Prostate-Specific Membrane Antigen: Gateway to Management of Advanced Prostate Cancer.

Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of 177Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.

Image-based dosimetry for [225Ac]Ac-PSMA-I&T therapy and the effect of daughter-specific pharmacokinetics.

PURPOSE: Although 221Fr and 213Bi have sufficient gamma emission probabilities, quantitative SPECT after [225Ac]Ac-PSMA-I&T therapy remains challenging due to low therapeutic activities. Furthermore, 221Fr and 213Bi may underlie a different pharmacokinetics due to alpha recoil. We conducted a quantitative SPECT study and a urine analysis to investigate the pharmacokinetics of 221Fr and 213Bi and the impact on image-based lesion and kidney dosimetry. METHODS: Five patients (7.7 ± 0.2 MBq [225Ac]Ac-PSMA-I&T) underwent an abdominal SPECT/CT (1 h) at 24 and 48 h (Siemens Symbia T2, high-energy collimator, 440 keV/218 keV (width 20%), 78 keV (width 50%)). Quantitative SPECT was reconstructed using MAP-EM with attenuation and transmission-dependent scatter corrections and resolution modelling. Time-activity curves for kidneys (CT-based) and lesions (80% isocontour 24 h) were fitted mono-exponentially. Urine samples collected along with each SPECT/CT were measured in a gamma counter until secular equilibrium was reached. RESULTS: Mean kidney and lesion effective half-lives were as follows: 213Bi, 27 ± 6/38 ± 10 h; 221Fr, 24 ± 6/38 ± 11 h; 78 keV, 23 ± 7/39 ± 13 h. The 213Bi-to-221Fr kidney SUV ratio increased by an average of 9% from 24 to 48 h. Urine analysis revealed an increasing 213Bi-to-225Ac ratio (24 h, 0.98 ± 0.15; 48 h, 1.08 ± 0.09). Mean kidney and lesion absorbed doses were 0.17 ± 0.06 and 0.36 ± 0.1 Sv RBE = 5 /MBq using 221Fr and 213Bi SPECT images, compared to 0.16 ± 0.05/0.18 ± 0.06 and 0.36 ± 0.1/0.38 ± 0.1 Sv RBE = 5 /MBq considering either the 221Fr or 213Bi SPECT. CONCLUSION: SPECT/CT imaging and urine analysis showed minor differences of up to 10% in the daughter-specific pharmacokinetics. These variances had a minimal impact on the lesion and kidney dosimetry which remained within 8%.

[68Ga]Ga-FAPI-46 PET/CT for penile cancer - a feasibility study.

PURPOSE: Penile cancer is a rare entity and has a good prognosis in localized stage. Delayed surgical treatment of lymphatic disease is associated with poor overall survival but conventional imaging cannot detect occult lymph node metastasis sufficiently. Imaging cancer related fibroblasts has shown promising results as non-invasive staging tool in various tumor entities but has not yet been evaluated in penile cancer. METHODS: In this single-center pilot study, patients planned for surgical treatment for penile cancer underwent preoperatively [68Ga]Ga-FAPI-46 PET/CT. Post-operative histopathology was compared to [68Ga]Ga-FAPI-46 PET/CT results. RESULTS: From January 2022 to June 2022, a total number 11 patients with histopathologically proven penile cancer underwent surgery and received [68Ga]Ga-FAPI-46 PET/CT prior therapy. 8 primary tumor sites and 4 lymph node regions were analyzed. FAPI uptake was increased on primary tumor site (SUVmax 16.2 (9.1 - 25.8)). Histopathological proven lymph node regions showed highly increased FAPI uptakes (SUVmax 17.9 (16.4 - 23.5) on [68Ga]Ga-FAPI-46 PET/CT. CONCLUSION: In this first pilot cohort, there were no false-positive FAPI uptake which might allow the detection of occult lymph node metastasis by [68Ga]Ga-FAPI-46 PET/CT and might consequently lead to omitting lymph node regions during surgery that had no increased FAPI uptake pre-operatively.

[68 Ga]Ga-FAPI-46 PET/CT for locoregional lymph node staging in urothelial carcinoma of the bladder prior to cystectomy: initial experiences from a pilot analysis.

