Five-alpha-reductase Inhibitors for prostate cancer prevention.

BACKGROUND: Five-alpha-reductase inhibitors (5ARI) are frequently used to treat bothersome lower urinary tract symptoms associated with benign prostatic hyperplasia and male androgenic alopecia. They have potential as chemopreventive agents. OBJECTIVES: We sought to estimate the effectiveness and harms of 5ARI in preventing prostate cancer. SEARCH STRATEGY: MEDLINE, PreMEDLINE, and the Cochrane Collaboration Library were searched through April 2007 to identify randomized trials. SELECTION CRITERIA: For prostate cancer outcomes we included randomized controlled trials of at least 1 year in duration published after 1984. For non-prostate cancer outcomes, randomized trials were included if: they were at least 6 months in duration published after 1999. DATA COLLECTION AND ANALYSIS: The primary outcome was prostate cancer period-prevalence "for-cause." "For-cause" was defined as prostate cancer clinically detected based on symptoms, an abnormal digital rectal exam, or detected as a result of an abnormal prostate specific antigen value. Trials were categorized as long (> 2 year), mid (1-2 years) and short (< 1 year) term. MAIN RESULTS: Nine trials reported prostate cancer period-prevalence. Three trials using finasteride lasted 4 years or longer but only one (the Prostate Cancer Prevention Trial) was specifically designed to assess the impact of 5ARI on prostate cancer period-prevalence. The mean age of enrollees was 64.6 years, 91% were white, mean PSA was 2.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected. Finasteride was associated with a 26% relative risk reduction in prostate cancers detected for-cause among all randomized subjects (relative risk 0.74 [95% CI 0.67 to 0.83]; absolute risk reduction = 1.4% (3.5% versus 4.9%). Six trials assessed prostate cancers detected overall with a pooled 26% relative reduction favoring 5ARI (relative risk 0.74 [95% CI 0.55 to1.00]; 2.9% absolute reduction (6.3% versus 9.2%). Reductions were observed regardless of age, race or family history of prostate cancer but not among men with baseline PSA > 4.0 ng/mL. A greater number of high Gleason score tumors (7-10 or 8-10) occurred in men on finasteride in the PCPT. Impaired sexual or erectile function or endocrine effects were more common with finasteride than placebo. AUTHORS' CONCLUSIONS: 5ARI reduce prostate cancer risk but may increase the risk of high-grade disease in men who are undergoing regular screening for prostate cancer using prostate specific antigen and digital rectal examination. Effects are consistent across race, family history and age and possibly 5ARI but were limited to men with baseline PSA values <4.0 ng/mL. The impact of 5ARI on absolute or relative rates of prostate cancer in men who are not being regularly screened is not clear. Information is inadequate to assess the impact of 5ARI on mortality.

Evidence of a healthy volunteer effect in the prostate, lung, colorectal, and ovarian cancer screening trial.

Volunteers for prevention or screening trials are generally healthier and have lower mortality than the general population. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) is an ongoing, multicenter, randomized trial that randomized 155,000 men and women aged 55-74 years to a screening or control arm between 1993 and 2001. The authors compared demographics, mortality rates, and cancer incidence and survival rates of PLCO subjects during the early phase of the trial with those of the US population. Incidence and mortality from PLCO cancers (prostate, lung, colorectal, and ovarian) were excluded because they are the subject of the ongoing trial. Standardized mortality ratios for all-cause mortality were 46 for men, 38 for women, and 43 overall (100 = standard). Cause-specific standardized mortality ratios were 56 for cancer, 37 for cardiovascular disease, and 34 for both respiratory and digestive diseases. Standardized mortality ratios for all-cause mortality increased with time on study from 31 at year 1 to 48 at year 7. Adjusting the PLCO population to a standardized demographic distribution would increase the standardized mortality ratio only modestly to 54 for women and 55 for men. Standardized incidence ratios for all cancer were 84 in women and 73 in men, with a large range of standardized incidence ratios observed for specific cancers.

Good for women, good for men, bad for people: Simpson's paradox and the importance of sex-specific analysis in observational studies.

