Primary Primary Prostate Cancer Research Articles

Improving diagnostic efficacy of primary prostate cancer with combined 99mTc-PSMA SPECT/CT and multiparametric-MRI and quantitative parameters.

This prospective study aimed to evaluate the difference between 99mTc-PSMA single-photon emission computed tomography (SPECT)/CT and multiparametric magnetic resonance imaging (mpMRI) in the detection of primary prostate cancer (PCa). Fifty-six men with suspected PCa between October 2019 and November 2022 were prospectively enrolled in this study. The median age of the patients was 70 years (range, 29-87 years). Patients were divided into high-(Gleason score>7, n=31), medium- (Gleason score=7, n=6) and low-risk groups (Gleason score < 7, n=6). All patients underwent 99mTc-PSMA SPECT/CT and mpMRI at an average interval of 3 days (range, 1-7 days). The maximum standardized uptake value (SUVmax), the minimum apparent diffusion coefficient (ADCmin), and their ratio (SUVmax/ADCmin) were used as imaging parameters to distinguish benign from malignant prostatic lesions. Of the 56 patients, 12 were pathologically diagnosed with a benign disease, and 44 were diagnosed with PCa. 99mTc-PSMA SPECT/CT and mpMRI showed no significant difference in the detection of primary PCa (kappa =0.401, P=0.002), with sensitivities of 97.7% (43/44) and 90.9% (40/44), specificities of 75.0% (9/12) and 75.0% (9/12), and AUC of 97.4% and 95.1%, respectively. The AUC of SUVmax/ADCmin was better than those of SUVmax or ADCmin alone. When SUVmax/ADCmin in the prostatic lesion was >7.0×103, the lesion was more likely to be malignant. When SUVmax/ADCmin in the prostatic lesion is >27.0×103, the PCa patient may have lymph node and bone metastases. SUVmax was positively correlated with the Gleason score (r=0.61, P=0.008), whereas ADCmin was negatively correlated with the Gleason score (r=-0.35, P=0.023). SUVmax/ADCmin was positively correlated with the Gleason score (r=0.59, P=0.023). SUVmax/ADCmin was the main predictor of the high-risk group, with an optimal cut-off value of 15.0×103. The combination of 99mTc-PSMA SPECT/CT and mpMRI can improve the diagnostic efficacy for PCa compared with either modality alone; SUVmax/ADCmin is a valuable differential diagnostic imaging parameter.

Higher Preoperative Maximum Standardised Uptake Values (SUVmax) Are Associated with Higher Biochemical Recurrence Rates after Robot-Assisted Radical Prostatectomy for [68Ga]Ga-PSMA-11 and [18F]DCFPyL Positron Emission Tomography/Computed Tomography.

This study aimed to investigate the association between the 68Ga- or 18F-radiolabeled prostate-specific membrane antigen (PSMA) tracer expression, represented by the maximum standardised uptake value (SUVmax) of the dominant intraprostatic lesion, and biochemical recurrence (BCR) in primary prostate cancer (PCa) patients prior to robot-assisted radical prostatectomy (RARP). This was a retrospective, multi-centre cohort study of 446 patients who underwent [68Ga]Ga-PSMA-11 (n = 238) or [18F]DCFPyL (n = 206) Positron Emission Tomography/Computed Tomography (PET/CT) imaging prior to RARP. SUVmax was measured in the dominant intraprostatic PCa lesions. [18F]DCFPyL patients were scanned 60 ([18F]DCFPyL-60; n = 106) or 120 ([18F]DCFPyL-120; n = 120) minutes post-injection of a radiotracer and were analysed separately. To normalise the data, SUVmax was log transformed for further analyses. During a median follow-up of 24 months, 141 (30.4%) patients experienced BCR. Log2SUVmax was a significant predictor for BCR (p < 0.001). In the multivariable analysis accounting for these preoperative variables: initial prostate-specific antigen (PSA), radiologic tumour stage (mT), the biopsy International Society of Urological Pathology grade group (bISUP) and the prostate imaging and reporting data system (PI-RADS), Log2SUVmax was found to be an independent predictor for BCR in [68Ga]Ga-PSMA-11 (HR 1.32, p = 0.04) and [18F]DCFPyL-120 PET/CT scans (HR 1.55, p = 0.04), but not in [18F]DCFPyL-60 ones (HR 0.92, p = 0.72). The PSMA expression of the dominant intraprostatic lesion proved to be an independent predictor for BCR in patients with primary PCa who underwent [68Ga]Ga-PSMA-11 or [18F]DCFPyL-120 PET/CT scans, but not in those who underwent [18F]DCFPyL-60 PET/CT scans.

