Should systematic prostatic biopsies be discontinued?

INTRODUCTION: The use of systematic biopsies in addition to targeted biopsies is based on multiple studies showing that 15-20% of "clinically significant" cancers are missed on targeted biopsies. Concern about these 'missed' cancers drives many interventions. This includes systematic biopsies in men with negative imaging and in men having targeted biopsies, and drives a preference for total gland treatment in men who may be candidates for partial gland ablation. This article summarizes recent genomic and clinical data indicating that, despite "clinically significant" histology, MRI invisible lesions are genomically and clinically favorable. These studies have demonstrated that the genetic aberrations associated with cancer visibility are the same aberrations that drive cancer invasiveness and metastasis. Thus invisible cancers, even if undiagnosed at baseline, are in most cases indolent and pose little threat to the patient. The implications are that patients should be monitored with imaging rather than systematic biopsy, and subject to repeat targeted biopsy for evidence of MR progression. Patients prefer this strategy. It has many advantages in terms of reduced burden of care, cost, psychological benefits, and less diagnosis of insignificant cancer. CONCLUSION: It is now appropriate to abandon systematic biopsies in most patients.

'Spin' in urology non-randomised studies comparing therapeutic interventions: a temporal analysis.

OBJECTIVE: To determine the prevalence of 'spin' (i.e., reporting practices that distort the interpretation of results by positively reflecting negative findings or downplaying potential harms) strategies and level of spin in urological observational studies and whether the use of spin has changed over time. MATERIALS AND METHODS: MEDLINE and Embase were searched to identify observational studies comparing therapeutic interventions in the top five urology journals and major urological subspecialty journals, published between 2000 and 2001, 2010 and 2011, and 2020 and 2021. RESULTS: A total of 235 studies were included. Spin was identified in 81% of studies, with a median of two strategies per study. The most commonly used strategies were inadequate implication for clinical practice (30%), causal language or causal claim (29%), and use of linguistic spin (29%). Moderate to high levels of spin were found in 55% of conclusions. From 2000 to 2020, the average number of strategies used has significantly decreased each decade (H = 27.459, P < 0.001), and the median level of spin in conclusions was significantly lower in studies published in the 2020s and 2010s than in the 2000s (H = 11.649, P = 0.003). CONCLUSIONS: Our results suggest that 81% of urological observational studies comparing therapeutic interventions contained spin. Over the past two decades, the use of spin has significantly declined, but this remains an area for improvement, with 70% of included studies published in the 2020s employing spin. Medical writing should scrupulously avoid words or phrases that are not supported by data in the manuscript.

Testosterone nadir and clinical outcomes in patients with advanced prostate cancer: Post hoc analysis of triptorelin pamoate Phase III studies.

Objective: The objective of the study is to evaluate whether low nadir testosterone during treatment with triptorelin pamoate, a luteinising hormone-releasing hormone (LHRH) agonist, is associated with improved clinical outcomes in patients with advanced prostate cancer using a retrospective analysis of clinical trial data. Patients and methods: Data were pooled from three prospective, 9-12-month Phase III studies of triptorelin monotherapy in patients with advanced prostate cancer (including NCT00751790). The serum testosterone concentration suppression targets evaluated were <0.35 nmol/L (<10 ng/dl), <0.7 nmol/L (<20 ng/dl), <1.7 nmol/L (<50 ng/dl) and ≥1.7 nmol/L. Overall survival (OS) and disease-specific survival (DSS) by testosterone suppression group were assessed by Kaplan-Meier analysis, with log-rank test. The time frame for the primary analysis was Days 1-518 (median OS follow-up 254 days [range, 29-518 days]) and for the sensitivity analyses was Days 1-262. Supplementary analyses combined the ≥0.7- to <1.7-nmol/L and ≥1.7-nmol/L groups. Results: The sample size comprised 592 patients (most received triptorelin monotherapy; four reported concomitant androgen receptor-axis-targeted therapy). Nadir testosterones of <0.35, ≥0.35 to <0.7, ≥0.7 to <1.7 and ≥1.7 nmol/L were achieved by 96%, 3.2%, 0.34% and 0.17% of patients, respectively. Better OS with decreasing level of nadir testosterone was observed (p < 0.001) and this persisted after sensitivity/supplemental analyses (all p < 0.001). Differences in DSS with decreasing levels of nadir testosterone were not statistically significant in the primary analysis. Sensitivity/supplemental analysis showed better DSS with decreasing level of nadir testosterone (Days 1-262, p = 0.01; combined groups Days 1-518, p = 0.03; combined groups Days 1-262, p = 0.005). Conclusion: Low nadir testosterone achieved during treatment with the LHRH agonist triptorelin was associated with improved OS and DSS in patients with advanced prostate cancer.