INTRODUCTION: [68 Ga]Ga-FAPI-46 PET/CT is a novel hybrid imaging method that previously showed additional diagnostic value in the assessment of distant urothelial carcinoma lesions. We hypothesized that patients with bladder cancer benefit from [68 Ga]Ga-FAPI-46 PET/CT prior to radical cystectomy for locoregional lymph node staging. MATERIALS AND METHODS: Eighteen patients underwent [68 Ga]Ga-FAPI-46 PET/CT for evaluation of lymph node (LN) status in predefined LN regions. Two hundred twenty-nine intraoperatively removed LN served as histopathological reference standard. RESULTS: Urothelial carcinoma (UC) spread was found in ten LN in seven different regions (14.3%). Hereby, [68 Ga]Ga-FAPI-46 PET/CT was positive in four out of seven regions (57.1%) and showed significantly increased FAPI uptake compared to non-pathological regions. In the remaining three out of seven (42.9%) regions, [68 Ga]Ga-FAPI-46 PET/CT was rated negative since no pathological increased FAPI uptake was detected or the proximity of the urinary tract prevented a differentiation from physiological uptake. CT was inconspicuous in these three regions. In total, two FAP-positive LN regions were found without histopathological counterpart. Overall, sensitivity, specificity, positive predictive value, and negative predictive value were 57.1%, 95.2%, 66.7%, and 93.0% for PET imaging. CONCLUSION: In summary, this innovative [68 Ga]Ga-FAPI-46 PET/CT method showed high specificity and negative predictive value in patients with bladder UC with a future potential to optimize therapy planning.

Whole pelvis vs. hemi pelvis elective nodal radiotherapy in patients with PSMA-positive nodal recurrence after radical prostatectomy - a retrospective multi-institutional propensity score analysis.

PURPOSE: Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT. METHODS: A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2α/ß=1.5 Gy) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis. CONCLUSIONS: Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity.

Reliability and practicability of PSMA-RADS 1.0 for structured reporting of PSMA-PET/CT scans in prostate cancer patients.

OBJECTIVES: As structured reporting is increasingly used in the evaluation of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) for prostate cancer, there is a need to assess the reliability of these frameworks. This study aimed to evaluate the intra- and interreader agreement among readers with varying levels of experience using PSMA-RADS 1.0 for interpreting PSMA-PET/CT scans, even when blinded to clinical data, and therefore to determine the feasibility of implementing this reporting system in clinical practice. METHODS: PSMA-PET/CT scans of 103 patients were independently evaluated by 4 readers with different levels of experience according to the reporting and data system (RADS) for PSMA-PET/CT imaging PSMA-RADS 1.0 at 2 time points within 6 weeks. For each scan, a maximum of five target lesions were freely chosen and stratified according to PSMA-RADS 1.0. Overall scan score and compartment-based scores were assessed. Intra- and interreader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: PSMA-RADS 1.0 demonstrated excellent interreader agreement for both overall scan scores (ICC ≥ 0.91) and compartment-based scores (ICC ≥ 0.93) across all four readers. The framework showed excellent intrareader agreement for overall scan scores (ICC ≥ 0.86) and compartment-based scores (ICC ≥ 0.95), even among readers with varying levels of experience. CONCLUSIONS: PSMA-RADS 1.0 is a reliable method for assessing PSMA-PET/CT with strong consistency and agreement among readers. It shows great potential for establishing a standard approach to diagnosing and planning treatment for prostate cancer patients, and can be used confidently even by readers with less experience. CLINICAL RELEVANCE STATEMENT: This study underlines that PSMA-RADS 1.0 is a valuable and highly reliable scoring system for PSMA-PET/CT scans of prostate cancer patients and can be used confidently by radiologists with different levels of experience in routine clinical practice. KEY POINTS: PSMA-RADS version 1.0 is a scoring system for PSMA-PET/CT scans. Its reproducibility needs to be analyzed in order to make it applicable to clinical practice. Excellent interreader and intrareader agreement for overall scan scores and compartment-based scores using PSMA-RADS 1.0 were seen in readers with varying levels of experience. PSMA-RADS 1.0 is a reliable tool for accurately diagnosing and planning treatment for prostate cancer patients, and can be used confidently in clinical routine.

Combination of pre-treatment dynamic [18F]FET PET radiomics and conventional clinical parameters for the survival stratification in patients with IDH-wildtype glioblastoma.