Evolution of non-perfused volume after transurethral ultrasound ablation of prostate: A retrospective 12-month analysis

BackgroundA detailed understanding of the non-perfused volume (NPV) evolution after prostate ablation therapy is lacking. The impact of different diseased prostate tissues on NPV evolution post-ablation is unknown. PurposeTo characterize the NPV evolution for three treatment groups undergoing heat-based prostate ablation therapy, including benign prostatic hyperplasia (BPH), primary prostate cancer (PCa), and radiorecurrent PCa. Materials and methodsStudy design and data analysis were performed retrospectively. All patients received MRI-guided transurethral ultrasound ablation (TULSA). 21 BPH, 28 radiorecurrent PCa and 40 primary PCa patients were included. Using the T1-weighted contrast-enhanced MR image, the NPV was manually contoured by an experienced radiologist. All patients received an MRI immediately following the ablation. Follow-up included MRI at 3- and 12 months for BPH and radiorecurrent PCa patients and at 6- and 12 months for primary PCa patients. ResultsA significant difference between BPH and radiorecurrent PCa patients was observed at three months (p < 0.0001, Wilcoxon rank sum test), with the median NPV decreasing by 77 % for BPH patients but increasing by 4 % for radiorecurrent PCa patients. At six months, the median NPV decreased by 97 % for primary PCa. Across all groups, although 40 % of patients had residual NPV at 12 months, it tended to be < 1 mL. ConclusionThe resolution of necrotic tissue after ablation was markedly slower for irradiated than treatment-naïve prostate tissue. These results may account for the increased toxicity observed after radiorecurrent salvage therapy. By 12 months, most necrotic prostate tissue had disappeared in every treatment group.

Racial Differences in Androgen Receptor (AR) and AR Splice Variants (AR-SVs) Expression in Treatment-Naïve Androgen-Dependent Prostate Cancer.

Androgen receptor splice variants (AR-SVs) contribute to the aggressive growth of castration-resistant prostate cancer (CRPC). AR-SVs, including AR-V7, are expressed in ~30% of CRPC, but minimally in treatment-naïve primary prostate cancer (PCa). Compared to Caucasian American (CA) men, African American (AA) men are more likely to be diagnosed with aggressive/potentially lethal PCa and have shorter disease-free survival. Expression of a truncated AR in an aggressively growing patient-derived xenograft developed with a primary PCa specimen from an AA patient led us to hypothesize that the expression of AR-SVs could be an indicator of aggressive growth both in PCa progression and at the CRPC stage in AA men. Tissue microarrays (TMAs) were created from formalin-fixed paraffin-embedded (FFPE) prostatectomy tumor blocks from 118 AA and 115 CA treatment-naïve PCa patients. TMAs were stained with AR-V7-speicifc antibody and with antibodies binding to the N-terminus domain (NTD) and ligand-binding domain (LBD) of the AR. Since over 20 AR-SVs have been identified, and most AR-SVs do not as yet have a specific antibody, we considered a 2.0-fold or greater difference in the NTD vs. LBD staining as indication of potential AR-SV expression. Two AA, but no CA, patient tumors stained positively for AR-V7. AR staining with NTD and LBD antibodies was robust in most patients, with 21% of patients staining at least 2-fold more for NTD than LBD, indicating that AR-SVs other than AR-V7 are expressed in primary treatment-naïve PCa. About 24% of the patients were AR-negative, and race differences in AR expression were not statistically significant. These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.

Head-to-Head Comparison of 68 Ga-P16-093 and 68 Ga-PSMA-617 PET/CT in Patients With Primary Prostate Cancer : A Pilot Study.

We aimed to compare the diagnostic performance of 68 Ga-P16-093 and 68 Ga-PSMA-617 PET/CT in primary prostate cancer (PCa) patients. Thirty untreated primary PCa patients were enrolled. Each patient underwent 68 Ga-P16-093 and 68 Ga-PSMA-617 PET/CT within a week. In addition to visual analysis, SUV was measured for semiquantitative comparison and correlation analysis. 68 Ga-P16-093 PET/CT detected more positive tumors than 68 Ga-PSMA-617 PET/CT (67 vs 56, P = 0.002), especially for intraprostatic lesions (29 vs 24, P = 0.025) and lymph node metastases (23 vs 17, P = 0.034). Further, 68 Ga-P16-093 PET/CT exhibited significantly higher SUV max of matched tumors (18.3 ± 14.4 vs 13.9 ± 11.8, P < 0.001). Besides, the SUV max of high-risk patients (based on D'Amico classification) on 68 Ga-P16-093 PET/CT was significantly higher than that of low- and intermediate-risk PCa patients (20.9 ± 9.9 vs 8.9 ± 9.1 vs 10.1 ± 5.2, P = 0.007). The SUV max of tumor measured by 68 Ga-P16-093 PET/CT had a moderate association with biopsy Gleason score ( r = 0.462, P = 0.005) and prostate-specific antigen value ( r = 0.491, P = 0.002), and significantly correlated with PSMA expression ( r = 0.732, P < 0.001). 68 Ga-P16-093 PET/CT exhibited higher tumor uptake and potentially better tumor detection capability than 68 Ga-PSMA-617 PET/CT, which suggested that 68 Ga-P16-093 may be more suitable in the diagnosis and staging of primary PCa patients.

