Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

PURPOSE: To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. PATIENTS AND METHODS: The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. RESULTS: At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. CONCLUSION: Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.     

Treatment of men with rising prostate-specific antigen levels following radical prostatectomy

Approximately one-third of patients who undergo radical prostatectomy for prostate cancer will develop a detectable prostate-specific antigen (PSA) level within 10 years. Biochemical recurrence of disease is defined as a rising PSA level in the absence of clinical or radiographic evidence of disease. Management of PSA recurrence is controversial, as prostate cancer may take an indolent course, or it may aggressively develop into metastatic disease. The only potentially curative treatment for biochemical failure after prostatectomy is salvage radiotherapy. Noncurative treatment options include hormone therapy or clinical trials of a novel systemic agent. This article will address management options for a rising PSA level after prostatectomy, as well as ongoing studies exploring molecular biomarkers as prognostic tumor markers and potential targets for prostate cancer therapy.     

Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era.

PURPOSE: To determine whether pretreatment risk groups shown to predict time to prostate cancer-specific mortality (PCSM) after treatment at a single institution retained that ability in a multi-institutional setting. PATIENTS AND METHODS: From 1988 to 2002, 7,316 patients treated in the United States at 44 institutions with either surgery (n = 4,946) or radiation (n = 2,370) for clinical stage T1c-2, N0 or NX, M0 prostate cancer made up the study cohort. A Cox regression analysis was performed to determine the ability of pretreatment risk groups to predict time to PCSM after treatment. The relative risk (RR) of PCSM and 95% confidence intervals (CIs) were calculated for the intermediate- and high-risk groups relative to the low-risk group. RESULTS: Estimates of non-PCSM 8 years after prostate-specific antigen (PSA) failure were 4% v 15% (surgery versus radiation; Plog rank =.002) compared with 13% v 18% (surgery versus radiation; Plog rank =.35) for patients whose age at the time of PSA failure was less than 70 as compared with >or= 70 years, respectively. The RR of PCSM after treatment for surgery-managed patients with high- or intermediate-risk disease was 14.2 (95% CI, 5.0 to 23.4; PCox <.0001) and 4.9 (95% CI, 1.7 to 8.1; PCox =.0037), respectively. These values were 14.3 (95% CI, 5.2 to 24.0; PCox <.0001) and 5.6 (95% CI, 2.0 to 9.3; PCox =.0012) for radiation-managed patients. CONCLUSION: This study provided evidence to support the prediction of time to PCSM after surgery or radiation on the basis of pretreatment risk groups for patients with clinically localized prostate cancer managed during the PSA era.     

Changing prostate-specific antigen outcome after surgery or radiotherapy for localized prostate cancer during the prostate-specific antigen era

PURPOSE: To evaluate the change in prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) or external beam radiotherapy (EBRT), controlling for follow-up during the PSA era. METHODS AND MATERIALS: The study cohort consisted of 1440 patients with clinically localized prostate cancer managed with RP (n = 1059) or EBRT (n = 381) between 1989 and 2000. A single genitourinary pathologist reviewed all pathology specimens. For patients with a 2-year minimal follow-up, the 2-year actual PSA outcome stratified by risk group (low vs. high) was calculated for three periods (January 1, 1989 to December 31, 1992; January 1, 1993 to December 31, 1996; and January 1, 1997 to December 31, 2000) and compared for each treatment modality. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition for all patients, and comparisons were made using a chi-square metric. RESULTS: During the study period, the proportion of patients treated with RP and EBRT with low-risk disease increased significantly (p <0.0001) from 60% to 89% and from 26% to 76%, respectively. In addition, the 2-year actual PSA outcome also improved from 60% to 82% (RP: p < 0.0001) and from 67% to 91% (RT: p = 0.0008). The 2-year actual PSA outcome was not significantly different in the low-risk patients but improved during the three periods in the high-risk patients treated with RP (from 20% to 39% to 75%, p = 0.0004) or EBRT (from 50% to 59% to 83%, p = 0.01). This improvement in PSA outcome could be explained by a shift toward a more favorable PSA level (RP: p = 0.0002; RT: p = 0.006) and clinical T stage (RP: p = 0.0008, RT: p < 0.0001) distribution for patients with biopsy Gleason score >or=7 disease. CONCLUSION: Improved PSA outcome during the PSA era after RP or EBRT has resulted from a shift in presentation toward low-risk disease and earlier detection of high-grade disease.     

Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy

BACKGROUND: The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. METHODS: Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases. RESULTS: One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups. CONCLUSIONS: Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting.     

