High-risk Primary Prostate Cancer Research Articles

The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer

PurposeProstate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard.MethodsA total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates.ResultsThe sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers.We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate.ConclusionIn a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial.

Optimization and validation of 18F-DCFPyL PET radiomics-based machine learning models in intermediate- to high-risk primary prostate cancer.

Radiomics extracted from prostate-specific membrane antigen (PSMA)-PET modeled with machine learning (ML) may be used for prediction of disease risk. However, validation of previously proposed approaches is lacking. We aimed to optimize and validate ML models based on 18F-DCFPyL-PET radiomics for the prediction of lymph-node involvement (LNI), extracapsular extension (ECE), and postoperative Gleason score (GS) in primary prostate cancer (PCa) patients. Patients with intermediate- to high-risk PCa who underwent 18F-DCFPyL-PET/CT before radical prostatectomy with pelvic lymph-node dissection were evaluated. The training dataset included 72 patients, the internal validation dataset 24 patients, and the external validation dataset 27 patients. PSMA-avid intra-prostatic lesions were delineated semi-automatically on PET and 480 radiomics features were extracted. Conventional PET-metrics were derived for comparative analysis. Segmentation, preprocessing, and ML methods were optimized in repeated 5-fold cross-validation (CV) on the training dataset. The trained models were tested on the combined validation dataset. Combat harmonization was applied to external radiomics data. Model performance was assessed using the receiver-operating-characteristics curve (AUC). The CV-AUCs in the training dataset were 0.88, 0.79 and 0.84 for LNI, ECE, and GS, respectively. In the combined validation dataset, the ML models could significantly predict GS with an AUC of 0.78 (p<0.05). However, validation AUCs for LNI and ECE prediction were not significant (0.57 and 0.63, respectively). Conventional PET metrics-based models had comparable AUCs for LNI (0.59, p>0.05) and ECE (0.66, p>0.05), but a lower AUC for GS (0.73, p<0.05). In general, Combat harmonization improved external validation AUCs (-0.03 to +0.18). In internal and external validation, 18F-DCFPyL-PET radiomics-based ML models predicted high postoperative GS but not LNI or ECE in intermediate- to high-risk PCa. Therefore, the clinical benefit seems to be limited. These results underline the need for external and/or multicenter validation of PET radiomics-based ML model analyses to assess their generalizability.

New method of using a convolutional neural network for 2D intraprostatic tumor segmentation from PET images

PurposeA new method of using a convolutional neural network (CNN) to perform automatic tumor segmentation from two-dimensional transaxial slices of positron emission tomography (PET) images of high-risk primary prostate cancer patients is introduced.MethodsWe compare three different methods including (1) usual image segmentation with a CNN whose continuous output is converted to binary labels with a constant threshold, (2) our new technique of choosing separate thresholds for each image PET slice with a CNN to label the pixels directly from the PET slices, and (3) the combination of the two former methods based on using the second CNN to choose the optimal thresholds to convert the output of the first CNN. The CNNs are trained and tested multiple times by using a data set of 864 slices from the PET images of 78 prostate cancer patients.ResultsAccording to our results, the Dice scores computed from the predictions of the second method are statistically higher than those of the typical image segmentation (p-value<0.002).ConclusionThe new method of choosing unique thresholds to convert the pixels of the PET slices directly into binary tumor masks is not only faster and more computationally efficient but also yields better results.

The Association Between [68Ga]PSMA PET/CT Response and Biochemical Progression in Patients with High-Risk Prostate Cancer Receiving Neoadjuvant Therapy.