Even if a medial intervention has a beneficial effect in both men and women, an observational study that combines data from men and women can lead to the incorrect conclusion that treatment has a harmful effect. This is an example of Simpson's paradox, which although uncommon in practice, does, in fact, occur (Wainer H. Simpson's paradox. Chance 1999;12:43). More importantly, it is likely that in an observational study, a related result will occur; namely, ignoring sex in the analysis will lead to biased results. To better understand why Simpson's paradox and the related result occur, we present a graphic explanation.

Relationship of demographic and clinical factors to free and total prostate-specific antigen.

OBJECTIVES: To characterize the role of demographic and clinical parameters in the measurements of prostate-specific antigen (PSA), free PSA (fPSA), and percent free PSA (%fPSA). METHODS: This was a cohort study of volunteers to a randomized screening trial. A central laboratory determined PSA and fPSA for the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A baseline evaluation of free and total PSA was done for 7183 white, black, Asian, Hispanic, and other male volunteers, aged 55 to 74 years. Comparisons were made across racial and ethnic groups and across a set of clinical parameters from a baseline questionnaire. RESULTS: The median levels of serum PSA were less than 2.1 ng/mL in each age-race grouping of the study participants. The levels of free and total PSA were higher in black (n = 868, 12%) participants than in white (n = 4995, 70%) and Asian (n = 849, 11.8%) participants. Individuals who identified themselves as ethnically Hispanic (n = 339, 4.7%) had median PSA levels higher than whites who were not Hispanic. The free and total PSA levels increased with age, particularly among men 70 to 74 years old. However, the %fPSA levels showed less variation among the four racial groups or by age. The free and total PSA levels were higher among those who had a history of benign prostatic disease. CONCLUSIONS: Demographic (age and race/ethnicity) and clinical (history of benign prostatic disease) variables had a moderate effect on the measures of PSA and fPSA and very little effect on %fPSA.

The paired availability design for historical controls.

BACKGROUND: Although a randomized trial represents the most rigorous method of evaluating a medical intervention, some interventions would be extremely difficult to evaluate using this study design. One alternative, an observational cohort study, can give biased results if it is not possible to adjust for all relevant risk factors. METHODS: A recently developed and less well-known alternative is the paired availability design for historical controls. The paired availability design requires at least 10 hospitals or medical centers in which there is a change in the availability of the medical intervention. The statistical analysis involves a weighted average of a simple "before" versus "after" comparison from each hospital or medical center that adjusts for the change in availability. RESULTS: We expanded requirements for the paired availability design to yield valid inference. (1) The hospitals or medical centers serve a stable population. (2) Other aspects of patient management remain constant over time. (3) Criteria for outcome evaluation are constant over time. (4) Patient preferences for the medical intervention are constant over time. (5) For hospitals where the intervention was available in the "before" group, a change in availability in the "after group" does not change the effect of the intervention on outcome. CONCLUSION: The paired availability design has promise for evaluating medical versus surgical interventions, in which it is difficult to recruit patients to a randomized trial.

Trends in biomarker research for cancer detection.

A key challenge in cancer control and prevention is detection of the disease as early as possible, enabling effective interventions and therapies to contribute to reduction in mortality and morbidity. Biomarkers are important as molecular signposts of the physiological state of a cell at a specific time. Active genes, their respective protein products, and other organic chemicals made by the cell create these signposts. As a normal cell progresses through the complex process of transformation to a cancerous state, biomarkers could prove vital for the identification of early cancer and people at risk of developing cancer. We discuss current research into the genetic and molecular signatures of cells, including microsatellite instability, hypermethylation and single-nucleotide polymorphisms. The use of genomic and proteomic high-throughput technology platforms to facilitate detection of early cancer by means of biomarkers, and issues on the analysis, validation, and predictive value of biomarkers based on these technologies are also discussed. We report on recent advances in identifying sources of biomarkers that can be accessed by noninvasive techniques, such as buccal-cell isolates, as well as traditional sources such as serum or plasma. We also focus on the work of the Early Detection Research Network at the National Cancer Institute, harnessing expertise from leading national and international institutions, to identify and validate biomarkers for the detection of precancerous and cancerous cells in assessing risk of cancer. The network also has a role in linking discovery to process development, resulting in early detection tests and clinical assessment.

