Although in the past decade we have made tremendous leaps forward in the detection, diagnosis, and treatment of prostate cancer, there remains much we don't know. For example, we don't fully understand the factors, genetic or environmental, that place a man at increased risk for prostate cancer. We don't know why some racial and ethnic groups - notably African Americans - are diagnosed with and die of prostate cancer at a significantly higher rate than others, while other groups, particularly Asians, experience a substantially reduced burden. We haven't fully addressed the unique needs of survivors of prostate cancer. And, although we have developed a number of interventions to reduce morbidity and mortality, including the PSA screening test and surgical, radiation, and hormonal therapies, we have yet to prove that all are truly efficacious. The lingering uncertainty about the risks and benefits of these interventions underscores the necessity for increased surveillance of the early detection, treatment, and outcomes of prostate cancer in the population. In short, measures of progress against prostate cancer include not only incidence and mortality but also risk factors, the use of interventions, costs, and long-term, health-related quality of life among survivors.
The NCI's professional judgment for addressing prostate cancer risk, burdens, and outcomes is multifaceted. We are undertaking the comprehensive study of prostate cancer epidemiology and risk in order to identify genes and environmental risk factors for this disease. Through our surveillance program, we would address deficiencies in the understanding of population trends in prostate cancer incidence, mortality, and use of screening and treatment, and assess the impact of these trends on both the general population and survivors of this disease. We would identify and address the unique concerns of the ever-growing population of prostate cancer survivors. Finally, we must and would address the alarming differences in prostate cancer incidence, aggressiveness, mortality, and treatment among men of different racial and ethnic groups.
Strategies & Plans: Epidemiology, Genetics and the Environment
Goals:
Identify the genetic and exogenous risk factors that account for differences in incidence and mortality between different racial and ethnic groups.
Identify the risk of cancers resulting from environmental exposures in the general population, and the susceptibility genes that modify that risk.
Identify the genes responsible for familial and hereditary forms of cancer.
Initiatives:
Gene Discovery for Inherited Predisposition to Prostate Cancer
Men with a family history of prostate cancer are at increased risk for the disease. The NCI, through its research programs, is committed to identifying the genetic bases of prostate cancer susceptibility.
The Cancer Genetics Network (CGN) would provide a new national resource to support collaborative investigations into the genetic basis of cancer susceptibility, integrate this new knowledge into medical practice, and address the psychosocial, ethical, legal, and public health issues associated with inherited susceptibility to cancer. The aim would be to create a multi-center and interdisciplinary collaborative structure that would enable the participating institutions to draw upon each other, and to have access to research resources, information, and expertise beyond the scope of any single institution. The result would be perhaps the largest virtual collaboration dedicated to the study of cancer genetics.
This year participating centers without existing programs for specific recruitment of probands/families at increased risk of prostate cancer may request a supplement for direct costs to implement recruitment programs targeted at this group. Participating centers currently recruiting probands/families for genetics studies in prostate cancer may request a supplement for direct costs to expand ongoing recruitment efforts or enhance the existing program.
In addition, we are planning studies that would augment the current linkage-based approaches for discovery of major genes responsible for familial prostate cancer, with a large study of affected sibling pairs with clinically significant disease. Men with prostate cancer diagnosed over a previous three-year period from population or hospital-based registries would be contacted to identify those with living affected brothers. These pairs would be evaluated by questionnaire and whole genome scanning. A study of 3,000 such pairs is planned.
Studies of Environmental/Lifestyle Causes and Gene-Environment Interactions that Lead to Prostate Cancer
The NCI supports several ongoing or planned efforts to study gene-environment interactions and lifestyle choices that may increase prostate cancer risk. Additional effort could be applied to the projects identified below.
An RFA entitled Interdisciplinary Studies in the Genetic Epidemiology of Cancer, would be offered jointly with the National Institute on Aging. This RFA would seek to support investigations to identify and evaluate the interactions of genetic and environmental risk factors leading to enhanced cancer susceptibility in individuals, families, and populations, and factors influencing the increase in susceptibility with age, a key feature of prostate cancer incidence and mortality.