Our previous study found that the prostate-specific membrane antigen (PSMA) PET/CT response of primary prostate cancer (PCa) to neoadjuvant therapy can predict the pathologic response. This study was designed to investigate the association between [68Ga]PSMA PET/CT changes and biochemical progression-free survival (bPFS) in high-risk patients who underwent neoadjuvant therapy before radical prostatectomy (RP). Methods: Seventy-five patients with high-risk PCa in 2 phase II clinical trials who received neoadjuvant therapy before RP were included. The patients received androgen deprivation therapy plus docetaxel (n = 33) or androgen deprivation therapy plus abiraterone (n = 42) as neoadjuvant treatment. All patients had serial [68Ga]PSMA PET/CT scans before and after neoadjuvant therapy. Age, initial prostate-specific antigen level, nadir prostate-specific antigen level before RP, tumor grade at biopsy, treatment regimen, clinical T stage, PET imaging features, pathologic N stage, and pathologic response on final pathology were included for univariate and multivariate Cox regression analyses to identify independent predictors of bPFS. Results: With a median follow-up of 30 mo, 18 patients (24%) experienced biochemical progression. Multivariate Cox regression analyses revealed that only SUVmax derived from posttreatment [68Ga]PSMA PET/CT and pathologic response on final pathology were independent factors for the prediction of bPFS, with hazard ratios of 1.02 (95% CI, 1.00-1.04; P = 0.02) and 0.12 (95% CI, 0.02-0.98; P = 0.048), respectively. Kaplan-Meier analysis revealed that patients with a favorable [68Ga]PSMA PET/CT response (posttreatment SUVmax < 8.5) or a favorable pathologic response (pathologic complete response or minimal residual disease) had a significantly lower rate of 3-y biochemical progression. Conclusion: Our results indicated that [68Ga]PSMA PET/CT response was an independent risk factor for the prediction of bPFS in patients with high-risk PCa receiving neoadjuvant therapy and RP, suggesting [68Ga]PSMA PET/CT to be an ideal tool to monitor response to neoadjuvant therapy.

Validation of 18F-DCFPyL PET radiomics-based machine learning models in intermediate- to high-risk primary prostate cancer

Validation of 18F-DCFPyL PET radiomics-based machine learning models in intermediate- to high-risk primary prostate cancer

EO1 - Multicenter validation of 18F-DCFPyL radiomics-based machine learning models in intermediate - To high risk primary prostate cancer

EO1 - Multicenter validation of 18F-DCFPyL radiomics-based machine learning models in intermediate - To high risk primary prostate cancer

Correlation of 68Ga-RM2 PET with Postsurgery Histopathology Findings in Patients with Newly Diagnosed Intermediate- or High-Risk Prostate Cancer.

68Ga-RM2 targets gastrin-releasing peptide receptors (GRPRs), which are overexpressed in prostate cancer (PC). Here, we compared preoperative 68Ga-RM2 PET to postsurgery histopathology in patients with newly diagnosed intermediate- or high-risk PC. Methods: Forty-one men, 64.0 ± 6.7 y old, were prospectively enrolled. PET images were acquired 42-72 min (median ± SD, 52.5 ± 6.5 min) after injection of 118.4-247.9 MBq (median ± SD, 138.0 ± 22.2 MBq) of 68Ga-RM2. PET findings were compared with preoperative multiparametric MRI (mpMRI) (n = 36) and 68Ga-PSMA11 PET (n = 17) and correlated to postprostatectomy whole-mount histopathology (n = 32) and time to biochemical recurrence. Nine participants decided to undergo radiation therapy after study enrollment. Results: All participants had intermediate- (n = 17) or high-risk (n = 24) PC and were scheduled for prostatectomy. Prostate-specific antigen was 8.8 ± 77.4 (range, 2.5-504) and 7.6 ± 5.3 ng/mL (range, 2.5-28.0 ng/mL) when participants who ultimately underwent radiation treatment were excluded. Preoperative 68Ga-RM2 PET identified 70 intraprostatic foci of uptake in 40 of 41 patients. Postprostatectomy histopathology was available in 32 patients in which 68Ga-RM2 PET identified 50 of 54 intraprostatic lesions (detection rate = 93%). 68Ga-RM2 uptake was recorded in 19 nonenlarged pelvic lymph nodes in 6 patients. Pathology confirmed lymph node metastases in 16 lesions, and follow-up imaging confirmed nodal metastases in 2 lesions. 68Ga-PSMA11 and 68Ga-RM2 PET identified 27 and 26 intraprostatic lesions, respectively, and 5 pelvic lymph nodes each in 17 patients. Concordance between 68Ga-RM2 and 68Ga-PSMA11 PET was found in 18 prostatic lesions in 11 patients and 4 lymph nodes in 2 patients. Noncongruent findings were observed in 6 patients (intraprostatic lesions in 4 patients and nodal lesions in 2 patients). Sensitivity and accuracy rates for 68Ga-RM2 and 68Ga-PSMA11 (98% and 89% for 68Ga-RM2 and 95% and 89% for 68Ga-PSMA11) were higher than those for mpMRI (77% and 77%, respectively). Specificity was highest for mpMRI with 75% followed by 68Ga-PSMA11 (67%) and 68Ga-RM2 (65%). Conclusion: 68Ga-RM2 PET accurately detects intermediate- and high-risk primary PC, with a detection rate of 93%. In addition, 68Ga-RM2 PET showed significantly higher specificity and accuracy than mpMRI and a performance similar to 68Ga-PSMA11 PET. These findings need to be confirmed in larger studies to identify which patients will benefit from one or the other or both radiopharmaceuticals.

