Focal high-intensity focused ultrasound therapy for localized prostate cancer: An interim analysis of the multinational FASST study.

BACKGROUND: High-intensity focused ultrasound (HIFU) emerged as a novel approach for the treatment of localized prostate cancer (PCa). However, prospective studies on HIFU-related outcomes and predictors of treatment failure (TF) remain scarce. MATERIALS AND METHODS: We conducted a multinational prospective cohort study among patients undergoing HIFU therapy for localized, low- to intermediate-risk PCa. Follow-up data on serial prostate specific antigen (PSA), multi-parametric magnetic resonance imaging (mpMRI), targeted/systematic biopsies, adverse events and functional outcomes were collected. The primary endpoint was TF, defined as histologically confirmed PCa requiring whole-gland salvage treatment. Uni- and multi-variable adjusted hazard ratios (HRs) were calculated using Cox proportional hazard regression models. RESULTS: At baseline, mean (standard deviation) age was 64.14 (7.19) years, with the majority of patients showing T-stage 1 (73.9%) and International Society of Urological Pathology grading system Grade 2 (58.8%). PSA nadir (median, 1.70 ng/mL) was reached after 6 months. Of all patients recruited, 16% had clinically significant PCa, as confirmed by biopsy, of which 13.4% had TF. Notably, T-stage and number of positive cores at initial biopsy were independent predictors of TF during follow-up (HR [95% CI] 1.27 [1.02-1.59] and 5.02 [1.80-14.03], respectively). Adverse events were minimal (17% and 8% early and late adverse events, respectively), with stable or improved functional outcomes in the majority of patients. CONCLUSIONS: This interim analysis of a multinational study on HIFU therapy for the management of low-to-intermediate-risk PCa reveals good functional outcomes, minimal adverse events and low incidence of TF over the short-term. Data on long-term outcomes, specifically as it relates to oncological outcomes, are awaited eagerly.

Clinical parameters for the prediction of occult lymph node metastasis in patients with negative PSMA-PET.

BACKGROUND: Depending on the risk of LN metastasis ePLND at RP is recommended. As ePLND has potential side effects, and diagnostics have improved substantially, our objective was to evaluate the performance of the Briganti 2019 nomogram in a contemporary cohort with preoperative negative PSMA-PET. METHODS: Patients with intermediate- and high-risk prostate cancer (CaP), undergoing RP and ePND at our center with preoperative negative [68Ga]Ga-PSMA-11 PET were included. The Accuracy of the nomogram was assessed using ROC analysis. The association of clinical parameters with the presence of LN metastasis was assessed using logistic regression. Specimen of prostate and LNs in patients with false negative PSMA-PET were additionally stained for AR and PSMA expression and assessed by IHC. RESULTS: The study included 108 patients, 28% intermediate- and 72% high-risk. Twelve patients harbored occult LN metastasis. Accuracy of the nomogram was 0.62. [68Ga]Ga-PSMA-11 PET showed a NPV of 89%. IHC showed expression of PSMA and AR in the primary and LN metastasis in all patients. On logistic regression analysis only DRE (OR 2.72; 95%CI 1.01-7.35; P = 0.05) and percentage of cores with significant CaP (OR 1.29; 95%CI 1.05-1.60; P = 0.02) showed a significant association with LN metastasis. CONCLUSION: The currently used nomogram is suboptimal in detecting patients with occult LNM. While the cut-off value to perform ePLND can be increased slightly following a negative PSMA-PET scan, more accurate methods of identifying these patients are needed. Whether ePLND can have a therapeutic benefit, as opposed to a diagnostic only, needs to be re-evaluated in the PSMA-PET era.

Which Patients with Prostate Cancer and Lymph Node Uptake at Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography Scan Are at a Higher Risk of Prostate-specific Antigen Persistence After Radical Prostatectomy? Identifying Indicators of Systemic Disease by Integrating Clinical, Magnetic Resonance Imaging, and Functional Imaging Parameters.

BACKGROUND: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease. OBJECTIVE: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters. DESIGN, SETTING, AND PARTICIPANTS: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics. RESULTS AND LIMITATIONS: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%). CONCLUSIONS: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront. PATIENT SUMMARY: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

Outcomes of Cytoreductive Radical Prostatectomy for Oligometastatic Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography: Results of a Multicenter European Study.

