Theranostic strategies in sarcoma: preliminary clinical evidence.

INTRODUCTION: Sarcomas encompass a highly diverse range of malignancies, characterized by varied morphological and molecular profiles. Treatment options in case of therapy-refractory or advanced disease are limited. In this context, theranostics emerges as an innovative platform seamlessly integrating diagnosis and therapy, offering promising prospects. AREAS COVERED: This special report delves into the initial clinical applications of theranostic-based approaches in sarcomas. Specifically, it examines various strategies targeting biomarkers associated with sarcomas, including fibroblast activation protein (FAP), prostate-specific membrane antigen (PSMA), C-X-C chemokine receptor type 4 (CXCR4) and somatostatin receptor 2 (SSTR2). EXPERT OPINION: The heterogeneous uptake of the CXCR4-targeted radioligand in lesions, along with its poor correlation with immunohistochemistry data, diminishes the attractiveness of this theranostic approach in the sarcoma oncological setting. SSTR2-targeted approaches in sarcoma, although potentially effective, are limited to a single case. Early experiences with FAP inhibitors in sarcoma patients have shown particularly promising outcomes, indicating effective disease control with minimal toxicity. While PSMA presents an enticing target for theranostic approaches in sarcomas, its utilization remains anecdotal and requires further investigation. Prospective and well-designed clinical trials are imperative to delineate the potential impact of FAPI- and PSMA-based approaches on sarcoma therapeutic landscapes, offering innovative and personalized treatment options.

Outstanding increase in tumor-to-background ratio over time allows tumor localization by [89Zr]Zr-PSMA-617 PET/CT in early biochemical recurrence of prostate cancer.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies. METHODS: Retrospective analysis of 38 consecutive men with BCR (median [minimum-maximum] prostate-specific antigen 0.52 (0.12-2.50 ng/mL) undergoing [89Zr]Zr-PSMA-617 PET/CT post-negative [68Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum-maximum) [89Zr]Zr-PSMA-617 tracer activity of 123 (84-166) MBq. RESULTS: [89Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [89Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients. LIMITATIONS: retrospective, single center design; infrequent histopathological and imaging verification. CONCLUSION: This large series provides further evidence that [89Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT.

Unusual Prostate-Specific Membrane Antigen (PSMA) Splenic Uptake in a Patient With Prostate Cancer.

There are many benefits to early detection of prostate cancer, including improved survival rates, less invasive treatment options, and better quality of life. Apart from traditional tests and imaging (including the prostate-specific antigen (PSA) test, digital rectal exam, biopsy, computed tomography (CT), and magnetic resonance imaging (MRI)), an imaging technique called prostate-specific membrane antigen positron emission tomography (PSMA PET) is more specific and sensitive, targeting PSMA expressed by prostate cancer cells on their surface. This case report describes a 62-year-old male with metastatic prostate adenocarcinoma and unusual PSMA uptake in the spleen. Elevated PSA levels and MRI indicated aggressive prostate cancer, confirmed by a Gleason score of 7 from biopsies. A PSMA PET/CT scan showed intense activity in both the prostate and spleen, initially suggesting metastasis. However, further imaging identified the splenic lesion as a benign hemangioma. This case showcases the importance of thorough diagnostic evaluations for distinguishing metastatic disease from benign conditions to ensure accurate diagnosis and appropriate treatment.

Impact of Baseline Renal Insufficiency on Piflufolastat F-18 Performance and Investigation of Changes in Renal Function Following Piflufolastat F-18 Administration: Results From the OSPREY Trial.

