to strengthen each type of study. Concurrent research is also needed to identify biologic mechanisms for the most plausible diet/nutrition and cancer associations, and to test such associations in clinical trials when justified on the basis of biologic and public health criteria.

In view of the importance of the tobacco and diet/nutrition areas to NCI's cancer prevention program, a senior and respected scientist, well positioned within the NCI organization, should be charged with the coordination and development of each of the two research areas.

There are a number of other modifiable risk factors that should not be overlooked in a renewed prevention program. These include physical activity patterns, as may be closely linked with diet in determining disease risk; the use of alcohol; exposure to environmental and physical carcinogens; and exposure to infectious agents. This chapter proceeds with some additional background and discussion of research opportunities and needs in each of these modifiable risk factor research areas, followed by a listing of corresponding summary recommendations.

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The Need to Better Achieve Tobacco Avoidance

Smoking remains the major known cause of human cancer. The role of tobacco as a human carcinogen has been proven beyond a reasonable doubt. In addition to the more than 40 direct carcinogenic compounds in tobacco smoke, nicotine has been recognized as a precursor of its nitrosated products (e.g., NNK) which have a carcinogenic role especially in the respiratory system. Most recently, nicotine has been recognized as a highly addictive drug by the Food and Drug Administration.

Major investments in tobacco control, along with a variety of health policy initiatives, have resulted in a reduction in the prevalence of smoking in the United States from more than 50 percent in 1965 to 28 percent in 1994 for males, and from 32 percent in 1965 to 23 percent in 1994 for females. The rate of prevalence reduction has slowed in the past several years, and more than 45 million Americans continue to smoke.

Smoking has become an activity of specific population subgroups, many of which are considered hard to reach. These include women of child-bearing age, ethnic and cultural minorities, and persons having low education, low income, and blue-collar occupations. Women appear to have greater difficulty quitting smoking than do men, and large numbers of pregnant women continue to smoke despite the known risks to the developing fetus. Heavy smokers appear to have great difficulty quitting, regardless of gender, ethnicity or socioeconomic status.

Various behavioral and pharmaceutical approaches to smoking cessation have been demonstrated to have efficacy, and some smokers have taken advantage of them. However, many smokers either are not yet ready to quit, have not had access to these approaches to quitting or have used them and failed to quit. Similarly, the mechanisms of addiction still are not completely understood, making it a challenge to provide better pharmaceutical aids.

Tobacco use prevention is a major concern in the United States. For nearly two decades the incidence of youth smoking remained high, but constant (about 27 percent of high school seniors ever smoked in the last 30 days in 1991). The recent rise in youth prevalence (34 percent ever smoked in the last 30 days and 22 percent smoked daily among high school seniors in 1996) is especially disturbing. The rates for tobacco use among adolescents not in school is two- to three-fold the rates of those in school. Most troublesome is that almost 90 percent of all smokers take up the habit during adolescence.

A major research investment in tobacco research is still required. Fundamental to understanding the problems associated with tobacco usage is knowledge of the mechanisms underlying addiction. Cessation interventions, relapse prevention, and addiction research need to be developed. More research is needed to understand the specific determinants of smoking in special population subgroups. Much more research is needed in understanding the smoking onset process, and to identify effective strategies to help children and adolescents avoid taking up smoking and other tobacco use. Because tobacco use is the major preventable source of cancer mortality, it is critical that NCI make a substantial commitment to discovery in this area.

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Understanding the Basic biology of Cancer and Diet and Nutrition

There are good reasons to postulate a prominent role for diet and nutrition in cancer causation. These include the observation that a single crude measure of per capita fat consumption can provide an explanation for much of the five- to ten-fold variation in the international incidence rates of several cancers, including cancers of the colon, rectum, breast, ovary, endometrium, prostate and kidney; the rather consistent observation from many (more than 200!) cohort and case-control studies that a high consumption of fruit and vegetables is associated with a relatively low incidence of several cancers, including cancers of the stomach, esophagus, oropharynx, lung, endometrium, pancreas and colon; and supportive results from a substantial history of animal feeding experiments. In fact, analyses of these and other data sources have led some reviewers to estimate that up to 40 percent of human cancer may be avoidable by means of practical changes in diet. Various organizations, including the National Academy of Sciences, the American Cancer Society, and NCI have issued dietary recommendations that call for a high consumption of fruit and vegetables and grains and the avoidance of an unnecessarily high consumption of calories and fat. The NCI-sponsored "5-a-Day Program" is also underway, with a goal of identifying effective strategies for increasing fruit and vegetable consumption.

