Prostate Cancer Risk Assessment Program

Prostate cancer is the most common form of cancer (except skin cancer) in men. Several factors have been associated with an increased risk for prostate cancer, including age, ethnicity, family history, lifestyle, and environmental exposures. Recognition of the importance of the interaction of these factors in prostate cancer has led to an interest in their evaluation as a model both for studying genetic susceptibility patterns and for studying and providing educational tools and preventive interventions. One such model has been developed at Fox Chase Cancer Center. Critical to the implementation of the model has been the establishment of the Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP). Together, they serve as a unique resource for investigating the interaction between environmental factors and genetic susceptibility patterns; exploring the early, premalignant biological markers of prostate cancer; and prospectively assessing the quality of life (QOL) of men at risk. In addition, PRAP facilitates the evaluation of models for prostate cancer risk counseling and screening in the community. This paper describes this model for early detection and risk reduction, along with preliminary data from its first two study aims. 3The program is particularly relevant in view of the wealth of genetic information emerging from the Human Genome Project. [ONCOLOGY 13 (3):325-334, 1999]

Introduction

An estimated 184,500 new cases of prostate cancer were diagnosed in 1998, and almost 40,000 men died from the disease.[1] Because of the high burden of morbidity and mortality from prostate cancer, the federal government, through the Medicare reform bill recently passed by Congress, has committed significant resources to expand efforts to improve the control and prevention of prostate cancer. The bill will cover annual prostate cancer screening for men over age 50 years beginning in the year 2000.

Despite this governmental support for prostate cancer screening, the issues of who, how, and when to screen for prostate cancer, and even whether such screening should be done at all, are still being debated at both the state and federal levels. These debates are due, in part, to conflicting and/or vague screening recommendations issued by medical organizations, such as the American Urologic Association, the American Cancer Society, and the American College of Physicians.

Divisiveness over prostate screening recommendations has arisen because, despite the development of sensitive and reliable screening methods, such as the prostate-specific antigen (PSA) level, questions have been raised about the cost-benefit of prostate cancer screening in asymptomatic

men and the cost-benefit of diagnosis and treatment of localized prostate cancer.[2-4] Most of the controversies center around two arguments: (1) that screening of asymptomatic men leads to the detection and costly treatment of latent tumors that would have remained clinically silent and would have been discovered only on autopsy; and (2) that treatment confers only a small survival benefit while having a large negative impact on patients’ quality of life.

Arguments in favor of continued screening include pathologic evidence that most of the cancers detected by screening are clinically significant tumors, and that only a small percentage (10% to 15%) are insignificant or latent tumors.[5,6]

Nevertheless, with the steadily rising cost of health care, resources for screening have come under close scrutiny. A more cost-effective approach to prostate cancer screening may be to screen only those men at high risk for the disease.

Based on these considerations, Dr. Gerald E. Hanks founded the Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP) at Fox Chase Cancer Center in 1996. This risk assessment program offers a unique opportunity for high-risk men to obtain information regarding their risk for prostate cancer within a defined research protocol that will study their risk factors within a biopsychosocial framework. After a brief discussion on risk factors for prostate cancer, this article will describe the establishment of the PCRR and PRAP, their objectives and aims, and preliminary results relating to two of those aims.

Defining “High Risk”

Primary Risk Factors

Men at “high risk” for prostate cancer have been defined by the American Cancer Society as those who have a strong family history or who are African-American.[7] Despite the fact that prostate cancer has a high prevalence (ie, there are many individuals whose prostate cancer results from a variety of causes), it has been theorized that the disease has a genetic component. Family history and a genetic predisposition to develop this common disease have been documented.[8-13] Hereditary prostate cancer is associated with a pattern of cancer distribution consistent with Mendelian inheritance of a susceptibility gene.[14-16] This inherited prostate cancer gene could be autosomal-dominant, x-linked, or recessive.[17]

Segregation analysis suggests the existence of a dominant susceptibility locus accounting for 9% of all prostate cancers and more than 40% of early-onset tumors.[9] The increased risk conferred by family history has been seen in men of all ages but is more pronounced in younger men (ie, those < 65 years old).[11]