BACKGROUND: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. OBJECTIVE: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. DESIGN, SETTING, AND PARTICIPANTS: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. INTERVENTION: Cytoreductive radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. RESULTS AND LIMITATIONS: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up. CONCLUSIONS: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. PATIENT SUMMARY: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.

Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool.

BACKGROUND: Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases. OBJECTIVE: To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting. DESIGN, SETTING, AND PARTICIPANTS: Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools. RESULTS AND LIMITATIONS: Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation. CONCLUSIONS: Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population. PATIENT SUMMARY: Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

Dual-Tracer PET-MRI-Derived Imaging Biomarkers for Prediction of Clinically Significant Prostate Cancer.

PURPOSE: To investigate if imaging biomarkers derived from 3-Tesla dual-tracer [(18)F]fluoromethylcholine (FMC) and [68Ga]Ga-PSMAHBED-CC conjugate 11 (PSMA)-positron emission tomography can adequately predict clinically significant prostate cancer (csPC). METHODS: We assessed 77 biopsy-proven PC patients who underwent 3T dual-tracer PET/mpMRI followed by radical prostatectomy (RP) between 2014 and 2017. We performed a retrospective lesion-based analysis of all cancer foci and compared it to whole-mount histopathology of the RP specimen. The primary aim was to investigate the pretherapeutic role of the imaging biomarkers FMC- and PSMA-maximum standardized uptake values (SUVmax) for the prediction of csPC and to compare it to the mpMRI-methods and PI-RADS score. RESULTS: Overall, we identified 104 cancer foci, 69 were clinically significant (66.3%) and 35 were clinically insignificant (33.7%). We found that the combined FMC+PSMA SUVmax were the only significant parameters (p < 0.001 and p = 0.049) for the prediction of csPC. ROC analysis showed an AUC for the prediction of csPC of 0.695 for PI-RADS scoring (95% CI 0.591 to 0.786), 0.792 for FMC SUVmax (95% CI 0.696 to 0.869), 0.852 for FMC+PSMA SUVmax (95% CI 0.764 to 0.917), and 0.852 for the multivariable CHAID model (95% CI 0.763 to 0.916). Comparing the AUCs, we found that FMC+PSMA SUVmax and the multivariable model were significantly more accurate for the prediction of csPC compared to PI-RADS scoring (p = 0.0123, p = 0.0253, respectively). CONCLUSIONS: Combined FMC+PSMA SUVmax seems to be a reliable parameter for the prediction of csPC and might overcome the limitations of PI-RADS scoring. Further prospective studies are necessary to confirm these promising preliminary results.

Accuracy of SelectMDx compared to mpMRI in the diagnosis of prostate cancer: a systematic review and diagnostic meta-analysis.

BACKGROUND: The SelectMDx test is a promising biomarker that is developed based on detecting urinary messenger RNA in combination with clinical prostate cancer (PCa) risk factors. We aimed to compare SelectMDx and mpMRI as a diagnostic test in detecting PCa and high grade(HG)-PCa in men suspected to have PCa. METHODS: According to PRISMA, a systematic search was performed using major web databases for studies published before September 30, 2021. Studies that compared sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of SelectMDx and/or mpMRI were included. The bivariate random model that plotted sensitivity, specificity, PPV, NPV, and likelihood ratio (LR) for PCa and HG-PCa detection was applied to compare SelectMDx, mpMRI, and combination strategies (both positive and one or both positive). RESULTS: Seven studies comprising 1328 patients who had undergone SelectMDx and mpMRI to detect PCa were included. Regarding PCa detection, SelectMDx had a pooled sensitivity of 81%, specificity of 69.8%, PPV of 64.7%, NPV of 85%, and LRs of +2.68 to -0.27, while mpMRI had a pooled sensitivity of 80.8%, specificity of 73.4%, PPV of 72.4%, NPV of 83.5%, and LRs of +3.03 to -0.26. The one or both positive strategy had the highest sensitivity (96.3%), NPV (95.7%), and the lowest -LR (0.06). While the both positive strategy had the highest specificity (80.9%), the PPV (76.5%) and +LR (3.68). In the scenario of PI-RADS 3 lesions not being biopsied in case of a negative SelectMDx (n = 44), unnecessary biopsies would be reduced by 42% (44/105) while the risk of missing HG-PCa would be 9% (4/44). CONCLUSION: The performance of SelectMDx is comparable to that of mpMRI with regards to PCa and HG-PCa detection. In addition, this biomarker could help refine the clinical decision-making regarding the necessity of a biopsy in patients suspected to has been PCa.

