Prostate-specific Antigen Slope Research Articles

Efficacy and Safety of Brazilian Green Propolis in Biochemically Recurrent Prostate Cancer after Radical Prostatectomy: A Single-Arm Phase II Study

Background: Radiation or hormonal therapy is considered for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, these therapies have their own complications. To delay the start of these therapies, we investigated the efficacy and safety of Brazilian green propolis for the treatment for BCR after RP. Materials and Methods: This single-center, single-arm open trial included 22 patients who experienced BCR after RP between 2016 and 2019. The patients received nine softgels of Brazilian green propolis (containing 40 mg propolis per capsule) daily for 6 months. The primary outcome was the prostate-specific antigen (PSA) response rate. The secondary outcomes included progression-free time, PSA slope (1/PSA doubling time) response rate, quality of life, and safety profile. Results: The PSA response rate was 0%. The mean PSA slopes before and after baseline were 0.12 month−1 and 0.08 month−1, respectively. Fifteen patients (68%) showed a decreased PSA slope after treatment. There were no negative effects on quality of life or serious adverse events leading to treatment discontinuation. Conclusion: There was no significant anticancer response in patients who received Brazilian green propolis. However, the PSA slope was decreased after propolis administration. Further, Brazilian green propolis may be safely consumed by patients.

Correlative Analysis of Vitamin D and Omega-3 Fatty Acid Intake in Men on Active Surveillance for Prostate Cancer

ObjectiveTo investigate the influence of targeted serum vitamin-D level and omega-6:3 fatty-acid ratio on prostate-specific antigen (PSA) level in men with prostate cancer managed with active surveillance by providing a nutritional intervention and vitamin supplementation. MethodsSixty-eight patients with biopsy-proven National Comprehensive Cancer Network very-low or low-risk prostate cancer were enrolled in the prostate cancer nutrition and genetics clinic at the Cleveland Clinic from July 2013-December 2019. Patients adhered to a specific dietary regimen devoid of animal-based products and foods containing omega-6 polyunsaturated fatty acids (PUFAs). The supplement regimen consisted of: Omega-3 PUFAs 720mg (3/day); curcumin 2000 mg/day; vitamin D3 dose titrated to achieve serum level of 60 ng/ml; and vitamin B-complex 1000 mg (4 times weekly). Patients underwent periodic monitoring of PSA, serum vitamin D, and PUFA levels and had frequent follow-up with the nutritionist which included a food frequency questionnaire. Interval prostate biopsy was performed as clinically indicated and/or at 9 months. ResultsThe mean and 95% confidence interval of PSA slope and Vitamin D serum levels slope were 0.11 (0-0.25) ng/mL/month and 4.65 (3.09-5.98) ng/mL/month, respectively. Patients with higher initial vitamin D levels were twice as likely to have a downward PSA trend (OR = 2.04, 95% confidence interval 1.04-4.01, P = .04). Fifty-five patients underwent follow-up biopsy, all showing no progression of disease. Three patients had loose bowel movements that required omega-3 and or curcumin dose adjustments. ConclusionIntensive nutritional intervention with Vitamin D and Omega-3 PUFA supplementation may benefit men on active surveillance for prostate cancer and further studies are warranted.

Comparison of Joint and Landmark Modeling for Predicting Cancer Progression in Men With Castration-Resistant Prostate Cancer