The Human Genome Project, an international research program designed to map the human genome and to localize the estimated 50,000 to 100,000 genes within the human genome, has already had an impact on common cancers, such as breast and colon cancers, by localizing specific chromosomal regions.[18] This project recently supported the genome-wide scan of high-risk prostate cancer families, which led to the identification of a genetic locus, HPC1, on chromosome 1, which is associated with prostate cancer predis position.[19] In 1996, Smith et al undertook a linkage analysis to search for evidence of loci contributing to risk for prostate cancer in 66 high-risk prostate cancer families.[19] This analysis showed linkage to the long-arm of chromosome 1 (1q24-25), thus providing strong evidence for a major prostate cancer susceptibility gene. New evidence indicates that a second prostate cancer susceptibility locus resides on chromosome X (Xq 27-28),[20] a finding consistent with results of previous population-based studies suggesting an x-linked mode of inheritence. Recommendations have been made to target future efforts at positional cloning of the gene in families who meet the proposed clinical criteria for hereditary prostate cancer.[21]

Advances in the isolation of genes associated with hereditary cancers not only will elucidate the basic mechanisms of carcinogenesis but also will provide precise tools for assessing an individual’s risk for cancer. The incorporation of genetic information into clinical cancer risk assessment paradigms is being proposed as a way of targeting preventive strategies to the most appropriate individuals and maximizing their effectiveness.[22]

Independent of family history, African-American males have the highest incidence of and mortality from prostate cancer in the world.[23] Mebane and colleagues[24] reported that black males have a two to three times higher rate of being diagnosed with prostate cancer before age 65 years, whereas the mean age at diagnosis among white men is 72.3 years.[25] In 1993, prostate cancer accounted for 9.4% of cancer deaths in African-Americans but only 6.2% of cancer deaths in Caucasians. Black men have a 9.6% risk of being diagnosed with prostate cancer and a 3% risk of dying from the disease, as compared with a 5.2% risk of diagnosis and a 1.4% risk of dying from the disease for US white men.[26]

Prostate cancer survival rates from the last period for which data are available (1986 to 1992) also show marked racial differences; the 5-year survival rate is 73% for blacks, as compared with 89% for whites.[27] Finally, the proportion of patients diagnosed with metastatic disease is higher in black compared with white Americans.[28]

Age is the primary risk factor for prostate cancer. Indeed, the age-adjusted incidence rate of prostate cancer among men ³ 65 years old increased by 82% according to a population-based study derived from Medicare claims data and National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) statistics accumulated between 1986 and 1991.[29] For men at high risk due to other factors, it is not only their age at the time of screening that heightens that risk but also the age of onset of prostate cancer in a first-degree relative.[14] For example, if a man is diagnosed before age 62 years, his brother or brothers have a four times higher relative risk of developing a malignancy.[30]

Additional Risk Factors

In addition to family history, ethnicity, and age, it has become clear that lifestyle risk factors are associated with the development of prostate cancer. Several studies have demonstrated an association between animal fat intake[31-33] and the risk of developing prostate cancer. Although other studies have not supported this association,[34-36] the strong correlation between national consumption of fat and national rates of prostate cancer has led to continued interest in the relationship.

Weaker associations have been found between the use of tobacco and occupational exposure to cadmium, a trace mineral found in alkaline batteries, and subsequent development of prostate cancer.[37]

Rationale for Family Cancer Programs

Since the multifactorial nature of prostate cancer makes it unlikely that the alteration of any one risk factor will prevent the disease, a great deal still needs to be learned about the etiology, biology, and genetic regulation of the disease. The recent growth of genetic information about prostate cancer and the imminent identification of a gene or genes responsible for prostate cancer susceptibility, coinciding with the efforts of the Human Genome Project, will have major public health implications. These implications include the development and evaluation of genetic screening policies, patient treatment preferences, quality of life (QOL) data, patient and physician education, counseling strategies, and health care policy. The demand for genetic testing, as well as confusion about the meaning of prostate cancer susceptibility, is likely to grow, and the need to educate men about their individual and familial risk for prostate cancer will become more acute.

Attempting to meet some of these needs, family cancer programs that offer a wide range of services, including risk analysis, screening, DNA testing and storage, chemoprevention, and assistance with treatment decision-making, are being developed at medical centers throughout North America and Europe. One of the most cost- and labor-efficient ways to approach the definition of prostate cancer risk is to study persons known to be at increased risk for the disease.

