68Ga-labelled PSMA ligand HBED-CC PET/CT imaging in patients with recurrent prostate cancer.

BACKGROUND: 68Ga-PSMA Positron Emission Tomography/Computerized Tomography (PET/CT) has shown promising results for the detection of recurrent prostate cancer (RPCa). However, the diagnostic value of this method is yet to be validated. The aim of this study was to determine the influence of clinical and biochemical variables on the detection rate of 68Ga-PSMA PET/CT in patients with RPCa. METHODS: This is a prospective study of 121 patients who underwent 68Ga-PSMA-PET/CT and conventional imaging (CI) for RPCa. Detection rates were analyzed and correlated with various clinical and biochemical variables such as Gleason score GS), androgen deprivation therapy (ADT), trigger PSA (tPSA), PSA doubling-time (PSAdt) and PSA velocity (PSAv). RESULTS: 68Ga-PSMA-PET/CT showed at least one focus of pathological 68Ga-PSMA uptake in 92/121 (76%) of patients. Nodal metastases (in 47% of patients) were the most common site of recurrent disease followed by bones (36%) and prostate (32%). Out of 121 patients, 57 (47%) had only positive findings on PSMA scan verified by biopsy or follow-up. The majority of these lesion were located in the lymph nodes (31/57, 54,5%), which were below the detection limit of CT. Univariate analysis showed higher detection rate of PET/CT with increasing tPSA, PSAv and short PSAdt. Best cutoff for tPSA, PSAv and PSAdt was 0.5 ng/ml, 2.25 ng/ml/year and 8.65 months, respectively. The detection rate of PSMA-PET/CT was higher in patients with high grade tumors (GS > 7, 23.7% vs 76.3%) and in patients who were on ADT during of PSMA scan (76.3% vs 96%). In multiple logistic regression analysis, PSAdt and concurrent ADT were identified as predictors of positive 68Ga-PSMA-PET/CT. CONCLUSION: 68Ga-PSMA-PET/CT is useful for re-staging patients with RPCa and has improved performance compared with CI for disease detection. Detection rates are improved in patients on ADT and with short PSAdt.

Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study.

BACKGROUND: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting. PATIENTS AND METHODS: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method. RESULTS: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml. CONCLUSION: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values. CLINICAL TRIAL NUMBER: NCT00672282.

PET/CT with (18)F-choline after radical prostatectomy in patients with PSA ≤2 ng/ml. Can PSA velocity and PSA doubling time help in patient selection?

PURPOSE: To investigate the performance of (18)F-fluorocholine ((18)F-FCH) PET/CT in relation to the prostate-specific antigen (PSA) kinetic indexes, PSA doubling time (PSAdt) and PSA velocity (PSAve), in detecting recurrent prostate cancer (PC) in a selected population of patients treated with radical prostatectomy and with PSA ≤2 ng/ml. METHODS: The study group comprised 79 patients (mean age 70 ± 7 years, range 58 - 77 years) who had been treated with radical surgery 30 to 90 months previously and with biochemical failure (defined as a measurable serum PSA level) who were evaluated with (18)F-FCH PET/CT. In order to establish the optimal threshold for PSAdt and PSAve, the diagnostic performance of PSA, PSAdt and PSAve were compared by receiver operating characteristic analysis. RESULTS: In the population examined, PSA (mean ± SD) was 1.37 ± 0.44 ng/ml (range 0.21 - 2 ng/ml) before PET/CT examination, PSAdt was 10.04 ± 16.67 months and PSAve was 2.75 ± 3.11 ng/ml per year. (18)F-FCH PET/CT was positive in 44 patients (55 %). PSAve and PSAdt were significantly different between patients with a positive and a negative (18)F-FCH PET/CT scan. Thresholds of 6 months for PSAdt and 1 ng/ml per year for PSAve were selected. For PSAdt ≤6 months the detection rate (DR) was 65 %, and for PSAve >1 ng/ml per year the DR was 67 %. PSA values were not significantly different between patients with a positive and a negative PET/CT scan. CONCLUSION: The results of our study suggest that (18)F-FCH PET/CT could be considered for the evaluation of patients with biochemical recurrence of PC and with low PSA levels. Fast PSA kinetics could be useful in the selection of these patients.