High prostate-specific membrane antigen (PSMA) positron emission tomography (PET) maximum standardized uptake value in men with PI-RADS score 4 or 5 confers a high probability of significant prostate cancer.

High prostate-specific membrane antigen (PSMA) positron emission tomography (PET) maximum standardized uptake value in men with PI-RADS score 4 or 5 confers a high probability of significant prostate cancer.

Time point-independent tumor positivity of 68Ga-PSMA-PET/CT pre- and post-biopsy in high-risk prostate cancer

ObjectiveProstate-specific membrane antigen (PSMA)-PET/CT imaging has gained increasing clinical importance for the detection and staging of high-risk primary prostate cancer (PCa). However, it is unclear whether the routine practice of prostate biopsy obscures the image finding of PSMA-PET/CT. This study aimed to compare the tumor positivity rate of PSMA-PET/CT performed pre- (PSMA-PET/CTpre) and post-biopsy (PSMA-PET/CTpost) in high-risk PCa patients.Patients and methodsWe matched 58 PSMA-PET/CTpost with 58 PSMA-PET/CTpre studies for primary detection of high-risk PCa according to clinical characteristics. Three subgroups of PSMA-PET/CTpost were defined by the intervals after biopsy (≤ 1 week, 1 ~ 2 weeks, and 2 ~ 5 weeks). Tumor positivity rates were determined, and SUVmax of primary tumors were compared separately for the two main groups and the related subgroups. Malignant prostate tissues from 20 of these patients were examined by immunohistochemical analysis of PSMA. In addition, the values of PSMA-PET/CTpre and PSMA-PET/CTpost in assessing seminal vesicle invasion (SVI) were evaluated in patients who underwent radical prostatectomy.ResultsAll the primary tumors were positive on PSMA-PET/CTpost and PSMA-PET/CTpre imaging, resulting in a patient-based positivity rates of 100% (58/58) in both groups. All examined IHC results (20/20) confirmed the high-level expression of PSMA. SUVmax of primary tumors did not differ between the two main groups (16.1, IQR 9.8–26.6 vs. 16.5, IQR 11.0–26.7, p > 0.05). Subgroup analysis of PSMA-PET/CTpost (≤ 1 week, 1 ~ 2 weeks, and 2 ~ 5 weeks) also showed no significant difference in tumor SUVmax (15.8, IQR 9.5–22.2; 17.8, IQR 9.8–29.2; and 15.4, IQR 10.1–30.3. p > 0.05). PSMA-PET/CTpost and PSMA-PET/CTpre exhibited similar value in SVI detection as well.ConclusionsThe tumor positivity rate was consistently high for PSMA-PET/CT pre- and post-biopsy. A prior biopsy does not seem to affect the tumor positivity rate of PSMA-PET/CT in high-risk PCa.

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]

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.

A Pilot Study of Dynamic 18F-DCFPyL PET/CT Imaging of Prostate Adenocarcinoma in High-Risk Primary Prostate Cancer Patients.