Prostate Cancer Registry and Risk Assessment Program

The Fox Chase Cancer Center (FCCC) Prostate Cancer Risk Assessment Program (PRAP) and Registry (PCRR) was founded in 1996 to investigate areas of controversy surrounding prostate cancer screening, including the risks and benefits.

Objectives and Aims

The primary objective of PCRR and PRAP is to establish a registry and screening clinic for prostate cancer high-risk families in order to further our understanding of the complex mechanisms of prostate cancer carcinogenesis and to provide medical and psychosocial interventions to unaffected individuals at high risk. Five aims stem from this first objective:

To identify eligibility and develop the components of a registry for men at risk for prostate cancer and develop a mechanism for the storage and retrieval of registry data;

To develop a prostate cancer screening clinic for men at high risk for prostate cancer to improve (1) the early detection and treatment of the disease while it is still curable and (2) document the epidemiologic, clinical, and behavioral profiles as case-cohort comparisons once prostate cancer develops;

To prospectively collect QOL and patient treatment preference data and to study changes over time once prostate cancer develops;

To examine men’s risk perceptions, adjustment to risk, and screening behaviors; and

To prospectively determine the cost-effectiveness of high-risk prostate cancer screening.

The second major objective of PRAP is to study the genetics of prostate cancer. Four strategies have been proposed to achieve this objective: (1) evaluating the risk associated with genetic markers of predisposition to prostate cancer; (2) modeling the breast-prostate phenotype based on familial aggregation of both cancers; (3) creating and maintaining a serum bank for future genetic testing of oncogenes and tumor-suppressor genes potentially involved in the near-Mendelian transmission of prostate cancer; and (4) developing protocols for genetic assessment and counseling.

The third major objective of PRAP is the development of tools for intervention and primary prevention of prostate cancer in high-risk men. This goal is to be achieved by: (1) devising a model that calculates the relative risk, absolute risk, and interval risk for developing prostate cancer in order to design risk reduction strategies; (2) developing, testing, and evaluating behavioral interventions to assist in the comprehension and processing of risk-related information, as well as in the enhancement of coping skills and adjustment to risk and disease status; (3) creating educational tools to assist primary care practitioners in counseling patients regarding prostate screening, risk assessment, risk reduction, and coping.

Prostate Risk Assessment Program

Fox Chase Cancer Center is an NCI-designated Comprehensive Cancer Center in Philadelphia, Pennsylvania, committed to the support of cancer prevention and early detection. This commitment is exemplified by the recent groundbreaking of the Cancer Prevention Institute.

The PRAP was developed as part of this state-of-the-art effort, building on the successful 8-year history of the Fox Chase’s Family Risk Assessment Program (FRAP). The FRAP originated as a program to assess, screen, and genetically test women with a strong family history of breast/ovarian cancer. Like the FRAP, the PRAP is a multidisciplinary effort that includes medical oncologists, urologists, radiation oncologists, genetic counselors, health educators, nurses, registered dieticians, phlebotomists, epidemiologists, behavioral scientists, molecular biologists and geneticists, laboratory technicians, computer programmers, data managers, biostatisticians, secretarial staff, and an administrator. This multidisciplinary team developed the model for a program for prostate cancer early detection, eventual risk reduction, and cancer prevention; this model is shown schematically in Figure 1.

Establishing the Prostate Cancer Registry and Clinic

Registry-Eligibility criteria for the PCRR, based on published literature, include: men with at least one first-degree relative with the diagnosis of prostate cancer; African-Americans with or without a first-degree relative with prostate cancer; and men 35 to 69 years of age. The lower age boundary was based on Mayo Clinic and Johns Hopkins reports of early age of onset for at-risk men and the upper boundary was based on the PRAP goal of targeting men at risk prior to the mean age of onset of prostate cancer for the general population.[16,38,39]

To develop the components of a registry and to create a mechanism for data storage and retrieval, the PRAP was modeled after the FRAP, Fox Chase’s already existing risk assessment program (see above). This registry includes the health history, family history, clinical information, QOL data and risk data, as well as an expanded family and medical history and, when possible, pathologic confirmation of familial cancer for men with at least three or more affected members. The system uses the relational database product Oracle as the primary software platform for data entry and validation, storage, retrieval, modification, and security.