Prostate Specific Antigen as a Tumor Marker in Prostate Cancer: Biochemical and Clinical Aspects.

In this chapter the use of prostate specific antigen (PSA) as a tumor marker for prostate cancer is discussed. The chapter provides an overview of biological and clinical aspects of PSA. The main drawback of total PSA (tPSA) is its lack of specificity for prostate cancer which leads to unnecessary biopsies. Moreover, PSA-testing poses a risk of overdiagnosis and subsequent overtreatment. Many PSA-based markers have been developed to improve the performance characteristics of tPSA. As well as different molecular subforms of tPSA, such as proPSA (pPSA) and free PSA (fPSA), and PSA derived kinetics as PSA-velocity (PSAV) and PSA-doubling time (PSADT). The prostate health index (phi), PSA-density (PSAD) and the contribution of non PSA-based markers such as the urinary transcripts of PCA3 and TMPRSS-ERG fusion are also discussed. To enable further risk stratification tumor markers are often combined with clinical data (e.g. outcome of DRE) in so-called nomograms. Currently the role of magnetic resonance imaging (MRI) in the detection and staging of prostate cancer is being explored.

The role of PSA kinetics in men with a negative MRI-targeted prostate biopsy.

OBJECTIVE: To evaluate rebiopsy rates and clinicopathologic outcomes in patients after a negative MRI-guided biopsy to better inform the management of these patients. METHODS: Patients were included with a clinical suspicion of prostate cancer (PCa) referred for fusion biopsy for a PI-RADS v2.1 lesion ≥ 3 on multiparametric MRI and a negative MRI fusion biopsy. Biopsies included targeted and systematic cores. Patients with a prior cancer diagnosis were excluded. Both baseline and follow-up clinicopathological data, and long-term PSA values were examined in these patients. Statistical analyses included Wilcoxon rank-sum test and one-way tests. RESULTS: Of 685 total patients, 188 (27%) had a negative fusion biopsy. Of these 88 (47%), 74 (39%), and 26 (14%) had PI-RADS 3, 4, 5 lesions, respectively. Complete follow-up was available for 182/188 patients (97%), with a median of 24 months (interquartile range: 12-38). Post-biopsy PSA levels decreased the first and the second year (-0.24; and -0.84 ng/ml/yrs respectively). In follow-up, 44 patients had an MRI (24%) and 20 had a biopsy (10%). A positive PSA velocity was the only predictive variable for repeat MRI in univariate analysis. On repeat MRI, 9 (27%) patients had disappearance of the initial lesion, 21 (48%) had a lower PIRADS score and 14 (32%) higher. Only 12/182 (6.6%) were found to have PCa during follow-up, of those 7 (3.8%) were clinically significant. CONCLUSION: For patients with nonmalignant biopsy findings after an initial mpMRI showing a suspicious PI-RADS lesion, the majority of patients will have their PSAs return to baseline over time. To support this, repeat MRI frequently demonstrated a disappearance or downgrading of PIRADS lesions. These data support monitoring patients with this clinical scenario.

Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy.

PURPOSE: Testosterone replacement therapy in men with prostate cancer is controversial, with concern that testosterone can stimulate cancer growth. We evaluated the safety and efficacy of testosterone in hypogonadal men with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We performed a review of 103 hypogonadal men with prostate cancer treated with testosterone after prostatectomy (treatment group) and 49 nonhypogonadal men with cancer treated with prostatectomy (reference group). There were 77 men with low/intermediate (nonhigh) risk cancer and 26 with high risk cancer included in the analysis. All men were treated with transdermal testosterone, and serum hormone, hemoglobin, hematocrit and prostate specific antigen were evaluated for more than 36 months. RESULTS: Median (IQR) patient age in the treatment group was 61.0 years (55.0-67.0), and initial laboratory results included testosterone 261.0 ng/dl (213.0-302.0), prostate specific antigen 0.004 ng/ml (0.002-0.007), hemoglobin 14.7 gm/dl (13.3-15.5) and hematocrit 45.2% (40.4-46.1). Median followup was 27.5 months, at which time a significant increase in testosterone was observed in the treatment group. A significant increase in prostate specific antigen was observed in the high risk and nonhigh risk treatment groups with no increase in the reference group. Overall 4 and 8 cases of cancer recurrence were observed in treatment and reference groups, respectively. CONCLUSIONS: Thus, testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer. However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

