Prostate-specific Antigen Criteria Research Articles

External validation of biochemical recurrence definition to predict oncologic outcomes following focal therapy for localized prostate cancer using high intensity focused ultrasound.

This is an external validation of several biochemical recurrence definitions based on prostate specific antigen criteria (PSA). The purpose is to predict the need of additional treatment and failure after focal therapy using high intensity focused ultrasound (HIFU) for localized prostate cancer (PCa). A total of 343 consecutive patients who underwent HIFU with Ablatherm® and Focal One® devices between June 2001 and November 2020 were identified. Treatment failure was defined as clinically significant PCa on postoperative biopsy, the need for salvage radical or systematic treatment, metastasis, or PCa-related death. The biochemical recurrence definitions tested were PSA nadir, time to PSA nadir, percentage of PSA reduction, Huber et al. criteria defined as PSA nadir + 1 ng/mL at 12 months or PSA nadir + 1.5 ng/mL at 24-36 months. Multivariable Cox regression analysis and decision-curve analysis were used to validate and compare criteria. Kaplan-Meier analysis was used to assess criteria associated with the highest accuracy. One hundred seventy-eight patients met the inclusion criteria and were analyzed. Overall, 61 (34%) and 41 (23%) patients had an additional treatment and failure with a median follow-up of 52 months. At multivariable analysis, model including Huber et al. criteria exhibited the highest Harrell's C-index for the prediction of the need of additional treatment (hazard ratio [HR]: 10, p < 0.001, c-index: 84%) and treatment failure (HR: 9.1, p < 0.001, c-index: 82%) as well as higher net benefit. The 60-months need of additional treatment and treatment failure-free survival were 89% and 98% compared to 26% and 49%, respectively, when stratified according to Huber et al. criteria (Log-rank test, p < 0.001). Similar results were found after excluding patient with non-clinically significant PCa at initial biopsy. We report an external validation of biochemical recurrence definitions predicting the need of additional treatment and failure after focal therapy using HIFU for localized PCa. Huber et al. criteria were identified as the most accurate and could be used to guide clinicians toward further evaluation and salvage treatments.

Prostate Specific Antigen Criteria to Diagnose Failure of Cancer Control following Focal Therapy of Nonmetastatic Prostate Cancer Using High Intensity Focused Ultrasound.

We determined whether prostate specific antigen criteria after focal high intensity focused ultrasound to treat prostate cancer could diagnose treatment failure. A total of 598 patients in a prospectively maintained national database underwent focal high intensity focused ultrasound with a Sonablate® 500 device from March 2007 to November 2016. Followup consisted of 3-month clinic visits and prostate specific antigen testing in year 1 with prostate specific antigen measurement every 6 to 12 months and multiparametric magnetic resonance imaging with biopsy for magnetic resonance imaging suspicious for recurrence. Treatment failure was considered any secondary treatment, tumor recurrence with Gleason 3 + 4 or greater disease on prostate biopsy without further treatment or metastasis and/or prostate cancer related mortality. To diagnose failure we evaluated a series of nadir + x thresholds with x values of 0.1 to 2.0 ng/ml. Median patient age was 65 years (IQR 60-71) and the median Gleason score was 7 (range 6-9). Gleason 3 + 4 or greater disease was present in 80% of cases. Tumors were radiologically staged as T1c-T2c in 522 of the 596 patients (88%) and as T3a/b in 74 (12.4%). Baseline median prostate specific antigen was 7.80 ng/ml (IQR 5.96-10.45) in failed cases and 6.77 ng/ml (IQR 2.65-9.71) in cases without failure. Optimal performance according to the Youden index to indicate the most appropriate nadir + x at all analyzed time points at 3-month intervals showed that nadir + 1.0 ng/ml would have 27.3% to 100% sensitivity and 39.4% to 85.6% specificity depending on the time of evaluation in the first 3 years. Nadir + 1.5 ng/ml showed 18.2% to 100% sensitivity and 60.6% to 91.8% specificity with nadir + 2.0 ng/ml leading to similar sensitivity and specificity ranges. Nadir + 1.0 ng/ml at 12 months and nadir + 1.5 ng/ml at 24 and 36 months had 100% sensitivity and 96.1% to 100% negative predictive value. Following focal high intensity focused ultrasound a prostate specific antigen nadir of 1.0 ng/ml at 12 months and 1.5 ng/ml at 24 to 36 months might be used to triage men requiring magnetic resonance imaging and biopsy. These data need prospective validation.

