The Impact of Positron Emission Tomography Imaging and Tumor Molecular Profiling on Risk Stratification, Treatment Choice, and Oncological Outcomes of Patients with Primary or Relapsed Prostate Cancer: An International Collaborative Review of the Existing Literature.

CONTEXT: The clinical introduction of next-generation imaging methods and molecular biomarkers ("radiogenomics") has revolutionized the field of prostate cancer (PCa). While the clinical validity of these tests has thoroughly been vetted, their clinical utility remains a matter of investigation. OBJECTIVE: To systematically review the evidence to date on the impact of positron emission tomography (PET) imaging and tissue-based prognostic biomarkers, including Decipher, Prolaris, and Oncotype Dx, on the risk stratification, treatment choice, and oncological outcomes of men with newly diagnosed PCa or those with biochemical failure (BCF). EVIDENCE ACQUISITION: We performed a quantitative systematic review of the literature using the MEDLINE, EMBASE, and Web of Science databases (2010-2022) following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. The validated Quality Assessment of Diagnostic Accuracy Studies 2 scoring system was used to assess the risk of bias. EVIDENCE SYNTHESIS: A total of 148 studies (130 on PET and 18 on biomarkers) were included. In the primary PCa setting, prostate-specific membrane antigen (PSMA) PET imaging was not useful in improving T staging, moderately useful in improving N staging, but consistently useful in improving M staging in patients with National Comprehensive Cancer Network (NCCN) unfavorable intermediate- to very-high-risk PCa. Its use led to a management change in 20-30% of patients. However, the effect of these treatment changes on survival outcomes was not clear. Similarly, biomarkers in the pretherapy primary PCa setting increased and decreased the risk, respectively, in 7-30% and 32-36% of NCCN low-risk and 31-65% and 4-15% of NCCN favorable intermediate-risk patients being considered for active surveillance. A change in management was noted in up to 65% of patients, with the change being in line with the molecular risk-based reclassification, but again, the impact of these changes on survival outcomes remained unclear. Notably, in the postsurgical primary PCa setting, biomarker-guided adjuvant radiation therapy (RT) was associated with improved oncological control: Δ↓ 2-yr BCF by 22% (level 2b). In the BCF setting, the data were more mature. PSMA PET was consistently useful in improving disease localization-Δ↑ detection for T, N, and M staging was 13-32%, 19-58%, and 9-29%, respectively. Between 29% and 73% of patients had a change in management. Most importantly, these management changes were associated with improved survival outcomes in three trials: Δ↑ 4-yr disease-free survival by 24.3%, Δ↑ 6-mo metastasis-free survival (MFS) by 46.7%, and Δ↑ androgen deprivation therapy-free survival by 8 mo in patients who received PET-concordant RT (level 1b-2b). Biomarker testing in these patients also appeared to be helpful in risk stratifying and guiding the use of early salvage RT (sRT) and concomitant hormonal therapy. Patients with high-genomic-risk scores benefitted from treatment intensification: Δ↑ 8-yr MFS by 20% with the use of early sRT and Δ↑ 12-yr MFS by 11.2% with the use of hormonal therapy alongside early sRT, while low-genomic-risk score patients did equally well with initial conservative management (level 3). CONCLUSIONS: Both PSMA PET imaging and tumor molecular profiling provide actionable information in the management of men with primary PCa and those with BCF. Emerging data suggest that radiogenomics-guided treatments translate into direct survival benefits for patients, however, additional prospective data are awaited. PATIENT SUMMARY: In this review, we evaluated the utility of prostate-specific membrane antigen positron emission tomography and tumor molecular profiling in guiding the care of men with prostate cancer (PCa). We found that these tests augmented risk stratification, altered management, and improved cancer control in men with a new diagnosis of PCa or for those experiencing a relapse.

The Prognostic Role of Preoperative PSMA PET/CT in cN0M0 pN+ Prostate Cancer: A Multicenter Study.