Predictive factors of oncologic outcomes in patients who do not achieve undetectable prostate specific antigen after radical prostatectomy.

PURPOSE: We identified factors predicting oncologic outcomes in cases of persistently detectable prostate specific antigen. MATERIALS AND METHODS: We reviewed the charts of patients treated with radical prostatectomy between 1998 and 2011 at a total of 14 centers. Study inclusion criteria were radical prostatectomy for presumed localized prostate cancer, absent positive nodes and detectable prostate specific antigen, defined as prostate specific antigen 0.1 ng/ml or greater 6 weeks postoperatively. Of the 9,735 radical prostatectomy cases reviewed 496 (5.1%) were eligible for analysis. Predictive factors for oncologic outcomes were assessed in time dependent analyses using the Kaplan-Meier method and Cox regression models. RESULTS: At 6 weeks prostate specific antigen was 0.1 to 6.8 ng/ml. Biochemical progression was noted in 74.4% of patients and clinical metastasis was noted in 5%. The 2 most powerful predictors of general salvage treatment (vs radiotherapy) were postoperative prostate specific antigen greater than 1 ng/ml (OR 3.46, p=0.032) and prostate specific antigen velocity greater than 0.2 ng/ml per year (HR 6.01, p=0.001). Positive prostate specific antigen velocity was the single factor that independently correlated with the risk of failed salvage therapy (HR 2.6, p=0.001). The 5-year disease-free survival rate was 81.0% in patients with stable or negative prostate specific antigen velocity compared with 58.4% in those with positive prostate specific antigen velocity (p<0.001). CONCLUSIONS: Patients with detectable prostate specific antigen after radical prostatectomy have a poor biochemical outcome. We identified postoperative prostate specific antigen and prostate specific antigen velocity as independent predictors of progression and failed salvage treatment. In addition to pathological prognostic factors, these factors should be considered early to better stratify patients for adjuvant therapy.

EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer.

OBJECTIVE: To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. METHODS: We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). RESULTS: Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70-3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46-2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95-1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97-1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99-1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. CONCLUSIONS: The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.

Predictive factors of tumor sink effect: Insights from 177Lu-Prostate-specific membrane antigen therapy.

