Prostate-specific Membrane Antigen PET Research Articles

Changes in Management After 18F-DCFPyL PSMA PET in Patients Undergoing Postprostatectomy Radiotherapy, with Early Biochemical Response Outcomes.

Prostate-specific membrane antigen (PSMA) tracers have increased sensitivity in the detection of prostate cancer, compared with conventional imaging. We assessed the management impact of 18F-DCFPyL PSMA PET/CT in patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) and report early biochemical response in patients who underwent radiation treatment. Methods: One hundred patients were enrolled into a prospective study, with a prior RP for prostate cancer, a PSA of 0.2-2.0 ng/mL, and no prior treatment. All patients underwent diagnostic CT and PSMA PET/CT, and management intent was completed at 3 time points (original, post-CT, and post-PSMA) and compared. Patients who underwent radiotherapy with 6-mo PSA response data are presented. Results: Ninety-eight patients are reported, with a median PSA of 0.32 ng/mL (95% CI, 0.28-0.36), pT3a/b disease in 71.4%, and an International Society of Urological Pathology grade group of at least 3 in 59.2%. PSMA PET/CT detected disease in 46.9% of patients, compared with 15.5% using diagnostic CT (PSMA PET, 29.2% local recurrence and 29.6% pelvic nodal disease). A major change in management intent was higher after PSMA than after CT (12.5% vs. 3.2%, P = 0.010), as was a moderate change in intent (31.3% vs. 13.7%, P = 0.001). The most common change was an increase in the recommendation for elective pelvic radiation (from 15.6% to 33.3%), nodal boost (from 0% to 22.9%), and use of concurrent androgen deprivation therapy (ADT) (from 22.9% to 41.7%) from original to post-PSMA intent because of detection of nodal disease. Eighty-six patients underwent 18F-DCFPyL-guided radiotherapy. Fifty-five of 86 patients either did not receive ADT or recovered after ADT, with an 18-mo PSA response from 0.32 to 0.02 ng/mL; 94.5% of patients had a PSA of no more than 0.20 ng/mL, and 74.5% had a PSA of no more than 0.03 ng/mL. Conclusion: 18F-DCFPyL PET/CT has a significant impact on management intent in patients being considered for salvage radiotherapy after RP with PSA recurrence. Increased detection of disease, particularly in the pelvic lymph nodes, resulted in increased pelvic irradiation and concurrent ADT use. Early results in patients who are staged with 18F-DCFPyL PET/CT show a favorable PSA response.

Quantitative evaluation of PSMA PET imaging using a realistic anthropomorphic phantom and shell-less radioactive epoxy lesions

BackgroundPositron emission tomography (PET) with prostate specific membrane antigen (PSMA) have shown superior performance in detecting metastatic prostate cancers. Relative to [18F]fluorodeoxyglucose ([18F]FDG) PET images, PSMA PET images tend to visualize significantly higher-contrast focal lesions. We aim to evaluate segmentation and reconstruction algorithms in this emerging context. Specifically, Bayesian or maximum a posteriori (MAP) image reconstruction, compared to standard ordered subsets expectation maximization (OSEM) reconstruction, has received significant interest for its potential to reach convergence with minimal noise amplifications. However, few phantom studies have evaluated the quantitative accuracy of such reconstructions for high contrast, small lesions (sub-10 mm) that are typically observed in PSMA images. In this study, we cast 3 mm–16-mm spheres using epoxy resin infused with a long half-life positron emitter (sodium-22; 22Na) to simulate prostate cancer metastasis. The anthropomorphic Probe-IQ phantom, which features a liver, bladder, lungs, and ureters, was used to model relevant anatomy. Dynamic PET acquisitions were acquired and images were reconstructed with OSEM (varying subsets and iterations) and BSREM (varying β parameters), and the effects on lesion quantitation were evaluated.ResultsThe 22Na lesions were scanned against an aqueous solution containing fluorine-18 (18F) as the background. Regions-of-interest were drawn with MIM Software using 40% fixed threshold (40% FT) and a gradient segmentation algorithm (MIM’s PET Edge+). Recovery coefficients (RCs) (max, mean, peak, and newly defined “apex”), metabolic tumour volume (MTV), and total tumour uptake (TTU) were calculated for each sphere. SUVpeak and SUVapex had the most consistent RCs for different lesion-to-background ratios and reconstruction parameters. The gradient-based segmentation algorithm was more accurate than 40% FT for determining MTV and TTU, particularly for lesions le 6 mm in diameter (R2 = 0.979–0.996 vs. R2 = 0.115–0.527, respectively).ConclusionAn anthropomorphic phantom was used to evaluate quantitation for PSMA PET imaging of metastatic prostate cancer lesions. BSREM with β = 200–400 and OSEM with 2–5 iterations resulted in the most accurate and robust measurements of SUVmean, MTV, and TTU for imaging conditions in 18F-PSMA PET/CT images. SUVapex, a hybrid metric of SUVmax and SUVpeak, was proposed for robust, accurate, and segmentation-free quantitation of lesions for PSMA PET.