Using active surveillance for Gleason 7 (3+4) prostate cancer: A narrative review.

The interest in broadening the application of active surveillance (AS) has been increasing, encompassing patients who may not strictly adhere to the conventional criteria for low-risk prostate cancer (PCa), particularly those diagnosed with small-volume Gleason grade group 2 disease. Nonetheless, accurately identifying individuals with low intermediate-risk PCa who can safely undergo AS without facing disease progression remains a challenge.This review aims to delve into the progression of this evolving trend specifically within this cohort of men, while also examining strategies aimed at minimizing irreversible disease advancement. Additionally, we address the criteria for patient selection, recommended followup schedules, and the indicators prompting intervention.

Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review.

Background: Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists. Objectives: This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists. Methods: Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: "myocardial infarction," "central nervous system hemorrhages and cerebrovascular conditions," and all-cause mortality. Bayesian meta-analysis models with random effects were fitted. Results: A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death. Conclusions: Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.

Magnetic Resonance Imaging-Targeted Versus Systematic Prostate Biopsies: 2-year Follow-up of a Prospective Randomized Trial (PRECISE).

BACKGROUND: The prospective randomized PRECISE trial demonstrated that magnetic resonance imaging (MRI) with only targeted biopsy (TBx) was noninferior to systematic transrectal ultrasound biopsy (SBx) in the detection of International Society of Urological Pathology grade group (GG) ≥2 prostate cancer (PC). An unanswered question is the outcome for patients who avoided a biopsy because of negative MRI findings. OBJECTIVE: To explore the rate of PC diagnosis based on 2-yr MRI for PRECISE participants who had no biopsy and for patients who had a negative result or GG 1 on TBx in comparison to those with a negative result or GG 1 on SBx. DESIGN, SETTING, AND PARTICIPANTS: The PRECISE prospective trial was conducted at five Canadian academic centers. The present analysis was for trial participants who were not diagnosed with clinically significant PC (csPC) at baseline. Of 453 randomized patients, 146 were diagnosed with GG ≥2 at baseline and were excluded. Eligible patients for this study included 83 men from the MRI arm who had negative MRI findings and no biopsy, 120 from the overall cohort who had a negative SBx or TBx, and 72 from the overall cohort who were diagnosed with GG 1 disease. INTERVENTION: MRI at 2 yr in all men in the MRI and SBx arms and TBx for lesions with a Prostate Imaging-Reporting and Data System score of ≥3 or on the basis of clinical suspicion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men diagnosed with GG ≥2 cancer. Secondary outcomes included the MRI outcome and the proportion of men diagnosed with GG 1 PC. RESULTS AND LIMITATIONS: Evaluable 2-yr MRI scans were available for 75 (56%) eligible patients in the MRI arm and 69 (49%) in the SBx arm. Of these patients, 55 (73%) in the MRI arm and 51 (67%) SBx arm had negative 2-yr MRI. Of the 76 patients in the SBx arm with 2-yr MRI, 16 (21%) had a biopsy, for which the result was negative in eight (10%), GG1 in two (2.6%), and GG ≥2 in six (7.9%) cases. Of the 75 men in the MRI arm with 2-yr MRI, eight (11%) were biopsied, for which the result was negative in four cases (5%) and GG ≥2 in the other four (5%). At 2 yr, including baseline biopsy results, 116/221 (52.5%) in the MRI arm and 113/204 (55%) in the SBx arm were free of GG ≥2 disease, treatment, death from any cause, or progression (OR 1.08; p = 0.66). CONCLUSIONS: After 2-yr follow-up including MRI for patients in both arms of PRECISE, there was no difference in the rate of csPC diagnosis between the MRI and SBx groups, even though 38% of men in the MRI group avoided an initial biopsy. PATIENT SUMMARY: The PRECISE trial compared systematic biopsy of the prostate to a strategy of magnetic resonance imaging (MRI) with targeted biopsy of any lesions suspicious for cancer on the scan. After 2 years of follow-up that included 2-year MRI with or without biopsy in both groups, there was no difference in the rate of diagnosis of significant cancer, even though 38% of men in the initial MRI arm avoided an initial biopsy, and 30% avoided biopsy altogether. The PRECISE trial is registered on ClinicalTrials.gov as NCT02936258.