Dynamic prediction models may help predict radiographic disease progression in advanced prostate cancer. To assess whether dynamic prediction models aid prognosis of radiographic progression risk, using ongoing longitudinal prostate-specific antigen (PSA) assessments. This prognostic study used data from the PREVAIL study to compare dynamic models for predicting disease progression. The PREVAIL study was a phase 3, multinational, double-blind, placebo-controlled randomized clinical trial of enzalutamide for prostate cancer conducted from September 2010 to September 2012. A total of 773 men with metastatic castration-resistant prostate cancer (CRPC) who had never received chemotherapy and had no baseline visceral disease were treated with enzalutamide. For illustration, 4 patients were selected based on PSA kinetics or PSA response in case studies. Data were analyzed from July 2018 to September 2019. Landmark and joint models were applied to dynamically predict radiographic progression-free survival (PFS) using longitudinal PSA profile, baseline PSA, lactate dehydrogenase, and hemoglobin levels. The main outcome was radiographic PFS as predicted using landmark and joint models. Current PSA and PSA change were considered longitudinal biomarkers possibly associated with radiographic PFS. Predictive performance was evaluated using Brier score for overall prediction errors (PEs) and area under the curve (AUC) for model discriminative capability. Case studies were illustrated using dynamic prediction plots. A total of 763 men with metastatic CRPC treated with enzalutamide (mean [SD] age, 71.2 [8.5] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 28.4 [4.6]) were included in the analysis. Current PSA and PSA change were associated with radiographic PFS in all models. Adding the PSA slope, compared with the landmark models using current PSA alone, improved the prediction of 5-month prospect of radiographic progression, with relative gains of 5.7% in prediction (PE [SE], 0.132 [0.008] vs 0.140 [0.008]) and 7.7% in discrimination (AUC [SE], 0.800 [0.018] vs 0.743 [0.018]) at month 10. In joint models with linear vs nonlinear PSA, prediction of 5-month risk of radiographic progression was improved when PSA trajectories were not assumed to be linear, with 8.0% relative gain in prediction (PE [SE], 0.150 [0.006] vs 0.138 [0.005]) and 19.4% relative gain in discrimination (AUC [SE], 0.653 [0.022] vs 0.780 [0.016]) at month 10. Predictions were affected by amount of marker information accumulated and prespecified assumptions. PSA changes affected progression risk more strongly at later vs earlier follow-up. This prognostic study found that prediction of radiographic PFS was improved when longitudinal PSA information was added to baseline variables. In a population of patients with metastatic CRPC, dynamic predictions using landmark or joint models may help identify patients at risk of progression.

Radiation dose-response (a Bayesian model) in the radiotherapy of the localized prostatic adenocarcinoma: the reliability of PSA slope changes as a response surrogate endpoint.

PurposeOne of the characteristics of Prostate-Specific Antigen (PSA) is PSA slope. It is the rate of diminishing PSA marker over time after radiotherapy (RT) in prostate cancer (PC) patients. The purpose of this study was to evaluate the relationship between increasing RT doses and PSA slope as a potential surrogate for PC recurrence.Patients and MethodsThis retrospective study was conducted on PC patients who were treated by radiotherapy in the Cancer Institute of Iran during 2007–2012. By reviewing the records of these patients, the baseline PSA measurement before treatment (iPSA), Gleason score (GS), clinical T stage (T. stage), and periodic PSA measurements after RT and the total radiation dose received were extracted for each patient separately. We used a Bayesian dose-response model, analysis of variance, Kruskal–Wallis test, Kaplan–Meier product-limit method for analysis. Probability values less 0.05 were considered statistically significant.ResultsBased on the D’Amico risk assessment system, 13.34% of patients were classified as “Low Risk”, 51.79% were “Intermediate Risk”, and 34.87% were “High Risk”. In terms of radiation doses, 12.31% of the patients received fewer than 50 Gy, 15.38% received 50 to 69 Gy, 61.03% received 70 Gy, and 11.28% received more than 70 Gy. The PSA values decreased after RT for all dose levels. The slope of PSA changes was negative for 176 of 195 patients. By increasing the dosage of radiation, the PSA decreased but these changes were not statistically significant (p = 0.701) and PSA slope as a surrogate end point cannot met the Prentice’s criteria for PC recurrence.ConclusionSignificant changes in the dose-response relationship were not observed when the PSA slope was considered as the response criterion. Therefore, although the absolute value of the PSA decreased with increasing doses of RT, the relationship between PSA slope changes and increasing doses was not clear and cannot be used as a reliable response surrogate endpoint.