Prostate-specific Membrane Antigen PET in Addition to Multiparametric Prostate MRI Triage in the Diagnosis of Prostate Cancer: The Future is Avid.

Prostate-specific Membrane Antigen PET in Addition to Multiparametric Prostate MRI Triage in the Diagnosis of Prostate Cancer: The Future is Avid.

Prostate-specific membrane antigen and fibroblast activation protein distribution in prostate cancer: preliminary data on immunohistochemistry and PET imaging

IntroductionFibroblast activation protein (FAP) has been recently presented as new imaging target for malignant diseases and offers high contrast to surrounding normal tissue. FAP tracer uptake has been reported in various tumor entities. The aim of this study was to compare FAP and Prostate-specific membrane antigen (PSMA) expression in primary prostate cancer employing histological analyses and PET imaging in two small patient collectives.MethodsTwo independent small patient collectives were included in this study. For cohort A, data of 5 prostate cancer patients and 3 patients with benign prostate hyperplasia were included. Patients with prostate cancer were initially referred for PSMA PET staging. Radical prostatectomy was performed in all patients and prostate specimen of patients and biopsies of healthy controls were available for further evaluation. Histological workup included HE and immunohistochemistry using PSMA Ab, FAP Ab. Cohort B consists of 6 Patients with diagnosed mCRPC and available PSMA as well as FAP PET.ResultsPatients with proven prostate cancer infiltration exhibited strong positivity for PSMA in both primary tumors and lymph node metastases while stainings for FAP were found positive in some cases, but not all (2/5). Controls with BPH presented moderate PSMA staining and in one case also with a positive FAP staining (1/3). PET imaging with FAP seemed to result in more precise results in case of low PSMA expression than PSMA-PET.ConclusionsWhile PSMA staining intensity is a valid indicator of prostate cancer in both primary tumor and lymph node metastases, the expression of FAP seems to be heterogeneous but not necessarily linked to cancer-associated fibroblasts. It is also present in inflammation-associated myofibroblasts. Therefore, its ultimate role in prostate cancer diagnosis remains a subject of discussion.

Radioligand Therapy for Metastatic Prostate Cancer.

