Prostate-specific Antigen Rate Research Articles

Trends in Prostate-specific Antigen Screening, Prostate Biopsies, Urology Visits, and Prostate Cancer Treatments From 2000 to 2012

To determine whether the rates of prostate-specific antigen (PSA) screening, related biopsies and subsequent prostate cancer utilization decreased between 2000 and 2012 in a large, managed care organization. Male members of Kaiser Permanente Southern California who were aged ≥40 years and had no history of prostate cancer (N = 15,326) were passively followed through electronic health plan files from January 1, 2000, through December 31, 2012 (N = 1,539,469). The rates of PSA testing, elevated PSA tests, prostate biopsies, prostate cancer treatment (surgery and radiation), and urology visits were calculated per year among eligible men and stratified by age group. A 59% decrease in PSA screening occurred among men aged ≥75 years beginning in 2008, followed by 49% in ages 65-74, 20% in ages 50-64, and 33% in ages 40-49 years in 2009. However, the number of elevated PSA tests remained largely unchanged in all groups except in men aged ≥75 years (45% decrease). Prostate biopsy rates and urology visits remained consistent among elderly men. Among men in this managed care setting, although there was a sharp decline in PSA testing among men aged ≥75 years after 2008, prostate biopsy rates remained constant, and subsequent prostate cancer treatment remained highest among men in this age group. These results suggest that the guidelines recommending against PSA and the subsequent provider-targeted interventions implemented in this system resulted in decreased screening across age groups and potentially led to more discriminant screening among those aged ≥75 years.

Association of ERG-PTEN expression profile of prostate biopsy with PSA velocity.

92 Background: Although ERG and PTEN expression has demonstrated to have a role in prostate carcinogenesis, its association with important clinical markers such as PSA velocity (rate of prostate specific antigen [PSA] change over time) is currently unknown. This novel pilot study presents the results of the above association with the aim of understanding its clinical utility. Methods: Data for this study was obtained from men enrolled in a phase 2 clinical trial conducted to determine the effect of selenium supplementation on prostate cancer progression. All men in this trial were diagnosed with prostate cancer and opted for watchful waiting as their treatment modality. Biopsy tissue collected at randomization was stained for ERG and PTEN using immunohistochemistry techniques. PSA was measured at baseline and at each follow-up visit (every three months). PSA velocity was calculated using mixed effects regression models and the study group was divided into three tertiles. Results: Data from 77 subjects indicates ERG and PTEN expression is independently associated with lower PSA velocity (p = 0.02 and 0.037 respectively). Joint effect of ERG and PTEN expression on PSA velocity was also analyzed using logistic regression. As compared to the wild type (ERG+/PTEN-), ERG-/PTEN- and ERG-/PTEN+ subjects demonstrated increased risk for high PSA velocity. Odds ratios (95% confidence intervals) are: 4.05 (0.68, 24.1) and 1.71 (0.12, 23.1), respectively. These models were adjusted for age, race and Gleason score. Conclusions: This is the first study to report on an association between ERG-PTEN expression and PSA velocity, an important clinical marker of aggressive prostate cancer. Results of this study are counterintuitive to the current understanding of ERG-PTEN mechanism in prostate carcinogenesis indicating presence of yet undiscovered molecular pathways. Hence further research is needed to delineate these pathways and determine clinical utility of ERG and PTEN expression in prostate cancer.

Prostate-specific antigen-based population screening for prostate cancer: current status in Japan and future perspective in Asia.

In Western countries, clinical trials on prostate cancer screening demonstrated a limited benefit for patient survival. In the Asia-Pacific region, including Japan, the rate of prostate-specific antigen (PSA) testing remains very low compared with Western countries, and the benefits of population-based screening remain unclear. This review describes the current status of population screening and diagnosis for prostate cancer in Japan and discusses the efficacy of population screening for the Asian population. Since the 1990s, screening systems have been administered by each municipal government in Japan, and decreases in the prostate cancer mortality rate are expected in some regions where the exposure rate to PSA screening has increased markedly. A population-based screening cohort revealed that the proportion of metastatic disease in cancer detected by screening gradually decreased according to the increased exposure rate, and a decreasing trend in the proportion of cancer with high serum PSA levels after population screening was started. The prognosis of the prostate cancer detected by population screening was demonstrated to be more favorable than those diagnosed outside of the population screening. Recent results in screening cohorts demonstrated the efficacy of PSA. These recent evidences regarding population-based screening in Japan may contribute to establishing the optimal prostate cancer screening system in Asian individuals.