This system generates multigenerational pedigrees summarizing the family history; these pedigrees are used both as educational tools and to identify those families appropriate for more intensive genetic investigation. The data used to generate pedigrees are easily updated to include recent developments, such as deaths or new cancers reported for previously listed family members, as well as new births. The software also can create the union of family histories provided by two or more distinct probands in the same family in order to create an “extended” pedigree.

In order to preserve participant confidentiality, which is a major concern in all studies dealing with family history and potential genetic data, only numerical identifiers are stored electronically with the study results. A linkage database with limited investigator access contains both names and numerical identifiers. In addition, completed hard copy data collection instruments are stored in locked filing cabinets.

Screening Clinic-Once eligibility was established, the clinical components of PRAP were developed. Currently, these include telephone registration; an initial screening visit; a 4- to 6-week feedback session, and either diagnostic, annual, or semiannual screening follow-up, depending on the findings. At present, screening is conducted in the outpatient department at Fox Chase, with anticipated expansion to network community sites over the next year.

Quality of Life Data-Consistent with the aims of PRAP, data on quality of life (QOL) and patient treatment preferences are prospectively collected to study changes over time if and when prostate cancer develops. Studies of QOL in men with prostate cancer have focused primarily on concerns about bladder and sexual function,[40] although alterations in bowel function, anxiety over treatment choice, and other issues may also have an impact on QOL.

Studies of QOL and the symptoms that affect it have not taken into account prospective baseline QOL or symptoms that men may experience with aging, such as urinary problems and sexual dysfunction. It is important to know what baseline symptoms men experience prior to diagnosis to determine the magnitude of change attributable to screening and treatment. The im-portance of these QOL issues in patient decision-making should not be underestimated.

In 1991, Singer et al reported trade-offs of quality vs quantity of life in men with prostate cancer.[41] These investigators documented that up to 68% of a group of men were willing to trade off at least a 10% chance of prolonged survival for treatment that offered a better chance of preserving potency after prostate cancer. The Fox Chase risk assessment program, therefore, provides a unique opportunity to evaluate the QOL of men who are at increased risk of prostate cancer while they are still unaffected and to follow them prospectively, using a battery of valid, reliable QOL instruments.

Risk Perceptions-In addition to collecting data on QOL and patient preferences, PRAP offers the opportunity to examine men’s risk perceptions, adjustment to risk, and screening behaviors. The few studies that have been conducted have demonstrated that, among African-Americans, those who have a first-degree relative with prostate cancer are more knowledgeable about the disease.[42] They also express greater interest in PSA screening.[43] In general, however, it has been reported that having a first-degree relative with prostate cancer is only marginally related to a person’s intention to undergo prostate cancer screening.[44]

Research in a number of other cancer-risk counseling contexts indicates that individuals need to be made sufficiently aware of threats to their health to motivate adaptive action but should not be made so anxious that they take no action.[45,46] However, what constitutes optimal education and counseling for prostate cancer remain to be established. Cultural differences in beliefs, attitudes, and feelings about genetic risks need to be appreciated and respected.

Risk perceptions research conducted by the PRAP is guided by the cognitive-social health information processing (C-SHIP) model, a theoretical framework that identifies the basic cognitive-affective processes that underlie how individuals encode, perceive, and react emotionally and behaviorally to potentially stressful information,[47] particularly health risks and medical options.[46] Our research focuses on assessing and facilitating comprehension, adjustment, and coping among participants via an innovative educational and counseling intervention.