OBJECTIVE: Tumor sink effect (TSE) has been defined as; decreased uptake in healthy tissue with increased tumor sequestration of the radiopharmaceuticals. It enables us to give high tumoral radiation doses while resulting in lower absorbed radiation to critical organs. However, the factors which influence this effect are yet to be defined. In this study, we have investigated the predictive factors of the tumor sink effect in a group of patients who received 177Lu-Prostate-specific membrane antigen (PSMA) therapy due to progressive metastatic castration-resistant prostate cancer (mCRPC). METHODS: We have retrospectively analyzed the pre-therapy 68Ga-PSMA positron-emission tomography (PET)-computed tomography (CT) and post-therapy planar whole-body scans of 65 patients who received at least two cycles of 7.4 GBq of 177Lu-PSMA therapy. All patients with mCRPC were referred to our department after multiple treatment lines. Age, previous therapies, International Society of Urological Pathology (ISUP) score, and pre-therapy serum tumor marker levels were recorded. Post 177Lu-PSMA therapy images were analyzed for TSE. 68Ga-PSMA PET-CT images were used for the calculation of SUVmax in malignant and healthy tissues as well as metabolic tumor volume (MTV) and total lesion PSMA index (TLPI). RESULTS: Based on the post-therapy scans, TSE was seen in 17/65 (26.2%) patients. In univariate analysis, patients with TSE had higher pre-therapy PSA, PSA velocity, and ALP (p < 0.0001). In relation to PET parameters, patients with TSE had higher 68Ga-PSMA MTV, 68Ga-PSMA TLPI and lower pretherapy renal SUVmax (p < 0.0001)), pretherapy liver SUVmax (p:0.012), pretherapy parotid gland SUVmax (p:0.032), and pretherapy parotid gland SUVmean (p:0.038). In the multivariant analysis, 68Ga-PSMA TLPI, pre-therapy PSA, and PSA velocity were found to be statistically significant. When analyzed according to Youden index, pretherapy PSA level of 133 ng/ml (sensitivity 0.765 and 0.875), PSA velocity of 246 ng/ml/year (sensitivity 0.765 and 0.833), and 68Ga-PSMA TLPI of 2969 g (sensitivity 0.765 and 0.875) was found to be the best cut-off points to predict TSE. CONCLUSION: The tumor sink effect was seen in 26.2% of patients. 68Ga- PSMA TLPI, pre-therapy PSA, and PSA velocity was found to be the predictors of TSE. Accurate prediction of TSE may lead to increased tumoral doses while sparing healthy organs. Clinical trials that consider this effect as a part of a dose algorithm may further increase therapeutic efficacy.

The Association between Prostate-Specific Antigen Velocity (PSAV), Value and Acceleration, and of the Free PSA/Total PSA Index or Ratio, with Prostate Conditions.

INTRODUCTION: Prostate-specific antigen velocity (PSAV) is used to monitor men with clinical suspicion of prostate cancer (PCa), with a normal cut-off point of 0.3-0.5 ng/mL/year. The aim of the study is to establish the predictive capacity of PSAV (value and acceleration) and of the free PSA/total PSA index or ratio. METHOD: Prospective multicentre observational study in 2035 men of over 47 years of age. INCLUSION CRITERIA: men who wished to be informed on the health of their prostate. EXCLUSION CRITERIA: men with a previously diagnosed prostate condition. Groups: GA: (n = 518): men with serum PSA equal to or greater than 2.01 ng/mL. GB: (n = 775): men with serum PSA greater than or equal to 0.78 ng/mL and less than 2.01 ng/mL. GC: (n = 742): men with serum PSA less than 0.78 ng/mL. VARIABLES: prostate-specific antigen (PSA); age; body mass index (BMI); PSA velocity (PSAV) (ng/mL per year); free PSA/total PSA index (iPSA); PSAV acceleration (increasing: positive, or decreasing: negative); prostate diagnosis (benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), or infectious and non-infectious prostatitis and prostatic adenocarcinoma (PCa)); de novo diagnoses of urinary tract diseases or conditions; concomitant treatments, diseases and conditions; final diagnosis of prostate health. RESULTS: Mean age 62.35 years (SD 8.12), median 61 (47-94); age was lowest in GC. Mean BMI was 27.89 kg/m2 (SD 3.96), median 27.58 (18.56-57.13); no differences between groups. Mean PSAV was 0.69, SD 2.16, median 0.13 (0.001-34.46); PSAV was lowest in GC. Mean iPSA was 27.39 u/L (SD 14.25), median 24.29 (3.7-115); iPSA was lowest in GA. PSAV had more positive acceleration in GA and more negative acceleration in GC. There were 1600 (78.62%) cases of normal prostate or BPH, 322 (15.82%) cases of PIN or non-infectious prostatitis, and 113 (5.55%) cases of PCa. There were more cases of BPH in GC and more cases of PIN or prostatitis and cancer in GA (p = 0.00001). De novo diagnoses: 15 cases of urinary incontinence (UI), 16 discomfort/pain in LUT, 112 cases of voiding disorders, 12 urethral strictures, 19 hematuria, 51 cystitis, 3 pyelonephritis, 4 pelvic inflammatory disease; no differences were found between groups. In the multivariate analysis, PSAV and the direction of PSAV acceleration (positive or negative) were the variables which were correlated most strongly with prostate health. iPSA was associated with the presence of prostatitis, PCa, and BPH. Men in GA had more prostatitis, PCa, treatment with alpha blockers, and history of previous smoking. GB had more cases of BPH and more positive acceleration of PSAV. GC had more normal prostates, more BPH, more use of ranitidine, and more PSAV with negative acceleration. CONCLUSIONS: PSAV, direction of PSAV acceleration, and iPSA in PSA cut-off points of 0.78 ng/mL and 2.01 ng/mL in a priori healthy men over 47 predict the probability of benign or malignant pathology of the prostate.