However, as previously mentioned, there are few diet and cancer associations that can be said to have been reliably determined, despite a substantial research effort for several decades. Efforts to identify the components of fruit and vegetables that may be responsible for their putative cancer preventive effect have typically been non-conclusive. Although macronutrient consumption may well account for the largest portion of cancer risk associated with diet, different types of epidemiologic studies appear to yield inconsistent results, and no consensus has arisen concerning, for example, the role of excess energy consumption, or the role of fat consumption, in determining cancer risk.

To understand these enormous knowledge gaps, it is worth remembering that the diet is the most complex mixture of chemical substances to which humans are exposed, including many components that are present in extremely low concentrations. Many attributes of the diet may influence health, including the nature of its constituents; excesses or deficits of specific components; substances added to it; or substances produced during its preparation for consumption. Health effects of diet may be characterized by marked individual differences in susceptibility.

Various components of the diet may be relevant to health: the energy it provides in terms of calories; specific macronutrients, particularly fat, protein, and carbohydrate; specific micronutrients; and a large number of non-nutrient constituents. This complexity, along with the substantial difficulties in assessing even the recent dietary habits of individuals, may seriously undermine the reliability of available sources of epidemiologic diet and cancer data.

Consider, for example, energy consumption and breast cancer. Experimental studies in rodents indicate that calorie restriction can substantially reduce mammary tumorigenesis, but the practical implications for human breast cancer prevention are unclear. An association between per capita calorie supply and breast cancer incidence can be detected in international correlational analyses, but available data do not permit a serious attempt to control for between-population confounding. Cohort and case-control studies have thus far relied on self reported energy consumption (e.g., using food records, recalls or frequencies) and have often been unable to detect any association between energy consumption and breast cancer.

These studies often allude to a control for measurement error in the dietary self-report data, but all available measurement error methods require at least one of the measurement instruments to be able to estimate exposures and confounding factors in an unbiased fashion. Total energy consumption is one of the few aspects of diet for which an excellent biomarker measure exists. Specifically, the doubly labeled water method can accurately estimate energy expenditure over short periods of time.

Recent studies relating self-report measures to the doubly labeled water measures of total energy indicate a systematic under reporting of energy on self-report instruments. The extent of under reporting increases with body mass and, for example, appears to be in the 25 to 50 percent range among obese women.

It is easy to see that systematic biases of this magnitude, in conjunction with the random measurement error that is evident from repeat applications of dietary self-report instruments, can dominate the results of cohort and case-control studies of energy consumption and breast (or other) cancer, to the point that even a very strong positive association would likely not be detected. On the other hand, the availability of an objective (biomarker) measure of energy intake on a subsample of study subjects, along with self-report dietary data, gives the potential for a proper measurement error correction of analyses that relate short-term calorie consumption to cancer risk, but such analyses have yet to appear in the literature. This example also illustrates the inadequacy of current epidemiologic procedures for controlling for total energy when examining the relationship between the consumption of specific nutrients or foods (e.g., fruit and vegetables) and cancer risk.

Even the availability of unbiased biomarkers does not ensure that nutrient cancer associations can be reliably studied in an observational fashion. For example, epidemiologic studies have consistently reported an inverse relationship between blood beta-carotene concentration and lung cancer risk, but recent large-scale clinical trials indicate that beta-carotene supplementation, if anything, increases lung cancer incidence. Though the reasons for such a possible adverse effect are still unclear, it may be that the high correlations of beta-carotene consumption, and blood beta-carotene, with the consumption of other micronutrients (including other carotenoids) effectively precludes a separation of their roles in observational studies. Also the consumption of foods rich in beta-carotene is negatively associated with exposure to tobacco smoke, so that observed associations between dietary, and blood, levels of beta-carotene and lung cancer may be due to residual confounding, unless an exquisite level of control for the history of cigarette and other tobacco exposures is included.

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Needed Diet/Nutrition and Cancer Research

The diet/nutrition and cancer research area needs a revitalization with strengthened studies of various types, and an orderly development of dietary/nutritional interventions for human testing. The prevention division should play a leadership role in this revitalization.