CONTEXT: Despite negative preoperative conventional imaging, up to 10% of patients with prostate cancer (PCa) harbor lymph-node involvement (LNI) at radical prostatectomy (RP). The advent of more accurate imaging modalities such as PET/CT improved the detection of LNI. However, their clinical impact and prognostic value are still unclear. We aimed to investigate the prognostic value of preoperative PET/CT in patients node positive (pN+) at RP. EVIDENCE SYNTHESIS: We retrospectively identified cN0M0 patients at conventional imaging (CT and/or MRI, and bone scan) who had pN+ PCa at RP at 17 referral centers. Patients with cN+ at PSMA/Choline PET/CT but cN0M0 at conventional imaging were also included. Systemic progression/recurrence was the primary outcome; Cox proportional hazards models were used for multivariate analysis. EVIDENCE ACQUISITION: We included 1163 pN+ men out of whom 95 and 100 had preoperative PSMA and/or Choline PET/CT, respectively. ISUP grade ≥4 was detected in 66.6%. Overall, 42% of patients had postoperative PSA persistence (≥0.1 ng/mL). Postoperative management included initial observation (34%), ADT (22.7%) and adjuvant RT+/-ADT (42.8%). Median follow-up was 42 months. Patients with cN+ on PSMA PET/CT had an increased risk of systemic progression (52.9% vs. 13.6% cN0 PSMA PET/CT vs. 21.5% cN0 at conventional imaging; P < .01). This held true at multivariable analysis: (HR 6.184, 95% CI: 3.386-11-295; P < .001) whilst no significant results were highlighted for Choline PET/CT. No significant associations for both PET types were found for local progression, BCR, and overall mortality (all P > .05). Observation as an initial management strategy instead of adjuvant treatments was related with an increased risk of metastases (HR 1.808; 95% CI: 1.069-3.058; P < .05). CONCLUSIONS: PSMA PET/CT cN+ patients with negative conventional imaging have an increased risk of systemic progression after RP compared to their counterparts with cN0M0 disease both at conventional and/or molecular imaging.

Focal therapy for prostate cancer: what is really needed to move from investigational to valid therapeutic alternative?-a narrative review.

Background and Objective: The most widely accepted therapeutic alternatives for men with intermediate risk prostate cancer (PCa) are mainly represented by whole gland therapies such as surgery or radiotherapy. However, these treatments can carry in some cases profound functional side effects. With the improvement of risk assessment tools and imaging modalities, in particular with the introduction of multiparametric magnetic resonance imaging of the prostate, a fine topographic characterisation of PCa lesions within the prostatic gland is now possible. This has allowed the development of gland-sparing therapies such as focal therapy (FT) as a means to provide an even more tailored approach in order to safely reduce, where feasible, the harms carried by whole gland therapies. Unfortunately, adoption of FT has been considered so far investigational due to some unsolved issues that currently hamper the use of FT as a valid alternative. Here, we aim to identify the main aspects needed to move FT forward from investigational to a valid therapeutic alternative for clinically localized PCa. Methods: The literature discussing the evolution of focal therapy in the years and its current landscape was broadly searched to identify the factors hindering FT adoption and possible solutions. Key Content and Findings: There are three broad areas hindering FT as a valid therapeutic alternative: (I) Correct patient selection; (II) harmonising the different FT technologies; (III) the lack of oncological outcomes. Conclusions: By targeting the three aforementioned weaknesses of FT, greater adoption is expected, finally making FT a valid therapeutic alternative, potentially reshaping prostate cancer treatment and functional outcomes.

Rates of metastatic prostate cancer in newly diagnosed patients: Numbers needed to image according to risk level.

BACKGROUND: The numbers needed to image to identify pelvic lymph node and/or distant metastases in newly diagnosed prostate cancer (PCa) patients according to risk level are unknown. METHODS: Relying on Surveillance, Epidemiology, and End Results (2010-2016), we tabulated rates and proportions of patients with (a) lymph node or (b) distant metastases according to National Comprehensive Cancer Network (NCCN) risk level and calculated the number needed to image (NNI) for both endpoints. Multivariable logistic regression analyses were performed. RESULTS: Of 145,939 newly diagnosed PCa patients assessable for analyses of pelvic lymph node metastases (cN1), 4559 (3.1%) harbored cN1 stage: 13 (0.02%), 18 (0.08%), 63 (0.3%), 512 (2.8%), and 3954 (14.9%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk levels. These resulted in NNI of 4619, 1182, 319, 35, and 7, respectively. Of 181,109 newly diagnosed PCa patients assessable for analyses of distant metastases (M1a-c ), 8920 (4.9%) harbored M1a-c stage: 50 (0.07%), 45 (0.1%), 161 (0.5%), 1290 (5.1%), and 7374 (22.0%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk. These resulted in NNI of 1347, 602, 174, 20, and 5, respectively. CONCLUSIONS: Our observations perfectly validated the NCCN recommendations for imaging in newly diagnosed high and very high-risk PCa patients. However, in unfavorable intermediate-risk PCa patients, in whom bone and soft tissue imaging is recommended, the NNI might be somewhat elevated to support routine imaging in clinical practice.