Evaluation of the Predictive Role of Blood-Based Biomarkers in the Context of Suspicious Prostate MRI in Patients Undergoing Prostate Biopsy.

The aim of this study was to assess the predictive value of pre-biopsy blood-based markers in patients undergoing a fusion biopsy for suspicious prostate magnetic resonance imaging (MRI). We identified 365 consecutive patients who underwent MRI-targeted and systematic prostate biopsy for an MRI scored Prostate Imaging-Reporting and Data System Version (PI-RADS) ≥ 3. We evaluated the neutrophil/lymphocyte ratio (NLR), derived neutrophil/lymphocyte ratio (dNLR), platelet/lymphocyte ratio (PLR), systemic immune inflammation index (SII), lymphocyte/monocyte ratio (LMR,) de Ritis ratio, modified Glasgow Prognostic Score (mGPS), and prognostic nutrition index (PNI). Uni- and multivariable logistic models were used to analyze the association of the biomarkers with biopsy findings. The clinical benefits of biomarkers implemented in clinical decision-making were assessed using decision curve analysis (DCA). In total, 69% and 58% of patients were diagnosed with any prostate cancer and Gleason Grade (GG) ≥ 2, respectively. On multivariable analysis, only high dNLR (odds ratio (OR) 2.61, 95% confidence interval (CI) 1.23-5.56, p = 0.02) and low PNI (OR 0.48, 95% CI 0.26-0.88, p = 0.02) remained independent predictors for GG ≥ 2. The logistic regression models with biomarkers reached AUCs of 0.824-0.849 for GG ≥ 2. The addition of dNLR and PNI did not enhance the net benefit of a standard clinical model. Finally, we created the nomogram that may help guide biopsy avoidance in patients with suspicious MRI. In patients with PI-RADS ≥ 3 lesions undergoing MRI-targeted and systematic biopsy, a high dNLR and low PNI were associated with unfavorable biopsy outcomes. Pre-biopsy blood-based biomarkers did not, however, significantly improve the discriminatory power and failed to add a clinical benefit beyond standard clinical factors.

Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer Progression During Active Surveillance: A Systematic Review and Meta-analysis.

CONTEXT: Although magnetic resonance imaging (MRI) is broadly implemented into active surveillance (AS) protocols, data on the reliability of serial MRI in order to help guide follow-up biopsy are inconclusive. OBJECTIVE: To assess the diagnostic estimates of serial prostate MRI for prostate cancer (PCa) progression during AS. EVIDENCE ACQUISITION: We systematically searched PubMed, Scopus, and Web of Science databases to select studies analyzing the association between changes on serial prostate MRI and PCa progression during AS. We included studies that provided data for MRI progression, which allowed us to calculate diagnostic estimates. We compared Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) accuracy with institution-specific definitions. EVIDENCE SYNTHESIS: We included 15 studies with 2240 patients. Six used PRECISE criteria and nine institution-specific definitions of MRI progression. The pooled PCa progression rate, which included histological progression to Gleason grade ≥2, was 27%. The pooled sensitivity and specificity were 0.59 (95% confidence interval [CI] 0.44-0.73) and 0.75 (95% CI 0.66-0.84) respectively. There was significant heterogeneity between included studies. Depending on PCa progression prevalence, the pooled negative predictive value for serial prostate MRI ranged from 0.81 (95% CI 0.73-0.88) to 0.88 (95% CI 0.83-0.93) and the pooled positive predictive value ranged from 0.37 (95% CI 0.24-0.54) to 0.50 (95% CI 0.36-0.66). There were no significant differences in the pooled sensitivity (p = 0.37) and specificity (p = 0.74) of PRECISE and institution-specific schemes. CONCLUSIONS: Serial MRI still should not be considered a sole factor for excluding PCa progression during AS, and changes on MRI are not accurate enough to indicate PCa progression. There was a nonsignificant trend toward improved diagnostic estimates of PRECISE recommendations. These findings highlight the need to further define the optimal triggers and timing of biopsy during AS, as well as the need for optimizing the quality, interpretation, and reporting of serial prostate MRI. PATIENT SUMMARY: Our study suggests that serial prostate magnetic resonance imaging (MRI) alone in patients on active surveillance is not accurate enough to reliably rule out or rule in prostate cancer progression. Other clinical factors and biomarkers along with serial MRI are required to safely tailor the intensity of follow-up biopsies.