Cost-Effectiveness of Screening-The last major aim related to establishing the PRAP focuses on prospectively determining the cost-effectiveness of screening for individuals at high risk for prostate cancer. Resource allocation for programs for the early detection and treatment of prostate cancer is currently the focus of much debate. Several recent decision analyses using cost-effectiveness and cost-utility models have shown little or no cost-benefit associated with the screening, early detection, or treatment of asymptomatic prostate cancer.[3,48,49]

Utility is derived from individual preferences for a condition or health state. Individual preferences are summed, and the ensuing value is used to weight survival or other health outcomes. In a cost-effectiveness analysis, a program may be evaluated and compared to the next best alternative. Investigators in our risk assessment program have laid the groundwork for assessing the cost-effectiveness of high-risk prostate cancer screening by using a measure of utility called the time trade-off (TTO) technique.[50,51]

Assessing Genetic Predisposition

The second major objective of the PRAP is to study the genetics of prostate cancer, in collaboration with the center’s Molecular Genetics Facility. This facility consists of basic science and computer laboratories staffed by a multidisciplinary group of scientists who span all three divisions of Fox Chase: basic science, medical science, and population science. The interests of this multidisciplinary group include the identification and description of tumor-suppressor genes, the regulation of oncogenes, the construction of multiple-point genetic maps, and the evaluation of the joint role of family history and allelic variation at candidate loci in explaining cancer susceptibility.

Genetic Markers-Research evaluating the risk associated with genetic markers of predisposition to prostate cancer is varied but includes studying the levels of the insulin-like growth factor–binding proteins in the serum of men at higher risk for the development of prostate cancer. Initial studies by others have shown the level of these proteins to be altered in men with prostate cancer.[52] However, an at-risk population has yet to be examined, and PRAP is facilitating this effort.

Breast-Prostate Cancer Phenotype-Fox Chase’s ongoing work with the FRAP among women with a family history of breast and/or ovarian cancer is providing the database on which to model the breast-prostate cancer phenotype based on familial aggregation of both cancers. The goal of this analysis will be to test specifically for compatibility with Mendelian inheritance of a combined breast-prostate cancer phenotype.[15] Other statistical models will be considered as the data accrue. In the future, this combined cancer phenotype might be subjected to linkage analysis for the identification of a common susceptibility locus.

Prostate Cancer Biospecimen Bank-The new risk assessment program is also designed to create and maintain a serum bank for future genetic testing of oncogenes and tumor-suppressor genes potentially involved in the near-Mendelian transmission of prostate cancer. To this end, the High-risk Prostate Cancer Biospecimen Bank has recently been established for the identification and validation of prognostic indicators in prostate cancer. The purpose of this addition to the Molecular Genetics Facility is to provide a mechanism for the collection of blood samples from all PRAP participants.

The collection of DNA and plasma from men with varying degrees of increased risk will provide a tremendous resource that ultimately will be used to describe the frequency of prostate cancer susceptibility genes in this population. It will also provide materials for investigating the role of hormones, nutritional factors, and markers of exposure to potential environmental carcinogens.

Protocols for Genetic Assessment-In order to select individuals and families for closer genetic investigation and counseling, PRAP also has been involved in developing protocols to identify, notify, and recruit eligible participants. An important task is to develop informed consent forms (in language amenable to the layperson) appropriate for the various stages of genetic assessment and eventual testing.

Genetic cancer risk protocols are being determined by establishing genetic risk criteria, including the number of affected relatives, age at onset of the disease, presence of other related cancers in the family, and apparent degree of penetrance. A case review panel, consisting of a medical oncologist, molecular geneticist, and genetic counselor, periodically reviews selected family histories to determine the appropriateness of further genetic investigation.

Protocols are being developed for use in network hospitals to contact eligible individuals, explain the purpose of genetic risk assessment, and arrange an initial counseling visit. Training of community physicians and nurses will be an ongoing activity to integrate these counseling protocols into the mainstream of medical care without jeopardizing the care and confidentiality of high-risk family members.

Tools for Intervention

The third and final major objective of PRAP is to develop tools for intervention and primary prevention of prostate cancer in men at high risk for the disease.

Calculating Risk-A multidisciplinary team is testing models that calculate the relative risk, absolute risk, and interval risk for developing prostate cancer. The logical extension of this work will be to design risk-reduction strategies, such as chemical modifiers, or behavioral interventions, such as dietary modifications.

Behavioral Interventions-In addition, this study has begun the development, testing, and evaluation of behavioral interventions to assist the increasing numbers of brothers and sons of men with prostate cancer who seek information and advice about the disease, their own potential risk, and available preventive options. Although men with a family history of prostate cancer are generally aware that they are at an increased risk for prostate cancer, they are often misinformed about the magnitude of their risk. Many men are confused about the interaction of environmental and lifestyle risk factors with hereditary risk,[41] and about the appropriateness of genetic risk assessment.