Hospital encounters and associated costs of prostate evaluation for clinically important disease MRI vs. standard evaluation procedures (PRECISE) study from a provincial-payer perspective.

INTRODUCTION: Systematic transrectal ultrasonography (TRUS) biopsy has been the standard diagnostic tool for prostate cancer (PCa) but is subject to limitations, such as a high false-negative rate of cancer detection. Multiparametric magnetic resonance imaging (mpMRI) prior to biopsy is emerging as an alternative diagnostic procedure for PCa. The PRECISE study found that MRI followed by a targeted biopsy was more accurately able to identify clinically significant cancer than TRUS biopsy. METHODS: PRECISE study patients recruited in Ontario between January 2017 and November 2019 were linked to various Ontario provincial administrative databases available at the Institute for Clinical and Evaluative Sciences (ICES ) to determine health resources used, associated costs, and hospitalizations in the 14 days after biopsy. Costs are presented in 2021 CAD. RESULTS: A total of 281 males were included in this study, with 48.4% of the patients in the TRUS biopsy group, 28.1% in the MRI+, and 23.5% in the MRI- group. Twenty-one patients (15%) from the TRUS biopsy group were seen at a hospital in the 14 days after their biopsy compared to fewer than five patients (6%) from the MRI+ group. The mean per person per year (PPPY) costs for the TRUS and all MRI groups (MRI- and MRI+) were $7828 and $8525, respectively. CONCLUSIONS: Patients in the TRUS biopsy group experienced more hospital encounters compared to patients who received an MRI prior to their biopsy. This economic analysis suggests that MRI imaging prior to biopsy is not associated with a significant increase in costs.

Primary Whole-gland Ablation for the Treatment of Clinically Localized Prostate Cancer: A Focal Therapy Society Best Practice Statement.

CONTEXT: Whole-gland ablation is a feasible and effective minimally invasive treatment for localized prostate cancer (PCa). Previous systematic reviews supported evidence for favorable functional outcomes, but oncological outcomes were inconclusive owing to limited follow-up. OBJECTIVE: To evaluate the real-world data on the mid- to long-term oncological and functional outcomes of whole-gland cryoablation and high-intensity focused ultrasound (HIFU) in patients with clinically localized PCa, and to provide expert recommendations and commentary on these findings. EVIDENCE ACQUISITION: We performed a systematic review of PubMed, Embase, and Cochrane Library publications through February 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. As endpoints, baseline clinical characteristics, and oncological and functional outcomes were assessed. To estimate the pooled prevalence of oncological, functional, and toxicity outcomes, and to quantify and explain the heterogeneity, random-effect meta-analyses and meta-regression analyses were performed. EVIDENCE SYNTHESIS: Twenty-nine studies were identified, including 14 on cryoablation and 15 on HIFU with a median follow-up of 72 mo. Most of the studies were retrospective (n = 23), with IDEAL (idea, development, exploration, assessment, and long-term study) stage 2b (n = 20) being most common. Biochemical recurrence-free survival, cancer-specific survival, overall survival, recurrence-free survival, and metastasis-free survival rates at 10 yr were 58%, 96%, 63%, 71-79%, and 84%, respectively. Erectile function was preserved in 37% of cases, and overall pad-free continence was achieved in 96% of cases, with a 1-yr rate of 97.4-98.8%. The rates of stricture, urinary retention, urinary tract infection, rectourethral fistula, and sepsis were observed to be 11%, 9.5%, 8%, 0.7%, and 0.8%, respectively. CONCLUSIONS: The mid- to long-term real-world data, and the safety profiles of cryoablation and HIFU are sound to support and be offered as primary treatment for appropriate patients with localized PCa. When compared with other existing treatment modalities for PCa, these ablative therapies provide nearly equivalent intermediate- to long-term oncological and toxicity outcomes, as well as excellent pad-free continence rates in the primary setting. This real-world clinical evidence provides long-term oncological and functional outcomes that enhance shared decision-making when balancing risks and expected outcomes that reflect patient preferences and values. PATIENT SUMMARY: Cryoablation and high-intensity focused ultrasound are minimally invasive treatments available to selectively treat localized prostate cancer, considering their nearly comparable intermediate- to long term cancer control and preservation of urinary continence to other radical treatments in the primary setting. However, a well-informed decision should be made based on one's values and preferences.