The primary aim of this study was to investigate the pharmacokinetics of 18F-DCFPyL, an 18F-labeled PSMA-based ligand, and to explore the utility of early time point positron emission tomography (PET) imaging extracted from PET data to distinguish malignant primary prostate from benign prostate tissue. Ten consecutive patients with biopsy-proven high-risk prostate cancer underwent a dynamic 18F-DCFPyL PET/CT scan of the pelvis for the first 45 min post-injection (p.i.) followed by a static PET/CT at 2 h p.i. 18F-DCFPyL uptake values and kinetics were compared between benign prostate tissue and prostate cancer, including quantitative pharmacokinetic PET parameters extracted from 18F-DCFPyL time activity curves generated from dynamic data using a two-tissue compartment model and Patlak plots. 18F-DCFPyL uptake values were significantly higher in primary prostate tumors than those in benign prostatic hyperplasia (BPH) and normal prostate tissue at 5 min, 30 min, and 120 min p.i. (P = 0.0002), when examining both SUVmax and SUVmean values. The two-tissue compartment model found an overall influx value (Ki) of 0.063 in primary prostate cancer, demonstrating a Ki over 15-fold higher in malignant prostate tissue compared with BPH (Ki = 0.004) and normal prostate tissue (Ki = 0.005) (P = 0.0001). High-risk primary prostate cancer is readily identified on dynamic and static, delayed, 18F-DCFPyL PET images. The tumor-to-background ratio increases over time, with optimal 18F-DCFPyL PET/CT imaging at 120 min p.i. for evaluation of prostate cancer, but not necessarily ideal for clinical application. Primary prostate cancer demonstrates different uptake kinetics in comparison to BPH and normal prostate tissue. The 15-fold difference in Ki between prostate cancer and non-cancer (BPH and normal) tissues translates to an ability to distinguish prostate cancer from normal tissue at time points as early as 5 to 10 min p.i.

Biphasic GA 68-labeled prostate specific membrane antigen-11 positron emission tomography/computed tomography scans in the differential diagnosis and risk stratification of initial primary prostate cancer.

This study aimed to assess the value of biphasic GA 68-labeled prostate-specific membrane antigen-11 (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) scan in the differential diagnosis and risk stratification of initial primary prostate cancer (PCa). A total of 51 patients with PCa (8 low- and intermediate-risk PCa patients and 43 high-risk PCa patients) and 36 patients with benign prostate lesions, who underwent standard whole-body imaging and delayed pelvic imaging of 68Ga-PSMA-11 PET/CT, were enrolled in this prospective study. The PET parameters, such as maximum and mean standard uptake value (SUVmax and SUVmean), and maximum and mean standard retention index of PET images were calculated and compared in different prostate lesions. The diagnostic performances of the PET parameters were evaluated by receiver operating characteristic (ROC) curves. All the PET parameters of PCa participants were significantly higher than those of participants with benign prostate lesions (P<0.001). The SUVmean of delayed imaging had the best performance in the diagnosis of PCa with an area under the curve (AUC) of 0.918 (95% CI: 0.858 to 0.977), the sensitivity of 90.0%, and specificity of 83.3%. The SUVmax and SUVmean of high-risk PCa participants were significantly higher than those of low- and intermediate-risk PCa participants (P<0.005). The SUVmax of standard imaging had the best performance in predicting high-risk PCa with an AUC of 0.890 (95% CI: 0.799 to 0.980), a sensitivity of 76.7%, and a specificity of 100.0%. The biphasic 68Ga-PSMA-11 PET/CT scan had good performance in discriminating prostate cancer from benign prostate diseases. The SUVmean of the prostate lesion at delayed imaging of 68Ga-PSMA-11 PET/CT had the best value in the differential diagnosis of PCa, and the SUVmax at standard imaging was most valuable in predicting the risk stratification of PCa.

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes.

A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear. We selected PD-L1-positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci. One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present. A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.

The Role of [18F]Fluciclovine PET/CT in the Characterization of High-Risk Primary Prostate Cancer: Comparison with [11C]Choline PET/CT and Histopathological Analysis.

Simple SummaryThe role of [18F]Fluciclovine Positron Emission Tomography/Computed Tomography (PET/CT) in the characterization of intra-prostatic lesions was evaluated in high-risk primary PCa patients, scheduled for radical surgery, comparing investigational [18F]Fluciclovine and conventional [11C]Choline PET/CT results with the reference standard of pathologic surgical specimen. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, unblinded, according to a pathology reference mapping. Among 19 pts, 45 malignant and 31 benign lesions were found. The highest SUVmax matched with the lobe of the index lesion in 89% of pts and a direct correlation between [18F]Fluciclovine uptake values and pISUP was demonstrated. Overall, the lesion-based performance of PET semiquantitative parameters (SUVmax, Target to background Ratio-TBRs) with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70), but still inadequate (AUCs ≤ 0.81) as standalone staging procedure. TBRs (especially with threshold higher than bone marrow) may be complementary to implement malignancy targeting.The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax; target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the “blinded” prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively; whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.