Uptake of prostate cancer screening and associated factors among Chinese men aged 50 or more: a population-based survey.

ObjectiveTo investigate the uptake rate of prostate specific antigen (PSA) testing among Hong Kong Chinese males aged 50 or above, and identify factors associated with the likelihood of undergoing a PSA test.MethodsA population-based telephone survey was conducted in Hong Kong in 2007. The survey covered demographic information, perceived health status, use of complementary therapy, cancer screening behavior, perceived susceptibility to cancer and family history of cancer. Descriptive statistics, percentages and logistic regression analysis were used for data analysis.ResultsA total of 1,002 men aged 50 or above took part in the study (response rate =67%), and the uptake rate of PSA testing was found to be 10%. Employment status, use of complementary therapy, perceiving regular visits to a doctor as good for health and the recommendations of health professionals were significant factors associated with PSA testing.ConclusionThe uptake rate of PSA testing in the study population was very low. Among all the factors identified, recommendations from health professionals had the strongest association with the uptake of PSA testing, and they should therefore take an active role in educating this population about cancer prevention and detection.

Prostate-Specific Antigen Testing in Men Aged 40-64 Years: Impact of Publication of Clinical Trials

We assessed the impact of the publication of trials and changes in recommendations on the rates of prostate-specific antigen (PSA) screening in men aged 40 to 64 years by analyzing monthly medical claims for PSA testing in a commercial insurance database from 2001 to 2011, covering more than 1.5 million men in each year. The testing rates for men aged 40 to 49 years, 50 to 59 years, and 60 to 64 years were 12.1%, 32.7%, and 42.7%, respectively, in 2001 vs 15.7%, 34.2%, and 42.0%, respectively, in 2011. Men aged 40 to 49 years experienced a gradual increase in testing rate from 2001 through 2008 (annual change in PSA testing per 10,000 men [AC] = 4.37; P < .001), which became flat from mid-2009 through 2011(AC = -0.06; P =.98). The slope of PSA testing rates did not change in men aged 50 to 59 years or 60 to 64 years with the publication of the results of the large trials in 2009 or with the subsequent changes in recommendations on PSA testing.

Prostate-specific antigen testing among primary care physicians and urologists: Patterns of care and impact of professional society guidelines.

40 Background: During the past decade, the incidence of prostate cancer in the United States has declined. We hypothesized this was related to lower rates of prostate-specific antigen (PSA) testing and sought to evaluate PSA testing rates nationally. Methods: Using the National Ambulatory Medical Care Survey, a nationally representative sample of outpatient visits in the United States, we analyzed rates of PSA testing in men age 40 years or older who visited PCPs or urologists from 1997 to 2008. Results: An estimated 26.6 million (95% CI: 24.8-28.4 million) PSA tests were ordered during 94.5 million (95% CI: 90.9-98.1 million) office visits to urologists and 95 million (95% CI: 87.5-102.8 million) tests were ordered during 1.17 billion (95% CI: 1.15-1.18 billion) visits to PCPs, with an annual increase of 3.4% and 6.0%, respectively (P=0.055 and P&lt;0.001 for trend). After adjusting for year, race, ethnicity, region, insurance and provider type, testing by PCPs was more likely among older men and highest among men aged 60 to 69 years (reference: 40-49 years; OR 2.32, 95% CI: 1.88-2.85). Compared to men without a chronic medical condition, those with one chronic condition had greater odds of receiving a PSA test (OR 1.28, 95% CI: 1.08-1.52). Conclusions: Prostate cancer incidence has declined over the past decade despite increasing rates of office-based PSA testing by PCPs and urologists during the period. Increasing rates of PSA testing merit scrutiny, especially in men with limited life expectancies who are unlikely to benefit from screening.

