Search

Background:The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score.Methods:Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort.Results:In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10−13) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10−6). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ2=89.0, P<10−20) and captured virtually all available prognostic information.Conclusions:The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment. [ABSTRACT FROM AUTHOR]

The prostate gland has among the highest level of polyamines in the body and prostate carcinomas have even greater elevated polyamine levels. These ubiquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulation, and protein synthesis. These properties have made polyamines a potential target for therapeutic intervention in diseases of excessive cell proliferation such as cancer. However, attempts to limit tumor growth by inhibition of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studies utilizing polyamine depletion by means of a combination of blockade of polyamine synthesis with DFMO (α-difluoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synthetic pathway, and ORI 1202, a novel inhibitor of polyamine transport into the cell. This cytostatic combination, even in the presence of excess extracellular polyamines, significantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC50 in the μM range. Other prostate cell lines were similarly growth inhibited including LNCaP.FGC and DU145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was also slowed significantly by this combination of compounds. Polyamine levels in the tumor were lowered from control tumor levels. This combination therapy could provide an effective and potentially non-toxic therapy for prostate tumors.Prostate Cancer and Prostatic Diseases (2000) 3, 275–279 [ABSTRACT FROM AUTHOR]

PSA complexed with alpha-1-anti-chymotrypsin (cPSA™) is the moiety in greatest proportion in the serum of men with prostate cancer (CAP). The performance of this analyte has been established primarily in retrospective archival serum. Studies indicate cPSA™ provides the specificity enhancement of the free-to-total PSA ratio, yet obviates the need to measure two markers. In the present investigation we sought to establish the stability of cPSA™ with long-term storage. Serum from men undergoing ultrasound-guided biopsy was utilized. Serum was assayed soon after collection and 18 months later. All serum was initially aliquotted and stored at -80°C. There was no freeze–thaw. cPSA™ was measured utilizing the Bayer Immuno 1 method according to manufacturer's recommendations. The mean (s.d.) PSA was 5.5 (3.8) and 5.6 (3.9) ng/ml at the initial and subsequent testing, respectively. The medians were 4.3 and 4.4 ng/ml, respectively. No significant differences exist between the two determinants (r2=1.0, slope=1.01, t-test P=0.9194). These data establish for the first time the long-term stability of cPSA™. Retrospective studies performed on archival material should give meaningful results. Prostate Cancer and Prostatic Diseases (2000) 3, 191–194 [ABSTRACT FROM AUTHOR]

Deals with presentations which covered different aspects of the epidemiology of and for screening prostate cancer. Discussion on the changing incidence and presentation of prostatic carcinoma; Incidence of prostate cancer among African-Americans; Update on the American Cancer Society Screening Project.

This session included five presentations in the areas of pathology of precursor lesions and carcinoma of the prostate, the value of determining neovascularity in the diagnosis and staging of prostate cancer, new ‘molecular’ markers, correlation between pre- and postoperative Gleason scores and a study dealing with transition zone PSA density. The abstracts and talks are summarized in the next few pages. [ABSTRACT FROM AUTHOR]

Because prostate cancer has a long latency and high incidence, it is a good target for chemoprevention by agents such as retinoids, antiandrogens, antiestrogens, and vitamin D analogs. Phase II chemoprevention trials are frequently conducted on cohorts of patients with previous cancers or premalignant lesions who are scheduled for prostate cancer surgery; such trials are currently in progress with several agents. Prostatic intraepithelial neoplasia (PIN) can be used as a surrogate endpoint biomarker for prostate cancer incidence. Studies of men with high-grade PIN (HGPIN) are particularly useful in that they require a much smaller cohort of 200–400 patients instead of the 18 000 patients required for typical Phase III trials. Even with a smaller sample size, statistically significant evidence of cancer prevention is achieved due to the high probability of HGPIN progressing to cancer (35–55%). A Bayesian sequential monitoring system allows interim analysis of biomarker modulation as early as the completion of 30 patients. Putting all these strategies together will help inhibit, delay, or modulate the natural history of prostate carcinogenesis. [ABSTRACT FROM AUTHOR]

Prostate-specific antigen (PSA) has emerged as the most predictive test of whether or not a man has prostatic carcinoma. The free to total PSA ratio provides important enhancement in specificity, thus obviating unnecessary negative biopsies. In the absence of an international standard for total PSA, much less free PSA, variation between manufacturers may cause confusing results. We sought to compare three different manufacturer’s free and total PSA assays in a population consisting of consecutive patients who had PSA testing in a reference laboratory in Germany. Between April 1994 and July 1996, serum specimens from 240 men were evaluated with three different free and total PSA assays. Indications for PSA determination were based on the referring physician, who also provided the clinical diagnosis. Total and free PSA were measured on the same freeze–thaw cycle with Chiron Diagnostics, Enzymun Boehringer Mannheim, and Hybritech Tandem-R assays. Seventy-nine men had carcinoma of the prostate, 120 had clinical evidence of benign prostatic hyperplasia and 27 were without evidence of prostatic disease. The Chiron ACS: 180 free to total ratio compared very well with the Tandem-R assay at the 95% sensitivity level, affording 17 and 22% specificity respectively. Using the range of total PSA of 4–10 ng/ml, the increase in specificity of the free to total PSA is quite significant, and the specificity of the Enzymun assays is greatly improved. (Specificity of 49%, 29% and 25% at 95% sensitivity for ACS, Enzymun and Tandem respectively.) This data, based on ‘real world’ clinical experience, shows significant variation between different manufacturers’ assays. There was significant equivalence between the Chiron and Hybritech assays. The Enzymun assay performed well only when data from the total PSA range of 4–10 ng/ml was included. Clinicians must be aware of which manufacturers’ assays for both the free and total PSA... [ABSTRACT FROM AUTHOR]

