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Prostate News Prostate Cancer and Prostatic Diseases (2008) 11, 108–111 & 2008 Nature Publishing Group All rights reserved 1365-7852/08 $30.00 www.nature.com/pcan RESEARCH HIGHLIGHTS Prostate News Prostate Cancer and Prostatic Diseases (2008) 11, 108–111; doi:10.1038/pcan.2008.24 Changing biopsy patterns affect Clinical trial recommendations screening predictive value In 1999, the Prostate-Specific Antigen Working Group A large body of literature establishes the contribution of offered consensus recommendations for the conduct prostate-specific antigen (PSA) screening to the improve- of clinical trials. Their focus was on the development ment of prostate cancer detection. However, much of the of trials for patients with progressive disease who had data derived from the early and mid 1990s, and since undergone castration specifically with regard to the use then prostate biopsy practice patterns have changed of PSA level. A year later, the New Guidelines to significantly. Early on the predictive power of PSA Evaluate the Response to Treatment in Solid Tumors screening depended on the high prevalence of the criteria were introduced from a broader and interna- disease, the higher prevalence of high-grade disease tional group of researchers. Their focus was on standar- and the low likelihood of prostate cancer diagnosis in dizing the criteria used in clinical trials to assess tumor men with low PSA titers. Biopsy factors that affect the response for all solid tumors, whether arising in the changes in value of PSA screening include the increased prostate or elsewhere. However, if trial outcomes were number of biopsy cores obtained routinely and changes based solely on either of these two sets of criteria, none of in how pathologists interpret biopsy samples. To the approved treatments for prostate cancer would be examine the cause and effect relationships more care- available to such patients. To resolve this discrepancy, the fully, a group of researchers from Weill-Cornell Medical Group examined the previous criteria and emerging trial Center carried out a retrospective analysis of prostate data and report their recommendations in the Journal of biopsy samples from their institution. Their results Clinical Oncology. appear in Cancer. The Working Group identified six areas in need of Of the 3634 prostate biopsies performed at the consensus with regard to clinical trials for evaluating investigators’ institution between 1993 and 2005, 1607 drugs to treat prostate cancer: categorizing the clinical satisfied the inclusion and exclusion criteria and were spectrum from diagnosis to metastasis, defining thera- included in the study. Specimens were divided into three peutic objectives, establishing eligibility criteria for time cohorts: 1993 through 1997, 1998 through 2001 and enrollment, standardizing treatment duration, measur- 2002 through 2005. The number of biopsies performed, ing and reporting outcomes and developing phase III the percentage of positive biopsy results, and patient age clinical trials. In establishing enrollment criteria, they did not change significantly over time. However, emphasize the need to authenticate disease progres- significant changes that did occur over time included sion by establishing pretreatment assessments and decreased median PSA level in patients undergoing identifying standard criteria for establishing disease biopsy (from 7.0 to 5.5 ng/ml) and increased median progression for entry, as well as emphasizing the need number of biopsy cores obtained (from 8 to 14). to define clinical subtypes based on patterns of spread Significant changes in biopsy indication over time and to assess prognosis. With regard to treatment included a smaller percentage of biopsies performed duration, they stress the importance of ensuring a because of suspicious digital rectal examination (DRE) sufficient window of drug exposure and of reducing results (from 46 to 27%) and an increased percentage of the reliance on early changes in PSA levels as well as the patients undergoing biopsy because of a PSA titer need to confirm time-to-event outcomes. Their recom- between 2.5 and 3.99 ng/ml (from 8 to 13%). The authors mendations have two overall objectives: (1) to control, conclude that biopsy practice patterns have improved relieve or eliminate the disease manifestations that are the detection of prostate cancer in men with normal DRE present when treatment is initiated; and (2) to prevent results, in particular in those whose PSA levels are or delay those disease manifestations that are expected between 2.5 and 3.99 ng/ml. These conclusions suggest to occur. that the predictive value of PSA testing with normal DRE results is lost. Original research paper Original research paper Scher HI et al. Design and end points of clinical trials for Schwartz MJ et al. Negative influence to changing biopsy patients with progressive prostate cancer and castrate practice patterns on the predictive value of prostate- levels of testosterone: recommendations of the Prostate specific antigen for cancer detection on prostate biopsy. Cancer Clinical Trials Working Group. J Clin Oncol 2008; Cancer 2008; e-pub ahead of print 10 March. 