Implementation of repeat biopsy and detection of cancer after a diagnosis of atypical small acinar proliferation of the prostate.

Current guidelines recommend a repeat biopsy within 3-6 months after an initial diagnosis of atypical small acinar proliferation (ASAP) due to the high incidence of cancer detection on repeat biopsy. The current study sought to investigate practice patterns after a diagnosis of ASAP in a real-world setting and examine the clinicopathological outcomes of repeat biopsy. The departmental database of the Hyogo Prefectural Nishinomiya Hospital identified 97 of 1,218 patients with a diagnosis of ASAP on initial biopsy from 2011 to 2016. Clinical and pathological data were retrospectively analyzed. Of the 97 patients, 34 (35.1%) underwent a repeat biopsy. Patients with a repeat biopsy had a significantly higher prostate-specific antigen (PSA) velocity and shorter PSA doubling time than patients without a repeat biopsy (P=0.0002), and of these 34 patients with a repeat biopsy, 16 (47.1%) were diagnosed as having cancer. Multivariate logistic regression analysis revealed that a small prostate (P=0.0250) and advanced age (P=0.0297) were associated with cancer detection on repeat biopsy. Of the 16 cancers identified, 13 (81.6%) were diagnosed with a Gleason score >6. The results indicated that the implementation of a repeat biopsy for patients with ASAP could be affected by clinical characteristics in real-world settings, despite the current recommendation of guidelines endorsing immediate repeat biopsy. Prostate volume and age would aid in the decision-making process to perform repeat biopsy in patients with high PSA velocity and short PSA doubling time after a diagnosis of ASAP.

Oncologic Outcomes of Definitive Treatments for Low- and Intermediate-Risk Prostate Cancer After a Period of Active Surveillance.

BACKGROUND: To compare oncologic outcomes of different definitive treatment (DT) modalities in a cohort of patients with prostate cancer (PCa) after active surveillance (AS). METHODS: We identified 237 patients with National Comprehensive Cancer Network (NCCN) low- and intermediate-risk prostate cancer diagnosed from 1990 to 2012 who did not undergo immediate DT within 12 months of diagnosis (ie, AS patients as well as watchful waiting and those refusing DT). Charts were examined for clinical/pathologic data and type of DT: surgery (RP), radiation including brachytherapy (XRT), cryotherapy, and androgen deprivation therapy monotherapy (ADT). The impact of DT on oncologic outcomes of biochemical recurrence (BCR), metastasis, disease-specific (DSS), and overall survival (OS) was examined with the Cox proportional hazards model, along with the Kaplan-Meier method and log-rank test. RESULTS: After median time on AS of 63.4 months, 40% of patients underwent DT: 47% XRT, 28% RP, 14% ADT, and 11% cryotherapy. On multivariable analysis, the use of XRT predicted higher BCR (hazard ratio [HR] 6.1, P = .001) and worse overall mortality (HR 2.1, P = .03) compared with other treatments, controlling for age, Charlson Comorbidity Index (CCI), stage, Gleason score, and NCCN risk category. Median follow-up was 71.7 months. On Kaplan-Meier analysis, 10-year OS was superior for RP versus XRT among patients with prostatic specific antigen (PSA) velocity >2.0 ng/mL/y. CONCLUSIONS: Low- and intermediate-risk patients with PCa who progress to DT after AS may be inadequately treated with radiation therapy compared with other DT modalities, especially when pretreatment PSA velocity is > 2 ng/mL/y.