The Impact of Peptide Amount on Tumor Uptake to Assess PSMA Receptor Saturation on 68Ga-PSMA-11 PET/CT in Patients with Primary Prostate Cancer.

68Ga-labeled prostate-specific membrane antigen (PSMA) is often produced on-site, where usually a fixed amount of peptide is conjugated to the generator eluate. However, fluctuations in specific activity might influence tracer distribution and tumor accumulation. Therefore, our aim was to investigate the potential effect of varying the administered peptide amount on 68Ga-PSMA-11 uptake in tumors using PET/CT in patients with primary prostate cancer (PCa). Additionally, the impact of tumor volume on this potential effect and on accumulation in reference organs was assessed. Methods: The imaging data of 362 men with primary PCa who underwent 68Ga-PSMA-11 PET/CT were retrospectively included. Scans were quantified for normal tissue and primary tumors. Patients were divided into 3 groups based on their tumor volume. Correlation and multivariable linear regression analyses were performed. Results: The median index lesion volume was 9.50 cm3 (range, 0.064-174 cm3). Groups were based on quartiles of prostatic lesion volume: ≤4.11 cm3 (group 1), 4.11-20.6 cm3 (group 2), and ≥20.6 cm3 (group 3). No correlation was found between administered peptide amount and tumor uptake (SUVmean or SUVpeak) for any group, except for a significant correlation for SUVmean in the first group (P = 0.008). Linear regression analysis supported these findings. Conclusion: The amount of administered peptide had no evident effect on 68Ga-PSMA-11 uptake in tumors, except for a significant positive correlation between administered peptide amount and tumor SUVmean for group 1. The findings imply that no receptor saturation occurs in men with primary PCa at peptide levels of about 2.5 μg.

PD22-01 ONCOLOGICAL OUTCOMES OF SENTINEL LYMPH NODE PROCEDURE-GUIDED RADIOTHERAPY VERSUS IMAGING-GUIDED RADIOTHERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER – A MULTICENTER, RETROSPECTIVE, PROPENSITY SCORE WEIGHTED COMPARISON

You have accessJournal of UrologyCME1 May 2022PD22-01 ONCOLOGICAL OUTCOMES OF SENTINEL LYMPH NODE PROCEDURE-GUIDED RADIOTHERAPY VERSUS IMAGING-GUIDED RADIOTHERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER – A MULTICENTER, RETROSPECTIVE, PROPENSITY SCORE WEIGHTED COMPARISON Hilda de Barros, Nikolaos Grivas, Jan Duin, Daan Mulder, Vincent van der Noort, Arjen Noordzij, Esther Wit, Eva Schaake, Pim van Leeuwen, and Henk van der Poel Hilda de BarrosHilda de Barros More articles by this author , Nikolaos GrivasNikolaos Grivas More articles by this author , Jan DuinJan Duin More articles by this author , Daan MulderDaan Mulder More articles by this author , Vincent van der NoortVincent van der Noort More articles by this author , Arjen NoordzijArjen Noordzij More articles by this author , Esther WitEsther Wit More articles by this author , Eva SchaakeEva Schaake More articles by this author , Pim van LeeuwenPim van Leeuwen More articles by this author , and Henk van der PoelHenk van der Poel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002564.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Insufficient sensitivity of current imaging techniques for nodal staging has led to the exploration of the sentinel lymph node biopsy (SLNB) to select primary prostate cancer (PCa) patients that might benefit from whole-pelvic nodal radiotherapy (WPRT). In this study, we aimed to evaluate oncological outcomes of SLNB-based RT compared to imaging-based RT in cN0M0 PCa patients with an increased estimated risk of nodal metastases. METHODS: This multicenter, retrospective cohort study included 522 cN0 primary PCa patients with a Briganti nomogram-estimated nodal risk >5% treated with external beam RT (EBRT) between 2007-2018. Nodal staging was performed either by radiological staging (261 (50%) patients) or by radiological staging and an additional robot-assisted laparoscopic SLNB (261 (50%) patients). All patients received RT to the prostate and 6 months to 3 years of androgen deprivation therapy (ADT), whereas patients with a histologically positive sentinel node (pN1) also received RT to the pelvic LNs with 3 years of ADT. Endpoints included biochemical recurrence-free survival (BCR-FS) and radiological recurrence-free survival (RR-FS). Propensity score weighted (PSW) multivariable Cox regression analysis was performed to determine independent predictors of BCR and RR. RESULTS: Patients staged with SLNB had a higher rate of extracapsular extension (63% vs 35%, P <0.001) and were at higher risk of nodal metastases (43% vs 29%, P=0.002) compared to imaging-only staged patients. Median follow-up after primary treatment was 64 months (IQR 41-95). In total, 111 patients developed a BCR (SLNB=51, non-SLNB=60) and 98 patients developed a radiological recurrence (SLNB=50, non-SLNB=48; Fig 1). In PSW multivariable Cox regression analyses, SLNB-based RT was an independent predictor of both BCR (HR 0.38, 95% CI 0.25-0.59, P <0.001) and RR (HR 0.44, 95% CI 0.28-0.69, P <0.001). CONCLUSIONS: SLNB-guided RT is associated with a decreased risk of BCR and RR when compared to prostate-only RT in cN0 PCa patients. These results suggest an important role for SLNB in selecting cN0 PCa patients that might profit from WPRT and ADT intensification, and justify a prospective comparison. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e402 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hilda de Barros More articles by this author Nikolaos Grivas More articles by this author Jan Duin More articles by this author Daan Mulder More articles by this author Vincent van der Noort More articles by this author Arjen Noordzij More articles by this author Esther Wit More articles by this author Eva Schaake More articles by this author Pim van Leeuwen More articles by this author Henk van der Poel More articles by this author Expand All Advertisement PDF DownloadLoading ...