Aims of the study: Retrospective studies investigating the use of percent free-PSA for early detection of prostate cancer were limited for various reasons: by their use of long-term stored sera, poor mix of non-cancer to cancer cases and the use of only men with PSA values between 4.0 and 10.0 ng/mL. This prospective study investigates the clinical utility of percent free-PSA and complexed-PSA for early detection of prostate cancer in 219 consecutive men presenting for prostate biopsy. Methods: Of 246 consecutive men who underwent ultrasound guided sextant biopsy of the prostate for PSA elevation and/or suspicious digital rectal exam, 219 men had serum total PSA levels between 2.0 and 20.0 ng/mL and were included in this study. Serum total, free and complexed (PSA–ACT) were measured (Hybritech Inc.). Results: Pathologic examinations demonstrated that 72% and 28% of the biopsies were non-cancer and cancer respectively. The mean percent free-PSA was statistically different between the groups (cancer 14%±6.4 and non-cancer 18±9%, P<0.001) and improved cancer detection. PSA–ACT provided only modest improvement in cancer detection over that of total PSA. Among this cohort of men, the optimal total PSA reflex range for percent free-PSA was 3.0–7.0 ng/mL (38% specificity) with a percent free-PSA cut-off of 20% (95% sensitivity) yet only affected 56% of the cases. Conclusions: PSA–ACT added very little additional value to the clinical utility of total PSA for early detection. Percent free-PSA performed well for all reflex ranges. A sensitivity and specificity of 95% and 20% respectively were obtained using a single cut-off of 25% for percent free-PSA for the group of men with total PSA values between 4.0 and 10.0 and correlated well with recently reported prospective analyses. [ABSTRACT FROM AUTHOR]

Due to the historically large number of patients with localized prostate cancer (CAP) treated by radiation therapy, an increasing number of patients are presenting local failure. The currently available concepts regarding its definition as well as management options are reviewed. The literature regarding radiation failure for localized prostate cancer was reviewed. Emphasis was made on articles concerning definition of radiation failure, patient evaluation and restaging and definitive as well as palliative management options. There is definitely a subset of patients with locally recurrent prostate cancer without evidence of metastasis that could potentially benefit from aggressive local therapy. A treatment algorithm is proposed but it should be emphasized that treatment options should be individualized to suit the need of a particular patient. [ABSTRACT FROM AUTHOR]

Context: The percentage of free prostate-specific antigen (PSA) in serum has been shown to enhance the specificity of PSA testing for prostate cancer detection, but earlier studies provided only preliminary cutoffs for clinical use.Objective: To develop risk assessment guidelines and a cutoff value for defining abnormal percentage of free PSA in a population of men to whom the test would be applied.Design: Prospective blinded study using the Tandem PSA and free PSA assays (Hybritech Inc, San Diego, Calif).Setting: Seven nationwide university medical centers.Participants: A total of 773 men (379 with prostate cancer, 394 with benign prostatic disease) 50 to 75 years of age with a palpably benign prostate gland, PSA level of 4.0 to 10.0 ng/mL, and histologically confirmed diagnosis.Main Outcome Measures: A percentage of free PSA cutoff that maintained 95% sensitivity for prostate cancer detection, and probability of cancer for individual patients.Results: The percentage of free PSA may be used in 2 ways: as a single cut-off (ie, perform a biopsy for all patients at or below a cutoff of 25% free PSA) or as an individual patient risk assessment (ie, base biopsy decisions on each patient's risk of cancer). The 25% free PSA cutoff detected 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients, and generally were less threatening in terms of tumor grade and volume. For individual patients, a lower percentage of free PSA was associated with a higher risk of cancer (range, 8%-56%). In the multivariate model used, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.5-4.1; P < .001) and contributed significantly more than age (OR, 1.2; 95% CI, 0.92-1.55) or total PSA level (OR, 1.0; 95% CI, 0.92-1.11) in this cohort of subjects with total PSA values between 4.0 and 10.0 ng/mL.Conclusions: Use of the percentage of free PSA can reduce unnecessary biopsies in patients undergoing evaluation for prostate cancer, with a minimal loss in sensitivity in detecting cancer. A cutoff of 25% or less free PSA is recommended for patients with PSA values between 4.0 and 10.0 ng/mL and a palpably benign gland, regardless of patient age or prostate size. To our knowledge, this study is the largest series to date evaluating the percentage of free PSA in a population representative of patients in whom the test would be used in clinical practice. [ABSTRACT FROM AUTHOR]