The use of multiphase nonlinear mixed models to define and quantify long-term changes in serum prostate-specific antigen: data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

PURPOSE: To test the hypothesis that the pattern of prostate-specific antigen (PSA) change in men diagnosed with high-risk prostate cancer (PrCA) differs from the pattern evident in men diagnosed with low-risk PrCA or those with no evidence of PrCA. METHODS: A retrospective cohort study from which PSA measures were taken before PrCA diagnosis from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Data were fitted using a nonlinear regression model to estimate the adjusted absolute and relative (%) change of PSA. RESULTS: Data on 20,888 men with an average age of 61.61 years were included in the analysis. Of these, the 324 (1.55%) diagnosed with high-risk PrCA had a steeper and earlier transition into an exponential pattern of PSA change than the 1368 men diagnosed with low-risk cancer. At 1 year before diagnosis and/or exit, the average absolute PSA rates were 0.05 ng/mL/year (0.05-0.05), 0.59 (0.52-0.66), and 2.60 (2.11-3.09) for men with no evidence of PrCA, men with low-risk PrCA and those with high-risk PrCA, respectively. CONCLUSIONS: The pattern of PSA change with time was significantly different for men who develop high-risk PrCA from those diagnosed with low-risk PrCA. Further research is required to validate this method and its utilization in PrCA screening.

Preliminary Case Series of Artemisinin for Prostate Cancer in a Naturopathic Practice.

OBJECTIVE: To determine if oral artemisinin is safe and has a short-term effect on prostate specific antigen (PSA) kinetics in patients with prostate cancer (CaP). DESIGN: Retrospective case series. SETTING: A private naturopathic urology clinic in Seattle, WA. PATIENTS: All artemisinin-treated CaP patients were identified retrospectively between 2005 and 2008. A total of 15 patients were identified who had taken artemisinin and included in the study, comprising 5 patients who had previously undergone radical prostatectomy (RP) and were having biochemical recurrences as well as 10 patients with no prior conventional therapy for CaP. INTERVENTIONS: High-dose, pulsed oral artemisinin 300-400 mg three times a day every other week for 3-24 months (median 9.5 months, IQR 5-12 months). All patients were treated with an array of other naturopathic therapies. OUTCOME MEASURES: The primary outcomes were the PSA doubling time and velocity; secondary outcome measures were signs and symptoms of metastasis and survival. RESULTS: Of those patients who have previously undergone RP, 2/5 (40%) had improved PSA kinetics after artemisinin therapy. Of those with no prior RP, 5/10 (50%) had improved PSA kinetics. No patient developed signs of metastasis and no patients died. There were no reported adverse effects. CONCLUSIONS: This pilot study provides preliminary evidence to suggest that high-dose, pulsed oral artemisinin therapy may have activity in patients with CaP. A larger controlled trial is warranted to confirm these preliminary beneficial effects.

Simple Risk Stratification to Detect Prostate Cancer with High Gleason Score in Repeat Biopsies in a Population Screening Follow-up Study.

BACKGROUND: To investigate the clinical usefulness of percentage free prostate-specific antigen (%fPSA) and PSA velocity (PSAV) for detecting prostate cancer in repeat biopsies in a population-based screening cohort. PATIENTS AND METHODS: In total, 178 men with serum PSA levels within 2.1-10 ng/ml who underwent repeat biopsies after initial negative biopsy results, were enrolled. Prostate cancer detection rates with a Gleason score of 7 or more according to age, serum PSA, %fPSA, and PSAV were investigated. The cumulative probability of detecting cancer according to risk factors was also investigated. RESULTS: Out of 178 men who underwent repeat biopsy, 48 (27.0%) were diagnosed with prostate cancer during the observation period, and pathological examination revealed prostate cancer with a Gleason score of 7 or more in 17 patients (35.4%). In the multivariate logistic regression analysis, %fPSA ≤ 12 at repeat biopsy and PSAV >0.40 ng/ml/year were determined to be independent risk factors for prostate cancer, and %fPSA ≤ 12 at initial biopsy and PSAV >0.40 for cancer of Gleason score 7 or greater. The cumulative probabilities of developing high-grade cancer after 5 years were 55.8% and 4.0% in men with %fPSA ≤ 12 at initial biopsy and PSAV >0.40, and in men without both, respectively. There was a statistically significant difference in probabilities between groups by the log-rank test. CONCLUSION: The present results demonstrated that %fPSA and PSAV were predictors of prostate cancer with a Gleason score of 7 or more in repeat biopsy after a negative initial biopsy on a population follow-up basis.