INTRODUCTION: Piflufolastat F-18, a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, is predominantly eliminated via urinary excretion, and the kidneys have one of the highest absorbed doses. Therefore, this subgroup analysis aimed to investigate the impact of piflufolastat F-18 on renal function and its diagnostic performance in patients stratified by baseline renal function. PATIENTS AND METHODS: The OSPREY clinical trial enrolled 2 cohorts: A-high-risk patients undergoing radical prostatectomy with pelvic lymphadenectomy, and B-patients with suspected recurrent/metastatic prostate cancer on conventional imaging. Baseline estimated glomerular filtration rates were calculated, and patients were stratified by baseline chronic kidney disease (CKD) stage. Changes in serum creatinine within 28 days postdose and diagnostic performance of piflufolastat F-18 were assessed for each CKD stage group in both cohorts. RESULTS: 385 patients (cohort A, n = 268; cohort B, n = 117) underwent piflufolastat F-18-PET/CT. Baseline and postpiflufolastat F-18 median creatinine levels (mg/dL) were similar for patients in cohort A (0.95 [n = 264] vs. 0.95 [n = 252], respectively) and cohort B (0.93 [n = 116] vs. 0.96 [n = 84], respectively). Among 332 men (cohort A, n = 249; cohort B, n = 83) with baseline and postpiflufolastat creatinine measurements, there were minimal changes in creatinine across all baseline CKD stage groups (median change ranged from -0.02 to 0.023 in groups with >1 patient). The diagnostic performance of piflufolastat F-18 showed no meaningful differences when stratified by baseline CKD stage. CONCLUSION: Piflufolastat F-18 appears to be safe and effective for imaging prostate cancer, including men with mild/moderate renal insufficiency.

Best Patient Care Practices for Administering PSMA-Targeted Radiopharmaceutical Therapy.

Optimal patient management protocols for metastatic castration-resistant prostate cancer (mCRPC) are poorly defined and even further complexified with new therapy approvals, such as radiopharmaceuticals. The prostate-specific membrane antigen (PSMA)-targeted agent 177Lu vipivotide tetraxetan ([177Lu]Lu-PSMA-617), approved after the phase III VISION study, presents physicians with additional aspects of patient management, including specific adverse event (AE) monitoring and management, as well as radiation safety. Drawing on our experience as VISION study investigators, here we provide guidance on best practices for delivering PSMA-targeted radiopharmaceutical therapy (RPT) to patients with mCRPC. After a comprehensive review of published evidence and guidelines on RPT management in prostate cancer, we identified educational gaps in managing the radiation safety and AEs associated with [177Lu]Lu-PSMA-617. Our results showed that providing sufficient education on AEs (e.g., fatigue and dry mouth) and radiation safety principles is key to effective delivery and management of patient expectations. Patient counseling by health care professionals, across disciplines, is a cornerstone of optimal patient management during PSMA-targeted RPT. Multidisciplinary collaboration is crucial, and physicians must adhere to radiation safety protocols and counsel patients on radiation safety considerations. Treatment with [177Lu]Lu-PSMA-617 is generally well tolerated; however, additional interventions may be required, such as dosing modification, medications, or transfusions. Urinary incontinence can be challenging in the context of radiation safety. Multidisciplinary collaboration between medical oncologists and nuclear medicine teams ensures that patients are monitored and managed safely and efficiently. In clinical practice, the benefit-to-risk ratio should always be evaluated on a case-by-case basis.

Role of [18F]-PSMA-1007 PET radiomics for seminal vesicle invasion prediction in primary prostate cancer.

PURPOSE: The purpose of this study is to investigate the diagnostic utility of [18F]-PSMA-1007 PET radiomics combined with machine learning methods to predict seminal vesicle invasion (SVI) after radical prostatectomy (RP) in prostate cancer (PCa) patients. METHODS: This is a post hoc retrospective analysis for a prospective clinical trial that included a consecutive sample of PCa patients (n = 140) who had [18F]-PSMA-1007 PET/CT prior to RP. The intraprostatic lesion's volume of interest (VOI) was semi-automatically sketched using a threshold of 40 % maximum standardized uptake value (SUVmax), namely 40%SUVmax-VOI, and seminal vesicle glands were manually contoured, namely SV-VOI. Models were built using a variety of machine learning methods such as logistic regression, random forest, and support vector machine. The area under the receiver operating characteristic curve (AUC) was calculated for different models, and the prediction performances of radiomics models were compared against the radiologists' assessment. Kaplan-Meier analysis was utilized to assess the effectiveness of selected radiomics features to determine the progression-free survival (PFS) probability. RESULTS: The training set had 112 patients and the test set had 28 patients. The highest AUC for the PET radiomics model of 40%SUVmax-VOI and the PET radiomics model of SV-VOI were 0.85 and 0.96 in the test set, respectively. The PET radiomics model of SV-VOI had a significantly higher AUC compared to the radiologists' assessment (P < 0.05). The Kaplan-Meier analysis showed that PET radiomics features were associated with PFS in patients with PCa. CONCLUSION: Radiomics models developed by preoperative [18F]-PSMA-1007 PET were proven useful in predicting SVI, and PSMA PET radiomics features were correlated with PFS, suggesting that the PSMA PET radiomics might be an accurate tool for PCa characterization.