Carboplatin-based adjuvant chemotherapy versus observation after radical cystectomy in patients with pN1-3 urothelial bladder cancer.

PURPOSE: To test the impact of carboplatin-based ACT on overall survival (OS) in patients with pN1-3 cM0 BCa. METHODS: A retrospective analysis was conducted on 1057 patients with pTany pN1-3 cM0 urothelial BCa treated with or without carboplatin-based ACT after radical cystectomy and bilateral lymph-node dissection between 2002 and 2018 at 12 European and North-American hospitals. No patient received neoadjuvant chemotherapy or radiation therapy. Only patients with negative surgical margins at surgery were included. A 3:1 propensity score matching (PSM) was performed using logistic regression to adjust for baseline characteristics. Univariable and multivariable Cox regression analyses were used to predict the effect of carboplatin-based ACT on OS. The Kaplan-Meier method was used to display OS in the matched cohort. RESULTS: Of the 1057 patients included in the study, 69 (6.5%) received carboplatin-based ACT. After PSM, 244 total patients were identified in two cohorts that did not differ for baseline characteristics. Death was recorded in 114 (46.7%) patients over a median follow-up of 19 months. In the multivariable Cox regression analyses, increasing age at surgery (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.06, p < 0.001) and increasing number of positive lymph nodes (HR 1.06, 95% CI 1.01-1.07, p = 0.02) were independent predictors of worse OS. The delivery of carboplatin-based ACT was not predictive of improved OS (HR 0.67, 95% CI 0.43-1.04, p = 0.08). The main limitations of this study are its retrospective design and the relatively low number of patients involved. CONCLUSIONS: Carboplatin-based might not improve OS in patients with pN1-3 cM0 BCa. Our results underline the need for alternative therapies for cisplatin-ineligible patients.

Cancer-specific survival after radical prostatectomy versus external beam radiotherapy in high-risk and very high-risk African American prostate cancer patients.

BACKGROUND: To test for differences in cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs external beam radiotherapy (EBRT) in National Comprehensive Cancer Network (NCCN) high-risk African American patients, as well as Johns Hopkins University (JHU) high-risk and very high-risk patients. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2010-2016), we identified 4165 NCCN high-risk patients, of whom 1944 (46.7%) and 2221 (53.3%) patients qualified for JHU high-risk or very high-risk definitions. Of all 4165 patients, 1390 (33.5%) were treated with RP versus 2775 (66.6%) with EBRT. Cumulative incidence plots and competing risks regression models addressed CSM before and after 1:1 propensity score matching between RP and EBRT NCCN high-risk patients. Subsequently, analyses were repeated separately in JHU high-risk and very high-risk subgroups. Finally, all analyses were repeated after landmark analyses were applied. RESULTS: In the NCCN high-risk cohort, 5-year CSM rates for RP versus EBRT were 2.4 versus 5.2%, yielding a multivariable hazard ratio of 0.50 (95% confidence interval [CI] 0.30-0.84, p = 0.009) favoring RP. In JHU very high-risk patients 5-year CSM rates for RP versus EBRT were 3.7 versus 8.4%, respectively, yielding a multivariable hazard ratio of 0.51 (95% CI: 0.28-0.95, p = 0.03) favoring RP. Conversely, in JHU high-risk patients, no significant CSM difference was recorded between RP vs EBRT (5-year CSM rates: 1.3 vs 1.3%; multivariable hazard ratio: 0.55, 95% CI: 0.16-1.90, p = 0.3). Observations were confirmed in propensity score-matched and landmark analyses adjusted cohorts. CONCLUSIONS: In JHU very high-risk African American patients, RP may hold a CSM advantage over EBRT, but not in JHU high-risk African American patients.