A Novel Tomato-Soy Juice Induces a Dose-Response Increase in Urinary and Plasma Phytochemical Biomarkers in Men with Prostate Cancer

Tomato and soy intake is associated with reduced prostate cancer risk or severity in epidemiologic and experimental studies. On the basis of the principle that multiple bioactives in tomato and soy may act on diverse anticancer pathways, we developed and characterized a tomato-soy juice for clinical trials. In this phase 2 dose-escalating study, we examined plasma, prostate, and urine biomarkers of carotenoid and isoflavone exposure. Men scheduled for prostatectomy were recruited to consume 0, 1, or 2 cans of tomato-soy juice/d before surgery (mean±SD duration: 24±4.6 d). The juice provided 20.6 mg lycopene and 66 mg isoflavone aglycone equivalents/177-mL can. Plasma carotenoids and urinary isoflavone metabolites were quantified by HPLC-photometric diode array and prostate carotenoids and isoflavones by HPLC-tandem mass spectrometry. We documented significant dose-response increases (P<0.05) in plasma concentrations of tomato carotenoids. Plasma concentrations were 1.86-, 1.69-, 1.73-, and 1.69-fold higher for lycopene, β-carotene, phytoene, and phytofluene, respectively, for the 1-can/d group and 2.34-, 3.43-, 2.54-, and 2.29-fold higher, respectively, for the 2-cans/d group compared with 0 cans/d. Urinary isoflavones daidzein, genistein, and glycitein increased in a dose-dependent manner. Prostate carotenoid and isoflavone concentrations were not dose-dependent in this short intervention; yet, correlations between plasma carotenoid and urinary isoflavones with respective prostate concentrations were documented (R2=0.78 for lycopene, P<0.001; R2=0.59 for dihydrodaidzein, P<0.001). Secondary clustering analyses showed urinary isoflavone metabolite phenotypes. To our knowledge, this is the first demonstration of the phytoene and phytofluene in prostate tissue after a dietary intervention. Secondary analysis showed that the 2-cans/d group experienced a nonsignificant decrease in prostate-specific antigen slope compared with 0 cans/d (P=0.078). These findings provide the foundation for evaluating a well-characterized tomato-soy juice in human clinical trials to define the impact on human prostate carcinogenesis. This trial is registered at clinicaltrials.gov as NCT01009736.

Cancer vaccine strategies: translation from mice to human clinical trials.

We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1year compared to their own baseline slopes (p=0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy boost and whole pelvic radiotherapy for intermediate- and high-risk prostate cancer.

Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after SBRT has not been well characterized. The objective of the current study is to analyze the rate of PSA decline and PSA nadir following SBRT boost after whole pelvis radiotherapy (WPRT) in intermediate- and high-risk prostate cancer. From March 2008 to July 2014, 42 patients newly diagnosed, intermediate- and high-risk (NCCN definition) localized prostate cancer were treated with SBRT boost using Cyberknife after WPRT. The whole pelvis dose was 45 Gy (25 fractions of 1.8 Gy) and the SBRT boost dose was 21 Gy (3 fractions of 7 Gy). No one received androgen deprivation therapy (ADT) before biochemical relapse. PSA nadir and rate of change in PSA (slope) were calculated and compared. With a median follow-up of 53.6 months (range, 14-74), the median rates of decline of PSA were -0.605, -0.229 and -0.166 ng/mL/month, respectively, for durations of 1, 2 and 3 years postradiotherapy, respectively. The median PSA nadir was 0.32 ng/mL after a median 36 months. 4-year biochemical failure (BCF) free survival was 100 percent for intermediate-risk and 71.4 percent for high-risk patients (P = 0.002). In this report of intermediate- and high-risk prostate cancer, continuously greater rates of decline PSA for duration 1, 2 and 3 year following SBRT boost after WPRT resulted in lower PSA nadir. Also, SBRT boost after WBPT leads to favorable BCF-free survival.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy for low- and intermediate-risk prostate cancer