PURPOSE: The aim of this study was to build and evaluate a prediction model which incorporates clinical parameters and radiomic features extracted from static as well as dynamic [18F]FET PET for the survival stratification in patients with newly diagnosed IDH-wildtype glioblastoma. METHODS: A total of 141 patients with newly diagnosed IDH-wildtype glioblastoma and dynamic [18F]FET PET prior to surgical intervention were included. Patients with a survival time ≤ 12 months were classified as short-term survivors. First order, shape, and texture radiomic features were extracted from pre-treatment static (tumor-to-background ratio; TBR) and dynamic (time-to-peak; TTP) images, respectively, and randomly divided into a training (n = 99) and a testing cohort (n = 42). After feature normalization, recursive feature elimination was applied for feature selection using 5-fold cross-validation on the training cohort, and a machine learning model was constructed to compare radiomic models and combined clinical-radiomic models with selected radiomic features and clinical parameters. The area under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive values were calculated to assess the predictive performance for identifying short-term survivors in both the training and testing cohort. RESULTS: A combined clinical-radiomic model comprising six clinical parameters and six selected dynamic radiomic features achieved highest predictability of short-term survival with an AUC of 0.74 (95% confidence interval, 0.60-0.88) in the independent testing cohort. CONCLUSIONS: This study successfully built and evaluated prediction models using [18F]FET PET-based radiomic features and clinical parameters for the individualized assessment of short-term survival in patients with a newly diagnosed IDH-wildtype glioblastoma. The combination of both clinical parameters and dynamic [18F]FET PET-based radiomic features reached highest accuracy in identifying patients at risk. Although the achieved accuracy level remained moderate, our data shows that the integration of dynamic [18F]FET PET radiomic data into clinical prediction models may improve patient stratification beyond established prognostic markers.

Biodistribution and dosimetry for combined [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy using multi-isotope quantitative SPECT imaging.

PURPOSE: Quantitative SPECT for patient-specific dosimetry is a valuable tool in the scope of radionuclide therapy, although its clinical application for 225Ac-based treatments may be limited due to low therapeutic activities. Therefore, the aim of this study was to demonstrate the feasibility of clinical quantitative low-count SPECT imaging during [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T treatment. METHODS: Eight prostate cancer patients (1000 MBq/8 MBq [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T) received a single-bed quantitative 177Lu/225Ac SPECT/CT acquisition (1 h) at 24 h post treatment (high-energy collimator, 16 projections p. head à 3.5 min, 128 × 128 pixel). The gamma peak at 440 keV (width: 10%) of the progeny 213Bi was imaged along with the peak at 208 keV (width: 15%) of 177Lu. Quantification included CT-based attenuation and window-based scatter correction plus resolution modelling. Gaussian post-filtering with a full-width-half-maximum of 30 mm and 40-45 mm was employed to match the signal-to-noise ratio of 225Ac and 177Lu, respectively. RESULTS: Kidney (r = 0.96, p < 0.01) and lesion (r = 0.94, p < 0.01) SUV for [177Lu]Lu-PSMA-I&T and [225Ac]Ac-PSMA-I&T showed a strong and significant correlation. Kidney SUV were significantly higher (p < 0.01) for [225Ac]Ac-PSMA-I&T (2.5 ± 0.8 vs. 2.1 ± 0.9), while for [177Lu]Lu-PSMA-I&T lesion SUV were significantly higher (p = 0.03; 1.8 ± 1.1 vs. 2.1 ± 1.5). For absorbed dose estimates, significant differences regarding the kidneys remained, while no significant differences for lesion dosimetry were found. CONCLUSION: Quantitative low-count SPECT imaging of the peak at 440 keV during [225Ac]Ac-PSMA-I&T therapy is feasible. Multi-isotope imaging for [177Lu]Lu-PSMA-I&T/[225Ac]Ac-PSMA-I&T therapy indicates accumulation of free 213Bi in the kidneys.

Metabolic patterns on [18F]FDG PET/CT in patients with unresectable stage III NSCLC undergoing chemoradiotherapy ± durvalumab maintenance treatment.