The NCI plans to conduct large cohort and case-control studies focused on the identification of susceptibility genes and gene-environment interactions. Efforts would be made to identify the risk factors and mechanisms underlying the suggestive associations reported from existing small studies, including hormones, growth factors, diet anthropometry, physical activity, sexually transmitted factors, and occupational exposures. Efforts also would be made to identify reasons for the high mortality rates for prostate cancer reported in certain parts of the country.
The NCI is very interested in the effects of diet and nutrition on prostate cancer incidence. Several associations of dietary patterns with prostate cancer have been reported, but the evidence needs much more interdisciplinary research and analysis. Diets high in vegetables have been reported to decrease risk, while diets high in fat, saturated fat, and animal fat to increase risk. Several micronutrients may affect prostate cancer occurrence, and the effect of food constituents on molecular events in the prostate is unknown. Studies in this area could lead to new chemoprevention studies in the future.
Research on the Natural History of Latent and Aggressive Prostate Cancer
It is critical that we define the epidemiology and natural history of screening-detected prostate cancer, including genetic and environmental risk factors, and serologic and molecular markers of those lesions most likely to be aggressive. This goal could be reached by additional funding for the Prostate, Lung, Colorectal, and Ovarian Cancer Trial (PLCO) to provide adequate data and specimen collections from prostate cancer cases subsequent to their diagnosis. In addition, to increase the numbers of early cases for evaluation who have been minimally treated or untreated, a similar collection of data and specimens could be obtained from patients entered into NCI-sponsored clinical trials for the treatment of early-stage disease.
Studies of the Underlying Biology of Intra-Prostatic Exposures
NCI anticipates opportunities for a focused, collaborative methodological and exploratory effort involving epidemiologists and laboratory scientists (analytic chemists, molecular biologists, geneticists) to study the difficult issues of intra-prostatic exposures, particularly from hormones and their metabolites, growth factors, infectious agents, and their relation to prostate cancer risk. A resource of fresh and fixed tissues from prostate cancer cases and controls along with questionnaire data and other biologic specimens (blood, urine) would be established. A variety of assays, including gene expression, protein and hormone determinations and a search for non-culturable viral sequences, would be performed to ascertain their presence and levels, determinants, interrelationships and surrogate measures in more accessible biologic specimens, plus their associations with prostate cancer risk.
Strategies & Plans: Surveillance
Goals:
Assess the reasons for and impact of trends in prostate cancer incidence and mortality, with particular focus on differences among population sub-groups;
Identify the effects of variations in the use of screening, diagnostic, and treatments on multiple measures of disease burden in the U.S. population;
Identify the impact of clinical decision making regarding screening and treatment on population trends in incidence, mortality, and quality of life outcomes.
Determine how the benefits, economic costs, and morbidity due to screening and treatment differ in subsets of the population (age groups, racial and ethnic groups, etc.)
Initiatives:
National Prostate Cancer Outcomes Studies
The Prostate Cancer Outcomes Study (PCOS) was initiated in 1994 to assess reasons for variations in prostate cancer practice patterns in the general population and evaluate the impact of therapies on disease-specific health related quality of life. This has been the most comprehensive survey ever undertaken of prostate cancer outcomes. The study was funded as a contract modification within the SEER Program, with six out of ten SEER registries participating since the inception. A five-year follow up survey is planned for October 1999. We see opportunities to expand the study over five years to assess differences in care by geography, race/ethnicity, socioeconomic status and insurance status.
NCI plans to continue follow-up of the PCOS cohort, consisting of approximately 3,500 men, through 10 years post-diagnosis. Beginning in 1999, all six original participating registries will be funded by contract and will continue to be directed by SEER Program staff. The main purpose of this follow up will be to ascertain and verify deaths, maintain contacts with respondents, and conduct a 10-year survey to assess long-term changes in disease-related quality of life. In addition, we would review and abstract medical records to identify endpoints such as disease progression, metastases, and the use of secondary treatments. Ongoing analyses of the data collected could also be supported.