A Machine Learning Approach for Predicting Biochemical Outcome After PSMA-PET-Guided Salvage Radiotherapy in Recurrent Prostate Cancer After Radical Prostatectomy: Retrospective Study.

BACKGROUND: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. OBJECTIVE: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer. METHODS: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. RESULTS: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram. CONCLUSIONS: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions.

Composite Prediction Score to Interpret Bone Focal Uptake in Hormone-Sensitive Prostate Cancer Patients Imaged with [18F]PSMA-1007 PET/CT.

Unspecific bone uptake (UBU) related to [18F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [18F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [18F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUVmax, SUVmean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HUmean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [18F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUVmax (P < 0.001) and HUmean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score's AUC was significantly higher than that of HUmean (AUC, 0.62) and remained high among lesions with HUmean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [18F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.

American Radium Society Appropriate Use Criteria for the Workup and Treatment of Local Intraprostatic Recurrence of Prostate Cancer Following Definitive Radiotherapy.

BACKGROUND AND OBJECTIVE: Local intraprostatic radiorecurrence of prostate cancer (IPR-PC) can be associated with an aggressive natural history and impact long-term disease-specific survival. While appropriate local salvage intervention can be curative, best practices for workup and local salvage of intraprostatic recurrence are poorly defined. The American Radium Society (ARS) Genitourinary Appropriate Use Criteria Committee sought to develop evidence-based recommendations to address this gap. METHODS: PubMed and Embase were searched to retrieve a comprehensive set of relevant peer-reviewed articles on four topics relevant to the workup and treatment of IPR-PC. The literature was evaluated and summarized by three investigators, and clinical variants were created for each of the four topics. The ARS Genitourinary AUC multidisciplinary expert panel voted on the most appropriate procedures for each variant, and a modified Delphi approach was used to summarize recommendations. KEY FINDINGS AND LIMITATIONS: The panel concluded that radiographic staging via prostate-specific membrane antigen positron emission tomography (PSMA PET) and multiparametric magnetic resonance imaging should be performed to exclude patients with metastatic disease and identify the local extent of radiorecurrence. Biopsy is required before local salvage to avoid excessive toxicity in patients whose radiographic recurrence represents a treatment effect. Consideration of local salvage is preferred in lieu of noncurative hormonal manipulation alone, although shared decision-making is critical. Salvage reirradiation approaches are recommended to limit toxicity. Hormonal therapy may be beneficial for radiosensitization when radiotherapeutic salvage is pursued, but only of short duration, and classic androgen deprivation therapies are preferred over novel hormonal agents. Focal salvage should be pursued when confidence in focal recurrence can be confirmed via multiple radiographic and tissue sampling modalities, although the toxicity associated with whole-gland salvage appears to be very tolerable. Several radiotherapeutic salvage regimens exist, most of which can be carried out in six or fewer fractions. The data informing this guideline are limited to individuals initially treated with conventionally fractionated external beam radiotherapy and with workup for recurrence before the PSMA PET era. CONCLUSIONS AND CLINICAL IMPLICATIONS: This consensus guideline provides evidence-based guidance on the appropriate procedures for workup and treatment of IPR-PC. Prospective evidence to enrich these guidelines is eagerly anticipated. PATIENT SUMMARY: We summarize evidence for the best workup and treatment for patients with local recurrence of prostate cancer after radiotherapy. A panel of experts evaluated previous studies and voted on the procedures that should be performed and those that should be avoided. This guideline is a useful tool for helping doctors to discuss the best treatment options that maximize the chance of cure while minimizing side effects.

Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

Cellular Membrane-Derived Nanovesicles Expressing hCD64 for Targeting Prostate Cancer.

Extracellular vesicles are ideal therapeutic potentiators for various diseases. However, they commonly lack targeting capability and are rapidly cleared by phagocytes. This requires appropriate administration at high doses, which can lead to toxic and adverse reactions. To overcome these limitations, we developed bleb nanovesicles containing human Fcγ receptor I (hCD64), known for their strong affinity to monomeric IgG. In this study, we focused on prostate cancer, which has a specific membrane antigen. We have utilized the hCD64-expressing bleb nanovesicles attaching anti-prostate-specific membrane antigen (PSMA) antibodies and confirmed their targeting ability in PSMA-related cell lines and prostate cancer xenograft models. Our findings underscore the promising potential of nanovesicle Fcγ receptor-IgG as a platform for cancer diagnosis and therapy systems, inspiring further research.