Adherence to Active Surveillance Protocols for Low-risk Prostate Cancer: Results of the Movember Foundation’s Global Action Plan Prostate Cancer Active Surveillance Initiative

BackgroundActive surveillance (AS) enrolment criteria and follow-up schedules for low-risk prostate cancer vary between institutions. However, uncertainty remains about adherence to these protocols. ObjectiveTo determine adherence to institution-specific AS inclusion criteria and follow-up schedules within the Movember Foundation’s Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative. Design, setting, and participantsWe retrospectively assessed the data of 15 101 patients from 25 established AS cohorts worldwide between 2014 and 2016. Outcome measurements and statistical analysisAdherence to individual AS inclusion criteria was rated on a five-point Likert scale ranging from poor to excellent. Nonadherence to follow-up schedules was defined as absence of repeat biopsy 1 yr after the scheduled date. Cohorts were pooled into annual and Prostate Cancer Research International: Active Surveillance (PRIAS)-based biopsy schedules, and a generalised linear mixed model was constructed to test for nonadherence. Results and limitationsSerum prostate-specific antigen (PSA) inclusion criteria were followed in 92%, Gleason score (GS) criteria were followed in 97%, and the number of positive biopsy cores was followed in 94% of men. Both age and tumour stage (T stage) criteria had 99% adherence overall. Pooled nonadherence rates increased over time—8%, 16%, and 34% for annual schedules and 11%, 30%, and 29% for PRIAS-based schedules at 1, 4, and 7 yr, respectively—and did not differ between biopsy schedules. A limitation is that our results do not consider the use of multiparametric magnetic resonance imaging. ConclusionsIn on-going development of evidence-based AS protocols, variable adherence to PSA and GS inclusion criteria should be considered. Repeat biopsy adherence reduces with increased duration of surveillance, independent of biopsy frequency. This emphasises the importance of risk stratification at the commencement of AS. Patient summaryWe studied adherence to active surveillance protocols for prostate cancer worldwide. We found that inclusion criteria were generally followed well, but adherence to repeat biopsy reduced with time. This should be considered when optimising future active surveillance protocols.

A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone: DRREEM trial.

329 Background: We previously reported a novel cell reprogramming approach, termed drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting the cancer stemness-related gene network, and identified ribavirin as a candidate drug for overcoming docetaxel-resistant castration-resistant prostate cancer (CRPC). We conducted this phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone. (DRREEM trial) Methods: In this clinical study, patients received intravenous docetaxel at 60-75 mg/m2is intravenously administered on Cycle1-Day1 in combination with the investigational drug (ribavirin). Docetaxel is administered at 3-week intervals (1 cycle) (total: 3 cycles). During administration, the dose may be reduced based on the subject’s condition if necessary. The primary endpoint was safety. Accessory evaluation items included prostate-specific antigen (PSA) response, objective response rate, health-related quality of lifel. Exploratory items included changes in CTC count, cfDNA, and exosome. Patients with progressive CRPC based on PSA and/or radiographic criteria, performance status (PS) 0–1, and normal renal and hepatic function were eligible. Results: Six patients were enrolled in this study; average age was 71.7±4.2. Average serum PSA concentration was 100.1±128.0 ng/ml (range: 3.0-336.8). The median cycle of docetaxel received before the study was 6 cycles. Safety: Grade 3/4 adverse events requiring dose modification were not observed. Two patients showed PSA reduction. Three patients showed stable disease. Changes in the blood concentrations of ribavirin, docetaxel, and prednisolone were within normal range. Conclusions: This combination of ribavirin with docetaxel was well tolerated with a promising response rate that justifies further investigations in docetaxel-resistant CRPC. This clinical study provides a useful drug re-positioning model in the area of translational medicine. Clinical trial information: UMIN000021107.