Since the initiation of the PCOS, there have continued to be changes in prostate cancer incidence, treatments, and PSA testing in the population. Therefore, a second PCOS could be supported to collect extensive new information not included in the first PCOS, address gaps in the first study, and examine new questions. The study would be designed to include more minority patients so that treatment patterns and quality of life could be compared across sub-populations. The second PCOS would be funded as an RFA Cooperative Agreement to permit broader participation outside SEER areas. Approximately 5,000 patients would be enrolled at between seven and ten sites with expertise in population-based outcomes research, starting in 2001 and continuing through 2003.
Prostate Cancer Screening Initiatives
One of the most difficult questions facing men today is whether to undergo screening for prostate cancer. Although there is no doubt that such tests as digital rectal examination and the PSA test do detect prostate cancer, we have yet to prove that they reduce prostate cancer mortality overall. The NCI has several ongoing or planned initiatives that will complement ongoing randomized trials of screening by describing trends and population impact of prostate cancer screening.
The objective of the Prostate Cancer Surveillance Consortium (PCSC) is to measure the operating characteristics (sensitivity and specificity) and clinical outcomes of PSA screening in the general population. The PCSC's activities include monitoring and tracking patterns of PSA testing in the community, and measuring the outcomes of PSA testing as performed in everyday community medical practices. Data collection methods would be pilot tested in two or three SEER sites as a contract modification to SEER. In 2002, the full consortium would be funded under a cooperative agreement, and would consist of between seven and ten sites with broad population representation of ethnic and socioeconomic sub-groups.
The Cancer Information and Surveillance Modeling Network (CISNET) would be a cooperative agreement centered around the use of microsimulation modeling to assess national trends in prostate, breast, and colorectal cancer. Comparing modeled and observed incidence and mortality trends can help us better understand the underlying disease process and the benefits of the PSA test in the U.S. population. This network would be created to facilitate collaboration among two to three groups of investigators with complementary expertise in modeling prostate cancer. The first two to three awards would be made in 2000. Two follow up awards would be planned to begin in 2002. These grants would span four years of research effort.
The California Health Interview Survey (CHIS) is designed to provide population-based standardized state and local health data for small population groups. This presents an opportunity to monitor and track the PSA testing in California counties as well as to follow up positive tests, including biopsies and cancers detected, in 30,000 respondents, through CHIS. In this way, NCI would obtain better estimates on certain racial-ethnic populations that compose a significant percentage of California's population. Support would be provided to the California Department of Health via an interagency agreement.
Clinical Decision Making Studies
Significant information about trends in prostate cancer screening and treatment can be gained by surveying health care providers, both physicians and insurers, and by examining the processes of patient decision making that influence patterns of medical practice.
No recent national studies of provider knowledge, attitudes, and practices regarding prostate cancer screening and management have been conducted. A series of surveys of primary care physicians and specialists involved in the screening, diagnosis, and treatment of prostate cancer in the U.S. would be valuable. This could be accomplished through a contract mechanism using the Surveillance Master Agreement Order. A nationally recognized survey research firm would conduct the surveys. A survey of approximately 1,000-1,500 primary care physicians would assess beliefs in the efficacy of screening and factors shaping physicians' screening recommendations. A survey of the same number of specialists would assess diagnostic follow-up and treatment recommendations. Both surveys would ascertain physicians' use of decision aids and perceptions of additional information needed to enhance their ability to make appropriate screening and treatment recommendations. A complementary survey of 300-400 health plans would provide information on the policies and organized programs of health plans regarding prostate cancer screening and treatments. These surveys would be conducted in 2001 and 2002.
A related initiative would develop innovative methods and materials for use by clinicians and patients for enhancing their ability to make informed decisions about prostate cancer screening and treatment. Given the extent of uncertainty about the efficacy of interventions, patients desire more information in order tailor medical decisions to their own preferences. This initiative would be designed to elucidate factors involved in decision making and how best to communicate information. The initiative would be achieved by soliciting administrative supplements from existing research grants, where clinical decision making is within the scope of work.