Cancer-specific mortality after radical prostatectomy vs external beam radiotherapy in high-risk Hispanic/Latino prostate cancer patients.

PURPOSE: To test for differences in cancer-specific mortality (CSM) rates in Hispanic/Latino prostate cancer patients according to treatment type, radical prostatectomy (RP) vs external beam radiotherapy (EBRT). METHODS: Within the Surveillance, Epidemiology, and End Results database (2010-2016), we identified 2290 NCCN (National Comprehensive Cancer Network) high-risk (HR) Hispanic/Latino prostate cancer patients. Of those, 893 (39.0%) were treated with RP vs 1397 (61.0%) with EBRT. First, cumulative incidence plots and competing risks regression models tested for CSM differences after adjustment for other cause mortality (OCM). Second, cumulative incidence plots and competing risks regression models were refitted after 1:1 propensity score matching (according to age, PSA, biopsy Gleason score, cT-stage, cN-stage). RESULTS: In NCCN HR patients, 5-year CSM rates for RP vs EBRT were 2.4 vs 4.7%, yielding a multivariable hazard ratio of 0.37 (95% CI 0.19-0.73, p = 0.004) favoring RP. However, after propensity score matching, the hazard ratio of 0.54 was no longer statistically significant (95% CI 0.21-1.39, p = 0.2). CONCLUSION: Without the use of strictest adjustment for population differences, NCCN high-risk Hispanic/Latino prostate cancer patients appear to benefit more of RP than EBRT. However, after strictest adjustment for baseline patient and tumor characteristics between RP and EBRT cohorts, the apparent CSM benefit of RP is no longer statistically significant. In consequence, in Hispanic/Latino NCCN high-risk patients, either treatment modality results in similar CSM outcome.

Differences in rates of pelvic lymph node dissection in National Comprehensive Cancer Network favorable, unfavorable intermediate- and high-risk prostate cancer across United States SEER registries.

Background: The National Comprehensive Cancer Network (NCCN) guidelines recommend pelvic lymph node dissection (PLND) in NCCN high- and intermediate-risk prostate cancer patients. We tested for PLND nonadherence (no-PLND) rates within the Surveillance Epidemiology and End Results (2010-2015). Materials and methods: We identified all radical prostatectomy patients who fulfilled the NCCN PLND guideline criteria (n = 23,495). Nonadherence rates to PLND were tabulated and further stratified according to NCCN risk subgroups, race/ethnicity, geographic distribution, and year of diagnosis. Results: Overall, the no-PLND rate was 26%; it was 41%, 25%, and 11% in the NCCN intermediate favorable, intermediate unfavorable, and high-risk prostate cancer patients, respectively (p < 0.001). Over time, the no-PLND rates declined in the overall cohort and within each NCCN risk subgroup. Georgia exhibited the highest no-PLND rate (49%), whereas New Jersey exhibited the lowest (15%). Finally, no-PLND race/ethnicity differences were recorded only in the NCCN intermediate unfavorable subgroup, where Asians exhibited the lowest no-PLND rate (20%) versus African Americans (27%) versus Whites (26%) versus Hispanic-Latinos (25%). Conclusions: The lowest no-PLND rates were recorded in the NCCN high-risk patients followed by NCCN intermediate unfavorable and favorable risk in that order. Our findings suggest that unexpectedly elevated differences in no-PLND rates warrant further examination. In all the NCCN risk subgroups, the no-PLND rates decreased over time.

Increasing rates of NCCN high and very high-risk prostate cancer versus number of prostate biopsy cores.