HomeRadiology: Imaging CancerVol. 3, No. 6 Previous Research HighlightsFree AccessRadioligand Therapy for Metastatic Prostate CancerBrian J. BurkettBrian J. BurkettBrian J. BurkettPublished Online:Nov 26 2021https://doi.org/10.1148/rycan.2021219026MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: Efficacy of lutetium-177 (177Lu)–prostate-specific membrane antigen (PSMA)–617 radioligand therapy with standard-of-care therapy compared to standard of care alone for castration-resistant metastatic prostate cancer.■ Key Result: 177Lu-PSMA-617, in addition to standard of care, prolongs progression-free survival and overall survival in patients with castration-resistant metastatic prostate cancer selected on the basis of PSMA-ligand PET/CT findings.■ Impact: The phase III VISION trial is the basis for U.S. Food and Drug Administration priority review of 177Lu-PSMA-617 as a new radioligand therapy for appropriately selected patients with pretreated, metastatic prostate cancer. Theranostic agent 177Lu-PSMA-617 is composed of 177Lu (a therapeutic beta-particle emitter) paired with PSMA, a cell surface glycoprotein expressed in most prostate cancer metastases. The pairing allows selective delivery of targeted radiation therapy to prostate cancer cells.The VISION trial is a phase III prospective clinical trial investigating 177Lu-PSMA-617 in the context of previously treated metastatic prostate cancer in combination with several standard-of-care options, including antiandrogen chemotherapeutic agents, external beam radiation therapy, bisphosphonates and denosumab, and steroids. Eligible patients must have progressed while receiving androgen receptor inhibitor and taxane-based chemotherapy and have undergone gallium-68–PSMA-11 PET/CT demonstrating one or more metastatic lesions with tracer uptake. Patients with PSMA-negative metastases 1 cm or larger were ineligible.Five hundred eighty-one patients were randomized to four to six cycles of 177Lu-PSMA-617 with trial-approved standard of care or only standard of care in a 2:1 ratio. 177Lu-PSMA-617 treatment significantly prolonged progression-free survival on the basis of imaging (8.7 vs 3.4 months, hazard ratio of 0.4 [95% CI: 0.29, 0.57]) and significantly prolonged median overall survival (15.3 vs 11.3 months, hazard ratio of 0.62 [95% CI: 0.52, 0.74]). 177Lu-PSMA-617 also significantly prolonged time to first symptomatic skeletal event or death, decreased prostate-specific antigen levels, and increased percentage of tumor response (complete and partial). Adverse events, most commonly fatigue, nausea, or dry mouth, happened more frequently in the group receiving 177Lu-PSMA-617. Five fatal events occurred in the 177Lu-PSMA-617 group due to pancytopenia, bone marrow failure, and intracranial bleeding.This trial complements the phase II TheraP trial that compared 177Lu-PSMA-617 alone to cabazitaxel chemotherapy. The survival benefit reported in the VISION trial ultimately may result in regulatory approval of 177Lu-PSMA-617 administered with other therapeutic options, even in heavily pretreated patients with refractory metastatic disease. PSMA-ligand PET also provides a companion diagnostic imaging marker for selecting appropriate patients and monitoring response to therapy if 177Lu-PSMA-617 receives regulatory approval.Highlighted ArticleSartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021;385(12):1091– 1103. doi: https://doi.org/10.1056/nejmoa2107322Highlighted ArticleSartor O, de Bono J, Chi KN, et al. Lutetium-177EN_DASHPSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021;385(12):1091–1103. doi: https://doi.org/10.1056/nejmoa2107322 Crossref, Medline, Google ScholarArticle HistoryPublished online: Nov 26 2021 FiguresReferencesRelatedDetailsRecommended Articles 177Lu–Prostate-specific Membrane Antigen Radioligand Therapy in Patients with Metastatic Castration-resistant Prostate CancerRadiology2022Volume: 306Issue: 2Prostate-specific Membrane Antigen PET in Prostate CancerRadiology2021Volume: 299Issue: 2pp. 248-260Revisiting Prostate Cancer Recurrence with PSMA PET: Atlas of Typical and Atypical Patterns of SpreadRadioGraphics2019Volume: 39Issue: 1pp. 186-212Radiotheranostics in Cancer Diagnosis and ManagementRadiology2018Volume: 286Issue: 2pp. 388-400Impact of 18F-DCFPyL PET on Staging and Treatment of Unfavorable Intermediate or High-Risk Prostate CancerRadiology2022Volume: 304Issue: 3pp. 600-608See More RSNA Education Exhibits Current Status and Future Prospects in Radioligand TherapyDigital Posters2020Peptide Receptor Radionuclide Therapy (PRRT): 2019 UpdateDigital Posters2019Advanced Prostate Cancer: Update on Evolving Concepts, Rationale, and Challenges of Imaging and Novel Therapeutic StrategiesDigital Posters2018 RSNA Case Collection Radioembolization of Liver Metastasis RSNA Case Collection2020Locally advanced, metastatic prostate adenocarcinomaRSNA Case Collection2020Parasagittal meningiomaRSNA Case Collection2022 Vol. 3, No. 6 Metrics Altmetric Score PDF download