MP41-11 A PILOT CLINICAL STUDY TO EVALUATE THE EFFICACY AND SAFETY OF DOCETAXEL WITH RIBAVIRIN IN PATIENTS WITH PROGRESSIVE CASTRATION-RESISTANT PROSTATE CANCER TARGETING STEM-CELL RELATED GENE NETWORK.

You have accessJournal of UrologyStem Cell Research1 Apr 2017MP41-11 A PILOT CLINICAL STUDY TO EVALUATE THE EFFICACY AND SAFETY OF DOCETAXEL WITH RIBAVIRIN IN PATIENTS WITH PROGRESSIVE CASTRATION-RESISTANT PROSTATE CANCER TARGETING STEM-CELL RELATED GENE NETWORK. Takeo Kosaka, Takahiro Maeda, Hirohiko Nagata, Shunsuke Yoshimine, Hiroshi Hongo, Toshiaki Shinojima, and Mototsugu Oya Takeo KosakaTakeo Kosaka More articles by this author , Takahiro MaedaTakahiro Maeda More articles by this author , Hirohiko NagataHirohiko Nagata More articles by this author , Shunsuke YoshimineShunsuke Yoshimine More articles by this author , Hiroshi HongoHiroshi Hongo More articles by this author , Toshiaki ShinojimaToshiaki Shinojima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1279AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We previously reported a novel cell reprogramming approach, termed drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting the cancer stemness-related gene network, and identified ribavirin as a candidate drug for overcoming docetaxel-resistant castration-resistant prostate cancer (CRPC). This nonrandomized, open-labeled pilot clinical study explored the safety and efficacy of ribavirin, an antiviral drug, in combination with docetaxel in patients with progressive CRPC. METHODS In this clinical study, patients received intravenous docetaxel 60–70 mg/mm2 on day 1 of 3–6-week cycles plus ribavirin 600 mg twice daily. The primary endpoint was safety, prostate-specific antigen (PSA) response and objective response rate. Secondary endpoints included health-related quality of life and overall survival. Patients with progressive CRPC based on PSA and/or radiographic criteria, performance status (PS) 0–1, and normal renal and hepatic function were eligible. RESULTS Five patients were enrolled in this study; medium age was 73. Median serum PSA concentration was 53.1 ng/ml (range: 5.1–370.5). The median cycle and total dose of docetaxel received before the study was 31 cycles and 3625 mg, respectively. Overall, 80% of patients had disease progression during docetaxel treatment. The median time from last docetaxel dose to disease progression before participation was 1.5 months. Safety: median number of treatment cycles were 7 (range: 3–8) cycles. Grade 3/4 adverse events requiring dose modification were not observed. Grade 3 anemia and neutropenia were seen in two patients. Common adverse events were less than Grade 2. Efficacy: 3 (60%) patients had some degree of PSA decline and 2 (40%) had a decline of ?30%. Median follow-up was 10.0 months. Median progression-free survival was 6 months. CONCLUSIONS This combination of ribavirin with docetaxel was well tolerated with a promising response rate that justifies further investigations in docetaxel-resistant CRPC. This clinical study provides a useful drug re-positioning model in the area of translational medicine. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e539-e540 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takeo Kosaka More articles by this author Takahiro Maeda More articles by this author Hirohiko Nagata More articles by this author Shunsuke Yoshimine More articles by this author Hiroshi Hongo More articles by this author Toshiaki Shinojima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prostate-specific antigen vs. magnetic resonance imaging parameters for assessing oncological outcomes after high intensity–focused ultrasound focal therapy for localized prostate cancer