PURPOSE: In patients with unresectable stage III non-small-cell lung cancer (NSCLC), durvalumab maintenance treatment after chemoradiotherapy (CRT) significantly improves survival. So far, however, metabolic changes of tumoral lesions and secondary lymphoid organs under durvalumab are unknown. Hence, we assessed changes on [18F]FDG PET/CT in comparison to patients undergoing CRT alone. METHODS: Forty-three patients with [18F]FDG PET/CT both before and after standard CRT for unresectable stage III NSCLC were included, in 16/43 patients durvalumab maintenance treatment was initiated (CRT-IO) prior to the second PET/CT. Uptake of tumor sites and secondary lymphoid organs was compared between CRT and CRT-IO. Also, readers were blinded for durvalumab administration and reviewed scans for findings suspicious for immunotherapy-related adverse events (irAE). RESULTS: Initial uptake characteristics were comparable. However, under durvalumab, diverging metabolic patterns were noted: There was a significantly higher reduction of tumoral uptake intensity in CRT-IO compared to CRT, e.g. median decrease of SUVmax -70.0% vs. -24.8%, p = 0.009. In contrast, the spleen uptake increased in CRT-IO while it dropped in CRT (median + 12.5% vs. -4.4%, p = 0.029). Overall survival was significantly longer in CRT-IO compared to CRT with few events (progression/death) noted in CRT-IO. Findings suggestive of irAE were present on PET/CT more often in CRT-IO (12/16) compared to CRT (8/27 patients), p = 0.005. CONCLUSION: Durvalumab maintenance treatment after CRT leads to diverging tumoral metabolic changes, but also increases splenic metabolism and leads to a higher proportion of findings suggestive of irAE compared to patients without durvalumab. Due to significantly prolonged survival with durvalumab, survival analysis will be substantiated in correlation to metabolic changes as soon as more clinical events are present.

Is PSMA PET/CT cost-effective for the primary staging in prostate cancer? First results for European countries and the USA based on the proPSMA trial.

PURPOSE: The proPSMA trial at ten Australian centers demonstrated increased sensitivity and specificity for PSMA PET/CT compared to conventional imaging regarding metastatic status in primary high-risk prostate cancer patients. A cost-effectiveness analysis showed benefits of PSMA PET/CT over conventional imaging for the Australian setting. However, comparable data for other countries are lacking. Therefore, we aimed to verify the cost-effectiveness of PSMA PET/CT in several European countries as well as the USA. METHODS: Clinical data on diagnostic accuracy were derived from the proPSMA trial. Costs for PSMA PET/CT and conventional imaging were taken from reimbursements of national health systems and individual billing information of selected centers in Belgium, Germany, Italy, the Netherlands, and the USA. For comparability, scan duration and the decision tree of the analysis were adopted from the Australian cost-effectiveness study. RESULTS: In contrast to the Australian setting, PSMA PET/CT was primarily associated with increased costs in the studied centers in Europe and the USA. Mainly, the scan duration had an impact on the cost-effectiveness. However, costs for an accurate diagnosis using PSMA PET/CT seemed reasonably low compared to the potential consequential costs of an inaccurate diagnosis. CONCLUSION: We assume that the use of PSMA PET/CT is appropriate from a health economic perspective, but this will need to be verified by a prospective evaluation of patients at initial diagnosis.

Next-generation PET/CT imaging in meningioma-first clinical experiences using the novel SSTR-targeting peptide [18F]SiTATE.

