Clinical Validation of IsoPSA™, a Single Parameter, Structure Based Assay for Improved Detection of High Grade Prostate Cancer.

PURPOSE: Current prostate specific antigen markers to detect prostate cancer are limited by low specificity for high grade disease. IsoPSA™ is a blood based, structure focused assay which predicts risk by partitioning the isoforms of prostate specific antigen that are linked to cancer in an aqueous 2-phase reagent system. We validated the clinical performance of this assay for identifying high grade disease in a new contemporary biopsy cohort. MATERIALS AND METHODS: We performed a multicenter prospective validation in 271 men scheduled for prostate biopsy at a total of 7 academic and community centers who were enrolled between May 2017 and March 2018. Blood samples were obtained for assay prior to biopsy. The discrimination power of the assay to detect high grade prostate cancer (Gleason 7 or greater) was evaluated by ROC analysis and compared to prior results. Clinical performance was further improved by comparison with multiparametric magnetic resonance imaging-ultrasound vs transrectal ultrasound guided biopsies. RESULTS: The assay AUC was 0.784 for high grade vs low grade cancer/benign histology, which was superior to the AUCs of total prostate specific antigen and percent free prostate specific antigen. If 1,000 patients were biopsied, the assay would have reduced the number of unnecessary biopsies from 705 to 402 (43%) with only 22 missed high grade cancers, of which 7 would have been Gleason sum 4 + 3 or higher. Subset analysis of multiparametric magnetic resonance imaging guided biopsy produced a substantial improvement of the AUC to 0.831. CONCLUSIONS: Validation of the structure based IsoPSA assay demonstrated statistical concordance with previously reported results and verified its superior performance vs concentration based prostate specific antigen and the free-to-total prostate specific antigen ratio. The assay improvement in detecting high grade prostate cancer using multiparametric magnetic resonance imaging-ultrasound guided biopsy may help define a new diagnostic paradigm.

IsoPSA Performance Characteristics are Unaffected by 5-Alpha Reductase Inhibitors or Alpha-Blockers: Results From the IsoPSA Validation Study.

OBJECTIVE: To. determine the impact of 5-α reductase inhibitors or α-blockers on IsoPSA performance for the detection of actionable prostate cancer. MATERIALS AND METHODS: This is a secondary analysis of data from an institutional review board approved, prospective, multicenter(8-sites) study evaluating IsoPSA in men ≥ 50 years of age with a total PSA ≥ 4 ng/mL with planned prostate biopsy who met previously described inclusion and exclusion criteria. Analytic groups included (i)all subjects, (ii-iii)+/- 5-ARI use, (iv-v)+/- α-blocker use. The performance characteristics of IsoPSA in these groups were assessed by ROC curve, sensitivity, and specificity (SP) analysis. RESULTS: A total of 1385 men were recruited with 888 men included in final analysis. Actionable prostate cancer, defined as GG2+, was identified in a total of 316 patients with 40 and 217 patients reporting 5-ARI and α-blocker use respectively. Sensitivity to detect both prostate cancer and actionable cancer was similar between patient subsets (P >.05). SP was similar between patients regardless of 5-ARI(P >.05). Increased SP was noted in patients on α-blockers(GG1+: No-α-blocker: 0.360 vs α-blocker: 0.529, P <.05; GG2+: No-α-blocker: 0.40 vs α-blocker: 0.61, P <.05). ROC analysis demonstrates that IsoPSA performance is unaffected by 5-ARI or α-blocker use for prostate cancer and actionable cancer (GG2+) detection. CONCLUSION: The performance of IsoPSA for detecting any prostate cancer and clinically actionable prostate cancer is unaffected by commonly used medications (5-ARI and α-blockers) for symptoms of benign prostatic hyperplasia.

Clinical validation of IsoPSA, a single parameter, structure-focused assay for improved detection of prostate cancer: A prospective, multicenter study.