Most of the educational and psychosocial interventions developed in oncology have targeted patients already diagnosed with cancer, and focus on coping with the illness and its treatment. In contrast, little attention has been paid to the informational and psychological needs of participants in cancer risk counseling programs.

There is currently no consensus on the optimal way of delivering prostate cancer risk information, who is best suited to provide this information, or the true impact of counseling programs on participants’ risk comprehension, psychological adaptation, or adoption of recommended health practices. The anticipated widespread availability of genetic testing for prostate cancer susceptibility genes in the near future mandates that we learn the most appropriate ways to evaluate these outcomes and to define the essential elements of psychosocial support needed to maximize positive outcomes to cancer risk counseling. The development of the PRAP and PCRR provide the opportunity to develop and evaluate educational and psychological strategies to optimize prostate cancer risk counseling in the community setting.

Educational Tools for Primary Care Practitioners-Finally, the PRAP aims to develop educational tools to assist primary care practitioners in counseling patients regarding prostate screening, risk assessment, risk reduction, coping skills enhancement, and anxiety reduction. Physicians can have a positive impact on their patients by encouraging them to reduce high-risk behaviors and adopt healthy lifestyles.[53] However, there is a gap between physicians’ knowledge of and general approval for preventive health guidelines and their actual performance of these practices.[54]

Several barriers to the incorporation of cancer control activities into the primary care setting exist. These include a lack of physician training and a lack of confidence in their ability to deliver preventive services.[2] As a result, methods to evaluate and reduce risk are often underutilized in the primary care setting. A computerized registry of prostate cancer–prone families will allow physicians caring for high-risk relatives to target prostate cancer screening and prevention programs to the appropriate individuals.

Data Collection Procedures

Recruitment-Men at increased risk for prostate cancer were initially recruited for participation through relatives diagnosed and treated for prostate cancer at Fox Chase Cancer Center and from the database and follow-up clinic maintained by the Department of Radiation Oncology. A mailing was sent to men in the database who had been treated within the last 3 years, describing PRAP and inviting them to participate. A relative identification form (RIF) was distributed, which requested permission to contact eligible adult first-degree male relatives to invite them to participate.

An ongoing plan for recruitment has also been developed. This includes the distribution of PRAP information by Fox Chase and network hospital medical, surgical, and radiation oncologists to their patients with prostate cancer. Radio and newspaper advertisements, direct mailings, and the dissemination of information at health fairs are other methods used to promote recruitment in the PRAP. A strategic plan for minority recruitment was developed and a minority consultant was hired.

The RIF continues to be distributed whenever the program brochure is given out to men previously diagnosed with prostate cancer. The RIF explains the purpose of the PCRR and requests permission to contact eligible relatives. The forms are forwarded to the PRAP office, where a trained protocol coordinator or health educator contacts each person listed by phone to confirm eligibility, explain the purpose of the registry, and offer an invitation to participate.

All men who are interested in participating receive, by mail, a packet of baseline questionnaires, as well as information that further describes the PRAP and PCRR. The questionnaires are designed to provide a complete database on family history, pertinent medical history, preventive health-care behaviors, risk perception, psychological status, and QOL. This information serves as the basis for making preliminary recommendations regarding further testing, and for gaining entry into a variety of Fox Chase prevention and detection programs, including programs for breast, ovarian, colorectal, and skin cancers.

Registration-The at-risk population registers by calling into the program or by being contacted by phone based on information received on the RIF. Once an individual asks or consents to participate, an appointment is scheduled and a written confirmation of the appointment is mailed. In addition, the man receives more information on the study, self-assessment forms, including the family history and QOL forms, and a consent form via mail 2 weeks prior to the scheduled screening visit to allow time for completion. He is instructed to bring the consent forms and completed questionnaires to the initial appointment.

Screening Appointment-At the screening appointment, the health educator explains the study in lay terms along with the individual’s right to refuse. The health educator obtains written informed consent, checks the questionnaires for completeness, answers any questions, and assists anyone with literacy or language needs.

