Combining PSMA-PET and PROMISE to re-define disease stage and risk in patients with prostate cancer: a multicentre retrospective study.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting. We aimed to compare the prognostic value of PSMA-PET by PROMISE (PPP) stage with established clinical nomograms in a large prostate cancer dataset with follow-up data for overall survival. METHODS: In this multicentre retrospective study, we used data from patients of any age with histologically proven prostate cancer who underwent PSMA-PET at the University Hospitals in Essen, Münster, Freiburg, and Dresden, Germany, between Oct 30, 2014, and Dec 27, 2021. We linked a subset of patient hospital records with patient data, including mortality data, from the Cancer Registry North-Rhine Westphalia, Germany. Patients from Essen University Hospital were randomly assigned to the development or internal validation cohorts (2:1). Patients from Münster, Freiburg, and Dresden University Hospitals were included in an external validation cohort. Using the development cohort, we created quantitative and visual PPP nomograms based on Cox regression models, assessing potential PPP predictors for overall survival, with least absolute shrinkage and selection operator penalty for overall survival as the primary endpoint. Performance was measured using Harrell's C-index in the internal and external validation cohorts and compared with established clinical risk scores (International Staging Collaboration for Cancer of the Prostate [STARCAP], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN] risk scores) and a previous nomogram defined by Gafita et al (hereafter referred to as GAFITA) using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) estimates. FINDINGS: We analysed 2414 male patients (1110 included in the development cohort, 502 in the internal cohort, and 802 in the external validation cohort), among whom 901 (37%) had died as of data cutoff (June 30, 2023; median follow-up of 52·9 months [IQR 33·9-79·0]). Predictors in the quantitative PPP nomogram were locoregional lymph node metastases (molecular imaging N2), distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases), tumour volume (in L), and tumour mean standardised uptake value. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases) and total tumour lesion count. In the internal and external validation cohorts, C-indices were 0·80 (95% CI 0·77-0·84) and 0·77 (0·75-0·78) for the quantitative nomogram, respectively, and 0·78 (0·75-0·82) and 0·77 (0·75-0·78) for the visual nomogram, respectively. In the combined development and internal validation cohort, the quantitative PPP nomogram was superior to STARCAP risk score for patients at initial staging (n=139 with available staging data; AUC 0·73 vs 0·54; p=0·018), EAU risk score at biochemical recurrence (n=412; 0·69 vs 0·52; p<0·0001), and NCCN pan-stage risk score (n=1534; 0·81 vs 0·74; p<0·0001) for the prediction of overall survival, but was similar to GAFITA nomogram for metastatic hormone-sensitive prostate cancer (mHSPC; n=122; 0·76 vs 0·72; p=0·49) and metastatic castration-resistant prostate cancer (mCRPC; n=270; 0·67 vs 0·75; p=0·20). The visual PPP nomogram was superior to EAU at biochemical recurrence (n=414; 0·64 vs 0·52; p=0·0004) and NCCN across all stages (n=1544; 0·79 vs 0·73; p<0·0001), but similar to STARCAP for initial staging (n=140; 0·56 vs 0·53; p=0·74) and GAFITA for mHSPC (n=122; 0·74 vs 0·72; p=0·66) and mCRPC (n=270; 0·71 vs 0·75; p=0·23). INTERPRETATION: Our PPP nomograms accurately stratify high-risk and low-risk groups for overall survival in early and late stages of prostate cancer and yield equal or superior prediction accuracy compared with established clinical risk tools. Validation and improvement of the nomograms with long-term follow-up is ongoing (NCT06320223). FUNDING: Cancer Registry North-Rhine Westphalia.

Implementation of PET/CT in radiation oncology-a patterns-of-care analysis of the German Society of Nuclear Medicine and the German Society of Radiation Oncology.