IntroductionFocal therapy for localized prostate cancer has the potential for oncological control without the side effects of radical therapies. However, there is currently no validated method for monitoring treatment success. We assessed the diagnostic performance of prostate-specific antigen (PSA) parameters and MRI compared to histological outcomes following focal therapy. Patients and methodsPatients from 3 Ethics Review Board approved prospective studies of focal high intensity–focused ultrasound (HIFU) (Sonablate 500) for localized prostate cancer (T1c–T3a, Gleason grade≤4+3, and PSA≤20). Post-HIFU PSA nadir, 6-month PSA, PSA density, and early (<3wk) and late (6mo) MRI (T2-weighted, dynamic contrast-enhanced±diffusion-weighted) was assessed for predictive accuracy of cancer on postoperative biopsy, using receiver operating characteristic (ROC) analysis and sensitivity, specificity, and positive and negative predictive estimates. ROC areas for MRI and PSA were compared. Calculations for statistical significance (P≤0.05) were obtained in a subset of patients comparing area under ROC for 6-month MRI and PSA criteria, across 4 different histological definitions of disease significance. ResultsOf 118 men, 111 underwent at least 1 postoperative biopsy (median 6 cores), with an overall positive biopsy rate of 37% (41/118), over a mean follow-up period of 716 days post-HIFU. Areas under ROC for early and late MRI were (depending on definition of significant disease) 0.65 to 0.76 and 0.77 to 0.85, respectively, with sensitivity, specificity, and negative predictive values of 68% to 91%, 52% to 55%, and 85% to 98% (early MRI), and 63% to 80%, 67% to 73%, and 86% to 97% (late MRI). The area under the ROC curve was statistically significantly higher for late MRI than 6 months and nadir PSA for residual disease >3mm or any Gleason 4 tumor. ConclusionsEarly and late MRI performed better than PSA measurements in the detection of residual tumor after focal therapy.

Beyond PSA: managing modern therapeutic options in metastatic castration-resistant prostate cancer.

Prostate cancer remains a significant cause of cancer-related deaths in men in the United States. Significant advances in the treatment of metastatic castration-resistant prostate cancer have been made in recent years with the arrival of new therapeutic targets and options. The definition of progression of disease must be thought of in the context of clinical symptoms and radiographic evidence rather than as changes in prostate-specific antigen (PSA). Ultimately, the use of PSA criteria alone should not be used to determine the progression of disease; instead, PSA should be evaluated in combination with other clinical data.

MP87-01 DO PRIMARY HORMONAL THERAPY OUTCOMES PREDICT SUBSEQUENT RESPONSE TO ABIRATERONE OR ENZALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?

INTRODUCTION AND OBJECTIVES: Abiraterone and enzalutamide are two novel androgen-receptor (AR)-targeting therapies that improve survival in men with metastatic castration-resistant prostate cancer (mCRPC). Factors that predict abiraterone and enzalutamide response are lacking. The objective of this study was to determine if prostate-specific antigen (PSA) outcomes on primary androgen deprivation therapy (ADT) could predict outcomes on subsequent novel ARtargeting therapies. METHODS: A multicenter retrospective review was performed to identify mCRPC patients who had received abiraterone or enzalutamide. Eligible patients must have received novel AR-targeting therapy for at least 8 weeks and must have been evaluable for response by PSA criteria. The clinical outcome measures evaluated included prostatespecific antigen (PSA) decline, biochemical progression-free survival (bPFS), and overall survival (OS) after initiating novel hormone therapy. Cox regression models were used to analyze the effects of primary therapy response and other clinicopathologic factors on novel hormone therapy outcomes. Survival probabilities were plotted using the KaplanMeier method and differences assessed with the log-rank test. RESULTS: The population consisted of 80 males who received abiraterone (N1⁄451) or enzalutamide (N1⁄429). The median age at diagnosis was 64.6 years, and the median age at start of novel ADT was 73.2 years. A subset of patients also received docetaxel treatment prior to start of novel ADT (N1⁄427). The median bPFS on primary ADT was 1.9 years (range 0.1-15.9 years) with a median PSA decline of 99%. bPFS on primary ADT showed a significant univariate effect on bPFS and OS after initiating novel ADT (p1⁄40.032 and p1⁄40.028, respectively). Patients who progressed on primary ADT prior to 1 year had a median bPFS on novel AR-targeting therapy of 3.4 months, compared to a median bPFS of 7.6 months and 8.1 months for patients whose time to PSA progression on primary ADT was 1 and < 5 years (p1⁄40.008), and 5 years (p1⁄40.026), respectively. CONCLUSIONS: In patients with mCRPC treated with novel ADT, time to PSA progression on primary ADT had a significant effect on time to progression on novel ADT in the univariate analysis. Patients who progressed on primary ADT within the first year of treatment had shorter bPFS on subsequent AR-targeting therapy. These potential predictive factors couldhelp guideclinical decisionswhen treatingmCRPCpatients.