The Burden of Uncontrolled Cardiovascular Risk Factors in Men With Prostate Cancer: A RADICAL-PC Analysis.

Background: Cardiovascular disease (CVD) incidence is higher in men with prostate cancer (PC) than without. Objectives: We describe the rate and correlates of poor cardiovascular risk factor control among men with PC. Methods: We prospectively characterized 2,811 consecutive men (mean age 68 ± 8 years) with PC from 24 sites in Canada, Israel, Brazil, and Australia. We defined poor overall risk factor control as ≥3 of the following: suboptimal low-density lipoprotein cholesterol (>2 mmol/L if Framingham Risk Score [FRS] ≥15 and ≥3.5 mmol/L if FRS <15), current smoker, physical inactivity (<600 MET min/wk), suboptimal blood pressure (BP) (≥140/90 mm Hg if no other risk factors, systolic BP ≥120 mm Hg if known CVD or FRS ≥15, and ≥130/80 mm Hg if diabetic), and waist:hip ratio >0.9. Results: Among participants (9% with metastatic PC and 23% with pre-existing CVD), 99% had ≥1 uncontrolled cardiovascular risk factor, and 51% had poor overall risk factor control. Not taking a statin (odds ratio [OR]: 2.55; 95% CI: 2.00-3.26), physical frailty (OR: 2.37; 95% CI: 1.51-3.71), need for BP drugs (OR: 2.36; 95% CI: 1.84-3.03), and age (OR per 10-year increase: 1.34; 95% CI: 1.14-1.59) were associated with poor overall risk factor control after adjustment for education, PC characteristics, androgen deprivation therapy, depression, and Eastern Cooperative Oncology Group functional status. Conclusions: Poor control of modifiable cardiovascular risk factors is common in men with PC, highlighting the large gap in care and the need for improved interventions to optimize cardiovascular risk management in this population.

Assessing "Spin" in Urology Randomized Controlled Trials With Statistically Nonsignificant Primary Outcomes.

PURPOSE: "Spin" refers to a form of language manipulation that positively reflects negative findings or downplays potential harms. Spin has been reported in randomized controlled trials of other surgical specialties, which can lead to the recommendation of subpar or ineffective treatments. The goal of this study was to characterize spin strategies and severity in statistically nonsignificant urology randomized controlled trials. MATERIALS AND METHODS: A comprehensive search of MEDLINE and Embase for the top 5 urology journals, major urology subspecialty journals, and high-impact nonurology journals from 2019 to 2021 was conducted. Statistically nonsignificant randomized controlled trials with a defined primary outcome were included. Screening, data extraction, and spin assessment were performed in duplicate by 2 independent reviewers. RESULTS: From the database search of 4,339 studies, 46 trials were included for analysis. Spin was identified in 35 studies (76%), with the majority of abstracts (n = 26, 57%) and main texts (n = 35, 76%) containing some level of spin. "Obscuring the statistical nonsignificance of the primary outcome and focusing on statistically significant secondary results" was the most frequently used strategy in abstracts, while "other" strategies not previously defined were the most commonly used strategies in main texts. Moderate or high spin severity was identified in 21 (46%) abstract and 22 (48%) main text conclusions. CONCLUSIONS: Overall, our results suggest that 76% of statistically nonsignificant urology randomized controlled trials contained some level of spin. Readers and writers should be aware of common spin strategies when interpreting nonsignificant results and critically appraise the significance of results when making decisions for clinical practice.