BACKGROUND: IsoPSA is a blood-based test that assesses prostate cancer (CaP) risk by partitioning and detecting cancer-specific structural isoforms of prostate specific antigen (PSA) with an aqueous 2- phase system. OBJECTIVE: To validate the diagnostic performance of IsoPSA for High-Grade CaP and Any CaP risk on biopsy in men age ≥ 50 with total PSA ≥ 4 ng/ml. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter study of 888 men scheduled for prostate biopsy at 8 academic and community sites between August 2015 and August 2020. INTERVENTION: IsoPSA test. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver operating characteristic and likelihood ratio analysis used to validate diagnostic performance for previously established IsoPSA Index cutoffs for High-Grade CaP (Gleason Score ≥ 7) and Any CaP (Gleason Score ≥ 6), compare IsoPSA to total PSA and % free PSA, and evaluate subgroups (total PSA 4-10 ng/ml, total PSA > 10 ng/ml, biopsy naïve, prior negative biopsy). RESULTS AND LIMITATIONS: The disease prevalence was 35.6% (High-Grade CaP) and 58.9% (Any CaP). The area under the receiver operating characteristic curve was 0.783 (High-Grade CaP) and 0.770 (Any CaP). IsoPSA outperformed total PSA and % free PSA on area under the receiver operating characteristic curve, specificity, positive and negative predictive value at similar sensitivity. Using selected IsoPSA Index cutoffs, an estimated 46% (High-Grade CaP) and 42% (Any CaP) of biopsies could be avoided in low-risk patients. IsoPSA displayed statistically informative likelihood ratio-based predictive characteristics. IsoPSA maintained accuracy in clinically relevant subgroups. CONCLUSIONS: IsoPSA diagnostic performance and predictive value is validated for High-Grade CaP and Any CaP in men age ≥ 50 with total PSA ≥ 4 ng/ml undergoing diagnostic biopsy. IsoPSA outperforms total and % free PSA in discriminating the risk of prostate cancer on biopsy. PATIENT SUMMARY: IsoPSA has the potential to reduce unnecessary biopsies and improve the risk-benefit ratio for CaP early detection.

The "male lumpectomy": focal therapy for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up.

BACKGROUND: The use of breast sparing surgery, i.e., "lumpectomy", revolutionized management of breast cancer. Lumpectomy confirmed that quality of life issues can successfully be addressed without compromising treatment efficacy. Complications of prostate cancer treatment, including impotence and incontinence, affect the male self image no less than the loss of a breast does a woman. Traditional thinking held that prostate cancer was multifocal and therefore not amenable to a focal treatment approach. Recent pathology literature indicates, however, that up to 25% of prostate cancers are solitary and unilateral. This raises the question of whether these patients can be identified and treated with a limited "lumpectomy" or focal cancer treatment. METHODS: Focal cryoablation was planned to encompass the area of known tumor based on staging biopsies. PSAs were obtained every 3 months for 2 years and then every 6 months thereafter. RESULTS: Forty-eight patients with at least 2-year follow-up had focal cryoablation. Follow-up ranged from 2 years 10 years with a mean of 4.5 years; 45 of 48 patients (94%) have stable PSAs [American Society of Therapeutic Radiology and Oncology (ASTRO) criteria] with no evidence for cancer, despite 25 patients being medium to high risk for recurrence. Of the 24 patients with stable PSAs who were routinely biopsied (n = 24) all were negative. No local recurrences were noted in areas treated. Potency was maintained to the satisfaction of the patient in of 36 of 40 patients who were potent preoperatively. Of the 48, all were continent. CONCLUSION: These preliminary results indicate a "male lumpectomy" in which the prostate tumor region itself is destroyed, appears to preserve potency in a majority of patients and limits other complications (particularly incontinence), without compromising cancer control. If confirmed by further studies and long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.

AUA White Paper on the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.