¿Impacta el criterio para indicar la biopsia prostática sobre su exactitud? Estudio prospectivo llevado a cabo sobre una población de pacientes ambulantes

Introduction Prostate specific antigen (PSA) and digital rectal examination (DRE) are the main tests for initial prostate investigation; there is no consensus about the best criterion for prostate biopsies. We aim to check the accuracy of different criteria in this context including PSA derivatives to detect prostate cancer. Material and methods Four different criteria for indication of prostate biopsy were compared: (A) PSA-density (>15 ng/ ml/ cc); (B) PSA > 2,5ng/ml; (C) PSA-velocity (> 0.7 ng/ ml/ year); (D) free/total PSA ratio (<15%). All biopsies and histopathological examinations were performed by the same urologist and pathologist, respectively. Results The study was performed on 180 consecutive biopsies with 37.7% overall cancer detection rate: 29 (16.1%) performed following criterion A, 42 (23.3%) criterion B, 65 (36.1%) criterion C and 44 (24.4%) criterion D. Based on PSA criteria alone, the predictive positive value (PPV) was 37.9% for criterion A, 33.3% for B, 32.3% for C and 50.0% for criterion D, respectively, (p > 0.05). Associating positive DRE with changed PSA, the PPV increased to 50%, 50%, 43.9% and 68.2% for criteria A, B, C and D, respectively (p > 0.05). In univariate analysis, DRE (positive versus negative), PSA level (>10 ng/ ml versus <4.0 ng/ ml), free/total PSA ratio (<10% versus >15%) and age were associated with PC. In multivariate analysis only positive DRE was associated with prostate cancer. Conclusions All the criteria of PSA derivatives are complementary and useful predictors of cancer risk. However, a positive DRE increased the PPV of PSA derivatives. New tools are needed to improve the accuracy of prostate cancer detection.

Sensitivity and specificity of a whole-blood RNA transcript-based diagnostic test for the diagnosis of prostate cancer (CaP) compared with prostate-specific antigen (PSA) alone

5052 Background: Screening for CaP with PSA testing is limited by a high number of false postives, particularly in the setting of benign prostatic hypertrophy (BPH). The goal of this study was to develop whole blood RNA transcript-based diagnostic tests that improve the diagnosis of CaP over PSA alone. Methods: From August 2006 to October 2008, three prospective cohorts of men consented to the collection of whole blood in PAXgene Blood RNA tubes for gene expression analysis: men with newly diagnosed, localized, untreated CaP, otherwise healthy men without CaP, and otherwise healthy men with BPH. 168 inflammation and CaP-related genes (Source MDx Precision Profiles) were assayed using optimized Q-PCR technology. Logistic regression methods were used to develop models to optimize prostate cancer diagnosis. Results: 182 men underwent expression analysis (n = 76, 76 and 30 for CaP, normal, and BPH cohorts, respectively). The CaP and normal cohorts were age matched (median age 60 yrs); the BPH cohort median age was 70. Considering only the CaP and normal cohorts, PSA alone (using a cut-off of 4 ng/ml) had a specificity of 94.7%, but sensitivity of only 71.1% for diagnosis of CaP, or 90.8% and 77.6%, respectively, when using age-adjusted PSA criteria. A model consisting of the expression analysis of 6 genes and PSA had a higher specificity (96.1%) and a much improved sensitivity (97.4%) for CaP diagnosis. When the BPH cohort was added, the improvement of the 6-gene model remained (sensitivity and specificity of 97.4% and 92.0% vs 77.6% and 88.1% using the age-adjusted PSA criteria). Further model development using the CaP and BPH cohorts yielded a 5-gene model which, integrated with PSA and age, correctly predicted 96.1% of the CaP pts and 93.3% of BPH pts. Conclusions: These results suggest that specific whole blood RNA transcript levels can assess abnormal gene expression associated with CaP. Such a molecular CaP biomarker would be a powerful tool to reduce unnecessary biopsies in patients without CaP and detect CaP in patients with PSA values below the current cutoff. Validation of these results is ongoing and will be available at the time of the meeting. [Table: see text]