Prostate Specific Membrane Antigen PET/MRI for the Management of Prostate Cancer: Current Status and Future Directions

Prostate cancer (PCa) is one of the most common malignancies and one major leading cause of cancer mortality in elder men. Due to its specific overexpression in PCa cells, the prostate-specific membrane antigen (PSMA) has become an ideal molecular imaging target for PCa. Currently, the value of PSMA PET/CT in the diagnosis and staging of PCa has been widely accepted. With the clinical application of simultaneous PET/MRI, it enables the possibility of combination of PSMA PET and MRI for the management of PCa. Here we present this review on the current status and future direction of the application of PSMA PET/MRI in the management of PCa.

Repeatability of 68Ga-PSMA-HBED-CC PET/CT-Derived Total Molecular Tumor Volume.

Molecular tumor volume (MTV) is a parameter of interest in prostate cancer for assessing total disease burden on prostate-specific membrane antigen (PSMA) PET. Although software segmentation tools can delineate whole-body MTV, a necessary step toward meaningful monitoring of total tumor burden and treatment response through PET is establishing the repeatability of these metrics. The present study assessed the repeatability of total MTV and related metrics for 68Ga-PSMA-HBED-CC in prostate cancer. Methods: Eighteen patients from a prior repeatability study who underwent 2 test-retest PSMA PET/CT scans within a mean interval of 5 d were reanalyzed. Within-subject coefficient of variation and repeatability coefficients (RCs) were analyzed on a per-lesion and per-patient basis. For the per-lesion analysis, individual lesions were segmented for analysis by a single reader. For the per-patient analysis, subgroups of up to 10 lesions (single reader) and the total tumor volume per patient were segmented (independently by 2 readers). Image parameters were MTV, SUVmax, SUVpeak, SUVmean, total lesion PSMA, and the related metric PSMA quotient (which integrates lesion volume and PSMA avidity). Results: In total, 192 segmentations were analyzed for the per-lesion analysis and 1,662 segmentations for the per-patient analysis (combining the 2 readers and 2 scans). The RC of the MTV of single lesions was 77% (95% CI, 63%-96%). The RC improved to 33% after aggregation of up to 10 manually selected lesions into subgroups assessed per patient (95% CI, 25%-46%). The RC of the semiautomatic MTVtotal (the sum of all voxels in the whole-body total tumor segmentation per patient) was 35% (95% CI, 25%-50%), the Bland-Altman bias was -6.70 (95% CI, -14.32-0.93). Alternating readers between scans led to a comparable RC of 37% (95% CI, 28%-49%) for MTVtotal, meaning that the metric is robust between scanning sessions and between readers. Conclusion:68Ga-PSMA-HBED-CC PET-derived semiautomatic MTVtotal is repeatable and reader-independent, with a change of ±35% representing a true change in tumor volume. Volumetry of single manually selected lesions has considerably lower repeatability, and volumetry based on subgroups of these lesions, although showing acceptable repeatability, is less systematic. The semiautomatic analysis of MTVtotal used in this study offers an efficient and robust means of assessing response to therapy.

PSMA Theranostics: Current Landscape and Future Outlook.

Simple SummaryThe prognosis for metastatic prostate cancer patients remains poor. Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a promising target for both imaging and therapy. In this review paper, we provide an overview of the evidence for PSMA-targeted imaging in prostate cancer, focusing on different imaging modalities and their theranostic applications. We will also review PSMA-targeted radioligand therapy, focusing on lutetium-177 radioligand therapy and alpha-emitting radioligand therapy with actinium-225. Combination regimens with lutetium-177 and other systemic therapy agents will be reviewed. Antibody-based radioimmunotherapy will also be discussed along with other noteworthy radionuclide agents.Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history. Methods: We utilized PubMed and Google Scholar for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic clinical trials throughout the various stages of prostate cancer. Conclusions: In this review, we presented the contemporary and future landscape of theranostic applications in prostate cancer with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for the management of prostate cancer, we underscore the importance of integrating nuclear medicine physicians into the multidisciplinary team.