Study design in the evaluation of breast cancer imaging technologies.

RATIONALE AND OBJECTIVES: Bringing a new imaging technology to market is a complex process. Beyond conceptualization and proof of concept, obtaining U.S. Food and Drug Administration (FDA) approval for clinical use depends on the documented experimental establishment of safety and efficacy. In turn, safety and efficacy are evaluated in the context of the intended use of the technology. The purpose of this study was to examine a conceptual framework for technology development and evaluation, focusing on new breast imaging technologies as a highly visible and current case in point. MATERIALS AND METHODS: The FDA views technology development in terms of a preclinical and four clinical phases of assessment. With a concept of research and development as a learning model, this phased-assessment concept of regulatory review against intended use was integrated with a five-level version of a hierarchy-of-efficacy framework for evaluating imaging technologies. Study design and analysis issues are presented in this context, as are approaches to supporting expanded clinical indications and new intended uses after a new technology is marketed. CONCLUSION: Breast imaging technologies may be intended for use as replacements for standard-of-care technologies, as adjuncts, or as complementary technologies. Study designs must be appropriate to establish claims of superiority or equivalence to the standard for the intended use. Screening technologies are ultimately judged on their demonstrated effectiveness in decreasing cause-specific mortality through early detection, but they may be brought to market for other uses on the basis of lesser standards of efficacy (eg, sensitivity, specificity, positive and negative predictive value, and stage of disease detected).

Cancer screening.

Especially in the emotionally charged field of cancer screening, which can have substantial public health implications for large numbers of healthy, asymptomatic people, it is important to achieve strong levels of evidence before promulgating new screening tools. This review of screening study methodology is intended to help the reader weigh such evidence and to evaluate reports which appear in the literature. It is an attempt to go beyond the often-stated intuition that early cancer detection finds cancers when they are easier to treat, at a time when survival is best. Examples tell us that sometimes this assumption has been true, sometimes not. A familiarity with the hidden biases in the supposition can be translated into everyday medical practice for screening tests in general. The practitioner can then match the strength of recommendation with the strength of the evidence behind the recommendation.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is enrolling 148,000 men and women ages 55-74 at ten screening centers nationwide with balanced randomization to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for prostate-specific antigen. For lung cancer, men and women receive a posteroanterior view chest X-ray. For colorectal cancer, men and women undergo a 60-cm flexible sigmoidoscopy. For ovarian cancer, women receive a blood test for the CA125 tumor marker and transvaginal ultrasound. Members of the control arm continue with their usual care. Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary endpoint is mortality from the four PLCO cancers, which accounts for about 53% of all cancer deaths in men and 41% of cancer deaths in women in the United States each year. Blood specimens are collected from screened participants, buccal cell DNA from controls, and histology slides from cases; these are maintained in a biorepository. Participants complete a baseline questionnaire (covering health status and risk factors) and a dietary questionnaire. More than 12,000 participants were enrolled in the pilot phase (concluded in September 1994). Changes in the eligibility criteria followed. As of April 2000, enrollment exceeded 144,500. Data are scanned into designated on-site computers for uploading by participant identification number to the coordinating center for quality checks, archival storage, and preparation of analysis datasets for use by the National Cancer Institute (NCI). Scientific direction is provided by NCI scientists, trial investigators, external consultants, and an independent data safety and monitoring board. Performance and data quality are monitored via data edits, site visits, random record audits, and teleconferences. The PLCO trial is formally endorsed by the American Cancer Society and has been ranked by the American Urological Association as one of the most important prostate cancer studies being conducted. Special efforts to enroll black participants are cosponsored by the U.S. Centers for Disease Control and Prevention.

Molecular and genetic targets in early detection.

Recent research has revealed the existence of specific mutations in cancer. These mutations are being investigated as targets to find subjects at high risk for cancer, to detect early cancer, to detect the early recurrence of established cancer, and to find micrometastasis. These mutations are reviewed for the major anatomic sites. Some of the clinical issues related to the application of these mutations and the limitations of using molecular targets are also considered. Current methods for determining the risk of cancer are reviewed. Risk assessment is essential for defining cohorts for chemoprevention and other interventions. The concept of using surrogate anatomic and functional sites for estimating risk is introduced. Finally, the increasing complexity of molecular genetic analysis and the biologic heterogeneity of cancer are discussed in relation to early detection.

