Opinion statement

PSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

Background

Understanding the characteristics of multiparametric MRI (mpMRI) in patients from different racial/ethnic backgrounds is important for reducing the observed gaps in clinical outcomes.

Purpose

To investigate the diagnostic performance of mpMRI and quantitative MRI parameters of prostate cancer (PCa) in African American (AA) and matched White (W) men.

Study type

Retrospective.

Subjects

One hundred twenty-nine patients (43 AA, 86 W) with histologically proven PCa who underwent mpMRI before radical prostatectomy.

Field strength/sequence

3.0 T, T2-weighted turbo spin echo imaging, a single-shot spin-echo EPI sequence diffusion-weighted imaging, and a gradient echo sequence dynamic contrast-enhanced MRI with an ultrafast 3D spoiled gradient-echo sequence.

Assessment

The diagnostic performance of mpMRI in AA and W men was assessed using detection rates (DRs) and positive predictive values (PPVs) in zones defined by the PI-RADS v2.1 prostate sector map. Quantitative MRI parameters, including K^trans and v_e of clinically significant (cs) PCa (Gleason score ≥ 7) tumors were compared between AA and W sub-cohorts after matching age, prostate-specific antigen (PSA), and prostate volume.

Statistical tests

Weighted Pearson's chi-square and Mann-Whitney U tests with a statistically significant level of 0.05 were used to examine differences in DR and PPV and to compare parameters between AA and matched W men, respectively.

Results

A total number of 264 PCa lesions were identified in the study cohort. The PPVs in the peripheral zone (PZ) and posterior prostate of mpMRI for csPCa lesions were significantly higher in AA men than in matched W men (87.8% vs. 68.1% in PZ, and 89.3% vs. 69.6% in posterior prostate). The K^trans of index csPCa lesions in AA men was significantly higher than in W men (0.25 ± 0.12 vs. 0.20 ± 0.08 min^-1; P < 0.01).

Data conclusion

This study demonstrated race-related differences in the diagnostic performances and quantitative MRI measures of csPCa that were not reflected in age, PSA, and prostate volume.

Evidence level

3 TECHNICAL EFFICACY: Stage 2.

PURPOSE: To evaluate whether quantitative whole-body (WB) PSMA-PET metrics under long-term androgen deprivation therapy (ADT) and/or androgen receptor signaling inhibitors (ARSi) are associated with PSA progression. METHODS: Patients who underwent at least 2 68Ga-PSMA-11 PET/CT scans between October 2016 and April 2021 (n = 372) and started a new line of ADT ± ARSi between PET1 and PET2 were retrospectively screened for inclusion. We investigated the association between PCWG3-defined PSA progression status at PET2 and the following PSMA-PET parameters: appearance of new lesions on PET2, ≥ 20% increase in WB-PSMA tumor volume (WB-PSMA-VOL), progression of disease (PD) by RECIP 1.0, and ≥ 30% increase in WB-PSMA-SUVmean from PET1 to PET2. Spearmans rank correlation coefficients and Fishers exact test were used to evaluate the associations. RESULTS: Thirty-five patients were included: 12/35 (34%) were treated with ADT only and 23/35 (66%) with ARSi ± ADT. The median time between PET1 and PET2 was 539 days. Changes (%) in median PSA levels, WB-PSMA-SUVmean, and WB-PSMA-VOL from PET1 to PET2 were -86%, -23%, and -86%, respectively. WB-PSMA-VOL ≥ 20%, new lesions, RECIP-PD, and WB-PSMA-SUVmean ≥ 30% were observed in 5/35 (14%), 9/35 (26%), 5/35 (14%), and 4/35 (11%) of the whole cohort, in 3/9 (33%), 7/9 (78%), 3/9 (33%), and 2/9 (22%) of patients with PSA progression at PET2, and in 2/26 (8%), 2/26 (8%), 2/26 (8%), and 2/26 (8%) of patients without PSA progression at PET2 (p = 0.058, p < 0.001, p = 0.058, p = 0.238, respectively). Changes in PSA were correlated to percent changes in WB-PSMA-VOL and WB-PSMA-SUVmean (Spearman ρ: 0.765 and 0.633, respectively; p < 0.001). CONCLUSION: Changes in PSA correlated with changes observed on PSMA-PET, although discordance between PSA and PSMA-PET changes was observed. Further research is necessary to evaluate if PSMA-PET parameters can predict progression-free survival and overall survival and serve as novel endpoints in clinical trials.

The impact of prostate-specific membrane antigen (PSMA) PET/CT on management of prostate cancer (PCa) patients with biochemical recurrence (BCR) is well established. However, whether and how PSMA PET/CT affects the management of patients undergoing scans for other clinical indications remains unknown. The goal of this study was to determine the impact of ⁶⁸Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications (i.e., a basket trial) excluding the 2 main classic indications: BCR and presurgical staging. Methods: This was a prospective study of 197 patients that aimed to determine the impact of ⁶⁸Ga-PSMA-11 PET/CT on PCa stage and management. The indications for PSMA PET/CT were initial staging of nonsurgical candidates (30 patients) and restaging after definitive treatment (167 patients). The restaging cohort comprised patients restaged with known advanced metastatic disease (n = 103), after androgen deprivation therapy only (n = 16), after surgery and with serum prostate-specific antigen levels lower than 0.2 ng/mL (n = 13), after radiation therapy and not meeting the Phoenix criteria (n = 22), and after other primary local treatments (i.e., high-intensity focused ultrasound, focal laser ablation, cryoablation, hyperthermia, or irreversible electroporation) (n = 13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review, or patient telephone calls. Results: PSMA PET/CT changed the disease stage in 135 of 197 (69%) patients (upstaging in 38%, downstaging in 30%, and no change in stage in 32%). Management was affected in 104 of 182 (57%) patients. Specifically, PSMA PET/CT impacted the management of patients who were restaged after radiation therapy without meeting the Phoenix criteria for BCR, after other definitive local treatments, and with advanced metastatic disease in 13 of 18 (72%), 8 of 12 (67%), and 59 of 96 (61%), respectively. Conclusion: PSMA PET/CT has a profound impact on stage and management of PCa patients outside the 2 main classic indications (BCR and presurgical staging) across all examined clinical scenarios.