BACKGROUND: The use of positron-emission tomography (PET)/computed tomography (CT) in radiation therapy (RT) has increased. Radiation oncologists (RadOncs) have access to PET/CT with a variety of tracers for different tumor entities and use it for target volume definition. The German Society of Nuclear Medicine (DGN) and the German Society of Radiation Oncology (DEGRO) aimed to identify current patterns of care in order to improve interdisciplinary collaboration. METHODS: We created an online survey on participating RadOncs' use of PET tracers for different tumor entities and how they affect RT indication, dose prescription, and target volume definition. Further topics were reimbursement of PET/CT and organizational information (fixed timeslots and use of PET with an immobilization device [planning/RT-PET]). The survey contained 31 questions in German language (yes/no questions, multiple choice [MC] questions, multiple select [MS] questions, and free-text entry options). The survey was distributed twice via the DEGRO member mailing list. RESULTS: During the survey period (May 22-August 7, 2023) a total of 156 RadOncs (13% of respondents) answered the survey. Among these, 59% reported access to diagnostic PET/CT within their organization/clinic and 24% have fixed timeslots for their patients. 37% of survey participants can perform RT-PET and 29% have the option of providing a dedicated RT technician for planning PET. Besides [18F]-fluorodeoxyglucose (FDG; mainly used in lung cancer: 95%), diagnostic prostate-specific membrane antigen (PSMA)-PET/CT for RT of prostate cancer is routinely used by 44% of participants (by 64% in salvage RT). Use of amino acid PET in brain tumors and somatostatin receptor PET in meningioma is low (19 and 25%, respectively). Scans are reimbursed through private (75%) or compulsory (55%) health insurance or as part of indications approved by the German Joint Federal Committee (Gemeinsamer Bundesausschuss; 59%). 98% of RadOncs agree that PET impacts target volume definition and 62% think that it impacts RT dose prescription. DISCUSSION: This is the first nationwide survey on the role of PET/CT for RT planning among RadOncs in Germany. We find high acceptance of PET results for treatment decisions and target volume definition. Planning PET comes with logistic challenges for different healthcare settings (e.g., private practices vs. university hospitals). The decision to request PET/CT is often based on the possibility of reimbursement. CONCLUSION: PET/CT has become an important tool for RadOncs, with several indications. However, access is still limited at several sites, especially for dedicated RT-PET. This study aims to improve interdisciplinary cooperation and adequate implementation of current guidelines for the treatment of various tumor entities.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT.

BACKGROUND: Historically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment. METHODS: The institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test. RESULTS: Patients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54-5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03-2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS. CONCLUSIONS: Baseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on [68Ga]Ga-/[18F]F-PSMA-11/-1007, [68Ga]Ga-FAPI-46 and 2-[18F]FDG PET/CT: a pilot study.

PURPOSE: In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET. MATERIAL AND METHODS: Patients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low [68Ga]Ga-/[18F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met. RESULTS: In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months). CONCLUSION: Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.

Response Evaluation Criteria in PSMA PET/CT (RECIP 1.0) in Metastatic Castration-resistant Prostate Cancer.