986 HOW SOON CAN WE IDENTIFY MEN AT HIGH RISK FOR PROSTATE CANCER DEATH? AN EARLY SURVEILLANCE STRATEGY FOR PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Detection and Screening1 Apr 2011986 HOW SOON CAN WE IDENTIFY MEN AT HIGH RISK FOR PROSTATE CANCER DEATH? AN EARLY SURVEILLANCE STRATEGY FOR PROSTATE CANCER Andrew Vickers, Caroline Savage, Thomas Bjork, Axel Gerdtsson, Jonas Manjer, Peter Nilsson, Anders Dahlin, Anders Bjartell, Peter Scardino, David Ulmert, and Hans Lilja Andrew VickersAndrew Vickers New York, NY More articles by this author , Caroline SavageCaroline Savage New York, NY More articles by this author , Thomas BjorkThomas Bjork Malmo, Sweden More articles by this author , Axel GerdtssonAxel Gerdtsson Malmo, Sweden More articles by this author , Jonas ManjerJonas Manjer Malmo, Sweden More articles by this author , Peter NilssonPeter Nilsson Malmo, Sweden More articles by this author , Anders DahlinAnders Dahlin Malmo, Sweden More articles by this author , Anders BjartellAnders Bjartell Malmo, Sweden More articles by this author , Peter ScardinoPeter Scardino New York, NY More articles by this author , David UlmertDavid Ulmert New York, NY More articles by this author , and Hans LiljaHans Lilja New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1018AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The Preventive Project (MPP) in Malmö, Sweden was a cardiovascular study enrolling a representative cohort (74% participation) of men aged 33–50 in 1974–1986. Until recently, rates of prostate-specific antigen (PSA) testing in Sweden have remained low; retrieval and analysis of archived blood plasma from MPP was previously used to demonstrate a strong association between PSA levels measured at age 44–50 and risk of advanced prostate cancer diagnosis up to 30 years subsequently. Our current objective was to determine the degree of risk concentration, that is, the proportion of cases found in men with the highest PSA levels. METHODS Death from prostate cancer was determined by case note review (74%) or from death certificate data (26%). A nested case-control design was used, with three controls matched to each death. Lorenz curve methodology was used to determine risk concentration. RESULTS The median follow up was 27 years. A total of 141 men died from prostate cancer. A single PSA at age 44–50 was strongly predictive of subsequent prostate cancer death at a median follow-up of 27 years (area-under-the-curve: 0.72). The figure shows the Lorenz curve for risk concentration: 44% of deaths occurred in men with the top 10% of PSA (≥ ∼1.5 ng / ml). As alternative strategy, we took the top quartile of men (PSA ≥ ∼1 ng / ml), measured free PSA and hK2, and took those at highest risk on the basis of a combined model of all markers. Doing so would lead to identification of an additional 2.4% of deaths in the top 10% of risk. We repeated all analyses using metastasis as the endpoint (215 events); the results were similar: for example, 42% of metastases occurred in top 10% of PSA with an additional 2.5% metastases were identified by free PSA and hK2. CONCLUSIONS Long-term risk of prostate cancer death can be predicted on the basis of a single blood test before the age of 50. Targeting a small proportion (10%) of men in an early intervention strategy–regular PSA screening with compliance monitoring, and possibly chemoprevention–could prevent almost half of all prostate cancer deaths. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e398 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers New York, NY More articles by this author Caroline Savage New York, NY More articles by this author Thomas Bjork Malmo, Sweden More articles by this author Axel Gerdtsson Malmo, Sweden More articles by this author Jonas Manjer Malmo, Sweden More articles by this author Peter Nilsson Malmo, Sweden More articles by this author Anders Dahlin Malmo, Sweden More articles by this author Anders Bjartell Malmo, Sweden More articles by this author Peter Scardino New York, NY More articles by this author David Ulmert New York, NY More articles by this author Hans Lilja New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Rectal Metastasis of Prostate Cancer: About a Case

