Introduction
Article Outline
Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer in the United States in men >50 years old.1, 2 With an estimated annual incidence of nearly 186 320 new cases, PCa accounted for about 25% of all new cancer diagnosis estimates in 2008.1 Although PCa is a disease that more often affects older men, men in their 40s are at risk, and nearly 40% of men diagnosed with the disease are <65 years of age.2 Within the United States, the 5-year survival rate of men with localized cancer at diagnosis has approached 100%; however, in patients diagnosed with metastatic PCa, the 5-year survival rate is only 32%.1 This discrepancy in survival according to the disease stage at diagnosis has been used as the rationale for early detection and screening, although survival data proving a mortality benefit to screening are not yet available.
The approved therapies for PCa include surgery (radical prostatectomy), various forms of radiotherapy, ablative therapies using heat or cold, and androgen-deprivation therapy. Each modality is associated with side effects of varying severity. Treatment-related side effects can take a tremendous toll on the patient's and his family's quality of life. In addition, the cost of treating PCa in the United States is high. Estimates from 2004, when the incidence of PCa was substantially lower, calculated the cost of treatment at about 8 billion dollars (Medicare treatment expenditure), with an average per patient Medicare cost of approximately $11 000.3
Given that a man's lifetime risk of being diagnosed with PCa is 15.78% (ie, 1 man in 6),2 efforts to reduce that risk become highly relevant. The benefits of reducing the risk of a PCa diagnosis are evident: diagnostic and treatment-associated human and economic costs can be averted. However, despite the high prevalence/incidence and treatment costs of PCa, as well as the poor side effect profiles of treatment of PCa, the perception of many is that PCa is a “benign” cancer. Many treating physicians perceive PCa as a cancer of the elderly and believe it is a disease that a man will die “with,” as opposed to “from.” This perception must be overcome, and the importance of increasing awareness about the disease, particularly in young men, should be stressed. PCa is a disease that is “worth preventing.”
This Supplement, titled “Prostate Cancer Risk: Overview of the Disease, Predictive Factors, and Potential Targets for Risk Reduction,” aims to increase awareness of the disease and of the science of PCa risk assessment. The Supplement consists of 5 reports, with each authored by a recognized authority in that topic. The first report, titled “Understanding the Epidemiology, Natural History, and Key Pathways Involved in Prostate Cancer,” was authored by E. David Crawford, and reviews the current science and understanding of the etiology of PCa. Although the exact cause of PCa is still largely unclear, much is known about its progression from precursor lesions to clinically significant invasive disease. It is widely accepted that androgens and dihydrotestosterone, specifically, play a key role in normal prostate growth and in the development of PCa.4 The current epidemiology of PCa and the mechanisms and key molecular pathways involved in the development and progression of the disease are outlined in the report by Crawford. The rationale for 5α-reductase inhibition and dihydrotestosterone suppression is discussed as a plausible strategy for slowing disease progression.
Prostate-specific antigen (PSA) measurement has been widely used as a leading indicator of prostatic disorders such as benign prostatic hyperplasia and PCa. The PSA test was initially approved by the Food and Drug Administration in 1986 to aid in the care of patients who had already been diagnosed with PCa.5 It was approved by the Food and Drug Administration as a diagnostic test for PCa in 1994. Its utility in helping to detect early-stage PCa has been continually substantiated in large-scale clinical trials. Moreover, these studies have done much to help us optimize its use by exploring the optimal PSA threshold for prostate biopsy. Although the optimal threshold for biopsy is unknown, data are emerging to support lowering this value to PSA levels <2.5 ng/mL.6 The importance of identifying the optimal PSA level for biopsy is very great, not only for contemporary clinical practice, but also from a public health perspective, because PSA screening has led to an increase in the diagnosed incidence of PCa and a decrease in the incidence of high-grade disease.7 Whether screening has contributed to the decrease in PCa mortality has yet to be shown in large randomized, controlled trials, and considerable concerns exist about the overdiagnosis and overtreatment of clinically insignificant cancer that could result from the use of lower PSA cutoffs. These issues are reviewed in detail by Kenneth Pienta in the second report, titled “Critical Appraisal of Prostate-specific Antigen in Prostate Cancer Screening: 20 Years Later,” in which a historical overview chronicling the rise of PSA as the most established PCa diagnostic marker and a discussion of the pros and cons of PSA screening are presented. Ongoing trials that address a potential mortality benefit through early detection by PSA screening, such as the European Randomized Study of Screening for Prostate Cancer and the Prostate, Lung, Colon, and Ovarian trials are detailed.