INTRODUCTION: Medication related problems are common but may be preventable outcomes of prescribing choices. Risks associated with medications in the older adult population are greater due to changes in physiological function with age or disease. Older adults and those with significant comorbidities are often excluded from the clinical trials used to develop medications. In 2012 the American Geriatrics Society published the most recent update of the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Several medications included in sections of the Beers Criteria are frequently used in clinical urology, including nitrofurantoin, alpha-1 blocker medications, and antimuscarinic anticholinergic medications for the treatment of urge incontinence and overactive bladder. We describe the challenges and considerations that are useful in prescribing medications for geriatric patients. METHODS: A literature review was performed targeting publications from 2003 to 2013 on the topics of the Beers Criteria, potentially inappropriate medications and specific urological medications included in the current version of the Beers Criteria. An expert panel was convened to evaluate this information and create this white paper with the purpose of educating the urological community on these issues. RESULTS: The rationale for the creation and implementation of the Beers Criteria and its implications for urological practice are reviewed. Careful examination of the Beers Criteria can help clinicians avoid potentially inappropriate prescribing choices for their geriatric patients. We also identified that the HEDIS® high risk medications list of potentially inappropriate medications has been implemented as a negative quality indicator, even though this was not an original purpose of the Beers Criteria. In other words, decisions of denial of coverage and/or requirements for preauthorization are being made using the Beers Criteria as justification by third party payers and other entities. CONCLUSIONS: The Beers Criteria were developed to improve prescribing practices for older adult patients to reduce or avoid potential risks and complications. We encourage clinicians to educate themselves about the Beers Criteria recommendations and associated initiatives that are aimed at improving the care of older adult patients. Urologists should have a key role in the development, evaluation, implementation and analysis of practice measures and the resulting policies.

An evaluation of the pharmacokinetics and pharmacodynamics of the histrelin implant for the palliative treatment of prostate cancer.

Seventeen patients with advanced prostate cancer were studied to evaluate the pharmacokinetics and pharmacodynamics of a hydrogel implant designed to deliver histrelin at a constant rate (50 microg/d) for 1 year. Serum histrelin levels were collected during the 52-week implantation period and after a second implant. Testosterone suppression was the primary pharmacodynamic endpoint, with treatment success defined as serum testosterone less than 50 ng/dL. The histrelin subdermal implant delivered constant histrelin levels, with mean serum histrelin of approximately 0.265 ng/mL over 52 weeks. At the end of 52 weeks, mean histrelin concentrations were 0.128 +/- 0.0652 ng/mL. Patients achieved chemical castration (testosterone less than 50 ng/mL) by week 4. In patients who had the first implant removed and received a new implant at the end of the first 52 weeks, testosterone suppression was not interrupted. The hydrogel implant provided consistent delivery of histrelin over 1 year and effectively suppressed testosterone in men with prostate cancer.

Use of a temporary prostatic stent after transurethral microwave thermotherapy reduced voiding symptoms and bother without exacerbating irritative symptoms.

OBJECTIVES: To evaluate the ability of a temporary prostatic stent (Spanner [Sp]) to manage voiding symptoms, irritative symptoms, and bother after transurethral microwave thermotherapy (TUMT) for prostatic obstruction. METHODS: Patients were randomized to the Sp (n = 100) or standard of care (SOC, n = 86) after TUMT with 3 to 10 days of routine catheterization. We evaluated International Prostate Symptom Score (IPSS) voiding subscore, IPSS irritative subscore, voiding diary data, and Benign Prostatic Hyperplasia Impact Index (BII) 7 to 10 days before TUMT and repeated them 1, 2, 4 (stent removal), 5, and 8 weeks after stent insertion. RESULTS: After 1 week of stent use, the Sp group experienced significantly greater improvements in the IPSS voiding subscore (Sp = -4.9 versus SOC = -2.3, P = 0.002) and individual voiding symptoms assessed by the IPSS (intermittency, weak stream, and straining) and voiding diary data (stream strength, and strain). After 2 weeks, the Sp group showed a trend toward greater improvements in IPSS voiding (P = 0.059) and irritative (P = 0.058) subscores and reported significantly less bother (BII, Sp = -2.1 versus SOC = -1.1, P = 0.033). After stent removal, the Sp group reported significantly greater improvements in the IPSS irritative subscore (5 weeks: Sp = -4.0 versus SOC = -2.7, P = 0.029; 8 weeks: Sp = -5.0 versus SOC = -4.0, P = 0.050), individual voiding (stream strength and dysuria), and irritative (frequency and urgency) symptoms and bother (5 weeks: Sp = -4.0 versus SOC = -2.3, P = 0.002; 8 weeks: Sp = -5.0 versus SOC = -3.1, P = 0.001). CONCLUSIONS: The Spanner, a temporary prostatic stent, improved voiding symptoms and bother without exacerbating irritative symptoms. Improvements in symptoms and bother were sustained after stent removal.