Prostate adenocarcinomas present a high risk of metastasis. We report a case of an atypical prostate cancer metastasis. A male patient presented a prostatic adenocarcinoma treated by surgery. A biological recurrence was discovered during the follow-up by an increased rate of Prostate Specific Antigen (PSA) and was treated by hormonotherapy. Several months later, there was a re-increase of the PSA rate. The CT scan showed a radiation proctitis aspect. An intermittent hormonotherapy was decided. Six months later, he presented abdominal pain. Examinations were performed and showed a rectal carcinosarcoma with prostate origins. A surgical management was realised. The outcomes were an early recurrence. A symptomatic treatment was decided. There are not any rectal localisations reported in the literature. Only loco-regional invasions of the rectum are described and no histological modification of metastasis compared to the primitive tumor has been reported. So, we report a metastasis of a prostate adenocarcinoma which transformed into a carcinosarcoma.KeywordsAdenocarcinoma; Carcinosarcoma; Metastasis; Prostate; Rectal neoplasm

The Number of Cores Positive for High Grade Prostatic Intraepithelial Neoplasia on Initial Biopsy is Associated With Prostate Cancer on Second Biopsy

We evaluated the association between the number of biopsy cores revealing high grade prostatic intraepithelial neoplasia and prostate cancer in an era of extended biopsy protocol. From December 2004 to September 2007 patients referred to our clinic with a prostate specific antigen of 4 ng/ml or greater or an abnormal digital rectal examination were scheduled for transrectal ultrasound prostatic biopsy with a 12-core template. In patients with high grade prostatic intraepithelial neoplasia we proposed a second prostate specific antigen evaluation and a new 12-core biopsy after 6 months independent of prostate specific antigen. Nonparametric tests were applied for statistical analysis. We evaluated 650 patients. Of the 147 patients (22%) with high grade prostatic intraepithelial neoplasia 117 underwent a second biopsy 6 months later. Patient characteristics (age, prostate specific antigen, free-to-total prostate specific antigen ratio, prostate volume, prostate specific antigen density) were similar at initial and repeat biopsy. On second biopsy 22 patients (18.8%) presented with prostate cancer (14 with Gleason score 6, 7 with Gleason score 7 and 1 with a Gleason score 8), 75 showed isolated high grade prostatic intraepithelial neoplasia (64.2%) and 20 (17%) had chronic prostatitis. The number of cores (4 or more) involved with high grade prostatic intraepithelial neoplasia on the first biopsy was significantly associated with prostate cancer on the second biopsy (p = 0.001). Prostate specific antigen could not be used to distinguish prostate cancer from benign disease or high grade prostatic intraepithelial neoplasia. The number of cores with high grade prostatic intraepithelial neoplasia seems to be associated with the presence of cancer on second biopsy. A 6-month biopsy is recommended in patients with high grade prostatic intraepithelial neoplasia when 4 or more cores with high grade prostatic intraepithelial neoplasia are detected in the initial biopsy sample independent of prostate specific antigen.

Racial differences in serum prostate‐specific antigen (PSA) doubling time, histopathological variables and long‐term PSA recurrence between African‐American and white American men undergoing radical prostatectomy for clinically localized prostate cancer

To determine if there are significant differences in biochemical characteristics, biopsy variables, histopathological data, and rates of prostate-specific antigen (PSA) recurrence between African-American (AA) and white American (WA) men undergoing radical prostatectomy (RP), as AA men are twice as likely to die from prostate cancer than their white counterparts. We established a cohort of 1058 patients (402 AA, 646 WA) who had RP and were followed for PSA recurrence. Age, race, serum PSA, biopsy Gleason score, clinical stage, pathological stage, and PSA recurrence data were available for the cohort. The chi-square test of proportions and t-tests were used to assess basic associations with race, and log-rank tests and Cox regression models for time to PSA recurrence. Forward stepwise variable selection was used to assess the effect on the risk of PSA recurrence for race, adjusted by the other variables added one at a time. The AA men had higher baseline PSA levels, more high-grade prostatic intraepithelial neoplasia (HGPIN) in the biopsy, and more HGPIN in the pathology specimen than WA men. The AA men also had a shorter mean (sd) PSA doubling time before RP, at 4.2 (4.7) vs 5.2 (5.9) years. However, race was not an independent predictor of PSA recurrence (P = 0.225). Important predictors for PSA recurrence in a multivariable model were biopsy HGPIN (P < 0.014), unilateral vs bilateral cancer (P < 0.006), pathology Gleason score and positive margin status (both P < 0.001). This study indicates that while there are racial differences in baseline serum PSA and incidence of HGPIN, race is not an independent risk factor for PSA recurrence. Rather, other variables such as pathology Gleason score, bilateral cancers, HGPIN and margin positivity are independently associated with PSA recurrence. The PSA doubling time after recurrence may also be important, leading to the increased mortality of AA men with prostate cancer.