Body mass index does not predict prostate-specific antigen or percent free prostate-specific antigen in men undergoing prostate cancer screening

ObjectivesBody mass index (BMI) may alter serum prostate specific antigen (PSA) and percent free PSA (%fPSA) and may mask the risk of prostate cancer. We investigated the relationship between BMI and PSA or %fPSA.Materials and methodsHeight, weight, PSA and %fPSA were assessed in 616 consecutive screened men without prostate cancer. Continuously coded and categorised BMI was studied. Statistical analyses consisted of ANOVA, linear regression, bivariate and partial correlations.ResultsMedian age was 57 years. Median PSA was 1.0 and median %fPSA was 26. Median BMI was 25.8 kg/m². Neither continuously coded nor categorised BMI correlated with either PSA or %fPSA in unadjusted or age-adjusted analyses (all p values ⩾0.3).ConclusionsBody mass index does not affect PSA or %fPSA in men without known prostate cancer, who undergo prostate cancer screening. Therefore, PSA or %fPSA-based screening or early detection efforts do not require an adjustment for BMI.     

The dynamics of prostate-specific antigen after definitive radiation therapy for prostate cancer.

We report the use of an exponential model for capturing the dynamics of serial measurements of prostate-specific antigen (PSA) made just before and after definitive radiation therapy of localized prostate cancer. Our study patients consisted of 164 men treated at a community hospital and without use of adjuvant hormonal therapy, and we had a mean of 5 years follow-up. We found that the model fits allowed us to condense PSA dynamic information into four parameters, including the initial pretreatment value of PSA, and three of these related significantly to subsequent outcome. The model also provided greater understanding of the prognosis of men with rising PSA after radiation therapy. Specifically, two of the model's parameters allowed us to compare the PSA status of these men to those with hormone-refractory disease, and we discovered that at the time of "biochemical relapse," there is a broad spectrum in expected probability of imminent death as well as in time to an adverse outcome. Thus, the model provides information that allows one to stratify men with rising PSA into a continuous spectrum from low to high risk for an adverse outcome. We believe these results show that exponential models have the potential for providing useful clinical information about men with rising PSA after definitive radiation therapy and that they could help us decide when further therapy is needed. Therefore, we recommend further study and development of these models as part of clinical research protocols involving radiation therapy of localized prostate cancer.     

Phase II study of sunitinib in men with advanced prostate cancer

BackgroundThis study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC).MethodsMen with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured.ResultsSeventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin.ConclusionsSunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.     

Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen

Our previous case-control study suggested that equol, a metabolite of isoflavone, has a preventive effect on prostate cancer. To examine the prostate cancer risk based on isoflavone intake and equol production, we carried out a phase II, randomized, double-blind, placebo-controlled trial of oral isoflavone (60 mg/day) for 12 months. The inclusion criteria were Japanese men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/mL, and a single, negative prostate biopsy within 12 months prior to enrollment. The study included 158 men in eight Japanese centers. Their median age was 66.0 years, and the numbers of equol producers and non-producers were 76 (48%) and 82 (52%), respectively. The majority of adverse events were mild or moderate in severity, and the scheduled intake of tablets was completed by 153 patients (96.8%). The prostate-specific antigen value showed no significant difference before and after treatment. Of the 89 patients evaluated by central pathological review, the incidence of biopsy-detectable prostate cancer in the isoflavone and placebo groups showed no significant difference (21.4%vs 34.0%, P = 0.140). However, for the 53 patients aged 65 years or more, the incidence of cancer in the isoflavone group was significantly lower than that in the placebo group (28.0%vs 57.1%, P = 0.031). These results support the value of isoflavone for prostate cancer risk reduction. A large-scale phase III randomized study of isoflavone tablets in men with different hereditary factors and living environments is warranted. Registered with the UMIN Clinical Trials Registry (UMIN-CTR) for clinical trials in Japan (C000000446).     

Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.     

血清cPSA对前列腺癌诊断价值的研究

 目的　探讨血清中结合前列腺特异性抗原 (c PSA)在前列腺癌 (PCa)诊断中的临床价值。方法　用磁微粒子免疫化学发光法测定 72例良性前列腺增生 (BPH)患者和 38例PCa患者c PSA、t PSA ,并计算c PSA/t PSA比值。结果　c PSA及c PSA/t PSA比值可有效地区分BPH和PCa(P <0 .0 0 5 ) ,尤其是在诊断灰值区 (t PSA为 4～ 1 0ng/ml)时效果更显著。在以t PSA≤1 0 .0ng/ml和c PSA/t PSA≥0 .72为筛选界值联合对PCa进行筛选时 ,临床概率敏感度为 93.8%。结论　c PSA的引入及c PSA/t PSA比值的应用 ,对PCa的诊断具有重要临床意义 ,尤其是在前列腺特异性抗原的诊断灰值区。     