As mentioned, the role of PSA measurement as a diagnostic tool is well established. The role of PSA as a predictor of the risk of developing future PCa continues to evolve. Several large-scale studies, including the European Randomized Study of Screening for Prostate Cancer, have shown that, in addition to assessing the current risk of PCa, PSA has the ability to predict an individual's risk of developing PCa in the future. This predictive ability was demonstrated for a range extending up to 30 years in the future.8, 9, 10, 11 These studies are succinctly reviewed by Neil Fleshner and Nathan Lawrentschuk in the third report of the Supplement, “Risk of Developing Prostate Cancer in the Future: An Overview of Prognostic Biomarkers.” In addition, data from the European Randomized Study of Screening for Prostate Cancer showed that PSA values as low as 1.5 ng/mL might forecast a risk of a diagnosis of PCa ≤4 years in the future.6 From a public health perspective, these findings are quite significant, because they could allow for the early identification of those men who might be at risk of future PCa and allow for pre-emptive clinical management to reduce that risk. The report also reviews other secondary risk factors and their prognostic ability, as well as promising novel biomarkers that might augment the armamentarium of tools in diagnosing PCa, such as PCA3 and EPCA-2.
It is essential for the urologic community to modify the current perspective held by some physicians that PCa is an indolent disease to a perspective that recognizes PCa as a disease worth preventing. The medical community needs to be cognizant of the toll, such as incontinence and sexual disorders, that various treatment modalities can inflict on the patient with PCa. Many of these treatment modalities, such as androgen-deprivation therapy, are chronic treatments, subjecting the patient to long-term side effects.12 The effect this has on a patient's quality of life is substantial and extends to the patient's family and caregivers, who are also affected by these treatments.13 These topics are covered in detail by Leonard Gomella et al. in the fourth report, titled “Current Prostate Cancer Treatments: Effect on Quality of Life.” In addition to the treatment complications and their negative effects on quality of life is the economic burden, in direct and indirect medical costs, inflicted on the healthcare system. The acknowledgment that pharmacologic strategies (such as 5α-reductase inhibitor [5-ARI] treatment) that reduce the risk of the future occurrence of PCa might be beneficial in terms of sparing patients the burden of treatment and costs is gaining momentum. The concluding portion of the report discusses the potential health and pharmacoeconomic benefits of risk reduction programs using 5-ARIs.
While the fourth report evaluates the concept of risk reduction strategies with 5-ARIs, the fifth and final report, titled “Overview of Pivotal Studies for Prostate Cancer Risk Reduction, Past and Present,” discusses the trials that provide evidence supporting the effect of 5-ARIs in reducing the incidence of PCa. The Prostate Cancer Prevention Trial (PCPT) has shown that patients treated with the 5-ARI finasteride experienced an approximately 25% reduction in the incidence of PCa and, despite controversy surrounding the increased detection of high-grade cancer,14 has provided enough impetus for additional studies with the dual 5-ARI, dutasteride. A key ongoing study, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, examines the effect of dutasteride in a high-risk population. That trial aims to determine whether dutasteride treatment will result in a reduction of risk for PCa.15 These 2 trials, PCPT and REDUCE, are compared in the fifth report. In addition, trials studying other aspects of PCa management with dutasteride, such as delaying the time to progression in men with low-volume, low-grade cancer (the Reduction by Dutasteride of Clinical Progression Events in Expectant Management [REDEEM] trial), are also outlined.
A clear understanding of the current state of PCa and PSA screening should be gained by readers of this Supplement, whose goal is to increase awareness of PCa, discuss how to improve patient diagnosis and risk assessment, and offer evidence that risk reduction strategies might provide significant benefit in reducing the incidence and public health effects of PCa.
This supplement is particularly timely, as the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) recently published a recommendation that physicians and patients consider the use of 5-ARIs in men undergoing screening for prostate cancer. Much of the first part of the supplement is dedicated to recommendations and data on PSA screening as well as an introduction to the science of 5-ARIs. The last chapter collates much of the data used by ASCO and AUA to formulate their recommendation for the use of 5-ARIs for chemoprevention, and will help the clinician provide up-to-date information to patients.
References
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- SEER cancer statistics review (based on November 2007 SEER data submission, posted to SEER Web site). http://seer.cancer.gov/csr/1975_2005/2008;Accessed May 30, 2008
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- Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging. Urology. 2001;58:411–416
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- The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–224
- Chemoprevention of prostate cancer in men at high risk: rationale and design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. J Urol. 2004;172(4 Pt. 1):1314–1317
G. L. Andriole serves as a consultant to Aeterna Zentaris, Nema Steba, Onconome, and GlaxoSmithKline and has received research funding from Envisioneering, Ferring Pharmaceuticals, GlaxoSmithKline, Veridex, Viking Medical, and Zeneca.
Editorial support and funding for medical writing assistance by IntraMed provided by GlaxoSmithKline.
PII: S0090-4295(09)00273-8
doi:10.1016/j.urology.2009.02.021
© 2009 Elsevier Inc. All rights reserved.