Translational Development of a Zr-89-Labeled Inhibitor of Prostate-specific Membrane Antigen for PET Imaging in Prostate Cancer

PurposeWe present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands.ProceduresThe precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7 in vitro by determination of the Kd value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously.Results[89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides.Conclusion[89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation.

Elective nodal radiotherapy in prostate cancer.

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy.

An 89Zr-Labeled PSMA Tracer for PET/CT Imaging of Prostate Cancer Patients.

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Because of its longer half-life, the 89Zr-labeled ligand 89Zr-PSMA-DFO allows acquisition of PET scans up to 6 d after injection, thereby overcoming the above limitation. We investigated whether 89Zr-PSMA-DFO allowed more sensitive detection of weak PSMA-positive prostate cancer lesions. Methods: We selected 14 prostate cancer patients with biochemical recurrence who exhibited no PSMA-positive lesions on a PET scan acquired with existing PSMA tracers (68Ga-PSMA-11, 18F-JK-PSMA-7). Within 5 wk after the negative scan result, we obtained a second PSMA PET scan using 89Zr-PSMA-DFO (117 ± 16 MBq, PET acquisition within 6 d of injection). Results:89Zr-PSMA-DFO detected 15 PSMA-positive lesions in 8 of 14 patients, who had a PET-negative reading of their initial PET scans with existing tracers. In these 8 patients, the new scans revealed localized recurrence of disease (3/8), metastases in lymph nodes (3/8), or lesions at distant sites (2/8). On the basis of these results, patients received lesion-targeted radiotherapies (5/8), androgen deprivation therapies (2/8), or no therapy (1/8). The plausibility of 14 of 15 lesions was supported by histology, clinical follow-up after radiotherapy, or subsequent imaging. Furthermore, comparison of the 15 89Zr-PSMA-DFO-positive lesions with their correlates on the original PET scan revealed that established tracers exhibited mild accumulation in 7 of 15 lesions; however, contrast-to-noise ratios were too low for robust detection of these lesions (contrast-to-noise ratios, 2.4 ± 3.7 for established tracers vs. 10.2 ± 8.5 for 89Zr-PSMA-DFO, P = 0.0014). The SUVmax of the 15 89Zr-PSMA-DFO-positive lesions (11.5 ± 5.8) was significantly higher than the SUVmax on the original PET scans (4.7 ± 2.8, P = 0.0001). Kidneys were the most exposed organ, with doses of 3.3 ± 0.7 mGy/MBq. The effective dose was 0.15 ± 0.04 mSv/MBq. Conclusion: In patients with weak PSMA expression, a longer period of time might be needed for ligand internalization than that offered by existing PSMA tracers to make lesions visible on PET/CT scans. Hence, 89Zr-PSMA-DFO might be of significant benefit to patients in whom the search for weak PSMA-positive lesions is challenging. Radiation exposure should be weighed against the potential benefit of metastasis-directed therapy or salvage radiotherapy, which we initiated in 36% (5/14) of our patients based on their 89Zr-PSMA-DFO PET scans.

Management of Metastatic Castration-Resistant Prostate Cancer

Notable developments in the management of metastatic castration-resistant prostate cancer (mCRPC) include newer, more sophisticated imaging methods based on prostate-specific membrane antigen (PSMA) PET and development of radionuclide ligands for use with this modality. In the therapeutic area, PSMA PET–guided therapeutics are under study, and PARP inhibitors are being used to treat patients with gene alterations directly or indirectly involved with the homologous recombination repair pathway. Cabazitaxel has emerged as an effective third-line option for patients treated with prior novel hormonal agents and/or prior docetaxel. As investigators learn more about sequencing therapies for mCRPC, previous exposure is an important consideration for choice of treatment at disease progression.