An example of an existing structure for conducting collaborative studies is the HMO Cancer Research Network (HMO-CRN), initiated in 1999 as a cooperative agreement among a consortium of 10 large HMOs covering approximately 10 million lives focusing on cancer control research activities. The HMO-CRN and grants addressing prostate cancer survivors are potentially useful mechanisms to conduct studies on prostate cancer decision making.
Strategies & Plans: Survivorship
Cancer Survivorship Research is the study of the unique physical, psychosocial, and economic sequelae of cancer diagnosis and its treatment. It also includes issues like health care delivery, access, and follow-up care within its domain. Survivorship research focuses on the health and life of a person with a medical history of cancer beyond the acute diagnosis and treatment phase and seeks to both prevent and control the aforementioned sequelae, and to provide guidelines for optimal follow-up care and surveillance. Interventions that enhance prevention or control of these sequelae, such as coping, dietary modifications, physical activity, and social support are also of significance.
The Office of Cancer Survivorship (OCS) was established in late 1996 to provide a focus within the NIH for the support of different facets of survivorship research. Since then, the OCS has supported two initiatives, one a supplement to existing cancer centers grants and cooperative agreements, and the other the generation of an RFA entitled "Long Term Cancer Survivors: Research Initiatives." Prostate cancer research was not well represented in the pool of applications submitted in response to either initiative. Additionally, a review of the 1998 NCI-wide portfolio of survivorship research revealed few studies (two R01 Grants) focusing solely on prostate cancer survivors.
Survivorship research in general, and prostate cancer survivorship research in particular, are still emerging areas. Thus, major efforts are needed to stimulate the development and establishment of this relatively new area of research. Major efforts are necessary to stimulate both extramural and in-house research. We need to evaluate the long term physical effects of survivorship from prostate cancer, the context of the prostate cancer survivorship experience across different age groups (men in their 40's or 50's versus older men) and ethnic, cultural, and socio-economic status categories. We also need to evaluate the development and evaluation of interventions specifically targeted towards ameliorating the negative consequences of survivorship.
Goals:
Improve "Quality of Survivorship" for men diagnosed with prostate cancer. This goal encompasses physical health, reproductive and sexual, cognitive, and economic issues, as well as overall quality of life.
Determine and address the unique survivorship issues faced by men in different age, racial, and ethnic groups.
Decrease the physiologic and psychologic morbidity associated with long-term prostate cancer survivorship by addressing specific prioritized research areas.
Initiatives:
Priority Areas for Prostate Cancer Survivorship Studies
NCI is planning qualitative and quantitative research to identify specific survivor concerns for men by age group, ethnicity, and culture:
As part of a larger national survivor prevalence study, we would describe the status of prostate cancer survivors in terms of physical health, quality of life, relationships with partners, and economic consequences.
We need to evaluate the quality of prostate cancer survivorship relating to adaptation of the patient to personal consequences of the cancer diagnosis and treatment, adjustment to the social consequences of cancer, and the impact on the family.
In addition, we would assess the prevalence and longitudinal incidence of physiologic late effects, incorporating two related areas: long-term effects (chronic physiologic sequelae persisting beyond the acute treatment phase), and late effects (delayed physiologic health effects occurring months to years after treatment).
Finally, the prevalence and magnitude of sexual dysfunction must be elucidated for prostate cancer survivors and their partners by age and ethno-cultural background.
Opportunities for Studies in Prostate Cancer Survivorship
Through the National Prevalence Study, we would use the contract mechanism in FY 2000 - 2003 to obtain data needed to create a national profile of men who have had prostate cancer. We would hope to study approximately 5000 prostate cancer survivors as part of this effort. These data are needed to develop effective behavioral interventions and to encourage epidemiologic investigations
A Program Announcement entitled "Prostate Cancer Survivorship Research" would seek to support investigations to evaluate the quality of prostate cancer survivorship in terms of adaptation to personal consequences of the disease and its treatment, adjustment to its social consequences, and impact on the family. The research plan would also target the prevalence and longitudinal incidence of physical late or long term effects and morbidities, including sexual dysfunction. This initiative would span 2000 through 2003.