Prior to the actual screening, the health educator also provides an educational session (partly standardized and partly individualized) regarding prostate anatomy, known risk factors, and possible risk modifiers of prostate cancer, along with an explanation of sporadic, familial, and hereditary types of cancers. A detailed explanation of the screening methods is also given.

Next, the participant is seen by the phlebotomist for blood work and then by the genetic counselor for an expanded family history. The participant next sees the physician for a review of the self-reported health history and the digital rectal examination. The entire screening appointment takes approximately 2 hours.

Follow-up-An appointment for the feedback of screening results is made before the participant leaves the initial screening visit for 4 to 6 weeks from the time of screening. In the interim, a pedigree is generated and reviewed, the prostate-specific antigen (PSA) results are obtained, and the percentage of free PSA is determined for any individual whose total PSA is between 2 and 10 ng/mL. In addition, the nutritional information is analyzed and a computer printout of nutritional intake is generated.

Men with abnormal results, particularly abnormal PSA levels, are contacted by the physician by telephone, informed of the need for diagnostic follow-up, and appropriately referred. All others return to the PRAP for their feedback visit.

At the feedback visit, the participant meets with the genetic counselor to review his pedigree and receive the physician’s follow-up instructions, which generally consist of annual or, when appropriate, semiannual screening for prostate cancer. Other familial or hereditary illnesses discovered on pedigree review are discussed, along with appropriate follow-up and referral. Implications of the findings for the participant and family members are discussed, together with potential preventive health behaviors. The genetic counselor also attempts to answer questions and keep concerns in perspective. The dietitian reviews the results of the nutritional analysis and gives recommendations for maintaining or improving good dietary habits. The participant receives a packet with the results of screening, nutritional information, and recommendations for follow-up.

Reimbursement-Fiscal viability is a concern with all screening programs. Initial venture capital was derived from multiple sources, including philanthropic gifts, unrestricted educational grants, and institutional support. Federal, state, organizational, and pharmaceutical grant funding provide program support until negotiations with managed care organizations and other third-party payors are complete. To date, one managed care organization has agreed to participate and has provided a billing code specifically for screening. Some third-party payors will reimburse specific parts of the program, including the digital rectal examination and PSA blood test.

Currently, there are no direct out-of-pocket costs to participants. The patient’s insurance carrier is billed; however, if the insurance does not reimburse screening or early detection services, the participant is not billed for the balance.

Preliminary Results

As this is a multifaceted program with numerous objectives and aims, many of which are long term, the following results represent only preliminary data related to the first two study aims of setting up the PCRR and PRAP.

PCRR Accrual

In the first 21 months of operation, from October 1996 to June 1998, accrual has included 101 men (49 white, 52 black) at increased risk for prostate cancer and 134 men with a diagnosis of prostate cancer. Demographics of these individuals are summarized in Table 1.

The initial mailing to men previously treated for prostate cancer generated a response rate of approximately 10%. Recruitment through the network hospitals has generated multiple inquiries and a few scheduled appointments; the number of these are anticipated to increase with greater recognition of the program. Many of the participants enter the program with the encouragement of relatives previously treated at Fox Chase.

To benchmark the PRAP initial accrual data, we compared our statistics to those of the FRAP. In 1991, the first year of FRAP operation, 14 subjects were accrued to the study. In the second year of FRAP, 195 subjects were enrolled, and by 1996, 417 subjects were accrued in a year. Over the first 12 months of its operation, from October 1996 through October 1997, PRAP surpassed initial FRAP accrual for the first year by approximately 60%.

Minority recruitment to the prostate program has been very successful. One recruitment strategy has been the recent development of a radio advertisement that targeted African-Americans and aired on local stations with significant minority patronage. Again, to benchmark our recruitment efforts, the PRAP has yielded an accrual of African-American men 40% greater than the African-American representation in the Fox Chase primary service area (which is 13.5%).

Preliminary Screening Results

Table 2 summarizes the PRAP clinical results. Of the total of 101 at-risk men screened (only one screening each, to date), 17 have had abnormal findings. Of these, 7/101 (7%) had a PSA level > 4 ng/mL (range, 4.5 to 10.1 ng/mL), another 7 (7%) had a PSA between 2 and 4 ng/mL and percentage of free PSA of £ 27%.[55] (The lower the free PSA, the more indicative it is of cancer, with abnormal cut-offs ranging from 28% to 14%). Three men had abnormal digital rectal examinations.