Oral Fenretinide in Biochemically Recurrent Prostate Cancer: A California Cancer Consortium Phase II Trial

Background Fenretinide is a synthetic retinoid that is cytotoxic to a variety of cancers. We conducted a phase II trial of oral fenretinide in patients with biochemically recurrent prostate cancer. Patients and Methods Eligible patients had histologically confirmed prostate cancer and a confirmed rising prostate-specific antigen (PSA) ≤ 2 ng/mL following either radical prostatectomy and/or pelvic radiation therapy, without clinical or radiographic evidence of metastasis. The primary endpoint was PSA response, which was defined as a confirmed decrease by ≤50%, and ≤5 ng/mL, from the pretreatment value. Treatment comprised oral fenretinide 900 mg/m 2 twice daily for 1 week, every 3 weeks, for 1 year. Results After a median follow-up of 17.7 months, out of 23 patients, 7 (30%) patients had PSA stable disease (SD), 11 (48%) patients had PSA progression within 3 months, 4 patients had minimal increases over 3 months that did not qualify as SD or progression (17%), and one patient (4%) was not evaluable. Median time to PSA progression was 4.6 months (95% CI, 3.2-8.2 months). Observed grade 3 toxicities included fatigue, pain, hypermagnesemia, a rise in lipase, and nyctalopia. Conclusion Although well-tolerated, oral fenretinide did not meet prespecified PSA criteria for response in biochemically recurrent prostate cancer; however, 30% of patients had SD, which suggests modest single-agent clinical activity. The role of different formulations of fenretinide, which might allow for higher serum concentrations of the drug, is currently under investigation.

A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer

BackgroundThe purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. Patients and methodsThis was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) ‘response’ defined as a ≥50% decrease for ≥4 weeks. ResultsIn all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1–8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline=10000 and nadir=1643 μg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8–6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%–52%. ConclusionsSorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response.

A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer

To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

The AKT Inhibitor Perifosine in Biochemically Recurrent Prostate Cancer: A Phase II California/Pittsburgh Cancer Consortium Trial

Background Perifosine is an oral alkylphospholipid that inhibits cancer cell growth through decreased Akt phosphorylation. We conducted a phase II trial of perifosine in patients with biochemically recurrent, hormone-sensitive prostate cancer. Patients and Methods Eligible patients had histologically confirmed prostate cancer, previous prostatectomy and/or radiation therapy, and rising prostate-specific antigen (PSA) without radiographic evidence of metastasis. Previous androgen deprivation therapy < 9 months in duration (completed ≤ 1 year before registration) was allowed. The primary endpoint was PSA response, defined as a decrease by ≤ 50% from the pretreatment value. Treatment was comprosed of a loading dose of perifosine 900 mg orally on day 1, then 100 mg daily starting 24 hours later. Results Of 25 patients, 24 were evaluable for response. After a median follow-up of 8 months, 5 patients (20%) had a reduction in serum PSA levels, but none met criteria for PSA response. Three patients immediately progressed with no response to therapy. Median progression-free survival was 6.64 months (range, 4.53-12.81 months). No change in the PSA doubling time (7 months) was observed before and after treatment initiation. Dose-limiting toxicities (all grade 3) included hyponatremia, arthritis, hyperuricemia, and photophobia. Conclusion Although well tolerated, perifosine did not meet prespecified PSA criteria for response as a single agent in biochemically recurrent prostate cancer. However, 20% of patients had evidence of PSA reduction, suggesting modest single-agent clinical activity. The role of perifosine in combination with androgen deprivation or chemotherapy is currently under investigation.