BACKGROUND: Somatostatin-receptor (SSTR)-targeted PET/CT provides important clinical information in addition to standard imaging in meningioma patients. [18F]SiTATE is a novel, 18F-labeled SSTR-targeting peptide with superior imaging properties according to preliminary data. We provide the first [18F]SiTATE PET/CT data of a large cohort of meningioma patients. METHODS: Patients with known or suspected meningioma undergoing [18F]SiTATE PET/CT were included. Uptake intensity (SUV) of meningiomas, non-meningioma lesions, and healthy organs were assessed using a 50% isocontour volume of interest (VOI) or a spherical VOI, respectively. Also, trans-osseous extension on PET/CT was assessed. RESULTS: A total of 107 patients with 117 [18F]SiTATE PET/CT scans were included. Overall, 231 meningioma lesions and 61 non-meningioma lesions (e.g., post-therapeutic changes) were analyzed. Physiological uptake was lowest in healthy brain tissue, followed by bone marrow, parotid, and pituitary (SUVmean 0.06 ± 0.04 vs. 1.4 ± 0.9 vs. 1.6 ± 1.0 vs. 9.8 ± 4.6; p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUVmax 11.6 ± 10.6 vs. 4.0 ± 3.3, p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUVmax 11.6±10.6 vs. 4.0±3.3, p<0.001). 93/231 (40.3%) meningiomas showed partial trans-osseous extension and 34/231 (14.7%) predominant intra-osseous extension. 59/231 (25.6%) meningioma lesions found on PET/CT had not been reported on previous standard imaging. CONCLUSION: This is the first PET/CT study using an 18F-labeled SSTR-ligand in meningioma patients: [18F]SiTATE provides extraordinary contrast in meningioma compared to healthy tissue and non-meningioma lesions, which leads to a high detection rate of so far unknown meningioma sites and osseous involvement. Having in mind the advantageous logistic features of 18F-labeled compared to 68Ga-labeled compounds (e.g., longer half-life and large-badge production), [18F]SiTATE has the potential to foster a widespread use of SSTR-targeted imaging in neuro-oncology.

Development of PSMA-PET-guided CT-based radiomic signature to predict biochemical recurrence after salvage radiotherapy.

PURPOSE: To develop a CT-based radiomic signature to predict biochemical recurrence (BCR) in prostate cancer patients after sRT guided by positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET). MATERIAL AND METHODS: Consecutive patients, who underwent 68Ga-PSMA11-PET/CT-guided sRT from three high-volume centers in Germany, were included in this retrospective multicenter study. Patients had PET-positive local recurrences and were treated with intensity-modulated sRT. Radiomic features were extracted from volumes of interests on CT guided by focal PSMA-PET uptakes. After preprocessing, clinical, radiomics, and combined clinical-radiomic models were developed combining different feature reduction techniques and Cox proportional hazard models within a nested cross validation approach. RESULTS: Among 99 patients, median interval until BCR was the radiomic models outperformed clinical models and combined clinical-radiomic models for prediction of BCR with a C-index of 0.71 compared to 0.53 and 0.63 in the test sets, respectively. In contrast to the other models, the radiomic model achieved significantly improved patient stratification in Kaplan-Meier analysis. The radiomic and clinical-radiomic model achieved a significantly better time-dependent net reclassification improvement index (0.392 and 0.762, respectively) compared to the clinical model. Decision curve analysis demonstrated a clinical net benefit for both models. Mean intensity was the most predictive radiomic feature. CONCLUSION: This is the first study to develop a PSMA-PET-guided CT-based radiomic model to predict BCR after sRT. The radiomic models outperformed clinical models and might contribute to guide personalized treatment decisions.

Cost-Effectiveness Analysis of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer poses a therapeutic challenge with poor prognosis. The VISION trial showed prolonged progression-free and overall survival in patients treated with lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) radioligand therapy compared with using the standard of care (SoC) alone. The objective of this study was to determine the cost-effectiveness of 177Lu-PSMA-617 treatment compared with SoC therapy. METHODS: A partitioned survival model was developed using data from the VISION trial, which included overall and progression-free survival and treatment regimens for 177Lu-PSMA-617 and SoC. Treatment costs, utilities for health states, and adverse events were derived from public databases and the literature. Because 177Lu-PSMA-617 was only recently approved, costs for treatment were extrapolated from 177Lu-DOTATATE. Outcome measurements included the incremental cost, effectiveness, and cost-effectiveness ratio. The analysis was performed in a US setting from a healthcare system perspective over the lifetime horizon of 60 months. The willingness-to-pay threshold was set to $50,000, $100,000, and $200,000 per quality-adjusted life years (QALYs). RESULTS: The 177Lu-PSMA-617 group was estimated to gain 0.42 incremental QALYs. Treatment using 177Lu-PSMA-617 led to an increase in costs compared with SoC ($169,110 vs $85,398). The incremental cost, effectiveness, and cost-effectiveness ratio for 177Lu-PSMA-617 therapy was $200,708/QALYs. Sensitivity analysis showed robustness of the model regarding various parameters, which remained cost-effective at all lower and upper parameter bounds. In probabilistic sensitivity analysis using Monte Carlo simulation with 10,000 iterations, therapy using 177Lu-PSMA-617 was determined as the cost-effective strategy in 37.14% of all iterations at a willingness-to-pay threshold of $200,000/QALYs. CONCLUSIONS: Treatment using 177Lu-PSMA-617 was estimated to add a notable clinical benefit over SoC alone. Based on the model results, radioligand therapy represents a treatment strategy for patients with metastatic castration-resistant prostate cancer with cost-effectiveness in certain scenarios.