Abstract Background Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate-specific antigen (PSA) kinetics after SBRT has not been well characterized. The objective of the current study is to analyze the rate of PSA decline and PSA nadir following hypofractonated SBRT in low- and intermediate-risk prostate cancer. Methods From 2008 to 2014, 36 patients newly diagnosed, low- and intermediate-risk (NCCN definition) prostate cancer were treated with SBRT using Cyberknife. Total dose of 36.25 Gy in 5 fractions of 7.25 Gy were administered. No one received androgen deprivation therapy (ADT). PSA nadir and rate of change in PSA (slope) were calculated and compared. Results With a median follow-up of 52 months (range, 13–71), the median rates of decline of PSA were −0.359, −0.199 and −0.127 ng/mL/month, respectively, for durations of 1, 2 and 3 years after radiotherapy, respectively. The decline of PSA was maximal in the first year and continuously decreased for durations of 2 and 3 year. The median PSA nadir was 0.27 ng/mL after a median 33 months. 5-year biochemical failure (BCF)-free survival was 100% for low- and intermediate-risk patients. Conclusions In this report of low- and intermediate-risk prostate cancer, continuous decrease of PSA level for duration 1, 2 and 3 year following SBRT using Cyberknife resulted in lower PSA nadir. Also, SBRT leaded to long-term favorable BCF-free survival in low- and intermediate-risk prostate cancer.

Prostate-specific antigen kinetics following hypofractionated stereotactic body radiotherapy boost as post-external beam radiotherapy versus conventionally fractionated external beam radiotherapy for localized prostate cancer.

BackgroundStereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. The purpose of this study was to compare the prostate-specific antigen (PSA) kinetics between conventionally fractionated external beam radiotherapy (CF-EBRT) and SBRT boost after whole pelvis EBRT (WP-EBRT) in localized prostate cancer.MethodsA total of 77 patients with localized prostate cancer [T-stage, T1–T3; Gleason score (GS) 5–9; PSA < 20 ng/mL] were enrolled. A total of 35 patients were treated with SBRT boost (21 Gy in 3 fractions) after WP-EBRT and 42 patients were treated with CF-EBRT (45 Gy WP-EBRT and boost of 25.2–30.6 Gy in 1.8-Gy fractions). PSA nadir and rate of change in PSA (slope) were calculated and compared.ResultsWith a median follow-up of 52.4 months (range, 14–74 months), the median PSA nadir and slope for SBRT boost were 0.29 ng/mL and −0.506, −0.235, −0.129, and −0.092 ng/mL/mo, respectively, for durations of 1 year, 2 years, 3 years, and 4 years postradiotherapy. Similarly, for CF-EBRT, the median PSA nadir and slopes were 0.39 ng/mL and −0.720 ng/mL/mo, −0.204 ng/mL/mo, −0.121 ng/mL/mo, and −0.067 ng/mL/mo, respectively. The slope of CF-EBRT was significantly different with a greater median rate of change for 1 year postradiotherapy than that of SBRT boost (P = 0.018). Contrastively, the slopes of SBRT boost for durations of 2 years, 3 years, and 4 years tended to be continuously greater than that of CF-EBRT. The significantly lower PSA nadir was observed in SBRT boost (median nadir 0.29 ng/mL) compared with CF-EBRT (median nadir 0.35 ng/mL, P = 0.025). Five-year biochemical failure (BCF) free survival was 94.3% for SBRT boost and 78.6% for CF-EBRT (P = 0.012).ConclusionPatients treated with SBRT boost after WP-EBRT experienced a lower PSA nadir and there tended to be a continuously greater rate of decline of PSA for durations of 2 years, 3 years, and 4 years than with CF-EBRT. The improved PSA kinetics of SBRT boost over CF-EBRT led to favorable BCF free survival.

Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy.