Background Response Evaluation Criteria in Prostate-specific Membrane Antigen (PSMA) PET/CT (RECIP 1.0) initially integrated software-based quantitative assessment of PSMA-positive total tumor volume (TTV). Clinical implementation of such software is not expected soon, limiting the use of RECIP in practice. Purpose To assess the agreement of RECIP determined using tumor segmentation software (quantitative RECIP) with RECIP determined by qualitative reads by nuclear medicine physicians (visual RECIP) for response evaluation in metastatic castration-resistant prostate cancer. Materials and Methods This multicenter retrospective study at three academic centers included men who received lutetium 177 (177Lu) PSMA treatment between December 2014 and July 2019. PSMA PET/CT images at baseline and 12 weeks were assessed qualitatively by five readers for changes in TTV and for new lesions. Quantitative changes in TTV were also measured using tumor segmentation software. The status of new lesions was combined with qualitative changes in TTV to determine visual RECIP and with quantitative changes in TTV to determine quantitative RECIP. The primary outcomes were the agreement between visual and quantitative RECIP and the interreader reliability of visual RECIP according to the Fleiss κ. The secondary outcome was the association of visual RECIP with overall survival according to Cox regression. Results A total of 124 men (median age, 73 years [IQR, 67-76 years]) were included. Forty (32%) and 84 (68%) men had quantitative RECIP progressive disease (PD) and non-PD, respectively. Agreement between visual versus quantitative RECIP was excellent (κ = 0.89; 118 of 124 men [95%]). Agreement among readers in classifying visual RECIP PD versus non-PD was excellent (κ = 0.81; 103 of 124 men [83%]). RECIP PD was associated with significantly shorter overall survival compared with non-PD (hazard ratio, 2.6 [95% CI: 1.7, 3.8]; P < .001). Conclusion Qualitatively assessed RECIP demonstrated excellent agreement with quantitative RECIP and excellent interreader reliability and can be readily implemented in clinical practice for response evaluation in men with metastatic castration-resistant prostate cancer undergoing 177Lu-PSMA therapy. © RSNA, 2023 Supplemental material is available for this article.

Evaluation of thresholding methods for the quantification of [68Ga]Ga-PSMA-11 PET molecular tumor volume and their effect on survival prediction in patients with advanced prostate cancer undergoing [177Lu]Lu-PSMA-617 radioligand therapy.

PURPOSE: The aim of this study was to systematically evaluate the effect of thresholding algorithms used in computer vision for the quantification of prostate-specific membrane antigen positron emission tomography (PET) derived tumor volume (PSMA-TV) in patients with advanced prostate cancer. The results were validated with respect to the prognostication of overall survival in patients with advanced-stage prostate cancer. MATERIALS AND METHODS: A total of 78 patients who underwent [177Lu]Lu-PSMA-617 radionuclide therapy from January 2018 to December 2020 were retrospectively included in this study. [68Ga]Ga-PSMA-11 PET images, acquired prior to radionuclide therapy, were used for the analysis of thresholding algorithms. All PET images were first analyzed semi-automatically using a pre-evaluated, proprietary software solution as the baseline method. Subsequently, five histogram-based thresholding methods and two local adaptive thresholding methods that are well established in computer vision were applied to quantify molecular tumor volume. The resulting whole-body molecular tumor volumes were validated with respect to the prognostication of overall patient survival as well as their statistical correlation to the baseline methods and their performance on standardized phantom scans. RESULTS: The whole-body PSMA-TVs, quantified using different thresholding methods, demonstrate a high positive correlation with the baseline methods. We observed the highest correlation with generalized histogram thresholding (GHT) (Pearson r (r), p value (p): r = 0.977, p < 0.001) and Sauvola thresholding (r = 0.974, p < 0.001) and the lowest correlation with Multiotsu (r = 0.877, p < 0.001) and Yen thresholding methods (r = 0.878, p < 0.001). The median survival time of all patients was 9.87 months (95% CI [9.3 to 10.13]). Stratification by median whole-body PSMA-TV resulted in a median survival time from 11.8 to 13.5 months for the patient group with lower tumor burden and 6.5 to 6.6 months for the patient group with higher tumor burden. The patient group with lower tumor burden had significantly higher probability of survival (p < 0.00625) in eight out of nine thresholding methods (Fig. 2); those methods were SUVmax50 (p = 0.0038), SUV ≥3 (p = 0.0034), Multiotsu (p = 0.0015), Yen (p = 0.0015), Niblack (p = 0.001), Sauvola (p = 0.0001), Otsu (p = 0.0053), and Li thresholding (p = 0.0053). CONCLUSION: Thresholding methods commonly used in computer vision are promising tools for the semiautomatic quantification of whole-body PSMA-TV in [68Ga]Ga-PSMA-11-PET. The proposed algorithm-driven thresholding strategy is less arbitrary and less prone to biases than thresholding with predefined values, potentially improving the application of whole-body PSMA-TV as an imaging biomarker.

PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0.

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed. This document provides clinicians and technicians with the best available evidence, to support the implementation of PSMA PET/CT imaging in research and routine practice.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Bone Metastases in Patients with Pancreatic NETs: Prevalence and Prognosis.

The clinical relevance of bone metastases (BM) in advanced pancreatic neuroendocrine tumors (PanNETs) is poorly described. We analyzed 314 consecutive PanNET patients treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2021 in terms of the occurrence and clinical and prognostic impact of BM using hybrid imaging with 68Ga-DOTATOC PET/CT. According to UICC staging, 171/314 (54.5%) patients had stage IV PanNETs. BM was diagnosed in 62/171 (36.3%) patients. Initially, 35% of BMs were visible by pathological tracer uptake only. Skeletal-related events (SREs) were detected in 11 of the 62 patients (17.7%). Patients with antiresorptive therapy had a significantly lower rate of SRE (2/36, 5.6%) than individuals without bone-specific therapy (9/26, 34.6%) (odds ratio 9.0, p=0.0054, Fisher's exact test). The median overall survival (OS) was 82 months (53.6-110.4, 95% CI) in the stage IV PanNET cohort. The median OS was significantly lower for patients with BM (63 months; 49.9-76.0, 95% CI) than for patients with distant metastases other than BM (116 months; 87.6-144.3, 95% CI) (p=0.016, log-rank test). BM occurs in more than one-third of advanced PanNETs and is associated with an unfavorable prognosis. One in five patients experiences a persistent quality-of-life-lowering SRE. Antiresorptive therapy is associated with a more favorable risk of SREs and should be offered to all patients with BM in PanNETs.

[18F]FDG PET/MRI in children suffering from lymphoma: does MRI contrast media make a difference?

OBJECTIVES: Evaluate the influence of an MRI contrast agent application on primary and follow-up staging in pediatric patients with newly diagnosed lymphoma using [18F]FDG PET/MRI to avoid adverse effects and save time and costs during examination. METHODS: A total of 105 [18F]FDG PET/MRI datasets were included for data evaluation. Two different reading protocols were analyzed by two experienced readers in consensus, including for PET/MRI-1 reading protocol unenhanced T2w and/or T1w imaging, diffusion-weighted imaging (DWI), and [18F]FDG PET imaging and for PET/MRI-2 reading protocol an additional T1w post contrast imaging. Patient-based and region-based evaluation according to the revised International Pediatric Non-Hodgkin's Lymphoma (NHL) Staging System (IPNHLSS) was performed, and a modified standard of reference was applied comprising histopathology and previous and follow-up cross-sectional imaging. Differences in staging accuracy were assessed using the Wilcoxon and McNemar tests. RESULTS: In patient-based analysis, PET/MRI-1 and PET/MRI-2 both determined a correct IPNHLSS tumor stage in 90/105 (86%) exams. Region-based analysis correctly identified 119/127 (94%) lymphoma-affected regions. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for PET/MRI-1 and PET/MRI-2 were 94%, 97%, 90%, 99%, 97%, respectively. There were no significant differences between PET/MRI-1 and PET/MRI-2. CONCLUSIONS: The use of MRI contrast agents in [18F]FDG PET/MRI examinations has no beneficial effect in primary and follow-up staging of pediatric lymphoma patients. Therefore, switching to a contrast agent-free [18F]FDG PET/MRI protocol should be considered in all pediatric lymphoma patients. CLINICAL RELEVANCE STATEMENT: This study gives a scientific baseline switching to a contrast agent-free [18F]FDG PET/MRI staging in pediatric lymphoma patients. This could avoid side effects of contrast agents and saves time and costs by a faster staging protocol for pediatric patients. KEY POINTS: • No additional diagnostic benefit of MRI contrast agents at [18F]FDG PET/MRI examinations of pediatric lymphoma primary and follow-up staging • Highly accurate primary and follow-up staging of pediatric lymphoma patients at MRI contrast-free [18F]FDG PET/MRI.