Performance of PSMA-targeted radiotheranostics in an experimental model of renal cell carcinoma.

Introduction: Renal cell carcinoma (RCC) represents cancer originating from the renal epithelium and accounts for > 90% of cancers in the kidney. Prostate-specific membrane antigen (PSMA) is overexpressed in tumor-associated neovascular endothelial cells of many solid tumors, including metastatic RCC. Although studied in several small clinical studies, PSMA-based imaging and therapy have not been pursued rigorously in preclinical RCC. This study aimed to evaluate the preclinical performance of PSMA-based radiotheranostic agents in a relevant murine model. Methods: A PSMA-overexpressing murine cell line, PSMA+ RENCA, was developed by lentiviral transduction. PSMA-based theranostic agents, 68Ga-L1/177Lu-L1/225Ac-L1, were synthesized in high radiochemical yield and purity following our reported methods. Immunocompetent BALB/c mice were used for flank and orthotopic tumor inoculation. 68Ga-L1 was evaluated in small animal PET/CT imaging in flank and PET/MR imaging in orthotopic models. Cell viability studies were conducted for 177Lu-L1 and 225Ac-L1. Proof-of-concept treatment studies were performed using 225Ac-L1 (0, 37 kBq, 2 kBq × 37 kBq, 1 week apart) using PSMA+ RENCA in the flank model. Results: Cellular uptake of 68Ga-L1, 177Lu-L1, and 225Ac-L1 confirmed the specificity of the agents to PSMA+ RENCA cells rather than to RENCA (wt) cells, which are low in PSMA expression. The uptake in PSMA+ RENCA cells at 1 h for 68Ga-L1 (49.0% incubated dose [ID] ± 3.6%ID/million cells), 177Lu-L1 (22.1%ID ± 0.5%ID)/million cells), and 225Ac-L1 (4.1% ± 0.2% ID)/million cells), respectively, were higher than the RENCA (wt) cells (~ 1%ID-2%ID/million cells). PET/CT images displayed > 7-fold higher accumulation of 68Ga-L1 in PSMA+ RENCA compared to RENCA (wt) in flank implantation at 1 h. A twofold higher accumulation of 68Ga-L1 was observed in orthotopic tumors than in normal kidneys during 1-3 h postinjection. High lung uptake was observed with 68Ga-L1 PET/MR imaging 3 weeks after orthotopic implantation of PSMA+ RENCA due to spontaneous lung metastases. The imaging data were further confirmed by immunohistochemical characterization. 225Ac-L1 (0-37 kBq) displayed a dose-dependent reduction of cell proliferation in the PSMA+ RENCA cells after 48 h incubation; ~ 40% reduction in the cells with treated 37 kBq compared to vehicle (p < 0.001); however, no effect was observed with 177Lu-L1 (0-3700 kBq) up to 144 h postinoculation, suggesting lower efficacy of ß-particle-emitting radiations in cellular studies compared to α-particle-emitting 225Ac-L1. Animals treated with 225Ac-L1 at 1 week posttumor inoculation in flank models displayed significant tumor growth delay (p < 0.03) and longer median survival of 21 days and 24 days for the treatment groups 37 kBq and 2 kBq × 37 kBq, respectively, compared to the vehicle group (12 days). Conclusion: The results suggest that a theranostic strategy targeting PSMA, employing PET and α-emitting radiopharmaceuticals, enabled tumor growth control and enhanced survival in a relevant immunocompetent murine model of RCC. These studies provide the rationale for clinical studies of PSMA-targeted theranostic agents in patients with RCC.

Pattern of Failure in Patients with Biochemical Recurrence After PSMA Radioguided Surgery.

Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (RGS) is evolving as a new treatment modality for patients with early biochemical recurrence of prostate cancer and disease limited to locoregional lymph nodes on PSMA-ligand PET/CT. Nevertheless, the pattern of failure (locoregional vs. systemic) after PSMA RGS remains unknown. Therefore, the aim of this retrospective analysis was to evaluate the pattern of disease using PSMA-ligand PET in patients experiencing relapse after PSMA RGS. Methods: We evaluated 100 patients with biochemical recurrence after previous PET-guided PSMA RGS who underwent PSMA-ligand PET (median prostate-specific antigen [PSA], 0.9 ng/mL; range, 0.2-14.2 ng/mL). All suspicious lesions for recurrent prostate cancer were grouped according to the molecular imaging TNM classification system. Detection rates and lesion localization were determined and stratified by PSA values and the International Society of Urological Pathology grade group. Further, lesion localization was compared before and after PSMA RGS. Results: The median time between PSMA RGS and PSMA-ligand PET for relapse was 11.4 mo (range, 5.5-25.6 mo). In total, 91 of 100 (91%) patients showed PSMA-ligand-positive findings. PSMA PET detection rates were 82.6%, 92.6%, 91.3%, and 96.3% for PSA levels of 0.2-0.49, 0.5-0.99, 1-1.99, and at least 2 ng/mL, respectively. More than half of the patients (53%; 48/91) showed local recurrence or pelvic lymph node metastases only. Extrapelvic lymph node metastases, bone metastases, and visceral metastases were present in 22% (20/91), 16% (15/91), and 9% (8/91) of the patients, respectively. With increasing International Society of Urological Pathology grade group, the percentage of patients with bone and visceral metastases increased, whereas the number of patients with only locoregional disease decreased. Conclusion: PSMA-ligand PET is a useful method to detect and localize recurrent disease in patients with biochemical failure after PSMA RGS, with more than half of the patients presenting with locoregional recurrence, offering the potential for a second local therapy (e.g., radiation therapy or repeated surgery).

A Meta-Analysis and Meta-Regression of the Efficacy, Toxicity, and Quality of Life Outcomes Following Prostate-Specific Membrane Antigen Radioligand Therapy Utilising Lutetium-177 and Actinium-225 in Metastatic Prostate Cancer.

BACKGROUND AND OBJECTIVE: Management of metastatic prostate cancer (mPCa) presents significant challenges. In this systematic review, meta-analysis, and meta-regression, the efficacy, safety, and quality of life (QoL) outcomes of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) utilising lutetium-177 ([177Lu]Lu-PSMA) and actinium-225 ([225Ac]Ac-PSMA) were assessed. METHODS: A detailed literature search across PubMed/Medline, EMBASE, Web of Science, Scopus, and Cochrane Library was conducted, culminating in the inclusion of 100 studies involving 8711 patients. Data on prostate-specific antigen (PSA) responses, toxicity profiles, and QoL and survival outcomes were analysed. Proportional meta-analyses and meta-regression analyses were performed. KEY FINDINGS AND LIMITATIONS: The estimated proportion of patients with PSA decline ≥50% was 0.49 for [177Lu]Lu-PSMA and 0.60 for [225Ac]Ac-PSMA in mPCa, particularly metastatic castration-resistant prostate cancer. A meta-regression analysis indicated an association between the cumulative amount of administered activity and the proportion of PSA ≥50% decline. Positive PSA responses were observed alongside improved overall survival across both therapies. Our analyses also identified the key factors associated with PSA responses and survival outcomes, including baseline haemoglobin level, and the presence of visceral metastases. Although anaemia was commonly observed, with [177Lu]Lu-PSMA, severe toxicities were infrequent. Improved QoL was observed following [177Lu]Lu-PSMA therapy, whereas it remained stable following the second cycle of [225Ac]Ac-PSMA treatment. Heterogeneity across studies for PSA responses and toxicity profiles is a limitation. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our findings suggest an association between PRLT and reductions in PSA levels, as well as associations with enhanced survival outcomes in mPCa. Furthermore, our analysis shows a low incidence of severe toxicity associated with this treatment. These observations highlight the important role of PRLT in the management of mPCa.

Prediction of biochemical recurrence after radical prostatectomy from primary tumour characteristics.