Increases in serum levels of prostate-specific antigen (PSA) occur commonly in prostate cancer after radical prostatectomy and are designated "biochemical recurrence." Because the phytochemical sulforaphane has been studied extensively as an anticancer agent, we performed a double-blinded, randomized, placebo-controlled multicenter trial with sulforaphane in 78 patients (mean age, 69 ± 6 years) with increasing PSA levels after radical prostatectomy. Treatment comprised daily oral administration of 60 mg of a stabilized free sulforaphane for 6 months (M0-M6) followed by 2 months without treatment (M6-M8). The study was designed to detect a 0.012 log (ng/mL)/month decrease in the log PSA slope in the sulforaphane group from M0 to M6. The primary endpoint was not reached. For secondary endpoints, median log PSA slopes were consistently lower in sulforaphane-treated men. Mean changes in PSA levels between M6 and M0 were significantly lower in the sulforaphane group (+0.099 ± 0.341 ng/mL) than in placebo (+0.620 ± 1.417 ng/mL; P = 0.0433). PSA doubling time was 86% longer in the sulforaphane than in the placebo group (28.9 and 15.5 months, respectively). PSA increases >20% at M6 were significantly greater in the placebo group (71.8%) than in the sulforaphane group (44.4%); P = 0.0163. Compliance and tolerance were very good. Sulforaphane effects were prominent after 3 months of intervention (M3-M6). After treatment, PSA slopes from M6 to M8 remained the same in the 2 arms. Daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy.

NADiA ProsVue prostate-specific antigen slope, CAPRA-S, and prostate cancer--specific survival after radical prostatectomy.

To assess whether NADiA ProsVue prostate-specific antigen slope, a prognostic biomarker for identifying men at a reduced risk of clinically recurrent prostate cancer after radical prostatectomy, is prognostic for prostate cancer--specific mortality (PCSM) and other outcomes. We examined long-term outcome in the cohort of 304 men selected for the ProsVue 510(k) clinical trial. We assessed the prognostic value of a ProsVue result ≤ 2.0 pg/mL/mo and pathologic risk stratified by the Cancer of the Prostate Risk Assessment Postsurgical nomogram for a reduced risk of prostate cancer--specific survival. We also assessed its value for predicting clinical outcome in men given salvage treatment for biochemical recurrence. Efficacy was assessed using univariate and multivariate Cox regression and the Kaplan-Meier analyses. Median (interquartile range) overall survival for the groups of men with a ProsVue slope result ≤ 2.0 and >2.0 pg/mL/mo were 11.0 (9.4-12.9) and 9.2 (4.9-11.6) years, respectively. The ProsVue univariate hazard ratio (95% confidence interval) for PCSM was 20.6 (6.8-62.7), with P <.0001 for a ProsVue result >2.0 pg/mL/mo vs a result ≤ 2.0 pg/mL/mo. The multivariate hazard ratio of ProsVue adjusted by Cancer of the Prostate Risk Assessment Postsurgical nomogram remained significant (16.7 [4.7-58.6]; P <.0001). The inverse of the hazard ratio translates to a 94.0% risk reduction for PCSM for men with a ProsVue result ≤ 2.0 pg/mL/mo. Salvage treatment for biochemical recurrence did not significantly reduce the hazard of clinical recurrence or PCSM; however, this is based on only 18 events. A NADiA ProsVue slope result ≤ 2.0 pg/mL/mo was prognostic for a reduced risk of PCSM in men after radical prostatectomy.

A Framework to Evaluate the Cost-Effectiveness of the NADiA ProsVue Slope to Guide Adjuvant Radiotherapy among Men with High-Risk Characteristics Following Prostatectomy for Prostate Cancer