Age-related disparities in cancer screening: analysis of 2001 Behavioral Risk Factor Surveillance System data.

Although few studies have explored age-related health care disparities, some researchers have asserted such disparities uniformly disfavor the elderly and are largely attributable to ageism in the health care system. We compared age-related patterns of screening for colorectal cancer with those for breast and prostate cancer in persons aged 50 years and older. We analyzed data for all adults aged 50 years and older (N = 88,213) in the 2001 Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative, telephone-administered survey of personal health behaviors. Main outcome measures were adjusted prevalence by 5-year age-groups of colorectal cancer screening using fecal occult blood testing, flexible sigmoidoscopy, or colonoscopy for men and women; rates of mammography screening for women; and rates of prostate-specific antigen (PSA) screening for men. After adjustment for race/ethnicity, education level, income, health insurance, and self-rated health, predicted reported colorectal cancer screening (all modalities) increased significantly from when patients reached age 50 years until 70 to 74 years (66.0%, standard error [SE] 0.8%), remained constant until age 80 years, and then declined. The age-related gain in colorectal cancer screening was confined to whites among patients older than 60 years. Reported PSA screening increased until age 75 to 79 years (79.3%, SE 1.1%) and then declined, whereas reported mammography screening peaked at age 55 to 59 years (83.3%, SE 1.2%) and then declined. Significant age-related disparities appear to exist for both evidence-based and non-evidence-based cancer-screening interventions. The issue of age-related disparities in cancer screening is complex, with the direction of disparity favoring the elderly for some services yet disfavoring them for others.

Serum levels of prostate-specific antigen and androgens after nasal administration of a gonadotropin releasing hormone-agonist in hirsute women

We aimed to determine whether ovarian suppression affects the production rate of prostate-specific antigen (PSA) in hirsute women. A total of 34 hirsute women who had a modified Ferriman-Gallwey (FG) score of ≥7 and 14, non-hirsute women as the control group were recruited for this prospective controlled study. Serum samples for evaluation of basal hormones and PSA concentration were collected and were analyzed by commercial kits and chemiluminescent enzyme immunoassay. The hirsute women were given 400 µg/day nafarelin acetate for 3 months. Basal hormones, PSA levels and FG scores were then assessed. ANOVA and Tukey test were used to compare differences in means between the hirsute and the non-hirsute group at the beginning of the study. Student's t test, Tukey test and repeated measures variance analysis were used to evaluate differences in the study group and between the women with polycystic ovary syndrome (PCOS) and idiopathic hirsutism after gonadotropin releasing hormone (GnRH)-agonist administration. Statistical significance was assumed with a value of p < 0.05. PCOS and idiopathic hirsutism were diagnosed in 58.8% and 41.2% of 34 hirsute women, respectively. Age and body mass index (BMI) were similar in the hirsute and the control group (p > 0.05). FG scores in the PCOS group (20.3 ± 1.7) were statistically similar to those of the group with idiopathic hirsutism (17.6 ± 1.7) (p > 0.05). The non-hirsute women had significantly lower serum PSA concentrations than the hirsute group (p < 0.001).The basal mean level of PSA was 0.095 ± 0.001 in the PCOS, 0.0061 ± 0.009 in the idiopathic hirsute and 0.0040 ± 0.004 ng/ml in the control group. No significant difference in the mean PSA levels was noted between the PCOS and the idiopathic hirsute subgroups before and after GnRH agonist treatment (0.0096 ± 0.01 and 0.0051 ± 0.032 ng/ml, respectively) (p > 0.05). FG scores, testosterone, 17α-hydroxyprogesterone and dehydroepiandrosterone sulfate levels were significantly decreased in the hirsute group following treatment (p < 0.001). PSA levels in hirsute women were higher than in non-hirsute women and independent of BMI, age and androgen deprivation. PSA concentration may be mediated through extragonadal sites and possibly through a long-standing hyperandrogenemic enviroment such as in PCOS and idiopathic hirsutism. Further investigation as to the significance of PSA in women with hirsutism and whether antiandrogens directly act to inhibit biosynthesis of PSA is warranted.

Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Daliani DD, Assikis V, Tu SM, Papandreou CN, Pagliaro LC, Holtkamp T, Wang X, Thall PF, Logothetis CJ, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX: Cancer 2003;97:561–567

Background In this Phase II study, the authors assessed the toxicity and antitumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa). Methods Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1–14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1–14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response. Results Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was 2 (range, 1–7 cycles). Twenty-nine percent of the patients were found to have a >50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal. Conclusions CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity. Copyright 2003 American Cancer Society.

Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression.

Prostate cancer (PCa) cells express vitamin D receptors (VDR) and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits the growth of epithelial cells derived from normal, benign prostate hyperplasia, and PCa as well as established PCa cell lines. The growth inhibitory effects of 1,25(OH)(2)D(3) in cell cultures are modulated tissue by the presence and activities of the enzymes 25-hydroxyvitamin D(3) 24-hydroxylase which initiates the inactivation of 1,25(OH)(2)D(3) and 25-hydroxyvitamin D(3) 1alpha-hydroxylase which catalyses its synthesis. In LNCaP human PCa cells 1,25(OH)(2)D(3) exerts antiproliferative activity predominantly by cell cycle arrest through the induction of IGF binding protein-3 (IGFBP-3) expression which in turn increases the levels of the cell cycle inhibitor p21 leading to growth arrest. cDNA microarray analyses of primary prostatic epithelial and PCa cells reveal that 1,25(OH)(2)D(3) regulates many target genes expanding the possible mechanisms of its anticancer activity and raising new potential therapeutic targets. Some of these target genes are involved in growth regulation, protection from oxidative stress, and cell-cell and cell-matrix interactions. A small clinical trial has shown that 1,25(OH)(2)D(3) can slow the rate of prostate specific antigen (PSA) rise in PCa patients demonstrating proof of concept that 1,25(OH)(2)D(3) exhibits therapeutic activity in men with PCa. Further investigation of the role of calcitriol and its analogs for the therapy or chemoprevention of PCa is currently being pursued.

The role of vitamin D in prostate cancer.

Prostate cancer (PCa) cells harbor receptors for vitamin D (VDR) as well as androgens (AR). 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] increases AR expression and enhances androgen actions linking the two receptor systems. 1,25(OH)2D3 exhibits antiproliferative activity in both AR-positive and AR-negative PCa cells. Less calcemic analogs of 1,25(OH)2D3, with more antiproliferative activity, are being developed and will be more useful clinically. The mechanisms underlying differential analog activity are being investigated. In target cells, 1,25(OH)2D3 induces 24-hydroxylase, the enzyme that catalyzes its self-inactivation. Co-treatment with 24-hydroxylase inhibitors enhances the antiproliferative activity of calcitriol. Primary cultures of normal or cancer-derived prostatic epithelial cells express 1alpha-hydroxylase, the enzyme that catalyzes the synthesis of 1,25(OH)2D3, the levels being much lower in the cancer-derived cells and in PCa cell lines. This finding raises the possibility of using 25-hydroxyvitamin D3 [25(OH)D3] as a chemopreventive agent in PCa. In LNCaP human PCa cells, 1,25(OH)2D3 and its analogs exert antiproliferative activity predominantly by cell cycle arrest, but also induce apoptosis, although to a much lesser degree. Growth arrest is mediated by induction of IGF binding protein-3 (IGFBP-3), which in turn increases the expression of the cell cycle inhibitor p21, leading to growth arrest. Other actions of 1,25(OH)2D3 in PCa cells include promotion of pro-differentiation effects and inhibition of tumor cell invasion, metastasis and angiogenesis. Combination therapy with retinoids, other anticancer agents or 24-hydroxylase inhibitors augments the inhibitory activity of 1,25(OH)2D3 in PCa and provides another effective approach in PCa treatment. Small clinical trials have shown that 1,25(OH)2D3 can slow the rate of prostate specific antigen (PSA) rise in PCa patients, demonstrating proof of concept that 1,25(OH)2D3 or its analogs will be clinically effective in PCa therapy. Current research involves further investigation of the role of 1,25(OH)2D3 and its analogs for the therapy or chemoprevention of PCa.