Focal Therapy for Prostate Cancer: Evolutionary Parallels to Breast Cancer Treatment.

PURPOSE: Our goal was to review the history of the adoption of focal therapy for breast and prostate cancer and review common barriers to implementation. MATERIALS AND METHODS: A narrative review of the literature was performed of English-language MEDLINE indexed articles of breast-conservation therapy and prostate cancer focal therapy. RESULTS: The introduction of focal therapy in breast cancer began with pioneering case series, and multiple randomized trials were performed prior to widespread adoption. Focal therapy for prostate cancer has just started the process of clinical trials with a single published randomized controlled trial. Commonly cited barriers to the adoption of prostate focal therapy include historical views of Halstedian tumor biology, tumor multifocality, over-detection, limitations in prostate imaging, and trial design end points. CONCLUSIONS: The adoption of breast-conserving therapy evolved over decades and used data from multiple large, randomized, clinical trials. Barriers to the adoption of prostate cancer local therapy are similar to those faced by breast cancer clinical trials. Completion of well-designed trials in prostate cancer focal therapy is essential for its evidence-based adoption.

Statin Use and Survival Among Men Receiving Androgen-Ablative Therapies for Advanced Prostate Cancer: A Systematic Review and Meta-analysis.

Importance: Epidemiological evidence supports a role for statins in improving survival in advanced prostate cancer, particularly among men receiving androgen-ablative therapies. Objective: To study the association between statin use and survival among men with prostate cancer receiving androgen deprivation therapy (ADT) or androgen receptor axis-targeted therapies (ARATs). Data Sources: This systemic review and meta-analysis used sources from MEDLINE, EMBASE, Epub Ahead of Print, Cochrane Clinical Trials, Cochrane Systematic Reviews, and Web of Science from inception to September 6, 2022. Study Selection: Observational studies reporting associations of concurrent statin use and survival outcomes (in hazard ratios [HRs]). Data Extraction and Synthesis: Two authors independently abstracted all data. Summary estimates pooled multivariable HRs with 95% CIs using the generic inverse variance method with random-effects modeling. A priori specified subgroup and sensitivity analyses were undertaken, and heterogeneity, study quality, and publication bias were evaluated. Confidence in the evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Main Outcomes and Measures: Overall mortality and prostate cancer-specific mortality (PCSM). Results: Twenty-five cohorts of 119 878 men (65 488 statin users [55%]) with more than 74 416 deaths were included. Concurrent statin use was associated with a 27% reduction in the risk of overall mortality (HR, 0.73 [95% CI, 0.66-0.82]; I2 = 83%) and a 35% reduction in the risk of PCSM (HR, 0.65 [95% CI, 0.58-0.73]; I2 = 74%), with substantial heterogeneity in both estimates. Subgroup analyses identified a PCSM advantage associated with statins for men receiving ARATs compared with ADT alone (HR, 0.40 [95% CI, 0.30-0.55] vs 0.68 [95% CI, 0.60-0.76]; P = .002 for difference). Confidence in the evidence was rated low for both outcomes. Conclusions and Relevance: The findings of this meta-analysis show that concurrent statin use was associated with reduced overall mortality and PCSM among men receiving androgen-ablative therapies for advanced prostate cancer. These findings are limited by the observational nature of the data and residual unexplained interstudy heterogeneity. Randomized clinical trials are warranted to validate these results.

Active Surveillance for Men Younger than 60 Years or with Intermediate-risk Localized Prostate Cancer. Descriptive Analyses of Clinical Practice in the Movember GAP3 Initiative.

Background: Active surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease. Objective: To assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease. Design setting and participants: We analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide). Outcome measurements and statistical analysis: Cumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice. Results and limitations: The probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048). Conclusions: Our descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management. Patient summary: Data from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.