Trends and black/white differences in treatment for nonmetastatic prostate cancer.

OBJECTIVES: Controversy and uncertainty surround use of radical prostatectomy, radiation therapy, and conservative symptomatic management in treating elderly men with nonmetastatic prostate cancer. Prior studies have demonstrated variations in use of these therapies by patient age, race, and geographic region. This study examined trends in treatment for nonmetastatic prostate cancer in black and white men aged 65 and older during the period 1986 to 1993. The study also explored factors related to use of initial therapies in these men. METHODS: A cohort of 52,915 men (48,410 white; 4,505 black) obtained from the linked SEER-Medicare dataset was used in an observational design. Various sociodemographic and clinical measures were incorporated in the analysis. RESULTS: For both races, use of aggressive therapy had increased with time, although this trend appears to be slowing. Black men were less likely to undergo radical prostatectomy than were white men, but use of radiation therapy did not differ markedly by race. High socioeconomic status and a lack of comorbid conditions were among the factors predictive of aggressive therapy receipt. The relation between race and receipt of aggressive therapy was dependent on whether prostate cancer was detected by transurethral resection of the prostate. Sociodemographic and clinical characteristics explained approximately half the difference between black men and white men in radical prostatectomy use. CONCLUSIONS: This study documents racial differences and changing practice patterns in the treatment of nonmetastatic prostate cancer in elderly men. Further research is required to more fully understand reasons for racial differences, as well as to promote rational use of health care resources.

The role of prostate-specific antigen (PSA) testing patterns in the recent prostate cancer incidence decline in the United States.

OBJECTIVES: Trends in first-time and later PSA procedure rates are ascertained using longitudinal data from a population-based cohort. These trends are compared to trends in prostate cancer incidence to determine the role of PSA in the recent decline in prostate cancer incidence. METHODS: Medicare data were linked with tumor registry data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. A 5 percent random sample (n = 39985) of Medicare beneficiaries from the SEER areas without a previous diagnosis of prostate cancer as of January 1, 1988 was followed through 1994. Trends in first-time PSA use were distinguished from those of second or later for men without diagnosed prostate cancer. RESULTS: Trends in the rate of first-time PSA procedures track closely with trends in prostate cancer incidence rates, increasing until 1992 and decreasing thereafter. Similar patterns were observed by race and age group. Geographic variability in the dissemination of PSA screening was observed, yet the association between testing and incidence remained. Men in the cohort had a 4.7 percent chance of being diagnosed within three months of an initial PSA test, with the percentage falling for subsequent tests. CONCLUSIONS: It is informative to distinguish first from later tests when assessing the effect of the diffusion of a test in a population. Taking this approach was useful in illuminating the role of PSA testing in a reversal of a long-term increase in prostate cancer incidence rates.

Phase III, large-scale chemoprevention trials. Approach to chemoprevention clinical trials and phase III clinical trial of tamoxifen as a chemopreventive for breast cancer--the US National Cancer Institute experience.

Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.

Tobacco addiction: implications for treatment and cancer prevention.

The American Society of Clinical Oncology and the National Cancer Institute convened a symposium in June 1996 on tobacco addiction. Additional support for the symposium was provided by the American Medical Women's Association and the American Society of Preventive Oncology. The goals of this conference were to describe the burden and public health consequences of tobacco addiction, to describe the state of science for the treatment of nicotine dependence, and to explore new strategies to increase quit rates and to prevent the uptake of tobacco use. This article summarizes and integrates the meeting presentations on tobacco addiction and includes the topics of smoking prevalence; psychobiologic aspects of nicotine dependence; and implications for disease, treatment, and prevention. Comments on regulatory approaches and national strategies for reducing dependence are also summarized in presentations by Dr. David Kessler, former Food and Drug Administration Commissioner, and Dr. C. Everett Koop, former U.S. Surgeon General.