ObjectivesThe NADiA ProsVue is a prognostic system that measures prostate-specific antigen slope to identify men at lower risk of clinical recurrence of prostate cancer after radical prostatectomy. We developed a decision-modeling framework to evaluate its cost-effectiveness to guide the use of adjuvant radiotherapy (ART). MethodsWe populated the model using patient-level data and external sources. Patients were classified as intermediate risk or high risk on the basis of Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) nomogram and then stratified by the ProsVue slope (≤2 pg/mL/mo; >2 pg/mL/mo) and receipt of ART. In sensitivity analyses, we varied the effect of the ProsVue slope on the use of ART and other model parameters. ResultsThe cost-effectiveness of the ProsVue-guided strategy varied widely because of small differences in quality-adjusted life-years (QALYs) at 10 years. In the intermediate-risk group, when the use of ART decreased from 20% (standard care) to 7.5% among patients with a ProsVue slope value of 2 pg/mL/mo or less, the incremental cost-effectiveness ratio was $25,160/QALY. In the high-risk group, the use of ART would have to decrease from 40% (standard care) to 11.5% among those with a ProsVue slope value of 2 pg/mL/mo or less to obtain a ratio of $50,000/QALY. The cost-effectiveness ratios were sensitive to varying benefits of salvage therapy, quality of life, and costs of ART and ProsVue testing. ConclusionsThe effect of the ProsVue system on costs will be dependent on the extent to which ART decreases among men identified as having a low risk of recurrence. Its effect on QALYs will remain conditional on uncertain clinical and quality-of-life benefits associated with ART.

NADiA ProsVue Prostate-specific Antigen Slope Is an Independent Prognostic Marker for Identifying Men at Reduced Risk of Clinical Recurrence of Prostate Cancer After Radical Prostatectomy

To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes ≤ 2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer. From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses. The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope ≤ 2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4-17.8), an 89.8% risk reduction for men with PSA slopes ≤ 2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs ≥ 7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004). Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of ≤ 2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors.

Development and validation of a nomogram for predicting a positive repeat prostate biopsy in patients with a previous negative biopsy session in the era of extended prostate sampling

To create a nomogram for predicting the probability of a positive biopsy in men with one or more previous negative biopsies, as the false-negative rate of prostate biopsy in contemporary series remains substantial, and there is a need to identify those with a negative result but with a high risk of having unrecognized prostate cancer. The study included 408 patients from Cleveland Clinic who had one or more repeat biopsies after an initial negative biopsy from 1999 to 2008. Another 470 men with the same criteria were used to validate the nomogram. Nomogram variables included age, family history of prostate cancer, body mass index, findings on a digital rectal examination, prostate-specific antigen (PSA) level, PSA slope, total prostate volume, months from initial negative biopsy session, months from previous negative biopsy, cumulative number of negative cores previously taken and history of high-grade intraepithelial neoplasia or atypical small acinar proliferation. We calculated the nomogram predicted probability in each patient. These predicted outcomes were compared with the actual biopsy results. The area under the receiver operating characteristic (ROC) curve was calculated as a measure of discrimination. The mean number of previous negative biopsies was 1.5, and the mean number of cores per session was 19.1. Of the original development data, 129 men (31.6%) had prostate cancer. A nomogram was constructed that had a concordance index of 0.72, which was greater than any single risk factor. In the validation group the area under the ROC curve was 0.62. Our nomogram for predicting a positive repeat biopsy can provide important additional information to aid the urologist and patient with a negative biopsy in evaluating clinical options.

Risk Factors for Prostate Cancer Detection After a Negative Biopsy: A Novel Multivariable Longitudinal Approach

To introduce a novel approach for the time-dependent quantification of risk factors for prostate cancer (PCa) detection after an initial negative biopsy. Data for 1,871 men with initial negative biopsies and at least one follow-up biopsy were available. Piecewise exponential regression models were developed to quantify hazard ratios (HRs) and define cumulative incidence curves for PCa detection for subgroups with specific patterns of risk factors over time. Factors evaluated included age, race, serum prostate-specific antigen (PSA) concentration, PSA slope, digital rectal examination, dysplastic glands or prostatitis on biopsy, ultrasound gland volume, urinary symptoms, and number of negative biopsies. Four hundred sixty-five men had PCa detected, after a mean follow-up time of 2.8 years. All of the factors were independent predictors of PCa detection except for PSA slope, as a result of its correlation with time-dependent PSA level, and race. PSA (HR = 3.90 for > 10 v 2.5 to 3.9 ng/mL), high-grade prostatic intraepithelial neoplasia/atypical glands (HR = 2.97), gland volume (HR = 0.39 for > 50 v < 25 mL), and number of repeat biopsies (HR = 0.36 for two v zero repeat biopsies) were the strongest predictors. Men with high-risk versus low-risk event histories had a 20-fold difference in PCa detection over 5 years. Piecewise exponential models provide an approach to longitudinal analysis of PCa risk that allows clinicians to see the interplay of risk factors as they unfold over time for individual patients. With these models, it is possible to identify distinct subpopulations with dramatically different needs for monitoring and repeat biopsy.