Prostate-Specific Membrane Antigen Expression in Patients With Differentiated Thyroid Cancer With Thyroglobulin Elevation and Negative Iodine Scintigraphy Using 68Ga-PSMA-HBED-CC PET/CT.

Prostate-specific membrane antigen (PSMA) is a member of superfamily of zinc-dependent exopeptidases that is robustly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature including microvessels of thyroid tumors. Its expression in differentiated thyroid cancer (DTC) has been confirmed in many recent studies, but systematic studies exploring PSMA expression in patients with DTC with thyroglobulin elevation and negative iodine scintigraphy (TENIS) are lacking. The aim of the present study was to evaluate the role of PSMA scan in TENIS patients with DTC. Nine consecutive patients with DTC with proven TENIS syndrome (6 men and 3 women with age range 29-68 years and mean age of 48 years) underwent 18F-FDG PET/CT as per the institution protocol. Thereafter, they were subjected to 68Ga-PSMA-HBED-CC PET/CT as per the institution protocol within a week of FDG PET imaging. Prostate-specific membrane antigen expression (SUVmax) in the lesions was compared with 18F-FDG PET and CT scan findings. In 5 of 9 patients with TENIS, the metastatic lesions showed PSMA expression. A total of 14 lesions were seen on the CT scan. Prostate-specific membrane antigen PET detected 9 of 14 lesions (64.28%) (SUVmax ranging from 10.1 to 45.67; median SUVmax of 16.31), whereas FDG PET was positive in 11 of 14 lesions (78.57%). The lesions that showed PSMA uptake was localized to bones (5 of 9) and lungs (4 of 9). Two lesions that were localized to iliac crest and acetabulum were missed on FDG PET but were seen on CT and PSMA PET scan. The results of this pilot study indicate that 68Ga-HBED-CC-PSMA PET/CT demonstrates PSMA expression in TENIS patients with lesions being localized to the bones and lungs. 68Ga-PSMA PET/CT could be useful for the identification of TENIS patients who might benefit from PSMA-targeted radionuclide therapy.

Concordance between Response Assessment Using Prostate-Specific Membrane Antigen PET and Serum Prostate-Specific Antigen Levels after Systemic Treatment in Patients with Metastatic Castration Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen positron emission tomography (PSMA PET) has recently gained interest as a promising tool for treatment response evaluation in metastatic castration-resistant prostate cancer (CRPC). We performed a systematic review and meta-analysis assessing the concordance between response evaluation using PSMA PET and serum prostate-specific antigen (PSA) level after systemic treatment and the association between PSMA PET and overall survival in metastatic CRPC patients. PubMed, Embase, and Cochrane library databases were searched until August 2020. Studies that reported the concordance between PSMA PET and PSA response were included. PSMA PET and PSA response evaluation were dichotomized into response vs. non-response to construct two-by-two contingency tables; an ≥30% increase in PSMA PET according to PET Response Criteria in Solid Tumors 1.0 and as an increase in serum PSA level of ≥25% as per Prostate Cancer Working Group 3 guidelines were defined as non-response. The percent agreement rates were pooled using random-effect model. Ten studies (268 patients) were included. The concordance rates ranged 0.50–0.84 with a pooled proportion of 0.73 (95% confidence interval 0.67–0.79). Patients were treated with 177Lu-PSMA therapy in five, chemotherapy in three, 223Ra in one, and more than one type in one study. Various PET parameters were used: the most widely evaluated was PSMA tumor volume (PSMA-TV). Similar proportions were found across different therapeutic agents, PET response parameters, and regarding directionality of discordance (PSA response/PSMA non-response vs. PSMA response/PSA non-response). Two studies reported that a decrease in PSMA-TV was associated with better overall survival. PSMA PET and PSA response assessments were discordant in nearly a fourth of metastatic CRPC patients. Further studies are warranted to establish the clinical meaning of this discordance and define appropriate management for such clinical situation.

Assessing Response to [177Lu]PSMA Radioligand Therapy using modified PSMA PET Progression Criteria.

Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate specific membrane antigen (PSMA) plays a key role in staging of patients with prostate cancer (PCa). Moreover, it is not only used for the assessment of adequate PSMA expression of PCa cells before PSMA-targeting radioligand therapy (PSMA RLT) but also for re-staging during the course of therapy to evaluate response to treatment. Whereas no established criteria exist for systematic response evaluation so far, recently proposed PSMA PET Progression (PPP) criteria might fill this gap. The aim of this study was to assess the feasibility of PPP criteria in patients undergoing PSMA RLT and their prognostic implications. Methods: In this retrospective analysis, PSMA PET/CT scans of 46 patients acquired before and after completion of PSMA RLT were analyzed separately by two readers using modified PPP criteria. After interobserver agreement assessment, consensus results (progressive vs. non-progressive disease) were compared in a multivariate cox regression model (endpoint overall survival, OS). Results: Interobserver agreement on modified PPP criteria was substantial (Cohens κ = 0.73) with a concordance in 87% of patients. Median OS of all patients after PSMA RLT (n = 46) was 9.0 [95% confidence interval (CI) 7.8 - 10.2] months. Progression according to modified PPP criteria was found in 32 patients and was a significant (p ≤0.001) prognostic marker for OS with a hazard ratio of 15.5 [95% CI 3.4 - 70.2]. Conclusion: Response assessment in patients undergoing PSMA RLT using modified PPP criteria are reproducible and highly prognostic for OS. Modified PPP criteria should be validated in future prospective trials.

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.

PSMA Expression in Glioblastoma as a Basis for Theranostic Approaches: A Retrospective, Correlational Panel Study Including Immunohistochemistry, Clinical Parameters and PET Imaging

AimThe aim of the current study was to enlighten the evolution of prostate-specific membrane antigen (PSMA) expression in glioblastoma between initial diagnosis and recurrence in order to provide preliminary insight for further clinical investigations into innovative PSMA-directed treatment concepts in neuro-oncology.MethodsPatients who underwent resection for de-novo glioblastoma (GBM) and had a re-resection in case of a recurrent tumor following radiochemotherapy and subsequent chemotherapy were included (n = 16). Histological and immunohistochemical stainings were performed at initial diagnosis and at recurrence (n = 96 tissue specimens). Levels of PSMA expression both in endothelial and non-endothelial cells as well as vascular density (CD34) were quantified via immunohistochemistry and changes between initial diagnosis and recurrence were determined. Immunohistochemical findings were correlated with survival and established clinical parameters.ResultsPSMA expression was found to be present in all GBM tissue samples at initial diagnosis as well as in all but one case of recurrent tumor samples. The level of PSMA expression in glioblastoma varied inter-individually both in endothelial and non-endothelial cells. Likewise, the temporal evolution of PSMA expression highly varied in between patients. The level of vascular PSMA expression at recurrence and its change between initial diagnosis and recurrence was associated with post recurrence survival time: Patients with high vascular PSMA expression at recurrence as well as patients with increasing PSMA expression throughout the disease course survived shorter than patients with low vascular PSMA expression or decreasing vascular PSMA expression. There was no significant correlation of PSMA expression with MGMT promoter methylation status or Ki-67 labelling index.ConclusionPSMA is expressed in glioblastoma both at initial diagnosis and at recurrence. High vascular PSMA expression at recurrence seems to be a negative prognostic marker. Thus, PSMA expression in GBM might present a promising target for theranostic approaches in recurrent glioblastoma. Especially PSMA PET imaging and PSMA-directed radioligand therapy warrant further studies in brain tumor patients.