Recurrent prostate cancer: combined role for MRI and PSMA-PET in 68Ga-PSMA-11 PET/MRI.

OBJECTIVES: To investigate the specific strengths of MRI and PET components in 68Ga-PSMA-11 PET/MRI for staging of patients with biochemically recurrent prostate cancer (PCa). METHODS: Patients with biochemical recurrence of PCa and contrast-enhanced whole-body 68Ga-PSMA-11 PET/MRI including a dedicated pelvic multiparametric MRI were included in this retrospective study. Imaging datasets of MRI and PET were evaluated separately regarding local PCa recurrence (Tr), pelvic lymph node metastases (N1), distant lymph node metastases (M1a), bone metastases (M1b), and soft tissue metastases (M1c) according to PROMISE version 1. Data evaluation was performed patient- and region-/lesion-based. Cox regression revealed a PSA of 1.69 ng/mL as a cut-off for subgroup analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were evaluated for each image component. Differences in staging accuracy were assessed using the Wilcoxon and McNemar test. RESULTS: Altogether 102 patients (mean aged 68 ± 8 years, median PSA 1.33 ng/mL) were included. PCa was found in 70/102 (68%) patients. Accuracy of MRI in the detection of Tr, N1, M + , M1a, and M1b was 100%, 79%, 90%, 97%, and 95% for PSA < 1.69 ng/mL and 100%, 87%, 87%, 91%, and 96% for PSA > 1.69 ng/mL. Accuracy of 68Ga-PSMA-11 PET was 93%, 97%, 93%, 98%, and 100% for PSA < 1.69 ng/mL and 87%, 91%, 96%, 100%, and 96% for PSA > 1.69 ng/mL. CONCLUSIONS: Combined assessment of 68Ga-PSMA-11 PET/MRI improves tumor localization in men with biochemical recurrence. The MRI detected local recurrence of PCa more often whereas 68 Ga-PSMA-11 PET detected lymph node metastases more often, especially for PSA < 1.69 ng/mL. CLINICAL RELEVANCE STATEMENT: This study gives a scientific baseline to improve the understanding and reading of 68Ga-PSMA-11 PET/MRI imaging in patients with biochemically recurrent PCa by showing the specific strength of each imaging component. KEY POINTS: • Combining the individual modality strengths of 68Ga-PSMA-11 PET/MRI improves tumor localization in men with biochemical recurrence of prostate cancer. • MRI component of 68 Ga-PSMA-11 PET/MRI shows its strength in detecting local recurrence of prostate cancer, especially at PSA < 1.69 ng/mL. • 68 Ga-PSMA-11 PET component shows its strength in detecting local and distant lymph node metastases, especially at PSA < 1.69 ng/mL.

Reduction of emission time for [68Ga]Ga-PSMA PET/CT using the digital biograph vision: a phantom study.