All but 1 of the 17 men with abnormal findings were referred for biopsy; the last was given the option of coming in for follow-up at 6 months. Compliance with recommendations has been 15/17 (88%), with two men lost to follow-up. Follow-up of noncompliance has included multiple phone calls from both the physician and health educator, along with a certified letter to the patient.

Of the 17 men with abnormal findings, 13 have had biopsies to date, with 7 pathologically confirmed prostate cancers. Biopsy results are summarized in Table 3. All seven tumors were clinically significant, with Gleason scores of 6 and 7. Five of the seven men with pathologically confirmed cancers had both normal digital rectal examinations and total PSAs, and were only detected based on their low percentage of free PSA.

Of the men diagnosed with cancer, four (57%) were black and three (43%) were white, mirroring national trends of increased incidence in the African-American population. Four of the men have opted for radical prostatectomy and three have received radiation therapy. From these short-term findings based on the initial 21 months of screening men at high-risk for prostate cancer, we have documented a 7% rate of clinically significant prostate cancer malignancies in men ages 44 to 56 years.

Lacking published reports for direct comparison, we used the American Cancer Society-National Prostate Cancer Detection Project (NPCDP) as our benchmark. Published reports from the NPCDP indicated that we could expect to detect 3% of cancers (first pass) had the screening included a general population of men 55 to 70 years old in whom the disease is highly prevalent due to age alone.[25] The fact that we are detecting clinically significant cancers in this younger population at more than twice the expected rate leads us to believe that we have been successful in detecting prostate cancers early in those men truly at high risk.

Discussion

The PCRR and PRAP will further our understanding of the mechanisms of prostate carcinogenesis, and will help us determine the best ways to provide risk information both to men at increased risk for prostate cancer and their primary care practitioners. Recruiting men at high-risk for prostate cancer, ie, those with at least one first-degree relative with the malignancy or those of African-American descent, has proven to be feasible.

African-American recruitment, an essential part of this program, has been remarkably successful. This may be attributed, in part, to the minority consultant. This success is of twofold significance, given that African-American men have the greatest risk of developing prostate cancer in the world, as well as the preponderance of literature citing the difficulties in recruiting minorities to screening programs and clinical trials.[56]

The registry, a large computerized database that includes genetic, lifestyle, and environmental risk information, will allow investigators to address a multitude of issues. These include: gene-environment interactions; the impact that risk, diagnosis, and treatment have on behavioral changes and QOL; and the underlying reasons for differences in morbidity and mortality from prostate cancer in different age and racial groups. Also, the registry will further our understanding of the genetic basis of prostate cancer by identifying families appropriate for linkage analysis studies.

The inclusion of a high-risk specimen bank in the design of this registry will allow investigators to identify and quantify early premalignant markers of prostate cancer risk and to estimate the true prevalence of prostate cancer gene(s) in the population. Despite widespread public interest in prostate cancer, many first-degree relatives of prostate cancer patients know very little about their risk status. The establishment of this registry provides the opportunity to test different counseling strategies so that we can best meet the needs and demands for information that will accompany the eventual identification of prostate cancer susceptibility genes.

Long-term follow-up of men enrolled in the PRAP will permit evaluation of the effectiveness of surveillance and prevention strategies. Finally, PRAP and PCRR will serve as catalysts for the development of educational training directed toward community-based health care professionals.

Conclusions

To be successful, the transfer of information generated by the Human Genome Project to the public health realm of cancer control must be put in the hands of primary care practitioners. Essential to this effort will be programs that develop, test, and evaluate the use of genetic information in cancer screening efforts. This article has presented a model for such a program.

The PRAP and PCRR have been established through the coordination of multiple components. The objectives of this program extend beyond the collection of a large, sophisticated epidemiologic, genetic, psychosocial, and behavioral data set from many sources to also include professional and lay education, technology transfer to the community, and preventive care.

Analyses of the first two aims of developing a registry and risk assessment program for prostate cancer have indicated that the program has succeeded in surpassing its initial benchmarks. This model for early detection and risk reduction has laid the foundation for both research and clinical practice in men at high risk for prostate cancer.

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