Consider again observational studies of diet and cancer. While cohort and case-control studies that rely exclusively on self reported diet appear to have passed the point of diminishing returns, further such studies could contribute valuably if adequate substudies are included that incorporate suitable biomarkers of dietary exposure and of dietary confounding factors. Hence a noteworthy research effort is needed to identify unbiased (even if noisy) biomarkers of nutrient and food consumption, with particular emphasis on macronutrients. Improved international correlation and migrant studies that include sample surveys of dietary and confounding factors could contribute usefully even if based on self report, since aggregation provides protection against the noise aspect of measurement error. Results from such strengthened observational studies can be expected to contribute to the scientific basis for diet and cancer prevention recommendations, and to provide valuable input to the choice of interventions for testing in clinical trials.

The costs and logistics of human diet and nutrition intervention trials demand a careful development of trial rationale. This rationale will typically involve an orderly development of supporting data in observational studies and in studies of potential mechanism, with subsequent evaluation in preclinical trials, pilot and feasibility studies, and eventually full-scale clinical trials. Note, however, that it may be imprudent to await a complete understanding of the mechanisms that may be involved in a putative diet and cancer prevention hypothesis before undertaking clinical testing or implementing widespread preventive measures. In particular, testing may be merited if the public health implications are sufficiently great, or if the agents in question are being used in the general population for other reasons (e.g., aspirin for the prevention of vascular diseases; folic acid supplementation for the prevention of neural tube defects; calcium supplementation for the prevention of fractures).

Interventions in the diet/nutrition and cancer prevention area can mostly be classified as behavioral or chemopreventive. Examples of the former include the low fat (high fruit and vegetable, high grains) eating pattern being taught and tested in the NCI Polyps Prevention Trial, and the National Institutes of Health Women's Health Initiative, while there have by now been several trials of specific nutrients or nutrient combinations as chemopreventive agents. Both types of trials are needed on an ongoing basis, to address the knowledge gaps previously noted.

Dietary behavioral trials are needed to test the best current concepts concerning a healthful diet. A systematic process is needed to identify the eating patterns that merit testing, and to develop and test nutritional and behavioral strategies for effecting the desired eating pattern changes. The type of strengthened observational studies mentioned above, as well as basic research into the mechanisms whereby eating pattern changes may protect against one or more cancers, are needed to direct this systematic process. For example, in support of an intervention to increase fruit and vegetable intake one can develop a long list of potential cancer preventive agents found in fruits and vegetables and can examine induction of detoxification enzymes, inhibition of nitrosamine formation, dilution and binding of carcinogens in the digestive tract, alteration in hormone metabolism, and antioxidant effects, as potentially important mechanisms of action.

Basic research into mechanisms as well as the other elements of the previously mentioned orderly process are likewise needed to identify the most promising nutrients, or nutrient combinations, for testing as chemopreventive agents. Other chapters of this report make recommendations concerning both the preclinical and clinical aspects of this process.

Much of the confusion and inaction in the diet and cancer prevention research area arises from methodologic issues concerning, for example, the role and reliability of observational studies in relation to intervention trials; the interplay between observational and mechanistic studies; and the ability to streamline comparative trials by focusing on very high risk study subjects or by relying on intermediate outcome measures. Research is also needed toward answering these types of questions, and toward identifying the data sources needed to address these diet and cancer methodologic issues.

Physical Activity and Cancer Risk

There is a large body of evidence of the beneficial effect of physical activity and physical fitness on various aspects of health and well being, including reductions in the risk of coronary heart disease, diabetes, stroke, osteoporosis, obesity and disability. Though understudied compared to other cancer prevention strategies, evidence also exists that physical activity may be associated with a lesser risk of several common forms of cancer, most notably colon and breast cancer.

For these cancers, persons having relatively high physical activity levels have been reported to have disease rates that are 25 to 50 percent lower than those among sedentary persons, making the further development and testing of these hypotheses a high priority in the cancer prevention research agenda. Physical activity has effects on fat tissue, obesity and body fat distribution, as well as immunological, mechanical and hormonal effects, providing a range of possible mechanisms whereby physical activity may reduce cancer risk.

Observational studies of physical activity and cancer are plagued by many of the same obstacles surrounding studies in the diet and cancer area; specifically, random and systematic measurement error in physical activity self-assessment and the need to control for the myriad of potential confounding factors, some of which also have severe measurement difficulties. In fact, the interplay between nutrition and physical activity (e.g., energy balance) may be a key determinant of the risk for colon, breast and other cancers. A greater research effort is needed to identify suitable biomarkers of short- and long-term physical activity patterns, and to identify plausible mechanisms whereby an increase in physical activity may reduce the risk of specific cancers. To date, there has been very little study of physical activity and cancer prevention using controlled intervention trials. Small scale trials to identify the effects of physical activity on disease risk factors can be justified currently with the possibility of full-scale disease prevention trials following additional hypothesis development research.