"Male lumpectomy": focal therapy for prostate cancer using cryoablation.

The introduction of breast-sparing surgery (ie, "lumpectomy") revolutionized the management of breast cancer. The use of lumpectomy showed that quality of life could be optimized without compromising treatment efficacy. Complications of prostate cancer treatment, including impotence and incontinence, adversely alter the male self-image similarly to the way the loss of a breast does for a woman. Traditional thinking holds that prostate cancer is multifocal and therefore is not amenable to focal treatment. However, histopathologic findings from published data have indicated that up to 25% of prostate cancers are solitary and unilateral. Furthermore, the significance of minute secondary cancers might be minimal. These observations raise the question of whether certain patients can be identified and treated with a limited "lumpectomy." In this study, focal cryoablation has been used to ablate the area of known cancer as determined by staging biopsies. The serum prostate-specific antigen (PSA) concentration was obtained every 3 months for 2 years and every 6 months thereafter. American Society for Therapeutic Radiology Oncology (ASTRO) criteria for PSA recurrence were used. A total of 55 patients with > or = 1 year of follow-up had undergone focal cryoablation. Follow-up ranged from 1 to 10 years (mean, 3.6 years). At the original transrectal ultrasound biopsy, the mean and median numbers of cores taken were 9.9 and 10 (SD, +/- 3.5), respectively. Mean and median numbers of positive cores were 1.8 and 1 (SD, +/- 1.3), respectively. Of the 55 study patients, 52 (95%) had stable PSA levels with no evidence of cancer despite a medium to high risk for recurrence in 29 patients. All biopsy findings were negative among the 26 patients with a stable PSA level who had undergone routine biopsy at 1 year. No local recurrence was noted in treated areas. Potency was maintained in 44 (86%) of 51 patients. Of the 54 patients without previous prostate surgery or radiotherapy, all were continent. These preliminary results indicate that "male lumpectomy"--in which the prostate tumor region itself is destroyed--preserves potency in most patients and limits other complications (particularly incontinence) without compromising cancer control. Additional studies and long-term follow-up are needed to confirm that this treatment approach could have a profound effect on prostate cancer management.

A temporary intraurethral prostatic stent relieves prostatic obstruction following transurethral microwave thermotherapy.

PURPOSE: The Spanner, a novel prostatic stent, was evaluated for safety, efficacy and patient tolerance when used to relieve prostatic obstruction following transurethral microwave thermotherapy. MATERIALS AND METHODS: Following transurethral microwave thermotherapy and routine post-procedure Foley catheterization at 1 of 9 clinical sites 186 patients meeting study criteria were randomized to receive a Spanner (100) or the standard of care (86). Baseline evaluations included post-void residual urine, uroflowmetry, International Prostate Symptom Score and International Prostate Symptom Score quality of life question. These evaluations were repeated at visits 1, 2, 4, 5 and 8 weeks after randomization (Spanner insertion) with the addition of the Spanner satisfaction questionnaire, ease of use assessment and adverse events recording. The Spanner was removed after 4 weeks, at which time the Spanner and standard of care groups underwent cystourethroscopy. RESULTS: At the 1 and 2-week visits the Spanner group showed significantly greater improvements from baseline in post-void residual urine, uroflowmetry and International Prostate Symptom Score compared to the standard of care group. The Spanner group experienced significantly greater improvements in quality of life at the 5 and 8-week visits. Patient satisfaction with the Spanner exceeded 86%. Cystourethroscopy findings in the Spanner and standard of care groups were comparable and adverse events associated with previous stents were rare. CONCLUSIONS: The Spanner is a safe, effective and well tolerated temporary stent for severe prostatic obstruction resulting from therapy induced edema after transurethral microwave thermotherapy. It may be a needed addition to the armamentarium for managing bladder outlet obstruction in a broad group of urological patients.