99mTc-PSMA targeted robot-assisted radioguided surgery during radical prostatectomy and extended lymph node dissection of prostate cancer patients.

The feasibility of tracer production of 99mtechnetium (Tc)-prostate-specific membrane antigen (PSMA)-I&S sterile cold kit, imaging with single photon emission tomography/computed tomography (SPECT/CT), and 99mTc-PSMA-radioguided robot-assisted laparoscopic radical prostatectomy (99mTc-PSMA-RG-RALRP) technique for lymph node (LN) dissection of primary prostate cancer (PCa) patients were evaluated prospectively. Fifteen primary PCa patients with intermediate- or high-risk score according to D'Amico risk stratification who had PSMA receptor affinity with Ga-68 PSMA-11 PET/CT were enrolled. After 99mTc-PSMA-I&S injection and SPECT/CT imaging, 99mTc-PSMA-RG-RALRP with DaVinci XI robotic platform and laparoscopic gamma probe were performed. Radioactive rating of resected tissue was compared with post-operative histopathology. Physiological and pathological uptakes of organs and tissues for both imaging modalities were compared. Physiological radiotracer distribution was similar for both imaging modalities. PCa lesions were much more visible on PET/CT. Metastatic LNs could not be visualized with SPECT/CT. Eighteen of 297 totally dissected LNs were metastatic, which were exactly the same with per-operative probe counts with sensitivity, specificity, accuracy, and negative and positive predictive value of all 100%. The median follow-up was 23.5 ± 4.6months. tPSA reduction was > 98%. The 2.5years biochemical recurrence-free survival, PCa-specific treatment-free survival and overall survival rates were 86,7%, 66,7% and 100%, respectively. Tc-99m-PSMA-RG-RALRP is a promising technique for extended pelvic lymph node dissection (ePLND) during robotic surgery, which may shorten the operation time and reduce complication risks. If LN metastases is detected during surgery with PSMA-targeted probe, it may be an early indicator of PCa-spesific treatment planning. Tc-99m-PSMA-I&S SPECT/CT is not as successful as Ga-68 PSMA-11 PET/CT for diagnosis of primary PCA lesions or LN metastases.