Alcohol Consumption and Cancer Risk

Although apparently not a direct carcinogen, alcohol use increases the risk of liver cancer and also upper aerodigestive cancer in smokers. The mechanism of its carcinogenic effect is not well understood but it is clear that alcohol interferes with the first pass clearance of carcinogens such as those found in tobacco smoke, and may enhance mechanisms for biotransformations of procarcinogens found in tobacco smoke. In the breast and possibly the liver, its apparent carcinogenic effect may be mediated through increases in the level of estrogens in the blood. The same mechanism may be linked to a decrease in the risk of coronary heart disease.

Data on the consumption of various types of alcoholic beverages are frequently collected in cohort and case-control studies. The measurement difficulties are not so severe as for diet and physical activity, in part because a fraction of the population do not consume alcohol, and it seems reasonable to expect that sufficiently reliable information on the basic associations will be forthcoming from observational study sources.

Occupational and Environmental Carcinogens

The recognition of the importance of environmental and occupational carcinogenesis derives from the original insightful observations of Sir Percival Pott in the 18th century on the occurrence of scrotal cancer in a young group of chimney sweeps. Since that time, considerable progress has evolved in the identification of carcinogenic agents that are present in the workplace and in the definition of their mechanisms of action. These carcinogens are either: a) produced or used in the workplace, such as polychlorinated biphenyls and asbestos; b) produced during a combustion process, such as the polycyclic aromatic hydrocarbons; c) formed during or following the process of chlorination of water, such as the chlorinated hydrocarbons; d) used as herbicides in agriculture or as pesticides around the home, such as chlordane; or e) incorporated in foodstuffs as additives, such as the azo dyes.

Although the occupational and environmental carcinogens have received much press, with the often noted adage-the carcinogen of the month-chronic exposure to these substances probably contributes to 5 to 10 percent of the deaths due to cancer. Nevertheless, these deaths are largely preventable, and regulatory agencies such as the U.S. Environmental Protection Agency and the Occupational Safety and Health Administration are involved in monitoring exposure of individuals to the occupational and environmental carcinogens.

NCI as well as other institutes of NIH have been involved, largely through the use of the traditional peer-reviewed grants, in studies on mechanisms of action of the environmental and occupational carcinogens, and on the development of unique ways to prevent their carcinogenic action. Within NCI, the Division of Cancer Prevention and Control (DCPC) has only played a minor role in this area. This role will undoubtedly expand in the recruitment of individuals into chemoprevention trials who are at high risk for cancer development by virtue of elevated exposures to occupational and environmental carcinogens. This is a research area which can benefit substantially from fruitful interactions between the various divisions of NCI, including the prevention division, to exploit any unique findings that might evolve from basic science. The prevention division should in fact take the lead in these interactions.

Infections Agents and Cancer Risk

The concept that viruses cause human cancer dates back to the first decade of the twentieth century when experiments on animals showed that tumors in chickens could be induced by an agent that could pass through a filter. The new tools of molecular biology have led over the last decade to profound discoveries about the role of viruses in human cancer and the mechanisms of disease causation and have provided the science base to direct efforts at preventive vaccine development.

Viruses must invade living cells in order to reproduce, generally by attaching to receptors on the surface of the target cell. Once inside the cell, they often integrate their genetic material into that of the host and alter the cell in ways which predispose to cancer through a variety of mechanisms. In some cases, the virus is thought to induce cancer directly, while in other cases, indirect effects of the virus (e.g., immunodeficiency) predispose to malignancy. Two major types of viruses that are linked to cancer have either DNA or RNA as their genetic materials.

Members of the DNA family of viruses include the papilloma viruses of humans (human papillomavirus, or HPV) and animals (bovine papillomavirus, or BPV), hepadnaviruses (hepatitis B), flavaviruses (hepatitis C), and herpes viruses (herpes simplex type 1 and 2, Epstein-Barr virus, and human herpes virus-6, -7 and -8). Members of the RNA family of viruses (retroviruses) include human T-cell lymphotropic virus types 1 and 2 (HTLV-1, HTLV-2), human immunodeficiency virus type I (HIV-1), and a variety of animal retroviruses including bovine immunodeficiency virus (BIV), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), caprine arthritis encephalitis virus (CAEV), and equine infectious anemia virus (EIAV).