26: 1148–1159. AR, black men and prostate cancer a group of British researchers carried out an extensive 109 review of the literature and report their results in the Among the known risk factors for prostate cancer are a British Journal of Cancer. family history of the disease and African ancestry. Thus, The authors searched eighteen electronic databases, the search for genetic risk factors is ongoing, and one of which produced 935 citations, from which 22 reports of the most studied genes in this regard is the androgen 17 studies (for a total of 3627 randomized patients) were receptor (AR) gene. In particular, research has shown an included in the analysis of effectiveness and safety. An inverse relationship between the lengths of the CAG and additional three studies, with a total of 82 patients, were GGN repeats in the gene and AR activity levels. Indeed, examined to analyze the relationship with either effec- studies comparing the distribution of allele sizes for tiveness or safety and dose of estrogen. The study these repeat polymorphisms in different populations characterizes the included trials as ‘generally poorly demonstrated shorter repeat lengths, overall, in men of reported or of poor quality’ and examines three studies African versus those of European descent. However, in particular, for a total of 1394 patients, that used only limited studies have examined the association polyestradiol phosphate, 240 mg/month. Given the between these AR repeat polymorphisms and the risk dearth of evidence of good quality that the authors of prostate cancer in black men. Writing in the Journal of discovered in their review, they were not able to draw Human Genetics, Lange and associates report their results any clear conclusions regarding the effectiveness and from an examination of this association, the first such safety of parenteral estrogen compared with other types study to do so. of hormone therapy. Indeed, the researchers call for The investigators used data from the Flint Men’s studies that directly compare the adverse event profile of Health Study, a community-based study of prostate parenteral estrogen with that of LHRH, with particular cancer in black men 40–79 years of age, which recruited attention paid to the accurate assessment of cardio- 730 men to participate in 1996. Of those 730 men, vascular morbidity and mortality, especially with regard genotype data for at least one of the AR repeats were to existing cardiovascular disease status and the meta- available for 131 patients with prostate cancer and 340 static status of the prostate cancer. controls. The mean number of repeats was similar for cases and controls for both repeats: CAG, 19.92 for cases and 19.91 for controls; GGN, 15.76 for cases and 15.41 Review article for controls. The authors conclude that their investiga- tions showed no significant evidence of an association Norman G et al. Parenteral estrogen in the treatment of between the shorter alleles for the two polymorphisms prostate cancer: a systematic review. Br J Cancer 2008; 98: and an increased risk of prostate cancer in this popula- 697–707. tion of African-American men. Further, they suggest that their results using AR CAG and GGN repeat lengths are not independent and that future studies should consider modeling the effects of the two repeats together as well The effect of PSA screening as separately. Among all cancers, PSA is one of the few molecular markers used routinely to detect, stratify the risk of and monitor a common disease. Although PSA is specific to the prostate, it is not specific to prostate cancer; indeed, Original research paper BPH and other benign diseases of the prostate also result Lange EM et al. The androgen receptor CAG and GGN in increased levels of PSA. In fact, most men with repeat polymorphisms and prostate cancer susceptibility increased levels of PSA do not have prostate cancer. The in African-American men: results from the Flint Men’s effect of PSA screening on treatment and prognosis has Health Study. J Hum Genet 2008; 53: 220–226. been profound since its inception in the early 1990s. In a recent issue of Nature Reviews Cancer, Lilja and colleagues examine the current evidence for the association between PSA level and risk of prostate cancer, disease outcome Is parenteral estrogen effective? and recurrence. They also examine the use of PSA screening for the long-term prediction of prostate cancer Androgen deprivation therapy is one of the few treat- and the use of PSA derivatives to improve PSA testing. ment options when prostate cancer is not amenable to The authors begin by evaluating the evidence regard- potentially curative therapy. Thus, many approaches to ing the biology of PSA, noting in particular that the two achieving a reduction in the circulating levels of human kallikrein genes that show major changes androgens exist, including surgical options (for example, through mammalian evolution, KLK3 and KLK2, have orchidectomy) and medical options.
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