OBJECTIVES: To construct and externally calibrate a predictive model for early biochemical recurrence (BCR) after radical prostatectomy (RP) incorporating clinical and modern imaging characteristics of the primary tumour. PATIENTS AND METHODS: Patients who underwent RP following multiparametric magnetic resonance imaging, prostate biopsy and prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT), from two centres in Australia and the Netherlands. The primary outcome was biochemical recurrence-free survival (BRFS), where BCR was defined as a rising PSA level of ≥0.2 ng/mL or initiation of postoperative treatment per clinician discretion. Proportional hazards models to predict time to event were developed in the Australian sample using relevant pre- and post-surgical parameters and primary tumour maximum standardised uptake value (SUVmax) on diagnostic PSMA-PET/CT. Calibration was assessed in an external dataset from the Netherlands with the same inclusion criteria. RESULTS: Data from 846 patients were used to develop the models. Tumour SUVmax was associated with worse predicted 3-year BRFS for both pre- and post-surgical models. SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 66% to 42% for a patient aged 65 years with typical pre-surgical parameters (PSA level 8 ng/mL, Prostate Imaging-Reporting and Data System score 4/5 and biopsy Gleason score ≥4 + 5). Considering post-surgical variables, a patient with the same age and PSA level but pathological stage pT3a, RP Gleason score ≥4 + 5 and negative margins, SUVmax change from 4 to 16 lessened the predicted 3-year BRFS from 76% to 61%. Calibration on an external sample (n = 464) showed reasonable performance; however, a tendency to overestimate survival in patients with good prognostic factors was observed. CONCLUSION: Tumour SUVmax on diagnostic PSMA-PET/CT has utility additional to commonly recognised variables for prediction of BRFS after RP.

Head-to-head comparison of PSMA PET/CT and mpMRI for detecting biochemical recurrence of prostate cancer: A systematic review and meta-analysis.

Objectives: This study aimed to evaluate the performance of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) in comparison to multiparametric magnetic resonance imaging (mpMRI) for detecting biochemical recurrence of prostate cancer (PCa). Materials and methods: We conducted a comprehensive search for articles published in PubMed, Web of Science, Embase, and the Cochrane Library, spanning the inception of the database until October 26, 2022, which included head-to-head comparisons of PSMA PET/CT and mpMRI for assessing the biochemical recurrence of PCa. Results: A total of 5 studies including 228 patients were analyzed. The overall positivity rates of PSMA PET/CT and mpMRI for detecting biochemical recurrence of PCa after final treatment were 0.68 (95% confidence interval [CI], 0.52-0.89) and 0.56 (95% CI, 0.36-0.88), respectively. The positivity rates of PSMA PET/CT and mpMRI for detecting local recurrence, lymph node metastasis, and bone metastases were 0.37 (95% CI, 0.30-0.47) and 0.38 (95% CI, 0.22-0.67), 0.44 (95% CI, 0.35-0.56) and 0.25 (95% CI, 0.17-0.35), and 0.19 (95% CI, 0.11-0.31) and 0.12 (95% CI, 0.05-0.25), respectively. Compared with mpMRI, PSMA PET/CT exhibited a higher positivity rate for detecting biochemical recurrence and lymph node metastases, and no significant difference in the positivity rate of local recurrence was observed between these 2 imaging modalities. Conclusions: Compared with mpMRI, PSMA PET/CT appears to have a higher positivity rate for detecting biochemical recurrence of PCa. Although both imaging methods showed similar positivity rates of detecting local recurrence, PSMA PET/CT outperformed PSMA PET/CT in detecting lymph node involvement and overall recurrence.

PSMA PET/CT imaging and its application to prostate cancer treatment.

Recognition of the importance of prostate-specific membrane antigen (PSMA) PET/CT in the diagnosis of prostate cancer has steadily increased following the publication of extensive data on its diagnostic accuracy and impact on patient management over the past decade. Several recent clinical trials and investigations regarding PSMA PET/CT have been ongoing in our country, and this examination is expected to become increasingly widespread in the future. This review explains the characteristics of PSMA PET/CT, its diagnostic capabilities and superiority over other modalities, the three proposed PSMA PET/CT interpretation criteria (the European Association of Nuclear Medicine [EANM], the Prostate Cancer Molecular Imaging Standardized Evaluation [PROMISE], and the PSMA Reporting and Data System [PSMA-RADS]), and the application of PSMA PET/CT to prostate cancer treatment (improvement of local control, irradiation of oligometastases, and salvage radiotherapy), incorporating actual clinical images and the latest findings.

Optimising prostate biopsies and imaging for the future-a review.