A Phase II, Open-label study to assess safety and management change using 68Ga-THP PSMA PET/CT in patients with high risk primary prostate cancer or biochemical recurrence after radical treatment: The PRONOUNCED study.

Objectives: To assess the safety and clinical impact of a novel, kit-based formulation of 68Ga-THP PSMA positron emission tomography/computed tomography (PET/CT) when used to guide the management of patients with prostate cancer (PCa). Methods: Patients were prospectively recruited in to one of: Group A: high-risk untreated prostate cancer; Gleason score >4+3, or PSA >20 ng/mL or clinical stage >T2c. Group B: biochemical recurrence (BCR) and eligible for salvage treatment after radical prostatectomy with two consecutive rises in prostate specific antigen (PSA) with a three month interval in between reads and final PSA >0.1 ng/mL or a PSA level >0.5 ng/mL. Group C: BCR with radical curative radiotherapy or brachytherapy at least three months prior to enrolment, and an increase in PSA level >2.0 ng/mL above the nadir level after radiotherapy or brachytherapy. Patients underwent evaluation with PET/CT 60 minutes following intravenous administration of 160±30 MBq of 68Ga-THP PSMA. Safety was assessed by means including vital signs, cardiovascular profile, serum haematology, biochemistry, urinalysis, PSA, and Adverse Events (AEs). A change in management was reported when the predefined clinical management of the patient altered as a result of 68Ga-THP PSMA PET/CT findings. Results: Forty-nine patients were evaluated with PET/CT; 20 in Group A, 21 in Group B and 8 in Group C. No patients experienced serious AEs discontinued the study due to AEs, or died during the study. Two patients had Treatment Emergent AEs attributed to 68Ga-THP-PSMA (pruritus in one patient and intravenous catheter site rash in another). Management change secondary to PET/CT occurred in 42.9% of all patients; 30% in Group A, 42.9% in Group B and 75% in Group C. Conclusion: 68Ga-THP PSMA was safe to use with no serious AE and no AE resulting in withdrawal from the study. 68Ga-THP PSMA PET/CT changed the management of patients in 42.9% of the study population, comparable to studies using other PSMA tracers. These data form the basis of a planned Phase III study of 68Ga-THP PSMA in patients with prostate cancer.

Primary lymph-node staging with 68Ga-PSMA PET in high-risk prostate cancer: pathologic correlation with extended pelvic lymphadenectomy specimens

Aim of the studyThis study aims to assess the diagnostic efficacy of Gallium-68-prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT) (68Ga PSMA PET-CT) in primary nodal staging of high-risk prostate cancer (PCa) when compared to pathologic findings of extended pelvic lymph-node dissection (eLND). Materials and methodsThe records of high-risk PCa patients who were preoperatively staged through 68Ga PSMA PET-CT and who underwent robot-assisted radical prostatectomy with eLND either alone or as part of multimodal definitive therapy between August 2016 and November 2019 were retrospectively reviewed. Surgeons were not blinded to the results of the 68Ga PSMA PET-CT scan. Pathologic uptake was defined as any anomalous uptake which was not better explained by another cause and was suggestive of PCa. The reference standard for this study was the pathologic confirmation using a node-based analysis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 68Ga PSMA PET-CT were calculated in a per-patient analysis using IBM SPSS Statistics version 25. ResultsSeventeen patients met the selection criteria. Mean age was 63 years (range 44–77) and mean and median preoperative serum prostate specific antigen was 19.25 and 9 ng/ml (range 6–131), respectively. The most common pathologic Gleason score was 8 (52.9% of cases). Seven patients (41%) had positive surgical margins and were submitted to adjuvant radiotherapy. Mean number of per patient removed lymph-nodes was 13 (±2.19). 68Ga PSMA PET-CT showed findings compatible with lymph node metastases in 4/17 patients and with locally-confined disease in 13/17 patients. Following pathologic confirmation, the per-patient sensibility of the 68Ga PSMA PET-CT was calculated at 75% (1 false negative) and the specificity at 92.3% (1 false positive) for detection of lymph node metastasis on primary staging of high-risk PCa patients. Positive and negative predictive value were 75% and 92.3%, respectively; accuracy of the test was calculated at 88.2%. All patients were submitted to 68Ga PSMA PET-CT re-evaluation 6 months after surgery and tested negative for local, nodal, or distant recurrence of disease. Conclusions68Ga PSMA PET-CT appears to have a high negative predictive value for local lymph node metastases in high-risk primary PCa when compared to pathologic findings of eLND. Its role in the primary nodal staging of high-risk PCa patients worths further evaluation.