The pursuit of prostate cancer in patients with a rising prostate-specific antigen and multiple negative transrectal ultrasound-guided prostate biopsies

To determine if patients with persistently elevated prostate-specific antigen (PSA) levels who have had transrectal ultrasound (TRUS)-guided prostate biopsies negative for carcinoma will benefit from additional saturation (> or =14 cores) TRUS biopsies with or without transurethral (TUR) biopsies. A retrospective review of 35 men between ages 51-74 with PSA values between 4.5-46 ng/mL, normal digital rectal examinations, and > or =2 previously negative sextant TRUS biopsies. Seventeen patients had TUR biopsies in addition to saturation TRUS biopsies. Eighteen patients had saturation TRUS biopsies only (median 20 cores). Seven patients who had no cancer detected with the combined TRUS/TUR biopsies had an additional saturation biopsy performed (median 20 cores). Seven (20%) of the 35 patients who had a saturation biopsy had cancer detected, and one (5.9%) cancer was detected in the 17 men that had a TUR biopsy. Five (71.4%) of the seven patients who had an additional TRUS biopsy had cancer detected (total core range 45-60). The overall yield of prostate cancer was therefore 37.1%, with 1-9 cores positive (median 5 cores). For patients with a rising PSA and > or =2 negative sextant TRUS biopsies, the cancer yield of the initial saturation TRUS biopsies was 20%. Furthermore, a significant proportion of patients with negative initial saturation biopsies had cancer detected on repeat TRUS biopsy. The cancer yield of adding TUR biopsies in this same group of patients is < 6.     

Optimal prostate-specific antigen screening interval for prostate cancer

BackgroundTo identify the optimal interval for repeat prostate-specific antigen (PSA) testing to screen for prostate cancer in healthy adults.Patients and methodsA retrospective cohort study was conducted on 7332 healthy males without prostate cancer at baseline from 2005 to 2008. Participants underwent annual health checkups including PSA testing at the Center for Preventive Medicine in Japan. Participants with high PSA (≥4.0 ng/ml) underwent further examination for prostate cancer. A subgroup analysis was conducted age group (<50 years, ≥50 years).ResultsMean age was 50 years. Mean PSA at baseline was 1.2 ng/ml. In over 50-year group, for those with initial PSA of <1.0, 1.0–1.9, 2.0–2.9, and 3.0–3.9 ng/ml at baseline, the 3-year cumulative incidence of prostate cancer was 0%, 0.1%, 0.3%, and 5.7%, respectively. No prostate cancer was identified in those <50 years, regardless of PSA level.ConclusionsIf PSA screening is recommended, males >50 years with PSA of 3.0–3.9 ng/ml at baseline should undergo rescreening at 2 years. For men with PSA <3.0 ng/ml, PSA rescreening at intervals of ≥3 years is appropriate. PSA screening may not be indicated in males of <50 years of age.     

Racial differences in prostate-specific antigen levels and prostate-specific antigen densities in patients with prostate cancer

To compare serum prostate-specific antigen (PSA) levels and PSA density (PSAD) among African American (AA), white, and Hispanic men with prostate cancer (PC) seen in an urban, equal-access urology clinic. Between January 1988 and January 1993, 1,105 men were screened for PC at Cook County Hospital in Chicago, Illinois. A total of 529 men underwent transrectal ultrasound-guided prostate gland biopsies for abnormal digital rectal examination, suspect transrectal ultrasound, elevated PSA, or any combination of these abnormalities. PC was found in 246 patients (204 AAs, 22 whites, and 20 Hispanics). We analyzed the differences in PSA and PSAD among the three racial groups using univariate and multivariate analyses adjusting for race, age, clinical stage, and grade. AAs have a higher mean serum PSA levels (21.56 ng/ml) than whites (mean PSA of 10.96 ng/ml) and Hispanics (mean PSA of 8.25 ng/ml) (p = 0.04). The mean PSAD also was higher in AAs than in the other two groups (0.68 versus 0.34 for whites and 0.31 for Hispanics, p = 0.05). On a multivariate analysis, the PC stage and grade were overwhelmingly significant, whereas the race and age lost their statistical significance. AAs have higher serum PSA and PSAD than whites or Hispanics in an equal-access healthcare environment. Race is a significant factor in determining PSA and PSAD on univariate but not on multivariate analysis. Preliminary studies suggest that these differences are due to sociological, not biologic causes. These findings warrant a large, prospective study to investigate the extent and the causes of the racial differences in PSA and PSAD.