BACKGROUND: Recently, an increase in the rates of high-risk prostate cancer (PCa) was reported. We tested whether the rates of and low, intermediate, high and very high-risk PCa changed over time. We also tested whether the number of prostate biopsy cores contributed to changes rates over time. METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database (2010-2015), annual rates of low, intermediate, high-risk according to traditional National Comprehensive Cancer Network (NCCN) and high versus very high-risk PCa according to Johns Hopkins classification were tabulated without and with adjustment for the number of prostate biopsy cores. RESULTS: In 119,574 eligible prostate cancer patients, the rates of NCCN low, intermediate, and high-risk PCa were, respectively, 29.7%, 47.8%, and 22.5%. Of high-risk patients, 39.6% and 60.4% fulfilled high and very high-risk criteria. Without adjustment for number of prostate biopsy cores, the estimated annual percentage changes (EAPC) for low, intermediate, high and very high-risk were respectively -5.5% (32.4%-24.9%, p < .01), +0.5% (47.6%-48.4%, p = .09), +4.1% (8.2%-9.9%, p < .01), and +8.9% (11.8%-16.9%, p < .01), between 2010 and 2015. After adjustment for number of prostate biopsy cores, differences in rates over time disappeared and ranged from 29.8%-29.7% for low risk, 47.9%-47.9% for intermediate risk, 8.9%-9.0% for high-risk, and 13.6%-13.6% for very high-risk PCa (all p > .05). CONCLUSIONS: The rates of high and very high-risk PCa are strongly associated with the number of prostate biopsy cores, that in turn may be driven by broader use magnetic resonance imaging (MRI).

Prostate-specific Membrane Antigen Imaging in Clinical Guidelines: European Association of Urology, National Comprehensive Cancer Network, and Beyond.

Prostate-specific membrane antigen (PSMA) imaging is characterized by superior accuracy compared to conventional imaging for identification of nodal and distant metastases in prostate cancer. The majority of international clinical guidelines recommend PSMA positron emission tomography/computed tomography for patients experiencing biochemical recurrence, even at low prostate-specific antigen values, to identify candidates for salvage therapies. However, its use in for primary staging is still not recommended.

Comparison of Mexican-American vs Caucasian prostate cancer active surveillance candidates.

BACKGROUND: We compared upgrading and upstaging rates in low risk and favorable intermediate risk prostate cancer (CaP) patients according to racial and/or ethnic group: Mexican-Americans and Caucasians. METHODS: Within Surveillance, Epidemiology and End Results database (2010-2015), we identified low risk and favorable intermediate risk CaP patients according to National Comprehensive Cancer Network guidelines. Descriptives and logistic regression models were used. Furthermore, a subgroup analysis was performed to test the association between Mexican-American vs. Caucasian racial and/or ethnic groups and upgrading either to Gleason-Grade Group (GGG II) or to GGG III, IV or V, in low risk or favorable intermediate risk CaP patients, respectively. RESULTS: We identified 673 (2.6%) Mexican-American and 24,959 (97.4%) Caucasian CaP patients. Of those, 14,789 were low risk (434 [2.9%] Mexican-Americans vs. 14,355 [97.1%] Caucasians) and 10,834 were favorable intermediate risk (239 [2.2%] Mexican-Americans vs. 10,604 [97.8%] Caucasians). In low risk CaP patients, Mexican-American vs. Caucasian racial and/or ethnic group did not result in either upgrading or upstaging differences. However, in favorable intermediate risk CaP patients, upgrading rate was higher in Mexican-Americans than in Caucasians (31.4 vs. 25.5%, OR 1.33, P = 0.044), but no difference was recorded for upstaging. When comparisons focused on upgrading to GGG III, IV or V, higher rate was recorded in Mexican-American relative to Caucasian favorable intermediate risk CaP patients (20.4 vs. 15.4%, OR 1.41, P = 0.034). CONCLUSION: Low risk Mexican-American CaP patients do not differ from low risk Caucasian CaP patients. However, favorable intermediate risk Mexican-American CaP patients exhibit higher rates of upgrading than their Caucasian counterparts. This information should be considered at treatment decision making.

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models.

PURPOSE: In search of novel strategies to improve the outcome of advanced prostate cancer, we considered that prostate cancer cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing prostate cancer preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation. EXPERIMENTAL DESIGN: We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor-positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the antiandrogen bicalutamide. We validated the results in vivo in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide. RESULTS: Iron was toxic for all prostate cancer cells. In particular, VCaP, LNCaP, and TRAMP-C2 were highly iron sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron sensitivity. Bicalutamide-iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells.In vivo, iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide-iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion. CONCLUSIONS: Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits prostate cancer cell proliferation, proposing a novel tool to strengthen antiandrogen treatment efficacy.

Prediction nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for prostate cancer.