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.

Abstract 2097: AI powered platform to identify primary prostate cancer patients with high risk of recurrence

Abstract Background: To-date, there is no approved adjuvant therapy for primary prostate cancer (PCa). Long time of recurrence and a lack of a strong biomarker predicting recurrence after the first line of therapy is prohibitory to short clinical trials within a reasonable time. Artificial intelligence (AI) offers a unique opportunity for extracting critical morphological features from PCa tissues as prognostic marker that have evaded human eyes. We have built a AI-based platform to analyze H&amp;E stained histological images of PCa. Our platform can accurately detect, grade and quantify PCa in patient tissue images. Here, we show how this platform can identify morphometric features that indicate biochemical recurrence within 3 years after radical prostatectomy (RP). Methods: Our dataset comprised of a cohort of 169 PCa patients who underwent RP. Whole slide H&amp;E images (WSI) of their tissue sections were scanned at 40x magnification. corresponding pathologic parameters such as Gleason grade, tumor volume, TNM staging, margin status and post-treatment follow-up data were also obtained. Among the 169 patients, 89 patients recurred within 3 years of RP. Our platform technology involved two different deep CNN (Convolutional Neural Network) architectures. The platform first divided each WSI into multiple tiles. Each tile was analyzed using a CNN that graded the tile and generated a high dimensional vector to provide a mathematical equivalent of the morphology. The combination of high dimensional vectors across the WSI was then fed into a second CNN that generated a morphological score. The clinical parameters were combined with the morphologic score using a logistic classifier to predict outcome. Results: Thus far, we have obtained 84% AUC (Area under the Curve) for the ROC (Receiver operating characteristics) curve, using 10-fold cross-validation. In contrast, the most predictive clinical covariate was the T stage with 71% AUC. Conclusion: Our AI based platform can identify high risk PCa patients early for tumor progression post RP and may be selected for more cost effective and much shorter Clinical Trials necessary to develop adjuvant therapy. Citation Format: Wei Huang, Parag Jain, Raman Randhawa, Bijay Jaiswal, Samuel Hubbard, Hirak Basu, Rajat Roy. AI powered platform to identify primary prostate cancer patients with high risk of recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2097.

Clinical impact of PSMA PET/CT in primary prostate cancer compared to conventional nodal and distant staging: a retrospective single center study

BackgroundTo evaluate the impact of Gallium-68 [68Ga] labeled prostate specific membrane antigen (PSMA) positron emission tomography (PET)/X-ray computed tomography (CT) compared with conventional imaging on staging and clinical management of men evaluated for primary prostate cancer (PCa).MethodsMen with newly diagnosed biopsy-proven PCa who had been staged with a conventional staging protocol including bone scintigraphy (BS) and additionally underwent [68Ga]PSMA PET/CT, were evaluated retrospectively. Imaging findings from BS, magnetic resonance imaging (MRI) and/or CT were categorized regarding locoregional nodal (N) and distant metastasis (M) status as negative, positive or equivocal before and after addition of the information of PET/CT. Also, the imaging-based level of confidence (LoC) in correct assessment of N and M status was scored. Impact of PET/CT on clinical management was evaluated by the percentage of treatment category changes after PET/CT as determined in the multidisciplinary tumour board.ResultsSixty-four men with intermediate and high-risk PCa were evaluated. With additional information of PET/CT, N status was upstaged in 23%, and downstaged in 9%. M status was upstaged in 13%, and downstaged in 23%. A net increase in LoC of 20% was noted, mainly regarding M status.Treatment category changed from palliative to curative in 9%, and from curative to palliative in 3%. An undecided treatment plan changed to curative in 14%, as well as to palliative in another 9%. In total, a 36% treatment category change was noted.High negative predictive value of PET/CT for M status was indicated by 27 patients that underwent robot-assisted radical prostatectomy and reached postoperative biochemical disease-free status or had a likely other site of disease recurrence.ConclusionsPSMA PET/CT can cause considerable changes in N and M staging, as well as in management compared to conventional staging. Findings of this study support the replacement of BS and CT by PSMA PET/CT in staging primary PCa.