Baseline PSA in a Spanish male population aged 40-49 years anticipates detection of prostate cancer.

INTRODUCTION: We researched the usefulness of optimizing prostate cancer (PC) screening in our community using baseline PSA readings in men between 40-49 years of age. MATERIAL AND METHOD: A retrospective study was performed that analyzed baseline PSA in the fifth decade of life and its ability to predict the development of PC in a population of Madrid (Spain). An ROC curve was created and a cutoff was proposed. We compared the evolution of PSA from baseline in patients with consecutive readings using the Friedman test. We established baseline PSA ranges with different risks of developing cancer and assessed the diagnostic utility of the annual PSA velocity (PSAV) in this population. RESULTS: Some 4,304 men aged 40-49 years underwent opportunistic screening over the course of 17 years, with at least one serum PSA reading (6,001 readings) and a mean follow-up of 57.1±36.8 months. Of these, 768 underwent biopsy of some organ, and 104 underwent prostate biopsy. Fourteen patients (.33%) were diagnosed with prostate cancer. The median baseline PSA was .74 (.01-58.5) ng/mL for patients without PC and 4.21 (.76-47.4) ng/mL for those with PC. The median time from the reading to diagnosis was 26.8 (1.5-143.8) months. The optimal cutoff for detecting PC was 1.9ng/mL (sensitivity, 92.86%; specificity, 92.54%; PPV, 3.9%; NPV, 99.97%), and the area under the curve was 92.8%. In terms of the repeated reading, the evolution of the PSA showed no statistically significant differences between the patients without cancer (p=.56) and those with cancer (P=.64). However, a PSAV value >.3ng/mL/year revealed high specificity for detecting cancer in this population. CONCLUSIONS: A baseline PSA level ≥1.9ng/mL in Spanish men aged 40-49 years predicted the development of PC. This value could therefore be of use for opportunistic screening at an early age. An appropriate follow-up adapted to the risk of this population needs to be defined, but an annual PSAV ≥.3ng/mL/year appears of use for reaching an early diagnosis.

Impact of PSA levels on second-round screening for the development of prostate cancer in men with low baseline PSA levels (≤2.0 mg/ml).

BACKGROUND: To investigate the cumulative probability of developing prostate cancer according to prostate-specific antigen (PSA) velocity (PSAV) from first-to second-round PSA-based population screening in men with low baseline serum PSA levels. PATIENTS AND METHODS: A total of 11,913 men aged between 54 and 69 years with baseline PSA levels of ≤2.0 ng/ml at the first population screening and who underwent population screening at least twice, were enrolled. The cumulative probability of developing prostate cancer according to age, baseline PSA and PSAV was investigated. The clinicopathological features of screen-detected cancer were also investigated. RESULTS: Out of the 11,913 men, 110 (0.92%) were pathologically diagnosed with prostate cancer during the observation period. The cumulative probability of developing prostate cancer in all participants after 5 and 10 years was 0.64% and 1.79%, respectively. Univariate and multivariate analyses determined that baseline PSA levels and PSAVs were significant predictors of developing cancer and the hazard ratio increased with increasing baseline PSA levels and PSAVs. The optimal PSAV cut-off levels for prostate cancer development were 0.069, 0.106 and 0.285 for the baseline PSA ranges of 0.0-1.0, 1.1-1.5 and 1.6-2.0 ng/ml, respectively. There were no significant differences in baseline PSA levels and PSAVs according to the clinical characteristics of the screen-detected prostate cancer patients. CONCLUSION: The present study demonstrated that serum PSA levels at second round screening were a strong predictor of cancer development in men with baseline PSA levels≤2.0 ng/ml at the first population screening.