Focal "nerve-sparing" cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency.

OBJECTIVES: To present a pilot study in which 9 patients treated with focal, unilateral nerve-sparing cryosurgery were followed for up to 6 years. Cryosurgery, in which the whole gland is frozen, has a high rate of impotence, similar to non-nerve-sparing radical prostatectomy. METHODS: Before focal nerve-sparing cryosurgery, all patients underwent repeated biopsy on the side opposite the previous positive biopsy. One neurovascular bundle was spared on the side opposite the positive biopsy. Just before the start of freezing, a 22-gauge spinal needle was placed into Denonvilliers fascia using a transperineal route, and saline was injected to separate the rectum from the prostate. Combined hormone therapy was stopped in all patients postoperatively. The prostate-specific antigen (PSA) level was obtained every 3 months for the first 2 years and then every 6 months thereafter. Patients were considered to have a stable PSA if they had two consecutive PSA measurements without a rise. All patients were strongly encouraged to undergo routine biopsies despite a stable PSA level. RESULTS: Between June 1995 and November 2000, 9 patients underwent focal, nerve-sparing cryosurgery. The follow-up ranged from 6 to 72 months (mean 36). All patients had stable PSA levels at last follow-up. Six patients routinely biopsied had negative biopsies. Potency (defined as an erection sufficient to complete intercourse to the satisfaction of the patient) was maintained in 7 of 9 patients. CONCLUSIONS: Focal nerve-sparing cryosurgery, in which one neurovascular bundle is spared, appears to preserve potency in most patients without compromising cancer control. These preliminary results warrant further study.

An eight-month clinical study of LA-2575 30.0 mg: a new 4-month, subcutaneous delivery system for leuprolide acetate in the treatment of prostate cancer.

OBJECTIVES: To investigate the safety, efficacy, and pharmacokinetics of a new 4-month subcutaneous depot of leuprolide acetate in patients with prostate cancer. METHODS: Ninety patients diagnosed with adenocarcinoma of the prostate were enrolled in an open-label, multicenter study. LA-2575 30.0 mg was administered subcutaneously once every 4 months for 8 months. The primary efficacy parameter was a serum testosterone level of 50 ng/dL or less. The pharmacokinetics of leuprolide acetate were analyzed in the first 24 enrolled patients. The values are reported as the mean +/- standard error. RESULTS: Of 90 enrolled patients, 82 (91%) completed the 8-month study. Eight patients voluntarily withdrew from the study for the following reasons: nonmedical reasons (n = 3), treatment-related adverse events (n = 3), disease progression (n = 1), and cardiovascular disease (n = 1). By day 28, 85 (94%) of the 90 patients had achieved a serum testosterone level less than 50 ng/dL. At study completion, 88 (98%) of the 90 patients had a testosterone value less than the castrate level (mean 12.4 +/- 0.8 ng/dL), with 81 (90%) at less than 20 ng/dL. From baseline to month 6, the mean luteinizing hormone level had decreased from 7.51 +/- 0.69 mIU/mL to 0.12 +/- 0.02 mIU/mL. The mean prostate-specific antigen level had decreased 90% from 13.2 +/- 2.0 ng/mL at baseline to 1.3 +/- 0.3 ng/mL at 8 months. No clinically significant flare reactions were observed. The most common treatment-related adverse event was mild hot flashes. CONCLUSIONS: LA-2575 30.0-mg depot consistently produced and maintained safe and effective suppression of serum testosterone, with total serum testosterone concentrations well below the medical castrate level of less than 50 ng/dL.