BACKGROUND: The aim of this phantom study was to optimize the [68Ga]Ga-PSMA PET/CT examination in terms of scan time duration and image reconstruction parameters, in combination with PSF and TOF modelling, in a digital Biograph Vision PET/CT scanner. METHODS: Three types of phantoms were used: 1) soft-tissue tumor phantom consisting of six spheres mounted in a torso phantom; 2) bone-lung tumor phantom; 3) resolution phantom. Phantom inserts were filled with activity concentrations (ACs) that were derived from clinical data. Phantom data were acquired in list-mode at one bed position. Images with emission data ranging from 30 to 210 s in 30-s increments were reconstructed from a reference image acquired with 3.5-min emission. Iterative image reconstruction (OSEM), point-spread-function (PSF) and time-of-flight (TOF) options were applied using different iterations, Gaussian filters, and voxel sizes. The criteria for image quality was lesion detectability and lesion quantification, evaluated as contrast-to-noise ratio (CNR) and maximum AC (peak AC), respectively. A threshold value of CNR above 6 and percentage maximum AC (peak AC) deviation range of ±20% of the reference image were considered acceptable. The proposed single-bed scan time reduction was projected to a whole-body examination (patient validation scan) using the continuous-bed-motion mode. RESULTS: Sphere and background ACs of 20 kBq/mL and 1 kBq/mL were selected, respectively. The optimized single-bed scan time was approximately 60 s using OSEM-TOF or OSEM-TOF+PSF (four iterations, 4.0-mm Gaussian filter and almost isotropic voxel size of 3.0-mm side length), resulting in a PET spatial resolution of 6.3 mm for OSEM-TOF and 5.5 mm for OSEM-TOF+PSF. In the patient validation, the maximum percentage difference in lesion quantification between standard and optimized protocol (whole-body scan time of 15 vs. 5 min) was below 19%. CONCLUSIONS: A reduction of single-bed and whole-body scan time for [68Ga]Ga-PSMA PET/CT compared to current recommended clinical acquisition protocols is postulated. Clinical studies are warranted to validate the applicability of this protocol.

Measuring response in metastatic castration-resistant prostate cancer using PSMA PET/CT: comparison of RECIST 1.1, aPCWG3, aPERCIST, PPP, and RECIP 1.0 criteria.

PURPOSE: To compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the adapted Prostate Cancer Working Group Criteria 3 (aPCWG3), the adapted Positron Emission Tomography Response Criteria in Solid Tumors (aPERCIST), the PSMA PET Progression (PPP), and the Response Evaluation Criteria In PSMA-Imaging (RECIP) 1.0 for response evaluation using prostate-specific membrane antigen (PSMA)-PET/CT in men with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy. METHODS: A total of 124 patients were included in this multicenter retrospective study. All patients received 177Lu-PSMA and underwent PSMA-PET/CT scans at baseline (bPET) and at 12 weeks (iPET). Imaging responses according to RECIST 1.1, aPCWG3, aPERCIST, PPP, and RECIP 1.0 were interpreted by consensus among three blinded readers. Changes in total tumor burden were obtained using the semi-automatic qPSMA software. The response according to each criterion was classified to progressive disease (PD) vs no-PD. Primary outcome measure was the prognostic value (by Cox regression analysis) for overall survival (OS). Secondary outcome measure was the inter-reader reliability (by Cohen's κ coefficient). RESULTS: A total of 43 (35%) of patients had non-measurable disease according to RECIST 1.1. Sixteen (13%), 66 (52%), 72 (58%), 69 (56%), and 39 (32%) of 124 patients had PD according to RECIST 1.1, aPCWG3, aPERCIST, PPP, and RECIP, respectively. PD vs no-PD had significantly higher risk of death according to aPCWG3 (HR = 2.37; 95%CI, 1.62-3.48; p < 0.001), aPERCIST (HR = 2.48; 95%CI, 1.68-3.66; p < 0.001), PPP (HR = 2.72; 95%CI, 1.85-4.01; p < 0.001), RECIP 1.0 (HR = 4.33; 95%CI, 2.80-6.70; p < 0.001), but not according to RECIST 1.1 (HR = 1.29; 95%CI, 0.73-2.27; p = 0.38). The κ index of RECIST 1.1, aPCWG3, aPERCIST 1.0, PPP, and RECIP 1.0 for identifying PD vs no-PD were 0.50 (95%CI, 0.32-0.76), 0.72 (95%CI, 0.63-0.82), 0.68 (95%CI, 0.63-0.73), 0.73 (95%CI, 0.63-0.83), and 0.83 (95%CI, 0.77-0.88), respectively. CONCLUSION: PSMA-PET-specific criteria for early response evaluation in men with mCRPC treated with 177Lu-PSMA achieved higher prognostic values and inter-reader reliabilities in comparison to conventional CT assessment or to criteria adapted to PSMA-PET from other imaging modalities. RECIP 1.0 identified the fewest patients with PD and achieved the highest risk of death for PD vs. no-PD, suggesting that other classification methods tend to overcall progression. Prospective validation of our findings on an independent patient cohort is warranted.