OBJECTIVE: The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure. MATERIALS AND METHODS: Seven hundred three (n = 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced-stage PCa before second-line systemic therapies: group 4). First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram's derived cutoff. Decision curve analysis (DCA) was implemented to quantify nomogram's clinical benefit. RESULTS: 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p < 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cutoff value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%. CONCLUSIONS: This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cutoff in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.

Consulting "Dr. Google" for Prostate Cancer Treatment Options: A Contemporary Worldwide Trend Analysis.

BACKGROUND: In the era of digital data, the Internet has become the primary source from which individuals draw healthcare information. OBJECTIVE: The aim of the present study is to determine worldwide public interest in prostate cancer (PCa) treatments, their penetrance and variation, and how they compare over time. DESIGN, SETTING, AND PARTICIPANTS: An analysis of worldwide search-engine trends included electronic Google queries from people who searched PCa treatment options from January 2004 to August 2018, worldwide. Join-point regression was performed. Comparisons of annual relative search volume (ARSV), average annual percentage change (AAPC), and temporal patterns were analysed to assess loss or gain of interest. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Evaluations were made regarding (1) interest in PCa treatments, (2) comparison of people's interest, and (3) impact of the US Preventive Service Task Force (USPSTF) screening recommendation and National Comprehensive Cancer Network (NCCN) guideline endorsements on Internet searching for PCa treatments. RESULTS AND LIMITATIONS: The mean ARSV for "prostatectomy" was 73% in 2004 and decreased thereafter, reaching a nadir of 36% in 2014 (APC: -7.2%; 95% confidence interval [CI] -7.8, -6.7; p < 0.01). Similarly, decreased interest was recorded for radiation therapy (AAPC: -3.2%; p = 0.1), high-intensity focused ultrasound (AAPC: -2.3%; p = 0.1), hormonal therapy (AAPC: -11.6%; p < 0.01), ablation therapy (AAPC: -4.1%; p < 0.01), cryotherapy (AAPC: -9.9%; p < 0.01), and brachytherapy (AAPC: -8.3%; p < 0.01). A steep interest was found in active surveillance (AS) (AAPC: +14.2%; p < 0.01) and focal therapy (AAPC: +27.5%; p < 0.01). When trends were compared before and after NCCN and USPSTF recommendations, a consistent decrease of all the treatment options was found, while interest in focal therapy and AS showed an augmented mean ARSV (+19.6 and +31.6, respectively). CONCLUSIONS: People are increasingly searching the Internet for PCa treatment options. A parallel decrease of interest was found for the nonmonitoring treatments, except for focal therapy, while an important growth of appeal has been recorded for AS. Understanding people inquisitiveness together with their degree of knowledge could be supportive to guiding counselling in the decision-making process and putting effort in certifying patient information. PATIENT SUMMARY: In the era of digital data, patients are increasingly searching the Internet for prostate cancer (PCa) treatment options. To safeguard patients' knowledge, it is mandatory to understand how people seek healthcare information, guaranteeing certified and evidence-based information pertaining to PCa treatments options.

Salvage Lymph Node Dissection for Nodal Recurrent Prostate Cancer: A Systematic Review.

CONTEXT: Identification of early nodal recurrence after primary prostate cancer (PCa) treatment by functional imaging may guide metastasis-directed therapy such as salvage lymph node dissection (SLND). OBJECTIVE: The aim of this systematic review was to assess the oncological role and the safety of SLND in the era of modern imaging in case of exclusive nodal recurrence after primary PCa treatment with curative intent. EVIDENCE ACQUISITION: A systematic literature search in the PubMed and Cochrane databases was performed up to August 2018 according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Overall, 27 SLND series have been selected for synthesis. EVIDENCE SYNTHESIS: Prostate-specific membrane antigen or choline positron emission tomography/computed tomography was the reference detection technique. SLND was performed by open or laparoscopic approach with <10% of grade 3 or more complication rate. Mean follow-up was 29.4 mo. Complete biochemical response after SLND was achieved in 13-79.5%of cases (mean 44.3%). The 2- and 5-yr biochemical progression-free survival rates ranged from 23% to 64% and from 6% to 31%, respectively. Fiver-year overall survival was approximately 84%. Main drawbacks limiting the interpretation of the effectiveness of SLND were the retrospective design of single-center series, heterogeneity between series in terms of adjuvant treatment, endpoints, definitions of progression and study population, as well as the absence of long-term follow-up. CONCLUSIONS: A growing body of accumulated data suggests that SLND is a safe metastasis-directed therapy option in nodal recurrence after primary treatment. However, to date, high level of evidence is still missing to draw any clinically meaningful conclusion about the oncological impact of SLND on long-term endpoints. PATIENT SUMMARY: When imaging identifies exclusive nodal recurrent prostate cancer, surgery directed to the positive lesions is safe and can offer at least a temporary biochemical response. The oncological role assessed by strong clinical endpoints remains uncertain.