Long-term prostate-specific antigen velocity in improved classification of prostate cancer risk and mortality.

BACKGROUND: It remains unclear whether adding long-term prostate-specific antigen velocity (PSAV) to baseline PSA values improves classification of prostate cancer (PCa) risk and mortality in the general population. OBJECTIVE: To determine whether long-term PSAV improves classification of PCa risk and mortality in the general population. DESIGN, SETTING, AND PARTICIPANTS: We studied 503 men aged 30-80 yr, with and without PCa, who had repeated PSA measurements over 20 yr and up to 28 yr before PCa diagnosis. These were selected from among 7455 men in the Copenhagen City Heart Study, a prospective, general population study with follow-up from 1981 through 2010. Results were subsequently applied to all 1 351 441 men aged 40-80 yr living in Denmark from 1997 through 2006. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCa risk and mortality were assessed using Cox regression. Improvement in risk classification was assessed using the net reclassification index (NRI). RESULTS: Age-adjusted hazard ratios for PCa risk and mortality were 2.7-5.3 and 2.3-3.4, respectively, for long-term PSAV when added to models already including baseline PSA values. For PCa risk and mortality, adding long-term PSAV to models already including baseline PSA values and age yielded continuous NRIs of 98-99% and 56-106%, respectively. Used on a nationwide scale (eg, for men aged 60-64 yr), long-term PSAV >0.35 versus ≤ 0.35 ng/ml per year appropriately reclassified 128 of 10 000 men with PCa and 8095 of 10 000 men with no PCa. Correspondingly, inappropriately reclassified were 49 of 10 000 men with PCa and 1658 of 10 000 men with no PCa. CONCLUSIONS: Long-term PSAV in addition to baseline PSA value improves classification of PCa risk and mortality. Applying long-term PSAV nationwide, the ratio of appropriately to inappropriately classified men would typically be 5:1.

What is the possible role of PSA doubling time (PSADT) and PSA velocity (PSAV) in the decision-making process to initiate salvage radiotherapy following radical prostatectomy in patients with prostate cancer?

This article is an attempt to present a contemporary view on the role of the kinetics of PSA levels as defined by PSA doubling time (PSADT) and PSA velocity (PSAV) in the decision-making process to initiate salvage radiotherapy in patients with prostate cancer after radical prostatectomy (RP). The dynamics of the rise of PSA levels may be an early endpoint parameter, preceding the diagnosis of distant metastasis or death due to prostate cancer based on a single PSA determination. Thus, it seems reasonable to include the kinetics of PSA levels, apart from single PSA determination, in the decision-making algorithm. In a group of patients after RP, PSADT might be an early endpoint that could replace cause-specific survival rate as a late endpoint. PSADT allows distinguishing subgroups of patients at high risk of distant metastases and death, which in turn may lead to a change in the further treatment strategy. Therefore, patients with short PSA doubling time should become a subgroup, in which hormonal therapy should be considered. To date, there is no unanimous consent to accept the criteria of assessment of the dynamics of PSA levels as determinants of treatment in case of recurrences following RP. However, a number of non-randomized clinical trials in patients after RP suggest it would be useful to include these parameters in the decision-making process. For instance, a relationship was found between increased PSA velocity (>2 ng/mL/year) before initiation of oncological treatment and increased (12-fold) risk of death. A number of well-documented retrospective analyses show that PSADT is one of the most important parameters to describe the disease aggressiveness. It has to be stressed that single determination of PSA levels is much less precise in terms of describing the biological aggressiveness of prostate cancer than PSADT. Of course, the question regarding the need to include the PSA levels kinetic parameters as crucial elements of patient management algorithms can be answered in a definitive manner only by randomized clinical trials.