[Show abstract][Hide abstract] ABSTRACT: Screening for prostate cancer using prostate-specific antigen (PSA) has been appealing. However, the significant associated decline in prostate cancer mortality comes at the cost of a very high rate of diagnosis, and many patients with indolent, non-life-threatening cancer are exposed to the risk of significant side effects from radical treatment. Most men with favourable-risk prostate cancer are not destined to die of their disease, even in the absence of treatment. The challenge is to identify the subset that harbour more aggressive disease early enough that curative therapy is still a possibility, thereby allowing the others to enjoy improved quality of life, free from the side effects of treatment. This article reviews current research into active surveillance in favourable-risk disease and some of the issues that arise when prostate cancer is monitored rather than being treated immediately.
[Show abstract][Hide abstract] ABSTRACT: The Prostate Cancer Prevention Trial (PCPT) showed a decreased prostate cancer rate but an increased rate of high Gleason grade disease on biopsy for finasteride versus placebo. The results from radical prostatectomy (RP) on 25% of the men undergoing RP have recently been reported and suggest that grading artifacts in biopsy Gleason scoring may have occurred. We used a statistical model to extrapolate the RP Gleason results to all men in the PCPT using a missing-at-random assumption. We estimated the rates of true high-grade (Gleason 7-10) and true low-grade disease, where true Gleason grade is what is (or would have been) found on RP. We also estimated misclassification rates on biopsy of true high-grade and low-grade disease. We show that the rate of upgrading of biopsy low-grade disease to high-grade on RP is a function of misclassification rates as well as the ratio of true low-grade to high-grade disease. The estimated relative risks for true low-grade and true high-grade disease for finasteride compared with placebo were 0.61 (95% confidence interval, 0.51-0.71) and 0.84 (95% confidence interval, 0.68-1.05), respectively. The misclassification rate of true high-grade disease (to low-grade disease on biopsy) was significantly lower for finasteride (34.6%) than for placebo (52.6%). Although misclassification rates differed, upgrading rates were similar in each arm due to the different ratios of true low-grade to high-grade disease in each arm. Results from RP show that misclassification rates on biopsy were higher in the placebo arm and that the rate of true high-grade disease may have been lower in the finasteride arm.
Cancer Prevention Research 09/2008; 1(3):182-6. DOI:10.1158/1940-6207.CAPR-07-0007 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prostate gland depends on androgen stimulation for its development and growth. However, testosterone is not the major androgen responsible for growth of the prostate. Testosterone is converted to dihydrotestosterone (DHT) by the enzyme Δ4, 3 ketosteroid, 5α-reductase in prostatic stromal and basal cells. DHT is primarily responsible for prostate development and the pathogenesis of benign prostatic hyperplasia (BPH). Inhibitors of 5α-reductase reduce prostate size by 20% to 30%. This reduction in glandular tissue is achieved by the induction of apoptosis, which is histologically manifested by ductal atrophy. Inhibition also diminishes the number of blood vessels in the prostate because of a reduction in vascular-derived endothelial growth factor. 5α-Reductase occurs as 2 isozymes, type 1 and type 2, with the prostate expressing predominantly the type-2 isozyme, and the liver and skin expressing primarily the type-1 isozyme. Patients have been identified with deficiencies in the type-2 5α-reductase, but not type 1. Knockout mice with the type-2 5α-reductase demonstrate a phenotype similar to that seen in men with 5α-reductase deficiency. Type-1 5α-reductase knockout male mice are phenotypically normal. Enzymatic activity for 5α-reductase or immunohistochemical detection has been noted in other genitourinary tissues, such as the epididymis, testes, gubernaculum, and corporal cavernosal tissue. Preputial skin predominately expresses the type-1 5α-reductase, whereas stromal cells in the seminal vesicle also express type-2 isozyme. However, epithelial cells in the epididymis, but not surrounding stroma, express type-1 5α-reductase. In addition to influencing prostatic growth, 5α-reductase also influences the expression of neuronal nitric-oxide synthase in the corpus cavernosum. The contribution of DHT in the serum, which is partially derived from type-1 5α-reductase in the liver and the small amount of type-1 5α-reductase in the prostate, may play a role in maintaining prostatic enlargement. Thus, in an effort to increase efficacy of treatment for BPH, clinical trials are under way using new drugs, such as GI-198745 (Glaxo-Wellcome, Research Triangle Park, NC), PNU 157706 (Pharmacia & Upjohn, Peapack, NJ), FR146687 (Fujisawa, Osaka, Japan), and LY 320236 (Lilly, Indianapolis, IN), which inhibit both the type-1 and type-2 5α-reductase.
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