Treatment of Biochemical Recurrence of Prostate Cancer With Granulocyte-Macrophage Colony-Stimulating Factor Secreting, Allogeneic, Cellular Immunotherapy

This phase I-II study evaluated the safety, clinical activity and immunogenicity of an immunotherapy developed from human prostate cancer cell lines (PC-3 and LNCaP) modified to secrete granulocyte-macrophage colony-stimulating factor. Patients with noncastrate prostate cancer (19) with biochemical (prostate specific antigen) recurrence following prostatectomy or radiation therapy and no radiological evidence of metastasis were enrolled in the study. Patients were injected with an initial dose of 5 x 10(8) cells followed by 12 biweekly administrations of 1 x 10(8) cells. The adverse event profile, prostate specific antigen response, changes in prostate specific antigen kinetics and immunogenicity were assessed. Immunotherapy was well tolerated with no serious treatment related adverse events and no autoimmune reactions. A negative deflection in prostate specific antigen slope was observed in 84% of patients after treatment with a significant increase in median prostate specific antigen doubling time from 28.7 weeks before treatment to 57.1 weeks after treatment (p = 0.0095). Median time to prostate specific antigen progression was 9.7 months. Immunoblot analysis of patient serum demonstrated new or enhanced production of PC-3 or LNCaP reactive antibodies in 15 of 19 (79%) patients after immunotherapy. Induction of antibody responses reactive against PC-3 in general, and to the PC-3 associated filamin-B protein specifically, were positively associated with treatment associated changes in prostate specific antigen kinetics. Granulocyte-macrophage colony-stimulating factor secreting cellular immunotherapy has a favorable toxicity profile with signals of clinical and immunological activity against hormone naïve prostate cancer. An association between immune response and prostate specific antigen changes was observed. Phase 3 trials in patients with advanced, metastatic, hormone refractory prostate cancer are under way.

Biological Mediators of Effect of Diet and Stress Reduction on Prostate Cancer

A 6-month pilot intervention trial was conducted to determine whether adoption of a plant-based diet, reinforced by stress reduction, could reduce the rate of prostate-specific antigen (PSA) increase, a marker of disease progression, in asymptomatic, hormonally untreated patients experiencing consistently increasing PSA levels after surgery or radiation. A pre-post design was used to examine (1) the effect of intervention on potential mediators of disease progression, including body composition and weight-related biomarkers (sex steroid hormones and cytokines), and (2) whether changes in these variables were associated with change in rate of PSA increase. The baseline rate of PSA increase (from the time of posttreatment recurrence to the start of intervention) was ascertained from medical records. Body composition and biomarkers were assessed at baseline (prior to intervention), during the intervention (3 months), and at the end of the intervention (6 months). Changes in body composition and biomarkers were determined and compared with rates of PSA increase over the corresponding time intervals. There was a significant reduction in waist-to-hip ratio (P=.03) and increase in circulating sex hormone binding globulin (P=.04). The rate of PSA increase decreased from the preintervention period (PSA slope=0.059) to the period from 0 to 3 months (PSA slope=0.002, P<.01) and increased slightly, although not significantly, from 0 to 3 months to the period from 3 to 6 months (0.029, P=.43). Adoption of a plant-based diet and stress reduction may reduce central adiposity and improve the hormonal milieu in patients with recurrent PC. Changes in the rate of increase in PSA were in the same direction as changes in waist-to-hip ratio and opposite those of sex hormone binding globulin, raising the possibility that the effect of the intervention may have been mediated, in part, by these variables.