Papillomaviruses are found in a wide variety of species and have an affinity for epithelial cells. They cause benign epithelial proliferations but have also been linked to cancers in humans and animals. There are approximately 70 different human papillomaviruses which are associated with a variety of clinical lesions, including plantar warts, hand warts, venereal warts, and flat cervical warts (which are now recognized as potentially precancerous). Approximately 25 of the HPV types are associated with genital tract lesions, and these types can be grouped into high risk and low risk categories based on their association with genital tract cancers. The low risk HPVs, such as HPV-6 and HPV-11, are associated with venereal warts (also known as condyloma acuminata) which only rarely progress to cancer. The high risk viruses, which include HPV-16 and HPV-18, have been associated with intra-epithelial neoplasias which are benign but may progress into cancers. For instance, it is estimated that a woman with HPV-16 positive cervical lesion has approximately a one-in-thirty lifetime risk of developing cervical cancer.

Infection with hepatitis B virus (HBV) has, through case-control and prospective cohort studies, been closely associated with hepatocellular carcinoma (HCC). This is particularly evident in high-risk geographic areas for liver cancer such as Taiwan, Senegal, South Africa, Hong Kong, the People's Republic of China and the Philippines. HCC is one of the most frequently occurring human cancers worldwide, causing more than 250,000 deaths annually throughout the world. A vaccine has been developed to prevent infection with HBV, and its ability to reduce liver cancer in humans is now being field-tested. Clearly, the widespread application of the HBV vaccine in regions where there is a high prevalence of infection with this virus could have a profound impact on reducing the risk of developing primary liver cancer.

Epstein-Barr virus (EBV) has been studied exhaustively for more than 25 years as a possible etiological agent in some forms of human cancer. These studies have established that this herpes virus is the causative agent of infectious mononucleosis, and that it is linked to at least four different types of human malignant tumors. Its role in the African form of Burkitt's lymphoma and in nasopharyngeal carcinoma (NPC) is well documented. Substantial evidence also links this virus infection to many B cell lymphomas in immunosuppressed individuals, particularly after organ transplantation or HIV infection. It has also been postulated that this virus contributes to Hodgkin's disease, and occasionally DNA and EBV have been found in tumor cells that are unique to Hodgkin's disease (called Reed-Sternberg cells) as well as in other tumors. Indeed, EBV appears to be a bona fide human cancer virus, thereby raising the realistic possibility of preventing EBV-associated disease, including virus-associated malignancies, through the use of an appropriate vaccine.

Retroviruses first attracted widespread attention as oncogenic agents that replicate through DNA intermediates and involve integration of DNA copies of their genomes in the host chromosomes. Because no other class of animal viruses exhibits such profound intimacy with the host genome information gathered concerning this relationship should increase understanding of the viral-associated transformation process. Indeed, animal retroviruses isolated form many mammalian species continue to provide valuable basic information on the etiology and mechanisms(s) of cancer induction by viruses. Retroviruses may be directly or indirectly involved in the development of malignancies. Retrovirus animal models may therefore aid in investigations of the initiation and progression of neoplasia of viral origin, provide a better understanding of the role of viruses in the etiology of human cancer, and contribute to prevention efforts against microbiological agents, especially viruses.

Helicobacter pylori is a bacterium whose causal association with gastric malignant neoplasms has been recently recognized. Acquisition and persistence of the infection are poorly understood and may be partially dependent on dietary practices and nutritional status. Research on the role of this bacterial infection in carcinogenesis may increase understanding of carcinogenesis in general, especially with regard to the role of DNA damage. The role of the this bacterium in carcinogenesis needs further exploration by epidemiologic and laboratory techniques. The mechanisms of transmission as well as the effects of this infectious agent on human health are still poorly understood. Research on strategies to eradicate the infection needs support especially the development and testing of vaccines which have been proven to prevent reinfection and cure active infection in experimental animals. Although gastric carcinoma incidence has decreased considerably in the United States, many special populations still have high rates, such as African Americans, Native Americans, and immigrants from certain geographic regions. Gastric lymphoma linked to Helicobacter infection, is not a frequent disease but research on it may yield results that are highly relevant to other lym