Phantom-based acquisition time and image reconstruction parameter optimisation for oncologic FDG PET/CT examinations using a digital system.

BACKGROUND: New-generation silicon-photomultiplier (SiPM)-based PET/CT systems exhibit an improved lesion detectability and image quality due to a higher detector sensitivity. Consequently, the acquisition time can be reduced while maintaining diagnostic quality. The aim of this study was to determine the lowest 18F-FDG PET acquisition time without loss of diagnostic information and to optimise image reconstruction parameters (image reconstruction algorithm, number of iterations, voxel size, Gaussian filter) by phantom imaging. Moreover, patient data are evaluated to confirm the phantom results. METHODS: Three phantoms were used: a soft-tissue tumour phantom, a bone-lung tumour phantom, and a resolution phantom. Phantom conditions (lesion sizes from 6.5 mm to 28.8 mm in diameter, lesion activity concentration of 15 kBq/mL, and signal-to-background ratio of 5:1) were derived from patient data. PET data were acquired on an SiPM-based Biograph Vision PET/CT system for 10 min in list-mode format and resampled into time frames from 30 to 300 s in 30-s increments to simulate different acquisition times. Different image reconstructions with varying iterations, voxel sizes, and Gaussian filters were probed. Contrast-to-noise-ratio (CNR), maximum, and peak signal were evaluated using the 10-min acquisition time image as reference. A threshold CNR value ≥ 5 and a maximum (peak) deviation of ± 20% were considered acceptable. 20 patient data sets were evaluated regarding lesion quantification as well as agreement and correlation between reduced and full acquisition time standard uptake values (assessed by Pearson correlation coefficient, intraclass correlation coefficient, Bland-Altman analyses, and Krippendorff's alpha). RESULTS: An acquisition time of 60 s per bed position yielded acceptable detectability and quantification results for clinically relevant phantom lesions ≥ 9.7 mm in diameter using OSEM-TOF or OSEM-TOF+PSF image reconstruction, a 4-mm Gaussian filter, and a 1.65 × 1.65 x 2.00-mm3 or 3.30 × 3.30 x 3.00-mm3 voxel size. Correlation and agreement of patient lesion quantification between full and reduced acquisition times were excellent. CONCLUSION: A threefold reduction in acquisition time is possible. Patients might benefit from more comfortable examinations or reduced radiation exposure, if instead of the acquisition time the applied activity is reduced.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Prostate-specific Membrane Antigen PET in Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals are playing a large role at the time of initial staging and biochemical recurrence for localizing prostate cancer, as well as in other emerging clinical settings. PSMA PET has demonstrated increased detection rate compared with conventional imaging and has been shown to change management plans in a substantial percentage of cases. The aims of this narrative review are to highlight the development and clinical impact of PSMA PET radiopharmaceuticals, to compare PSMA to other agents such as fluorine 18 fluciclovine and carbon 11 choline, and to highlight some of the individual PSMA PET agents that have contributed to the advancement of prostate cancer imaging.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

Just another "Clever Hans"? Neural networks and FDG PET-CT to predict the outcome of patients with breast cancer.