Validation of a Nomogram for Predicting a Positive Repeat Prostate Biopsy in a Multi-Specialty Group Practice Model with a Rural, Referral-Based Population

Background: An earlier biopsy nomogram model was designed at an international cancer referral center and validated in a patient population in New York City. We believe that the rural demographics of our multispecialty institution would be useful in further validation of the nomogram prior to advocating widespread clinical application. Patients and Methods: We retrospectively reviewed 247 patients who un-derwent repeat prostate biopsies over a 2-year period. Results: Data sets were created by extracting such informations as: high-grade prostatic intraepithelial neoplasia, prostate specific antigen, prostate specific antigen slope, and family history, among other variables. Conclusion: Ultimately we found that our nomogram carried out upon a rural community responded similarly to the urban population in which it was originally established and validated.

A Dietary Intervention for Recurrent Prostate Cancer After Definitive Primary Treatment: Results of a Randomized Pilot Trial

Considerable evidence has shown that diet can affect both the incidence and the progression of prostate cancer. The objective of this study was to determine whether men in this situation could make a change to a diet emphasizing plant-based foods and fish and to examine the effect on quality of life (QOL) and prostate-specific antigen (PSA) velocity. A total of 36 men and their partners were randomly assigned to attend a series of 11 dietary and cooking classes that also integrated mindfulness practice as a support in making the change or a wait-list control group. Assessments were made of dietary intake, QOL, and PSA at baseline, after intervention (11 weeks), and 3 months after intervention. The intervention group showed significant reductions in the consumption of saturated fat and increased consumption of vegetable proteins with accompanying reductions in animal proteins, including dairy products. They also showed increased QOL. Although no significant change was found in the rate of PSA increase between the two groups, the mean PSA doubling time for the intervention group was substantially longer at the 3-month follow-up visit than that of the controls. Men with a increasing PSA level after primary treatment were able to make a change to a prostate-healthy diet, accompanied by increases in QOL. No significant difference was found in the log PSA slope between the two groups; however, the PSA doubling time increased substantially in the intervention group compared with that in the controls. Future trials should examine the effect of the prostate-healthy diet with a larger sample of men for a longer period.

Optimal Measure of PSA Kinetics to Identify Prostate Cancer

To compare different tools for evaluate prostate-specific antigen (PSA) kinetics before prostate biopsy, such as PSA velocity, PSA slope, natural logarithm PSA slope (lnPSA slope), and PSA doubling time (PSADT). This study was conducted involving 325 male patients evaluated with transrectal ultrasound-guided biopsy of prostate. Patients with at least three consecutive PSA measurements taken in at least 24 months entered in the study. We estimated PSA slope from the slope of the least squares regression line fit to PSA versus time in years; PSA velocity was calculated as the running average of the rate of change during at least three consecutive assays. The acceleration of PSA (lnPSA slope) was calculated as the slope of lnPSA versus time, where ln is the natural logarithm. PSADT was calculated using the formula: PSADT = ln 2/(lnPSA slope). We found a total of 74 cancers at the ultrasound guided prostate biopsies. At the receiver operating characteristic (ROC) analysis, lnPSA slope (area under the curve [AUC], 0.793) evidenced better results than PSA (AUC, 0.585; P <0.001), PSA velocity (AUC, 0.734; P <0.009), PSA slope (AUC, 0.752; P <0.043), and PSADT (AUC, 0.516; P <0.001). The results for PSA, PSA velocity, PSA slope, and lnPSA slope were significantly higher in patients with prostate cancer than in controls. The results of the present study suggest that lnPSA slope may be useful for prostate cancer diagnosis. At the ROC analyses, the lnPSA slope AUC was better than that of PSA, PSA velocity, PSA slope, and PSADT.