The role of androgen ablation in patients with biochemical or local failure after definitive radiation therapy: a survey of practice patterns of urologists and radiation oncologists in the United States

To identify therapeutic patterns for putative prostate cancer treatment failures and the role played by androgen ablation therapy in these patients, a questionnaire study was undertaken with urologists and radiation oncologists who had attended a brachytherapy forum at the Seattle Prostate Institute (SPI). Hypothetical questions were asked about recommendations the physicians would give to a patient demonstrating biochemical or local failure after external-beam radiation therapy. Most of the physicians queried were in private practice; 53% were radiation oncologists and 47% were urologists. The respondents’ recommendations for a hypothetical patient, who was 45 to 65 years of age, with a biopsy-proven local recurrence was treatment with androgen ablation (35% of respondents), radical prostatectomy (25%), interstitial brachytherapy (20%), and observation (19%). In the 65- to 75-year-old patient with a local recurrence, the respondents recommended observation (43%), androgen ablation (35%), interstitial brachytherapy (17%), and radical prostatectomy (4%). In patients receiving androgen ablation for a biochemical failure alone, there was no consensus on whether to use luteinizing hormone–releasing hormone agonist alone, total androgen ablation, orchiectomy, or intermittent androgen ablation. Criteria that prompted physicians to initiate androgen ablation were based on the rate of prostate-specific antigen (PSA) increase (67%), an absolute PSA number (24%), or clinical failure (9%). In the younger patient with a local recurrence, local intervention with radical prostatectomy or interstitial brachytherapy was recommended most often, followed by androgen ablation, then by observation. In the older patient, observation was recommended most often, followed closely by androgen ablation. Overall, there was a lack of consensus on how to deliver androgen ablation. However, there was remarkable agreement between urologists and radiation oncologists on virtually all issues queried.

SIGNIFICANCE AND METABOLISM OF COMPLEXED AND NONCOMPLEXED PROSTATE SPECIFIC ANTIGEN FORMS, AND HUMAN GLANDULAR KALLIKREIN 2 IN CLINICALLY LOCALIZED PROSTATE CANCER BEFORE AND AFTER RADICAL PROSTATECTOMY

We studied plasma concentrations and elimination rates of prostate specific antigen (PSA) complexed to alpha1-antichymotrypsin and alpha2-macroglobulin, free PSA, total PSA (free PSA plus PSA alpha1-antichymotrypsin) and human glandular kallikrein 2 before, during and after radical retropubic prostatectomy for clinically localized prostate cancer. Plasma was collected and frozen within 10 minutes after sampling from 18 patients undergoing radical retropubic prostatectomy for prostate cancer. One sample was drawn preoperatively. Subsequent sampling intervals were 5 to 20 minutes perioperatively, 2 to 4 hours during the first 12 postoperative hours and 24 to 48 hours until postoperative day 14. Free PSA, PSA alpha1-antichymotrypsin, total PSA, PSA alpha2-macroglobulin and human glandular kallikrein 2 were measured with time resolved immunofluorometric assays. Preoperatively PSA alpha2-macroglobulin was undetectable (less than 2 ng./ml.) in 17 of 18 patients. Human glandular kallikrein 2, free PSA and total PSA but not PSA alpha1-antichymotrypsin were significantly higher in patients with extraprostatic cancer (pT3a-pT4a, pN1) compared to those with organ confined cancer (pT2a/b). Surgical manipulation of the prostate caused no detectable elevation of human glandular kallikrein 2, PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. In contrast, a mean 9.6-fold increase (range 3.4 to 22) in free PSA was noted 5 minutes after prostatectomy. Free PSA was eliminated from plasma in a biphasic exponential pattern with an early plasma half-life of 55 minutes and a late plasma half-life of 18 hours. PSA alpha1-antichymotrypsin decreased slowly, whereas human glandular kallikrein 2 was detectable only 12 hours after prostatectomy. PSA alpha2-macroglobulin remained at insignificant, nondetectable concentrations during the entire perioperative and postoperative period. Release of free PSA contributes to the elevation of plasma total PSA after prostatectomy. Free PSA is enzymatically inactive as the release does not result in subsequent elevation of PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. Biphasic exponential elimination of free PSA may be explained by rapid extracellular redistribution (early half-life) and glomerular filtration in the kidneys (late half-life). Our data suggest rapid metabolism of human glandular kallikrein 2 but do not support suggestions of the significance in vivo of complex formations with alpha2-macroglobulin as a major means to eliminate PSA from plasma in patients with clinically localized prostate cancer.