A clinical study of 22.5 mg. La-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer.

PURPOSE: The safety, efficacy and pharmacokinetics of a unique 3-month subcutaneous depot of leuprolide acetate were investigated in patients with prostate cancer. MATERIALS AND METHODS: This open label, noncomparative, 6-month multicenter study enrolled 117 patients diagnosed with adenocarcinoma of the prostate. LA-2550 (22.5 mg. depot) (Atrix Laboratories, Fort Collins, Colorado) was administered subcutaneously once every 3 months. The primary efficacy parameter was serum testosterone 50 ng./dl. or less. Pharmacokinetics were analyzed in a subset of 22 patients. RESULTS: Of the 117 enrolled patients 111 (98%) completed the 6-month study. Five patients withdrew for nontreatment related events and 1 was withdrawn because he received less than a full dose of the study drug. By day 28, 98% of patients had serum testosterone 50 ng./dl. or less and 84% had achieved 20 ng./dl. or less. By day 35 all patients had 50 ng./dl. or less testosterone. A patient with a breakthrough response after testosterone suppression on day 49 (112 ng./dl.) regained suppression (27 ng./dl.) 14 days after the second injection (day 98). At study completion all patients had 50 ng./dl. or less testosterone (mean plus or minus standard error of mean 10.1 +/- 0.07) and 104 of the 111 (94%) had 20 ng./dl. or less. From baseline to month 6 mean luteinizing hormone decreased from 9.2 +/- 1.1 to 0.08 +/- 0.01 mIU/ml. and mean prostate specific antigen decreased more than 98%. No flare reactions were observed and patient assessments of bone pain and urinary symptoms were unchanged. The most common treatment related adverse event was hot flashes, which were mild in 57% of cases, moderate in 12% and severe in 0%. CONCLUSIONS: LA-2550 (22.5 mg. depot) produced and maintained safe and effective suppression of serum testosterone to well below the medical castrate level of 50 ng./dl. or less.

2003 American Urological Association Gallup survey: physician practice patterns, cryosurgery/brachytherapy, male infertility, female urology and insurance/professional liability.

PURPOSE: The Health Policy Survey and Research Committee of the American Urological Association and the Gallup Organization have performed 10 surveys of American urologists since 1992 for the purpose of assessing demographics and practice patterns. The results of the 2003 survey are presented. MATERIALS AND METHODS: A random sample of 510 urologists who have completed urological residencies was interviewed by telephone in February 2003. Major content areas were physician practice patterns, cryosurgery/brachytherapy, male infertility, female urology and insurance/ professional liability. RESULTS: Urologists are older, staying in practice longer and planning to retire later than ever before. Urologists are also seeing more patients in the office every year. Most urologists treat male infertility and female voiding dysfunction. CONCLUSIONS: American urologists are older, working harder and planning on continuing to do so for longer than in any year sampled in the last decade.

2001 American Urological Association Gallup Survey: changes in physician practice patterns, satisfaction with urology, and treatment of prostate cancer and erectile dysfunction.

PURPOSE: The Health Policy Survey and Research Committee of the American Urological Association and the Gallup organization have performed 9 surveys of American urologists since 1992 for the purpose of assessing demographics and practice patterns. The results of the 2001 survey are presented. MATERIALS AND METHODS: A random sample of 507 urologists was interviewed in February and March 2001. Major content areas were physician practice patterns, cryosurgery/brachytherapy, prostate specific antigen, erectile dysfunction, Medicare and the Internet. RESULTS: Membership in the American Urological Association continues to increase among American urologists. The number of patients seen weekly in the office also continues to increase. While age at retirement has not changed significantly, most urologists are satisfied with the specialty and increasing numbers are using the Internet. CONCLUSIONS: Minimally invasive procedures such as brachytherapy for prostate cancer continue to proliferate and there is evidence that the specialty of urology is continuing to become more office based. The demand for urological services appears to be continuing to increase.