Phase II Evaluation of Oral Estramustine, Oral Etoposide, and Intravenous Paclitaxel in Patients with Hormone-Sensitive Prostate Adenocarcinoma

Purpose The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy. Patients and Methods Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a ≤ 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m 2 orally on days 1-14, and paclitaxel 135 mg/m 2 intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF). Results Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively. Conclusion The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.

THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO CANCER OF THE PROSTATE RISK ASSESSMENT SCORE: A STRAIGHTFORWARD AND RELIABLE PREOPERATIVE PREDICTOR OF DISEASE RECURRENCE AFTER RADICAL PROSTATECTOMY

Multivariate prognostic instruments aim to predict risk of recurrence among patients with localized prostate cancer. We devised a novel risk assessment tool which would be a strong predictor of outcome across various levels of risk, and which could be easily applied and intuitively understood. We studied 1,439 men diagnosed between 1992 and 2001 who had undergone radical prostatectomy and were followed in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a longitudinal, community based disease registry of patients with prostate cancer. Disease recurrence was defined as prostate specific antigen (PSA) 0.2 ng/ml or greater on 2 consecutive occasions following prostatectomy or a second cancer treatment more than 6 months after surgery. The University of California, San Francisco-Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score was developed using preoperative PSA, Gleason score, clinical T stage, biopsy results and age. The index was developed and validated using Cox proportional hazards and life table analyses. A total of 210 patients (15%) had recurrence, 145 by PSA criteria and 65 by second treatment. Based on the results of the Cox analysis, points were assigned based on PSA (0 to 4 points), Gleason score (0 to 3), T stage (0 to 1), age (0 to 1) and percent of biopsy positive cores (0 to 1). The UCSF-CAPRA score range is 0 to 10, with roughly double the risk of recurrence for each 2-point increase in score. Recurrence-free survival at 5 years ranged from 85% for a UCSF-CAPRA score of 0 to 1 (95% CI 73%-92%) to 8% for a score of 7 to 10 (95% CI 0%-28%). The concordance index for the UCSF-CAPRA score was 0.66. The UCSF-CAPRA score is a straightforward yet powerful preoperative risk assessment tool. It must be externally validated in future studies.

Prostate-Specific Antigen, Digital Rectal Examination and Transrectal Ultrasonography: A Meta-Analysis for This Diagnostic Triad of Prostate Cancer in Symptomatic Korean Men

We conducted a meta-analysis using results from the Korean literature to determine whether prostate-specific antigen (PSA) or digital rectal examination (DRE) or transrectal ultrasonography (TRUS) provides a better diagnostic outcome for possible prostate cancer patients. An extensive literature search of MedRIC database et al. (1980 to 2003) was performed using the medical subject headings "PSA", "DRE", "TRUS" and "prostate cancer". Of the 108 articles that we retrieved, 13 studies (2,029 subjects) were selected for this meta-analysis. The criteria for quality evaluation were as follows: the study subjects must have been compared clinically for suspected prostate cancer, and the articles must have included individual data about sensitivity and specificity for this diagnostic triad based on the biopsy results as a reference standard. For the quantitative meta-analysis process the Hasselblad method was utilized. The pooled sensitivity and specificity for a PSA level greater than 4 ng/mL were 91.3% and 35.9%, respectively; and those for a PSA level greater than 10 ng/mL were 77.3% and 67.5%, respectively; and those for DRE were 68.4% and 71.5%, respectively; and those for TRUS were 73.6% and 61.3%, respectively. According to the results in a fixed effect model for PSA criteria, the estimates of d for PSA4 and PSA10 were 0.8517 [95% confidence interval (CI): 0.6694, 1.0340] and 1.0996 (95% CI: 0.9459, 1.2534), respectively. Also, according to the results using a random effect model for both DRE and TRUS criteria, the estimates of d for DRE and TRUS were 0.8398 (95% CI: 0.7169, 0.9627) and 0.8002 (95% CI: 0.6714, 0.9289), respectively. The detection rate for combination testing of PSA, DRE and TRUS for the diagnosis of prostate cancer jumped further to 68.3% or to 76.8%. In conclusion, this study suggests that this diagnostic triad for prostate cancer was noneffective when they were used separately. Therefore, we recommend that the urologists should use PSA together with DRE and TRUS for the primary diagnosis of prostate cancer in men with lower urological symptoms.