A Request for Applications (RFA) entitled "Coping Interventions and HRQL [Health-Related Quality of Life] in Prostate Cancer" would stimulate the development and evaluation of interventions focusing on coping mechanisms that could significantly decrease the negative sequelae of treatment. The RFA would be released in 2000 for funding through 2003. Based on results from research conducted for other disease sites, it is likely that positive coping strategies thus developed would enhance the quality of life of long-term survivors of prostate cancer.
This research is especially important since some of the side effects experienced by survivors of prostate cancer, such as incontinence and sexual dysfunction, affect not only the patients themselves but also their families. Additionally, these side effects may have different social or emotional consequences in younger men compared to older individuals, and across cultural and ethnic groups.
In conjunction with the surveys proposed for surveillance of prostate cancer, we could conduct a national survey to assess health care providers' knowledge, attitudes, beliefs, and behaviors regarding the unique issues faced by prostate cancer survivors. This survey of approximately 1000 physicians who see cancer survivors would be conducted under a Master Agreement Order. The information from this survey is critical if we are to develop effective medical and continuing education programs for providers. Based on the survey results, we would develop practical tools for providers to use in communicating with patients.
Strategies & Plans: Special Populations
The scientific questions concerning prostate cancer are pertinent and pressing to men of all races. There are pronounced racial disparities in prostate cancer incidence and mortality; indeed, the disparity in mortality rates from prostate cancer is greater between white and black men than for any other type of cancer in the U.S. and possibly in the world. Significant questions regarding racial differences include: What are the causes of prostate cancer and what is the basis of differences noted in incidence and mortality among different racial/ethnic groups? Why are some prostate tumors high-grade and aggressive, whereas others exhibit low-grade, less aggressive behavior? What is the underlying biological basis of such differences, and why do black men tend to have more aggressive disease? Why do men of Asian heritage tend to have less aggressive disease? How can the benefits of medical research best be applied so that all may benefit?
Goals:
Understand and address the reasons for differences in prostate cancer incidence, aggressiveness, mortality, and treatment patterns among men in different racial and ethnic groups.
Educate diverse publics about prostate cancer screening and treatment using concepts and materials appropriate to each age, racial, and ethnic group.
Determine the ways in which the benefits of treatment differ in subsets of patients by age, morbidity, race, etc.
Initiatives:
Studies to Understand Racial/Ethnic Differences in Prostate Cancer
The NCI has several efforts ongoing to understand the differences in prostate cancer by race and ethnic group:
A Program Announcement entitled Molecular Epidemiology of Prostate Carcinogenesis has been established. This program emphasizes interdisciplinary collaborations among laboratory scientists. Areas to be investigated include molecular genetics and biology and cancer, epidemiology of developing and validating biomarkers for assessment of risk in population subgroups (for example, racial or ethnic groups), evaluating gene-environment interactions, and developing resources such as cohorts and repositories.
A Program Announcement entitled Diet, Lifestyle, and Cancer in U.S. Special Populations focuses on the causes of cancer in population groups that experience unusually high cancer incidence and mortality.
Further investigate the differences in prostate cancer incidence through a population-based, interdisciplinary case-control study in Asia and Africa, and among Asian Americans, African Americans and Caucasians in the U.S. This effort could focus on establishing a South African tumor registry and tissue bank. These major efforts could focus on elucidating the origins of prostate cancer. Special attention would be given to identifying the genetic and environmental determinants of the marked racial/international differences in the risk of clinically significant disease and the changing patterns among migrant populations. The South African Tumor Registry and Tissue Bank would address the observations that men of African heritage in the U.S., Brazil and Jamaica have been shown to have relatively high prostate cancer rates. Although age-adjusted incidence and mortality rates suggest that sub-Saharan Africans may also have elevated prostate cancer rates, cancer incidence data from the developing countries of Africa are largely inadequate and incomplete. In order to clarify this issue, the NCI, in collaboration with the Medical University of South Africa, could establish a population-based registry of cancer incidence and mortality in four provinces (Eastern Cape, Western Cape, Northern Province, and Gauteng Province) in South Africa. Such a registry would allow for comparisons between black Americans and black Africans with regard to demographic data and a variety of postulated risk factors related to hormones, diet and nutrition, and other lifestyle characteristics. It also would provide data allowing comparisons of cancer rates among white and black Africans. The registry would be augmented and its value to epidemiologic research enhanced by establishing a tumor and serum bank allowing for genetic studies.