BACKGROUND: Manual quantification of the metabolic tumor volume (MTV) from whole-body 18F-FDG PET/CT is time consuming and therefore usually not applied in clinical routine. It has been shown that neural networks might assist nuclear medicine physicians in such quantification tasks. However, little is known if such neural networks have to be designed for a specific type of cancer or whether they can be applied to various cancers. Therefore, the aim of this study was to evaluate the accuracy of a neural network in a cancer that was not used for its training. METHODS: Fifty consecutive breast cancer patients that underwent 18F-FDG PET/CT were included in this retrospective analysis. The PET-Assisted Reporting System (PARS) prototype that uses a neural network trained on lymphoma and lung cancer 18F-FDG PET/CT data had to detect pathological foci and determine their anatomical location. Consensus reads of two nuclear medicine physicians together with follow-up data served as diagnostic reference standard; 1072 18F-FDG avid foci were manually segmented. The accuracy of the neural network was evaluated with regard to lesion detection, anatomical position determination, and total tumor volume quantification. RESULTS: If PERCIST measurable foci were regarded, the neural network displayed high per patient sensitivity and specificity in detecting suspicious 18F-FDG foci (92%; CI = 79-97% and 98%; CI = 94-99%). If all FDG-avid foci were regarded, the sensitivity degraded (39%; CI = 30-50%). The localization accuracy was high for body part (98%; CI = 95-99%), region (88%; CI = 84-90%), and subregion (79%; CI = 74-84%). There was a high correlation of AI derived and manually segmented MTV (R2 = 0.91; p < 0.001). AI-derived whole-body MTV (HR = 1.275; CI = 1.208-1.713; p < 0.001) was a significant prognosticator for overall survival. AI-derived lymph node MTV (HR = 1.190; CI = 1.022-1.384; p = 0.025) and liver MTV (HR = 1.149; CI = 1.001-1.318; p = 0.048) were predictive for overall survival in a multivariate analysis. CONCLUSION: Although trained on lymphoma and lung cancer, PARS showed good accuracy in the detection of PERCIST measurable lesions. Therefore, the neural network seems not prone to the clever Hans effect. However, the network has poor accuracy if all manually segmented lesions were used as reference standard. Both the whole body and organ-wise MTV were significant prognosticators of overall survival in advanced breast cancer.

PSMA PET total tumor volume predicts outcome of patients with advanced prostate cancer receiving [177Lu]Lu-PSMA-617 radioligand therapy in a bicentric analysis.

INTRODUCTION: [177Lu]Lu-PSMA-617 (Lu-PSMA) radioligand therapy is an emerging treatment option for patients with end-stage prostate cancer. However, response to Lu-PSMA therapy is only achieved in approximately half of patients. It is clinically important to identify patients at risk of poor outcome. Therefore, the aim of this study was to evaluate pretherapeutic PSMA PET derived total tumor volume and related metrics as prognosticators of overall survival in patients receiving Lu-PSMA therapy. METHODS: A total number of 110 patients form the Departments of Nuclear Medicine Münster and Essen were included in this retrospective analysis. Baseline PSMA PET-CT was available for all patients. Employing a previously published approach, all tumor lesions were semi-automatically delineated in PSMA PET-CT acquisitions. Total lesion number, total tumor volume (PSMA-TV), total lesion uptake (PSMA-TLU = PSMA-TV * SUVmean), and total lesion quotient (PSMA-TLQ = PSMA-TV / SUVmean) were quantified for each patient. Log2 transformation was used for regressions. RESULTS: Lesion number, PSMA-TV, and PSMA-TLQ were prognosticators of overall survival (HR = 1.255, p = 0.009; HR = 1.299, p = 0.005; HR = 1.326, p = 0.002). In a stepwise backward Cox regression including lesion number, PSMA-TV, PSA, LDH, and PSMA-TLQ, only the latter two remained independent and statistically significant negative prognosticators of overall survival (HR = 1.632, p = 0.011; HR = 1.239, p = 0.024). PSMA-TLQ and LDH were significant negative prognosticators in multivariate Cox regression in contrast to PSA value. CONCLUSION: PSMA-TV was a statistically significant negative prognosticator of overall survival in patients receiving Lu-PSMA therapy. PSMA-TLQ was an independent and superior prognosticator of overall survival compared with PSMA-TV.

False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial.

PURPOSE: Readers need to be informed about potential pitfalls of [68Ga]Ga-PSMA-11 PET interpretation. METHODS: Here we report [68Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer. RESULTS: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake. CONCLUSION: [68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [68Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.