Long-term multi-institutional analysis of stage T1–T2 prostate cancer treated with radiotherapy in the PSA era

Purpose To report the long-term outcome for patients with Stage T1–T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era. Methods and materials Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received ≥60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition. Results The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received ≥70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5–3.5 years after treatment. The failure rate was 3.5–4.5% annually after 5 years, except in patients with Gleason score 8–10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group. Conclusion As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

Simultaneous Radiotherapy for Prostate Cancer: 125I Prostate Implant Followed by External-Beam Radiation

Using a rigorous prostate-specific antigen definition of disease-freedom, the 10-year disease-free survival rates after simultaneous radiation of prostate cancer are presented.From January 1984 through December 1996, 1020 men with clinical stage T1T2N0 prostate cancer were treated by simultaneous radiation: radioactive 125I prostate implantation followed by external-beam radiation. The median pretreatment prostate-specific antigen was 7.5 ng/mL (range, 0.2-188 ng/mL). Implantation was performed by both the retropubic and the transperineal technique, always followed by external-beam radiation. None received hormone treatment. Disease freedom is defined as achieving and maintaining a posttreatment prostate-specific antigen of < or = 0.5 ng/mL. The median follow-up is 3 years (range, 1-14 years).The overall 5- and 10-year disease-free survival rates are 79% and 72%, respectively, after which a plateau is reached. At 5 years posttreatment, significantly better disease-free survival results are documented with simultaneous radiation by the ultrasound technique (92%) compared with the retropubic implant technique (73%). On multivariate analysis, pretreatment prostate-specific antigen is the most significant factor associated with disease-free survival, followed by implant technique.The 10-year disease-free survival rate after simultaneous radiation is comparable to the 10-year results after radical prostatectomy. Disease freedom is defined by the same prostate-specific antigen criteria used for surgery. A plateau in the disease-free curve suggests cure. Of equal importance, the information described in this report should form only a baseline relative to future results as men treated with simultaneous radiation using the transperineal implant technique reach longer follow-up.

A Phase II Trial of Oral Trimethylcolchicinic Acid in Patients with Hormone Refractory Prostate Cancer

AbstractHormone refractory prostate cancer (HRPC) will affect more than 40,000 men in the United States in 1999, and only a few drugs have activity in this disease. We studied trimethylcolchicinic acid (TMCA), an oral colchicine derivative, in a Phase II trial involving 18 chemotherapy‐naive men with HRPC. TMCA, 5 mg/m2/day, was given orally for 4 or 5 days with cycles repeated every 3 weeks. No patients showed an objective response by clinical or prostate specific antigen criteria. Neutropenia and stomatitis were common on this schedule. One fatal episode of neutropenic fever occurred. Pharmacokinetics suggested drug accumulation on Days 4 and 5. The cumulative area under the curve (AUC) of concentration × time correlated with the log neutrophil nadir, the log platelet nadir, and the severity of stomatitis. We conclude that TMCA has no clinical effect on HRPC despite severe hematologic toxicity and stomatitis, and that its hematologic toxicity is related to the AUC.