Diagnostic accuracy of 18F-PSMA-1007 PET/CT for prostate cancer in primary staging and biochemical recurrence with different serum PSA levels: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis to evaluate the application value of fluorine-18-prostate specific membrane antigen (18F-PSMA-1007) positron emission tomography/computed tomography (PET/CT) in patients with different serum prostate specific antigen (PSA) levels and primary prostate cancer (PCa) or the biochemical recurrence of PCa. A comprehensive electronic literature search of the PubMed, Embase and Cochrane Library databases was conducted in accordance with the PRISMA statement. We calculated the pooled sensitivity and specificity of 18F-PSMA-1007 PET/CT in PCa. A summary receiver operator characteristic (SROC) curve and the area under the curve (AUC) were used to assess the accuracy of 18F-PSMA-1007 PET/CT for PCa. The final analysis included 11 studies that described 799 patients and 4261 lesions with 18F-PSMA-1007 PET/CT in PCa. The pooled sensitivity and specificity of 18F-PSMA-1007 PET/CT in PCa were 0.836 and 0.946, respectively. The per-patient pooled sensitivity and specificity of 18F-PSMA-1007 PET/CT in PCa were 0.934 and 0.453, and the per-lesion values were 0.816 and 0.979, respectively. The pooled sensitivity and specificity of 18F-PSMA-1007 PET/CT in PCa with PSA>2ng/mL were 0.923 and 0.442 in a patient-based analysis and 0.799 and 0.961 in a lesion-based analysis, respectively. The pooled sensitivity and specificity of 18F-PSMA-1007 PET/CT in PCa with PSA≤2ng/mL were 0.832 and 0.277 in a patient-based analysis, respectively. This meta-analysis showed that 18F-PSMA-1007 PET/CT has a higher diagnostic value for prostate cancer in the setting of primary PCa and biochemical recurrence. As serum PSA levels increase, the diagnostic accuracy of 18F-PSMA-1007 PET/CT also improves.

Comparative genomics of primary prostate cancer and paired metastases: insights from 12 molecular case studies.

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for the heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration‐resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole‐exome sequencing (WES) and amplicon‐based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intratumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (eight patients). Activating AR alterations were seen in nine (75%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES‐based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC‐assisted pathology review and genomic analysis are highly concordant in nominating the ‘index’ primary PCa area. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Implementation of PSMA-PET in focal dose-escalated radiotherapy of primary prostate cancer patients: Results of a planned safety analysis of a phase II trial.

260 Background: Positron emission tomography targeting prostate specific membrane antigen (PSMA-PET) changes treatment management of primary prostate cancer (PCa) patients and might improve focal dose escalation in radiotherapy (RT) due to superior coverage of intraprostatic tumour burden. The 2-armed, non-randomized HypoFocal phase II trial investigates the safety of implementation of PSMA-PET-based focal therapy planning in external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT). Here we present results from the planned safety analysis after 6 months of follow-up (FU). Methods: Intermediate- and high risk PCa Patients with cN0 and cM0 staged by mpMRI and PSMA PET were included. EBRT was delivered in 20 fractions with 60 Gy to the prostate and up to 75 Gy to mpMRI- and PSMA-PET defined boost volumes (arm A). HDR-BT was delivered with 15 Gy to the prostate and a boost of up to 19 Gy, followed by EBRT with 44Gy in 20 fractions (arm B). 36% of patients received androgen deprivation therapy. Volumes, treatment plans, gastrointestinal (GI) and genitourinary (GU) toxicities according to CTCAE v5.0 and Quality of Life (QoL) was assessed. Results: 25 patients were enrolled in each study arm in two centers (Freiburg and Berlin). Clinical T stage was significantly different between mpMRI and PSMA-PET (p=0.007) with upstaging towards ≥ cT2c stages in PET. GTV-PET and GTV-Union were significantly larger than GTV-MRI, resulting in large boost volumes (see table). Boost volumes received a median mean dose of 70 Gy in EBRT and a median D90 of 19 Gy in HDR-BT At 6 months FU, prevalence of ≥ grade 2 GU and GI toxicity was 4% and 0% for arm A and 12 and 4% for arm B. Two patients experienced grade 3 GI toxicitiy 9 and 12 months after RT, related to biopsy. No signification change of QoL was observed after 6 months of FU. cT stages and target volumes. Conclusions: Implementation of PSMA-PET in primary PCa patients relevantly alters cT-stage and RT treatment management with significantly larger GTVs and subsequent boost volumes. Still, boost delivery was feasible with acceptable acute toxicities and good QoL. Putative oncological benefits should be evaluated in larger cohorts. Clinical trial information: DRKS00017570. [Table: see text]

PSMA-PET/MRI-Based Focal Dose Escalation in Patients with Primary Prostate Cancer Treated with Stereotactic Body Radiation Therapy (HypoFocal-SBRT): Study Protocol of a Randomized, Multicentric Phase III Trial.

Simple SummaryProstate cancer (PCa) is the most diagnosed malignancy of men worldwide, and radiotherapy (RT) is a main treatment option for patients in all disease stages. Modern diagnostic imaging and RT techniques enable an effective and safe delivery of high RT doses and a reduction of treatment time. We present a study protocol of a phase III trial implementing most modern imaging techniques and RT approaches. We compare the standard RT treatment with an RT concept of reduced treatment time and focal dose escalation based on the patient’s individual tumor morphology. This HypoFocal-SBRT trial aims to individualize treatment of PCa patients.Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose–response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.