The Prognostic Association of Prostate MRI PI-RADS™ v2 Assessment Category and Risk of Biochemical Recurrence after Definitive Local Therapy for Prostate Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Although the Prostate Imaging-Reporting and Data System™ version 2 (PI-RADS™ v2) is a reliable diagnostic tool for significant prostate cancer, less is known about the prognostic significance of the structured reporting scheme for estimating oncologic outcomes after treatment. We aimed to synthesize the available evidence regarding the association of PI-RADS v2 score and risk of biochemical recurrence (BCR) among patients undergoing primary definitive treatment for prostate cancer. MATERIALS AND METHODS: We systematically queried the PubMed® and Web of Science™ databases to identify studies addressing the association between the PI-RADS v2 and treatment outcomes. We included studies through November 2020 that assessed the independent prognostic significance of PI-RADS v2. After assessing risk of bias and quality, we conducted a formal meta-analysis to estimate the pooled effects of prostate magnetic resonance imaging (MRI) classification on the risk of BCR. RESULTS: We identified 9 and 7 eligible studies including 2,274 and 1,215 patients for the systematic review and meta-analysis, respectively. Eight were conducted in the context of radical prostatectomy and 1 post-radiation. Among patients treated with radical prostatectomy, higher PI-RADS v2 scores were significantly associated with risk of BCR (pooled HR 3.06, 95% CI 2.16-4.33; p <0.01). There was no significant heterogeneity among studies. For all studies, PI-RADS v2 score remained significantly associated with BCR (pooled HR 3.19, 95% CI 2.28-4.45; p <0.01). CONCLUSIONS: Prostate MRI findings assessed with the PI-RADS v2 classification were independently associated with risk of BCR after definitive local therapy, primarily based on data from radical prostatectomy. These findings support the prognostic significance of MRI, in addition to its role in prostate cancer diagnosis.

An up-to-date catalogue of urinary markers for the management of prostate cancer.

PURPOSE OF REVIEW: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Poor specificity and sensitivity of total PSA often results in over and sometimes underdetection/treatment. Therefore, more specific and sensitive biomarkers for the detection and monitoring especially of clinically significant PCa as well as treatment-specific markers are much sought after. In this field, urine has emerged as a promising noninvasive source of biomarkers. RECENT FINDINGS: RNA-based biomarkers are the most extensively studied type of urinary nucleic acids. ERG-Score/MiPS (Mi-Prostate Score) and SelectMDx might be considered as additional parameters together with clinical and imaging modalities to decrease unnecessary biopsies. miR Sentinel Tests could make it possible to accurately detect the presence of cancer and to distinguish low-grade from high-grade disease. In men with previous negative biopsies, PCA3 may suggest the need to repeat biopsy. SUMMARY: The definitive role of these markers and their clinical benefit needs future validation.

The role of taxane-based chemotherapy in the treatment of prostate cancer.

PURPOSE OF REVIEW: Indications for chemotherapy have increased in prostate cancer (PCA), many of which are shared with new hormonal agents (NHA). With no head to head comparison available, defining the optimal sequence and identifying biomarkers to predict response, has been a focus of intense research in PCA. We aim to summarize the best currently available evidence in all stages of disease to help guide therapy. RECENT FINDINGS: In metastatic castration-resistant prostate cancer, Cabazitaxel has shown improved radiographic progression-free survival over another NHA after Docetaxel and one NHA. For hormone sensitive PCA (mHSPC) multiple meta-analyses have shown combination therapy with Docetaxel or an NHA to be superior to androgen deprivation therapy alone, yet no clear benefit over each other. For peri-interventional chemotherapy with local therapy, there is currently only one positive prospective trial, for very high-risk disease. SUMMARY: Cabazitaxel is underutilized and should be used earlier. NHAs should not be used in succession as there is significant cross resistance. Combination therapy should be used in mHSPC, yet there is no clear benefit for any combination. Peri-interventional chemotherapy might have a benefit for a small group of patients with very high-risk disease, yet this must be carefully evaluated, and side effects must be taken into account.