Current and Emerging Clinical Applications of PSMA PET Diagnostic Imaging for Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PCa) cells, and several PSMA ligands for PET imaging are now available worldwide. 68Ga-PSMA-11 has already received U.S. Food and Drug Administration and European Medicines Agency approval, and use of PSMA PET is currently suggested by several international guidelines for investigating PCa in different clinical settings. In primary PCa, PSMA PET has been shown to be superior to cross-sectional imaging for the detection of pelvic lymph nodes and distant metastases with subsequent clinical management changes. Additionally, it might also have a role in intraprostatic tumor localization, especially when combined with multiparametric MRI. In a setting of PCa recurrence, higher detection rates have been observed than for any other available imaging techniques, especially at low prostate-specific antigen values. Furthermore, PSMA PET consistently led to a shift in clinical management, thus increasing the proportion of radiotherapy, surgery, or other focal therapies at the expense of systemic options or no treatment. In oligometastatic disease after radical surgery, PSMA PET may be relevant in guiding a metastasis-directed therapy approach, as preliminary data seem to suggest a benefit in terms of progression-free survival after treatment of PSMA PET-positive lesions. As a staging and gatekeeping technique, PSMA PET represents a reliable whole-body imaging procedure in combination with second-line therapy of castration-resistant PCa, as well as being pivotal when assessing patients eligible for radioligand therapy such as 177Lu-PSMA. This critical review aims at providing a comprehensive overview of the latest literature on the current or emerging main indications, as well as a general outlook on the recommended interpretation criteria for PSMA PET imaging.

18F-DCFPyL PSMA PET imaging compared to conventional imaging in the detection of pelvic nodal metastases in patients with locally advanced or oligometastatic prostate cancer.

36 Background: Interest has arisen in the use of prostate specific membrane antigen (PSMA) PET/CT imaging to detect prostate cancer at metastatic sites using different tracers. Here, we examined the ability of 18F-DCFPyL (DCFPyL) PSMA-based PET imaging to detect nodal disease in comparison to conventional imaging in a cohort of men with locally advanced or oligometastatic prostate cancer (PC). Methods: UW17009 is an IRB-approved open-label, single-arm trial that enrolled 26 patients with newly diagnosed advanced PC. Patients received androgen deprivation therapy and docetaxel for 3 months followed by radical prostatectomy (RP) and pelvic lymph node dissection (PLND). Exploratory interventions include PSMA PET/CT and MRI imaging as a method for determining treatment response and heterogeneity in primary PC and metastatic lesions performed before and after chemohormonal therapy. Prior to randomization, patients received DCFPyL PET/CT and PET/MR imaging as well as CTs and Bone Scans. A mean dose of 7.86 mCi DCFPyL was administered. Whole-body PET/CT images were acquired starting at approximately 60 minutes after radiotracer injection followed by dedicated pelvic PET/MR and whole-body PET/MR. PET imaging findings were compared to conventional dedicated CT imaging and were correlated to the results of final pathologic examination of each pelvic nodal dissection. Results: 26 patients underwent conventional and exploratory imaging with subsequent neoadjuvant treatment, RP and PLND. The mean diagnostic PSA was 32.1 ng/dl and 88.5% had Gleason 9 PCa. Using conventional imaging, pelvic nodal disease was identified in 6/26 patients. Pelvic lymph node uptake was identified in 12/26 patients using DCFPyL-based PSMA PET. Initial correlation of the pathologic specimens with pretreatment PSMA PET imaging revealed pelvic nodal metastatic PC in 10/12(83%) patients. On a per-lymph node packet basis (6 per patient), there were 156 evaluable regions, including 65 from patients with positive nodes. PSMA detected 14 packets that were positive for PC and 102 packets that were negative on imaging and final pathology. PC was missed in 5 packets. The mean tumor size in the missed nodes was 2.3 mm(range 1-4 mm). Calculated sensitivity was 73.7%(95% CI [48.8, 90.8]), 85.7 % specificity(95% CI[78.1, 91.4]), and 95.3 % negative predictive value(95% CI[90.5, 97.7]). Conclusions: In comparison to conventional imaging, in this cohort, DCFPyL PSMA-based PET imaging identified nodal positive disease at twice the rate and when evaluating on a per-packet basis, there was high negative predictive value. Ongoing analysis of post-chemohormonal therapy PET imaging may provide more information regarding tumor response in this cohort.

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade &gt; 3 heme toxicity or grade &gt; 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had &gt; 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.