Prospective analysis of clinically significant prostate cancer detection with [18F]DCFPyL PET/MRI compared to multiparametric MRI: a comparison with the histopathology in the radical prostatectomy specimen, the ProStaPET study

PurposeMultiparametric magnetic resonance imaging (mpMRI) is a well-established imaging method for localizing primary prostate cancer (PCa) and for guiding targeted prostate biopsies. [18F]DCFPyL positron emission tomography combined with MRI (PSMA-PET/MRI) might be of additional value to localize primary PCa. The aim of this study was to assess the diagnostic performance of [18F]DCFPyL-PET/MRI vs. mpMRI in tumour localization based on histopathology after robot-assisted radical-prostatectomy (RARP), also assessing biopsy advice for potential image-guided prostate biopsies.MethodsThirty prospectively included patients with intermediate to high-risk PCa underwent [18F]DCFPyL-PET/MRI and mpMRI prior to RARP. Two nuclear medicine physicians and two radiologists assessed tumour localization on [18F]DCFPyL-PET/MRI and on mpMRI respectively, and gave a prostate biopsy advice (2 segments) using a 14-segment model of the prostate. The uro-pathologist evaluated the RARP specimen for clinically significant PCa (csPCa) using the same model. csPCa was defined as any PCa with Grade Group (GG) ≥ 2. The biopsy advice based on imaging was correlated with the final histology in the RARP specimen for a total-agreement analysis. An additional near-agreement correlation was performed to approximate clinical reality.ResultsOverall, 142 of 420 (33.8%) segments contained csPCa after pathologic examination. The segments recommended for targeted biopsy contained the highest GG PCa segment in 27/30 patients (90.0%) both for [18F]DCFPyL-PET/MRI and mpMRI. Areas under the receiver operating characteristics curves (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the total-agreement detection of csPCa per segment using [18F]DCFPyL-PET/MRI were 0.70, 50.0%, 89.9%, 71.7%, and 77.9%, respectively. These results were 0.75, 54.2%, 94.2%, 82.8%, and 80.1%, respectively, for mpMRI only.ConclusionBoth [18F]DCFPyL-PET/MRI and mpMRI were only partly able to detect csPCa on a per-segment basis. An accurate detection (90.0%) of the highest GG lesion at patient-level was observed when comparing both [18F]DCFPyL-PET/MRI and mpMRI biopsy advice with the histopathology in the RARP specimen. So, despite the finding that [18F]DCFPyL-PET/MRI adequately detects csPCa, it does not outperform mpMRI.

Metastatic Castration-Resistant Prostate Cancer Remains Dependent on Oncogenic Drivers Found in Primary Tumors.

PURPOSEMetastatic prostate cancer is initially sensitive to androgen receptor inhibition, but eventually becomes castration-resistant prostate cancer (mCRPC). Early use of more intensive therapies targeting androgen receptor and other oncogenic drivers in treatment-naïve primary prostate cancer (PC) may be more effective than that in advanced mCRPC. However, analysis of primary tumors may not reveal targetable metastatic drivers that are subclonal in the primary tumor or acquired at metastatic sites.METHODSPC samples spanning one patient's clinical course: diagnostic biopsies, pre- or post-enzalutamide metastatic biopsies, and rapid autopsy samples including a patient-derived xenograft (PDX) were analyzed by targeted exome sequencing followed by phylogenetic analysis.RESULTSLeft- and right-lobe primary PC tumors appeared to diverge, with the right acquiring additional shared mutations and striking differences in copy number alterations that later appeared in metastatic samples during the treatment course and at autopsy, whereas the left base tumor maintained a quiet copy number alteration landscape and partitioned into a dead-end node. RB1 loss, a common finding in advanced castration-resistant disease, was identified throughout mCRPC samples, but not in the primary tumor. Significantly, a truncal EGFR-activating mutation (R108K) was identified in the primary tumor and was also found to be maintained in the mCRPC samples and in a PDX model. Furthermore, the PDX model remained sensitive to the EGFR inhibitor erlotinib, despite the presence of both RB1 and BRCA2 losses.CONCLUSIONThese findings indicate that truncal alterations identified in primary PC can drive advanced mCRPC, even in the presence of additional strong oncogenic drivers (ie, RB1 and BRCA2 loss), and suggest that earlier detection and targeting of these truncal alterations may be effective at halting disease progression.