BACKGROUND: PSMA expression is influenced by hormonal status. We evaluated changes in PSA and whole-body 68Ga-PSMA-11 PET/CT (WB-PSMA PET) after initiation of androgen receptor signaling inhibitors (ARSi). METHODS: Prospectively enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) initiating ARSi underwent serial PSA measurements and WB-PSMA PET at baseline, 1-week, and 3-months post-ARSi. We correlated WB-PSMA PET metrics and PSA kinetics after ARSi to 1-year clinical outcome. RESULTS: Due to low enrollment rate, the study was closed before reaching the recruitment goal of 30 patients. Nine patients were enrolled. At 1-year, unfavorable outcome was documented in 6/9 (66%) patients. Nine/9 patients completed PSMA PET at 1-week, 5/9 at 3-months. Changes in PSA, PSMA-VOL, SUVmean and SUVmax were - 12%, + 5%, + 3%, and + 10% at 1-week, - 42%, - 16%, - 15% and - 17% at 3-months, respectively. CONCLUSIONS: Our prospective trial involving 9 mCRPC patients initiating ARSi did not show significant modulation of PSMA expression measured on WB-PSMA PET at 1-week. This study was registered on clinicaltrials.gov (NCT04279561).

The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of ⁶⁸Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) (P < 0.001) but not between PSMA PET/CT and mpMRI (P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE (P = 0.002) and SVI (P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.

Introduction

Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed.

Methods

We developed a visual interpretation method for ¹⁸F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted ¹⁸F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern.

Results

Global visual scores were reliable, correlated with global cortical ¹⁸F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like ¹⁸F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI.

Discussion

This ¹⁸F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using ⁶⁸Ga-PSMA-11 PET/CT (⁶⁸Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on ⁶⁸Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the ⁶⁸Ga-PSMA PET, respectively, masked from each other. The coverage of the ⁶⁸Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different ⁶⁸Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and ⁶⁸Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that ⁶⁸Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.

284 Background: Multiparametric MRI (mpMRI) and PSMA-PET are complementary imaging modalities used in the pre-surgical evaluation of patients with prostate cancer (PCa). The aim of this study was to evaluate the imaging and pathology parameters associated with PSMA-PET and mpMRI disagreement with each other and with gold standard histopathology. Methods: Patients undergoing radical prostatectomy (RP) with pre-surgical PSMA-PET and mpMRI were screened for inclusion in this retrospective analysis. Patients had the imaging scans done <3 months from each other, and whole mount histopathology (WMHP) slides available. Two nuclear medicine physicians and 2 radiologists independently contoured PCa lesions on PSMA-PET and mpMRI, respectively. A consensus read was done with a third reader for each modality, and a majority rule was applied (2:1). Quantitative measures were extracted on a lesion-basis (SUVmean, SUVmax, tumor volume). A PET/MRI fusion was obtained, and agreement/disagreement was assessed visually, based on the overlapping lesion contours. WMHP slides were used to establish the disagreement of imaging-identified lesions with the gold standard pathology. Independent samples t-test and one-way ANOVA were used to assess group differences. Univariable and multivariable logistic regression models were used to assess the association of clinical, pathological, and imaging variables with PSMA-PET and mpMRI agreement/disagreement with each other and with pathology. Results: The cohort included 114 patients, and 175 pathology lesions were identified (ISUP 3, n=22; ISUP>3, n=153). mpMRI and PSMA PET identified 138 and 170 lesions, respectively. Sensitivity for ISUP>3 lesions was 79% and 87% for mpMRI and PSMA-PET, respectively. 115/153 (76%) ISUP> 3 lesions were correctly identified, and 14/153 (9%) were missed by both imaging modalities, respectively. 5/153 (3%) were correctly identified by mpMRI and missed by PSMA-PET, 17/153 (11%) were correctly identified by PSMA-PET and missed by mpMRI. Lesion’s ISUP grade group and size on pathology were significantly lower in mpMRI- compared to mpMRI+ and in PET- compared to PET+ lesions. SUVmax and SUVmean were significantly higher in PET+/MRI+ than PET+/MRI- lesions. Lesion’s ISUP grade group and size were significantly correlated to PSMA-PET and mpMRI agreement, whereas PSMA-PET metrics were not. Logistic regression model showed that lesions with lower ISUP, smaller size, and lack of aggressive prostate cancer features on pathology (cribriform pattern and intraductal carcinoma) have higher likelihood of being missed by PET and mpMRI and of PET/MRI disagreement. Conclusions: Higher SUVmax, SUVmean, and tumor volume on PSMA-PET were associated with a TP finding on PSMA-PET, higher ISUP grade group and size on pathology were associated with a TP finding on both PSMA-PET and mpMRI, and with agreement between PSMA-PET and mpMRI.

For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6-77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.