Feasibility of [68Ga]Ga-FAPI-46 PET/CT for detection of nodal and hematogenous spread in high-grade urothelial carcinoma.

BACKGROUND: [68Ga]Ga-FAPI-46 is a novel positron emission tomography (PET) ligand that targets fibroblast activation protein (FAP) expression as FAP inhibitor (FAPI) and could already show promising results in several tumor entities. It could be demonstrated that an increased FAP expression correlates with tumor aggressivity in urothelial carcinoma (UC). Given the limited value of [18F]FDG in UC, [68Ga]Ga-FAPI-46 could add diagnostic information in staging and response assessment in UC. We present the first data of [68Ga]Ga-FAPI-46 PET imaging in a pilot cohort of UC patients evaluating uptake characteristics in metastases and primary tumors. METHODS: Fifteen patients with UC prior to or after local treatment underwent [68Ga]Ga-FAPI-46 PET/CT imaging for detection of metastatic spread. We compared the biodistribution in non-affected organs and tumor uptake of UC lesions by standard uptake value measurements (SUVmean and SUVmax). Additionally, metastatic sites on PET were compared to its morphological correlate on contrast-enhanced computed tomography (CT). RESULTS: Overall, 64 tumor sites were detected on PET and/or CT. The highest uptake intensity was noted at the primary site (SUVmax 20.8 (range, 8.1-27.8)) followed by lymph node metastases (SUVmax 10.6 (range, 4.7-29.1)). In 4/15 (26.7%) patients there were [68Ga]Ga-FAPI-46-positive lesions that were missed on standard routine CT imaging. On the other hand, 2/15 patients had suspicious prominent bipulmonary nodules as well as pelvic lymph nodes previously rated as suspicious for metastatic spread on CT, but without increased FAPI expression; here histopathology excluded malignancy. CONCLUSION: [68Ga]Ga-FAPI-46 PET shows distinctly elevated uptake in UC lesions. Therefore, the tracer has potential as a promising new biomarker in metastatic UC patients, as [68Ga]Ga-FAPI-46 PET might improve detection of metastatic sites compared to CT alone. These findings highly emphasize larger studies investigating FAPI imaging in UC patients.

The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis.

PURPOSE: This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. METHODS: Patients who underwent 68 Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. RESULTS: Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results. CONCLUSION: The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary.

Impact of the Reference Multiple-Time-Point Dosimetry Protocol on the Validity of Single-Time-Point Dosimetry for [177Lu]Lu-PSMA-I&T Therapy.

Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid et al., one by Jackson et al., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.

The Vanishing Clinical Value of PD-L1 Status as a Predictive Biomarker in the First-Line Treatment of Urothelial Carcinoma of the Bladder.

BACKGROUND: Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). METHODS: Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 at our tertiary referral center. The clinical outcome, defined as the progression-free survival (PFS) and overall survival (OS) on systemic treatment, was analyzed using an χ2-test, Mann-Whitney U-test, the Kaplan-Meier method, and a log-rank test. RESULTS: A total of 648 patients were included following an RC performed within January 2017 to December 2022. Their PD-L1 status was analyzed with the primary PD-L1-specific antibody (clone SP263, Ventana) and defined both by the CPS and IC-score in 282 patients (43.5%) with a high risk (pT3-pT4 and/or lymph node involvement) or metastatic UCB. While the median PFS was significantly prolonged 5-fold in PD-L1+ patients, we found no difference in OS, regardless of PD-L1 status, or treatment regimen. CONCLUSIONS: While PD-L1 positivity indicates prolonged PFS, the presence of PD-L1 does not influence OS rates, suggesting its limited usefulness as a prognostic biomarker in bladder cancer. However, the positive correlation between an PD-L1 status and a sustained response to ICI treatments indicates its potential role as a predictive biomarker. Further research is required to understand how the predictive value of PD-L1 positivity may extend to the use of ICIs in combination with antibody-drug conjugates.

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma.

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.