Clinical aspects in the diagnosis and treatment of prostate cancer

Diagnosis and treatment of primary prostate cancer (PCA) have undergone significant changes in the last few years due to modern imaging. Established and modern diagnostic and therapeutic modalities for detection and treatment of primary PCA are presented and discussed critically. Background knowledge and guideline recommendations on primary PCA are summarized and additional information from relevant publications is given. Modern imaging, in particular multiparametric magnetic resonance imaging (mpMRI), has revolutionized the diagnostic work-up of primary PCA. Due to mpMRI, tumors are detected significantly better in both initial and re-biopsy with asignificant reduction of overdiagnosis of clinically insignificant PCA. Therapeutic approaches such as active surveillance, radical prostatectomy and focal therapies are increasingly being planned and carried out relying on MR-imaging information concerning tumor extent and tumor aggressiveness. In addition, prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT) has shown superiority in assessing patients with suspected biochemical recurrence and in primary staging of PCA compared to conventional imaging in terms of detection of metastases. Modern imaging, especially mpMRI and PSMA-PET/CT, has added substantial benefits in modern diagnosis and treatment of primary PCA. Moreover, multiparametric ultrasound is also apromising addition to the radiological armamentarium in the management of primary PCA.

Diagnostic value of computed high b-value whole‐body diffusion-weighted imaging for primary prostate cancer

PurposeTo investigate the utility of post-acquisition computed diffusion-weighted imaging (cDWI) for primary prostate cancer (PCa) evaluation in biparametric whole‐body MRI (bpWB-MRI). MethodsPatients who underwent pelvic MRI for PCa screening and subsequent bpWB-MRI for staging were included.Two radiologists assessed the diagnostic performance of the following datasets for clinically significant PCa diagnosis (grade group ≥2 according to the Prostate Imaging-Reporting and Data System, version 2.1): bpMRI2000 (axial DWI scans with a b-value of 2,000 s/mm2 + axial T2WI scans from pre-biopsy pelvic MRI), computed bpWB-MRI2000 (computed WB-DWI scans with a b-value of 2,000 s/mm2 + axial WB-T2WI scans), and native bpWB-MRI1000 (native axial WB-DWI scans with a b-value of 1,000 s/mm2 + axial WB-T2WI scans). Systemic biopsy was used as reference standard. ResultsFifty-one patients with PCa were included. The areas under the curve (AUCs) of bpMRI2000 (0.89 for reader 1 and 0.86 for reader 2) and computed bpWB-MRI2000 (0.86 for reader 1 and 0.83 for reader 2) were significantly higher (p < 0.001) than those of native bpWB-MRI1000 (0.67 for both readers). No significant difference was observed between the AUCs of bpMRI2000 and computed bpWB-MRI2000 (p = 0.10 for reader 1 and p = 0.25 for reader 2). ConclusionsThe diagnostic performance of computed bpWB-MRI2000 was similar to that of dedicated pelvic bpMRI2000 for primary PCa evaluation. cDWI can be recommended for implementation in standard WB-MRI protocols to facilitate a one-step evaluation for concurrent detection of primary and metastatic PCa.

Comparison of Manual and Semi-Automatic [18F]PSMA-1007 PET Based Contouring Techniques for Intraprostatic Tumor Delineation in Patients With Primary Prostate Cancer and Validation With Histopathology as Standard of Reference.

PurposeAccurate contouring of intraprostatic gross tumor volume (GTV) is pivotal for successful delivery of focal therapies and for biopsy guidance in patients with primary prostate cancer (PCa). Contouring of GTVs, using 18-Fluor labeled tracer prostate specific membrane antigen positron emission tomography ([18F]PSMA-1007/PET) has not been examined yet.Patients and MethodsTen Patients with primary PCa who underwent [18F]PSMA-1007 PET followed by radical prostatectomy were prospectively enrolled. Coregistered histopathological gross tumor volume (GTV-Histo) was used as standard of reference. PSMA-PET images were contoured on two ways: (1) manual contouring with PET scaling SUVmin-max: 0–10 was performed by three teams with different levels of experience. Team 1 repeated contouring at a different time point, resulting in n = 4 manual contours. (2) Semi-automatic contouring approaches using SUVmax thresholds of 20–50% were performed. Interobserver agreement was assessed for manual contouring by calculating the Dice Similarity Coefficient (DSC) and for all approaches sensitivity, specificity were calculated by dividing the prostate in each CT slice into four equal quadrants under consideration of histopathology as standard of reference.ResultsManual contouring yielded an excellent interobserver agreement with a median DSC of 0.90 (range 0.87–0.94). Volumes derived from scaling SUVmin-max 0–10 showed no statistically significant difference from GTV-Histo and high sensitivities (median 87%, range 84–90%) and specificities (median 96%, range 96–100%). GTVs using semi-automatic segmentation applying a threshold of 20–40% of SUVmax showed no significant difference in absolute volumes to GTV-Histo, GTV-SUV50% was significantly smaller. Best performing semi-automatic contour (GTV-SUV20%) achieved high sensitivity (median 93%) and specificity (median 96%). There was no statistically significant difference to SUVmin-max 0–10.ConclusionManual contouring with PET scaling SUVmin-max 0–10 and semi-automatic contouring applying a threshold of 20% of SUVmax achieved high sensitivities and very high specificities and are recommended for [18F]PSMA-1007 PET based focal therapy approaches. Providing high specificities, semi-automatic approaches applying thresholds of 30–40% of SUVmax are recommend for biopsy guidance.