Temporal Trend in Incidental Prostate Cancer Detection at Surgery for Benign Prostatic Hyperplasia.

OBJECTIVE: To assess changes in the rate of incidental prostate cancer (PCa) after benign prostatic hyperplasia (BPH) surgery over the last decade. MATERIALS AND METHODS: We identified 1177 patients surgically treated for BPH (open prostatectomy, transurethral resection or holmium laser enucleation [HoLEP] of the prostate) in 2007-2016 at a single European academic center. Local polynomial regression was used to explore changes in the rate of incidental PCa detected after BPH surgery and of preoperative biopsy performed over time. Logistic regression analyses tested the association of incidental PCa diagnosis with year of surgery and preoperative biopsy. RESULTS: Incidental PCa was found in 6.4% (74) of cases, 67 (91%) with Grade group 1 disease. We observed an increased incidence of PCa diagnosis after BPH surgery over time (odds ratio [OR]: 1.12; 95%confidence interval [CI]: 1.02-1.24, P = .02) along with a concomitant decrease in the rate of preoperative prostate biopsies (OR: 0.83; 95%CI: 0.79-0.88, P < .0001). Patients undergoing a preoperative biopsy showed a lower risk of being diagnosed with PCa after surgery (OR: 0.29; 95% CI: 0.12, 0.72 P = .007). Patients treated with HoLEP had a higher chance of incidental PCa detection (OR: 2.28; 95%CI: 1.30-4.00; P = .004), although this may be related to the significantly higher number of HoLEP performed over the last years. CONCLUSION: The increased rate of low-risk PCa detected after BPH surgery in the last decade reflects the clinical practice changes in PCa screening and diagnosis leading to a reduced number of unnecessary biopsies and indolent cancer diagnosis.

Adherence to pelvic lymph node dissection recommendations according to the National Comprehensive Cancer Network pelvic lymph node dissection guideline and the D'Amico lymph node invasion risk stratification.

PURPOSE: To assess adherence rates to pelvic lymph node dissection (PLND) according to National Comprehensive Cancer Network (NCCN) PLND guideline (2% or higher risk) and D'Amico lymph node invasion (LNI) risk stratification (intermediate/high risk) in contemporary North American patients with prostate cancer treated with radical prostatectomy (RP). MATERIAL AND METHODS: We relied on 49,358 patients treated with RP and PLND (2010-2013) in SEER database. Adherence rates were quantified and multivariable (MVA) logistic regression analyses tested for independent predictors. RESULTS: According to NCCN PLND guideline and D'Amico LNI classification, PLND was recommended in 63.3% and 64.9% of patients, respectively. Corresponding adherence rates were 68.8% and 69.1%. Adherence rates improved from 67.3% to 71.6% and from 67.6% to 72.0%, respectively, over time. In MVA, more advanced clinical stage, higher biopsy Gleason score and higher number of positive biopsy cores predicted PLNDs that were performed below NCCN LNI nomogram risk threshold. Conversely, lower clinical stage, lower PSA and lower biopsy Gleason score predicted PLND omission in individuals with risk level above NCCN LNI nomogram risk threshold. MVA results for D'Amico classification were virtually identical. CONCLUSIONS: Adherence to NCCN PLND guideline and D'Amico LNI classification for purpose of PLND is suboptimal in SEER population-based patients treated with RP. However, adherence rates have improved over time. Patients, who did not undergo PLND despite elevated LNI risk, had more favorable PCa characteristics than the average. Conversely, patients, who underwent PLND despite low-risk, had worse PCa characteristics than the average.