There is a suggestion that a gene or genetic mutation is associated with an increased risk for prostate cancer. The National Human Genome Research Institute, working with the NCI, is now conducting a study of genetic determinants of prostate cancer in cohorts of black families with a strong history of prostate cancer. The study is focused on determining whether a mutation in HPC-1 or other genes may be associated with the increased prostate cancer risk noted in African American men. Expanding this search for a prostate cancer gene could increase the number of families studied and intensify the search for new genes related to prostate cancer.
Opportunities exist to augment recruitment to the Cancer Genetics Network so that established centers can carry out educational efforts to recruit volunteers from minority communities. Funds could be used to contract with medical care facilities serving ethnic/racial minority communities that do not traditionally participate in research.
Strategies & Plans: Special Populations Networks
Education of special populations about prostate cancer issues is crucial. The Institute is committed to funding programs to help convey accurate and up-to-date information concerning prostate cancer and encouraging participation of special populations in clinical trials and studies so that the many important questions in this disease can be answered.
To this end, beginning in 1999, NCI is funding a new initiative entitled Special Populations Networks for Cancer Awareness, Research and Training (SPN). This is an effort to foster cancer awareness, community-based educational activities, and, particularly, the establishment of an infrastructure to support research in cancer control in minority populations and to enable investigators from these communities to compete successfully for research support. The SPN will be critical in efforts to support minority accrual to treatment, prevention, and control trials. The SPN will also carry out educational activities concerning cancer screening. The SPN could be expanded to emphasize prostate cancer awareness and other educational activities and to enhance prostate cancer control efforts focused specifically on African American men. An individual responsible for special populations efforts would be appointed to each region covered by the NCI's Cancer Information Service. This person would coordinate work in the Special Populations Networks with other NCI- and CDC-funded organizations to educate men about prostate cancer and the need for participation in clinical trials.
Supplements to Prostate SPORE
The NCI currently funds three Specialized Programs of Research Excellence (SPOREs) conducting prostate cancer research. These programs could be augmented to increase their emphasis on cancer etiology, especially etiology in African American populations and comparisons between African American and Asian American men.
Strategies & Plans: Investigator-Initiated Research
Goal:
Maintain excellence and accelerate progress in investigator-initiated research by increasing the pool of scientists, clinicians and health care practitioners and the number of grants funded for risk, surveillance and outcome research.
Initiatives:
Research Project Grants in Risk, Burdens, and Outcomes Science
A principal support mechanism used by the NCI to foster enhanced investigator-initiated research into prostate cancer is the Research Project Grant. This mechanism permits both basic investigations into cellular and molecular questions, and research into creating interventions that translate our knowledge into improvements in treatment, prevention, and care. NCI fully expects the research community to respond with research proposals applicable to prostate cancer, and will pay particular attention to applications that address those aspects of prostate cancer research identified by the Prostate Cancer Progress Review Group. It is anticipated that during the course of this Five-Year Plan, approximately 215 additional investigator-initiated research grants focused on prostate cancer would be supported. Of these, approximately 20 would specifically address risk, burdens, and outcomes science questions in prostate cancer.
Additional Investigator-Initiated Research Grants in Prostate Cancer: Funding Grants as Exceptions to the Payline
NCI expects to use a portion of its grant funds to support high-priority applications relevant to prostate cancer. We expect to give special attention to applications that fall within the defined areas of extraordinary opportunity in the Bypass Budget but fail to meet the established payline. The NCI would pay particular attention to applications addressing aspects of prostate cancer research that are described by the Prostate Cancer Progress Review Group as high-priority and important gap areas.