Lamin B1 promotes tumor progression and metastasis in primary prostate cancer patients.

Aims: To determine the role of lamin B1 (LMNB1) in the progression and metastasis of primary prostate cancer (PC). Patients & methods: Two PC cohorts were used to investigate the clinical relationship between LMNB1 expression and tumor progression and metastasis. Results: The qRT-PCR results revealed that LMNB1 expression was markedly increased in patients with aggressive featuresand was associated with worse prognosis. Logisticregression analyses indicated that LMNB1 expression is anindependent risk factorfor distant metastasis. Kaplan-Meier analysis showed that increased LMNB1 levels were related to poor disease-free survival in the primary PC cohort. Conclusion: This study reveals that upregulation of LMNB1 is associated with cancer metastasis and poor survival outcomes in primary PC patients.

Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial

PurposeIn primary prostate cancer (PCa) patients, accurate staging and histologic grading are crucial to guide treatment decisions. 18F-DCFPyL (PSMA)-PET/CT has been successfully introduced for (re)staging PCa, showing high accuracy to localise PCa in lymph nodes and/or osseous structures. The diagnostic performance of 18F-DCFPyL-PET/CT in localizing primary PCa within the prostate gland was assessed, allowing for PSMA-guided targeted-prostate biopsy.MethodsThirty patients with intermediate-/high-risk primary PCa were prospectively enrolled between May 2018 and May 2019 and underwent 18F-DCFPyL-PET/CT prior to robot-assisted radical prostatectomy (RARP). Two experienced and blinded nuclear medicine physicians assessed tumour localisation within the prostate gland on PET/CT, using a 12-segment mapping model of the prostate. The same model was used by a uro-pathologist for the RARP specimens. Based on PET/CT imaging, a potential biopsy recommendation was given per patient, based on the size and PET-intensity of the suspected PCa localisations. The biopsy recommendation was correlated to final histopathology in the RARP specimen. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for clinically significant PCa (csPCa, Gleason score ≥ 3 + 4 = 7) were assessed.ResultsThe segments recommended for potential targeted biopsy harboured csPCA in 28/30 patients (93%), and covered the highest Gleason score PCa segment in 26/30 patient (87%). Overall, 122 of 420 segments (29.0%) contained csPCa at final histopathological examination. Sensitivity, specificity, PPV and NPV for csPCa per segment using 18F-DCFPyL-PET/CT were 61.4%, 88.3%, 68.1% and 84.8%, respectively.ConclusionsWhen comparing the PCa-localisation on 18F-DCFPyL-PET/CT with the RARP specimens, an accurate per-patient detection (93%) and localisation of csPCa was found. Thus, 18F-DCFPyL-PET/CT potentially allows for accurate PSMA-targeted biopsy.

Identification of AR-V7 downstream genes commonly targeted by AR/AR-V7 and specifically targeted by AR-V7 in castration resistant prostate cancer

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) under androgen deprivation therapy, by mechanisms e.g. expression of androgen receptor (AR) splice variant-7 (AR-V7). Here we conducted comprehensive epigenome and transcriptome analyses comparing LNCaP, primary PC cells, and LNCaP95, AR-V7-expressing CRPC cells derived from LNCaP. Of 399 AR-V7 target regions identified through ChIP-seq analysis, 377 could be commonly targeted by hormone-stimulated AR, and 22 were specifically targeted by AR-V7. Among genes neighboring to these AR-V7 target regions, 78 genes were highly expressed in LNCaP95, while AR-V7 knockdown led to significant repression of these genes and suppression of growth of LNCaP95. Of the 78 AR-V7 target genes, 74 were common AR/AR-V7 target genes and 4 were specific AR-V7 target genes; their most suppressed genes by AR-V7 knockdown were NUP210 and SLC3A2, respectively, and underwent subsequent analyses. NUP210 and SLC3A2 were significantly upregulated in clinical CRPC tissues, and their knockdown resulted in significant suppression of cellular growth of LNCaP95 through apoptosis and growth arrest. Collectively, AR-V7 contributes to CRPC proliferation by activating both common AR/AR-V7 target and specific AR-V7 target, e.g. NUP210 and SLC3A2.