Characterization of Patients with Androgen-Independent Prostatic Carcinoma Whose Serum Prostate Specific Antigen Decreased Following Flutamide Withdrawal

Purpose We confirmed the reported rate of prostate specific antigen (PSA) suppression after flutamide withdrawal in patients with metastatic prostatic carcinoma, increasing serum PSA and tumor progression following treatment with total androgen blockade (castration and flutamide). The value of clinical variables in predicting the rate of PSA decrease after flutamide withdrawal was assessed and adrenal androgen metabolism was correlated with the rate of PSA suppression following flutamide withdrawal. Materials and Methods A total of 41 consecutive patients with metastatic prostatic adenocarcinoma and an increasing serum PSA while effectively castrated (plasma testosterone level less than 50 ng./ml.) who were receiving 250 mg. flutamide 3 times daily was evaluated prospectively before cessation of the flutamide. Responses were determined at 6 weeks. Only 2 of the 41 study patients (3 percent) had stable disease at 6 weeks, that is they had not met objective criteria for response or progression at analysis. Results Of 39 patients studied 11 (28.2 percent, 95 percent confidence interval 14 to 45 percent) had a PSA decrease (more than 50 percent from baseline) following flutamide withdrawal and they were treated with initial complete androgen blockade. Median duration of PSA decrease was only 13 weeks (range 7 to 52), and 3 of the 11 patients had continued suppression of serum PSA concentrations at 12+, 13+ and 20+ weeks. The serum PSA decrease was associated with improved clinical symptoms, although objective regression of the disease was found in only 1 to 2 patients with measurable disease. No statistical correlation between endocrine studies or serum bombesin secretion and PSA decrease was found, although patients with a PSA decrease after flutamide withdrawal tended to have a lower dehydroepiandrosterone concentration than those with PSA progression. No correlation between known prognostic variables and decreased serum PSA after flutamide withdrawal was detected. Conclusions We confirmed the existence of the reported paradoxical PSA decrease in patients with androgen-independent carcinoma of the prostate, and that the delivery of simultaneous initial flutamide with castration predicts for PSA decrease. Individual patients appear to benefit from flutamide withdrawal although the overall impact was slight. The differences in frequency compared to those reported by others may be accounted for by patient selection and the number of patients receiving sequential castration therapy followed by flutamide.

Comparison of hyperfractionated conformal photon with conformal mixed neutron/photon irradiation in locally advanced prostate cancer

In an attempt to improve the probability of complication-free local control for patients with locally advanced prostate cancer, a series of dose-finding studies have been conducted at Wayne State University using conformal neutron and hyperfractionated photon irradiation. In total, 96 patients with locally advanced prostate cancer (T3/T4 N0/N1 M0, and/or Gleason score > or = 8) were treated in two prospective studies. Forty-seven patients received conformal neutron/photon (15 NGy + 18 PhGy) and 49 patients were treated in a dose-escalation study using conformal photons (25 patients/78 Gy and 24 patients/83 Gy minimum dose). The median follow-up for both studies was 20 months (range 6-36 months). There was no significant difference in the rate of chronic gastrointestinal (GI) or gastrourinary (GU) morbidity between the two groups. However, the neutron treated patients had a significantly higher rate of moderate (14%) and severe (12%) hip stiffness. The rates of prostate-specific antigen (PSA) decline and 12-month negative biopsy were comparable. In conclusion, the therapeutic gain of neo-adjuvant hormonal therapy in combination with photon hyperfractionation to 83 Gy appears identical to that seen with the mixed neutron-photon dose of 15 NGy + 18 PhGy. Further efforts at improving the therapeutic ratio of radiotherapy for patients with locally advanced prostate cancer should be undertaken.

Reliability of prostate-specific antigen evaluation according to age-specific range

Reliability of prostate-specific antigen evaluation according to age-specific range