Conventionally, transrectal ultrasound guided prostate biopsy (TRUS-Bx) was the main technique used for the diagnosis of prostate cancer since it was first described in 1989 [1]. However, the PROMIS trial showed that this random, nontargeted approach could miss up to 18% of clinically significant cancer (csPCa) [2]. Furthermore, risk of sepsis post TRUS-Bx can be as high as 2.4% [3]. Understanding the demerits of TR-biopsy have led to the introduction of transperineal prostate biopsy (TP-Bx). The incorporation of mpMRI revolutionized prostate cancer diagnostics, allowing visualization of areas likely to harbor csPCa whilst permitting some men to avoid an immediate biopsy. Furthermore, the advent of prostate specific membrane antigen-positron emission tomography (PSMA-PET) is highly promising, because of its role in primary diagnosis of prostate cancer and its higher diagnostic accuracy over conventional imaging in detecting nodal and metastatic lesions. Our narrative review provides an overview on prostate biopsy techniques and an update on prostate imaging, with particular focus on PSMA-PET.

An Analysis of the Diagnostic Performance of Tc-99m PSMA SSPECT/CT in Biochemically Recurrent Prostate Cancer Compared with Ga-68 PSMA PET/CT: A Single-center, Prospective Study.

Objective: Biochemical recurrence (BCR) after initial management of Prostate Carcinoma (PC) is frequent. Subsequent interventions rely on disease burden and metastasis distribution. 68Ga prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is an excellent imaging modality in BCR. However, 68Ga is radionuclide generator produced and has restricted availability. 99mTc-labeled PSMA could be a potential cost-effective alternative. We compared the performance of 99mTc-PSMA single-photon emission CT (SPECT)/CT and 68Ga-PSMA PET/CT in BCR with a serum prostate surface antigen (PSA) level of <20 ng/mL. Materials and Methods: The prospective study included 25 patients with BCR and at least one lesion on a 68Ga-PSMA PET/CT. All patients underwent 99 mTc-PSMA SPECT/CT, and disease distribution and metastatic burden were compared with 68Ga-PSMA PET/CT. The maximum standard uptake value (SUVmax) and the tumor-to-background ratio (TBR) were computed and analyzed. Results: The mean age and serum PSA (SPSA) were 69.72 ± 6.69 years and 5.65 ± 6.07 ng/mL. Eleven patients (44%) had SPSA ≤2 ng/mL. Recurrent sites were noted in the prostate (19, 76%), prostatic bed (3, 12%), and pelvis lymph nodes (LNs) (13, 52%). Distant metastasis to bones (13, 52%), lungs (5, 20%), and retroperitoneal LNs (2, 8%) were noted. Both modalities were concordant for the recurrent disease at the prostate, prostatic bed, bone, and lung lesions. 99mTc-PSMA could localize pelvis LNs in most patients (10/13, 76.9%). The site-specific sensitivity and specificity between the two modalities were not significantly different (P > 0.05). TBR shows excellent correlation with SUVmax (0.783, P < 0.001). Four (16%) patients were understaged with 99mTc-PSMA due to the nonvisualization of the subcentimeter size LNs. No patient with systemic metastases was understaged. Conclusions: 99mTc-PSMA SPECT/CT has good concordance with 68Ga-PSMA PET/CT in BCR, even at low PSA levels. However, it may miss a few subcentimeter LNs due to lower resolution. 99mTc-PSMA SPECT/CT could be a simple, cost-effective, and readily available imaging alternative to PET/CT.

Detection of Docetaxel-induced Interstitial Pneumonitis on Ga-68 PSMA PET/CT Imaging.

Ga-68 labeled prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT) is increasingly recognized as the best imaging modality for disease staging and detection of recurrent prostate cancer. Despite its name, PSMA expression has been reported in the neovasculature of several nonprostatic benign and malignant pathologies. Docetaxel, a taxane antineoplastic agent, is the mainstay of treatment in castration-resistant prostate cancer and high-volume hormone-sensitive prostate cancer. Although the occurrence of docetaxel-related interstitial lung disease is rare, it may lead to respiratory failure if treatment is delayed. We present a case of metastatic castration-resistant prostate cancer, wherein docetaxel-induced interstitial pneumonitis was detected on Ga-68 PSMA PET/CT after docetaxel administration.