Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

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

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

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

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

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

Impact of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography on Prostate Cancer Salvage Radiotherapy Management: Results from a Prospective Multicenter Randomized Phase 3 Trial (PSMA-SRT NCT03582774).

BACKGROUND AND OBJECTIVE: Both imaging and several prognostic factors inform the planning of salvage radiotherapy (SRT). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can localize disease unseen by other imaging modalities. The main objective of the study was to evaluate the impact of PSMA-PET on biochemical recurrence-free survival rate after SRT. METHODS: This prospective randomized, controlled, phase 3 clinical trial randomized 193 patients with biochemical recurrence of prostate cancer after radical prostatectomy to proceed with SRT (control arm, n = 90) or undergo a PSMA-PET/computed tomography (CT) scan prior to SRT planning (investigational arm, n = 103) from June 2018 to August 2020. Any other approved imaging modalities were allowed in both arms (including fluciclovine-PET). This is a secondary endpoint analysis: impact of PSMA-PET on SRT planning. Case-report forms were sent to referring radiation oncologists to collect the management plans before randomization and after completion of SRT. The relative frequency (%) of management changes within each arm were compared using chi-square and Fisher's exact tests. KEY FINDINGS AND LIMITATIONS: The delivered SRT plan was available in 178/193 patients (92.2%;76/90 control [84.4%] and 102/103 PSMA-PET [99%]). Median prostate-specific antigen levels at enrollment was 0.30 ng/ml (interquartile range [IQR] 0.19-0.91) in the control arm and 0.23 ng/ml (IQR 0.15-0.54) in the PSMA-PET arm. Fluciclovine-PET was used in 33/76 (43%) in the control arm. PSMA-PET localized recurrence(s) in 38/102 (37%): nine of 102 (9%) outside of the pelvis (M1), 16/102 (16%) in the pelvic LNs (N1, with or without local recurrence), and 13/102 (13%) in the prostate fossa only. There was a 23% difference (95% confidence interval [CI] 9-35%, p = 0.002) of frequency of major changes between the control arm (22% [17/76]) and the PSMA-PET intervention arm (45%[46/102]). Of the major changes in the intervention group, 33/46 (72%) were deemed related to PSMA-PET. There was a 17.6% difference (95% CI 5.4-28.5%, p = 0.005) of treatment escalation frequency between the control arm (nine of 76 [12%]) and the intervention arm (30/102 [29%]). Treatment de-escalation occurred in the control and intervention arms in eight of 76 (10.5%) and 12/102 (11.8%) patients, and mixed changes in zero of 76 (0%) and four of 102 (3.9%) patients, respectively. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this prospective randomized phase 3 study, PSMA-PET findings provided information that initiated major management changes to SRT planning in 33/102 (33%) patients. The final readout of the primary endpoint planned in 2025 may provide evidence on whether these changes result in improved outcomes. PATIENT SUMMARY: Prostate-specific membrane antigen positron emission tomography leads to management changes in one-third of patients receiving salvage radiotherapy for post-radical prostatectomy biochemical recurrence of prostate cancer.

Correlation of FAPI PET Uptake with Immunohistochemistry in Explanted Lungs from Patients with Advanced Interstitial Lung Disease.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of 68Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis (n = 2), rheumatoid arthritis-associated ILD (n = 1), and nonspecific interstitial pneumonia (n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUVmax and SUVmean showed a positive correlation with the immunohistochemical FAP expression score (SUVmax: r = 0.57, P = 0.001; SUVmean: r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD.

Differences and Common Ground in 177Lu-PSMA Radioligand Therapy Practice Patterns: International Survey of 95 Theranostic Centers.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy effectively treats metastatic castration-resistant prostate cancer. Patients requiring treatment, and consequently the number of theranostic centers, are expected to increase significantly after Food and Drug Administration and European Medicines Agency approval. This requires standardization or harmonization among theranostic centers. The aim of this study was to assess operational differences and similarities among 177Lu-PSMA treatment centers. Methods: A questionnaire comprising 62 items, designed by a core team of 5 physicians and externally reviewed by international experts, was developed. Study participants were asked to provide answers about their center, patient selection, radiopharmaceuticals, clinical assessment before and after 177Lu-PSMA treatments, laboratory values, treatment discontinuation, posttreatment imaging, and general information. An invitation e-mail to participate in the study was sent in June 2022. Duplicates were removed to allow for only one valid response per center. Results: Ninety-five of 211 (45%) contacted centers completed the questionnaire. Most participating centers were in Europe (51%), followed by America (22%) and Asia (22%). During the 12 mo before this study, a total of 5,906 patients received 177Lu-PSMA therapy at the 95 participating centers. Most of these patients were treated in Europe (2,840/5,906; 48%), followed by Asia (1,313/5,906; 22%) and Oceania (1,225/5,906; 21%). PSMA PET eligibility for 177Lu-PSMA was determined most frequently using 68Ga-PSMA-11 (77%). Additional pretherapy imaging included 18F-FDG PET/CT, CT, renal scintigraphy, and bone scintigraphy at 41 (49%), 27 (32%), 25 (30%), and 13 (15%), respectively, of the 84 centers for clinical standard of care, compassionate care, or local research protocols and 11 (26%), 25 (60%), 9 (21%), and 28 (67%), respectively, of the 42 centers for industry-sponsored trials. PSMA PET eligibility criteria included subjective qualitative assessment of PSMA positivity at 33% of centers, VISION criteria at 23%, and TheraP criteria at 13%. The mean standard injected activity per cycle was 7.3 GBq (range, 5.5-11.1 GBq). Sixty-two (65%) centers applied standardized response assessment criteria, and PSMA PET Progression Criteria were the most applied (37%). Conclusion: Results from this international survey revealed interinstitutional differences in several aspects of 177Lu-PSMA radionuclide therapy, including patient selection, administered activity, and the response assessment strategy. Standardization or harmonization of protocols and dedicated training are desirable in anticipation of increasing numbers of patients and theranostic centers.

Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.

PURPOSE: To characterize the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-based metastatic spread. MATERIALS AND METHODS: We identified patients from four institutions who underwent PSMA PET/CT scans pretreatment for primary staging or postradical prostatectomy (RP) for suspected recurrence and had Decipher transcriptomic data available from biopsy or RP specimens. PSMA PET/CT-based patterns of spread were classified as localized (miT + N0M0) or nonlocalized (miN1M0 or miM1a-c). We calculated the association between Decipher scores and the risk of nonlocalized disease on PSMA PET/CT using multivariable logistic regression for pretreatment patients and multivariable Cox regression for post-RP patients. We also compared select transcriptomic signatures between patients with localized and nonlocalized diseases. RESULTS: Five hundred eighty-six patients were included (pretreatment: n = 329; post-RP: n = 257). Higher Decipher scores were associated with nonlocalized disease on PSMA PET/CT both pretreatment (odds ratio, 1.18 [95% CI, 1.03 to 1.36] per 0.1 increase in Decipher score, P = .02) and post-RP (hazard ratio, 1.15 [95% CI, 1.05 to 1.27] per 0.1 increase in Decipher score, P = .003). In the pretreatment setting, nonlocalized disease was associated with higher rates of TP53 mutations and lower rates of PAM50 luminal A subtype compared with localized disease. In the post-RP setting, overexpression of signatures related to metabolism, DNA repair, and androgen receptor signaling were associated with higher rates of nonlocalized disease. CONCLUSION: Higher Decipher scores were associated with nonlocalized disease identified on PSMA PET/CT both pretreatment and post-RP. There were several transcriptomic differences between localized and nonlocalized diseases in both settings.

FAPI PET Signal in Hibernoma Reflects FAP Expression in Tumor Vasculature Cells.

ABSTRACT: A 43-year-old man with a growing mass in the right groin, concerned for liposarcoma, underwent MRI and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT before surgery. Fibroblast activation protein inhibitor PET/CT demonstrated increased uptake (SUV max , 3.2) predominantly in the solid portion, where MRI showed gadolinium enhancement. The patient subsequently underwent surgery and was diagnosed with hibernoma. The immunohistochemistry of the tumor revealed the fibroblast activation protein expression in the fibrovascular network and myofibroblastic cells of the tumor. This case suggests that the FAPI uptake can be affected by the vascular cells, and thus, a careful interpretation of the FAPI PET signal may be needed.

Developing a Patient-Reported Outcome Measure for Radionuclide Therapy for Prostate Cancer.

The field of radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly, with recent Food and Drug Administration approval of the first 177Lu-PSMA ligand. We aimed to develop the first patient-reported outcome (PRO) measure for PC patients receiving RNT. Methods: We identified relevant symptoms and toxicities by reviewing published trials and interviews with PC patients receiving RNT (n = 29), caregivers (n = 14), and clinicians (n = 11). Second, we selected items for measure inclusion. Third, we refined the item list with input from experts in RNTs and PROs. Fourth, we finalized the Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) with patient input. Results: This multistep process yielded a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusion: The FACT-RNT is a new standardized tool to monitor relevant symptoms and toxicities among PC patients in RNT trials and real-world settings.

Presurgical 68Ga-PSMA-11 Positron Emission Tomography for Biochemical Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging Trial.

BACKGROUND: In the initial staging of patients with high-risk prostate cancer (PCa), prostate-specific membrane antigen positron emission tomography (PSMA-PET) has been established as a front-line imaging modality. The increasing number of PSMA-PET scans performed in the primary staging setting might be associated with decreases in biochemical recurrence (BCR)-free survival (BCR-FS). OBJECTIVE: To assess the added prognostic value of presurgical PSMA-PET for BCR-FS compared with the presurgical Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores in patients with intermediate- to high-risk PCa treated with radical prostatectomy (RP) and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This is a follow-up study of the surgical cohort evaluated in the multicenter prospective phase 3 imaging trial (n = 277; NCT03368547, NCT02611882, and NCT02919111). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. PSMA-PET prostate uptake (low vs high), PSMA-PET extraprostatic disease (N1/M1), and CAPRA and CAPRA-S scores were used to assess the risk of BCR. Patients were followed after RP by local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level increasing to ≥0.2 ng/ml after RP or initiation of PCa-specific secondary treatment (>6 mo after surgery). Univariate and multivariable Cox models, and c-statistic index were performed to assess the prognostic value of PSMA-PET and for a comparison with the CAPRA and CAPRA-S scores. RESULTS AND LIMITATIONS: From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. The median follow-up after surgery was 32.4 (interquartile range 23.3-42.9) mo. Of 240 BCR events, 91 (38%) were observed. PSMA-PET N1/M1 was found in 41/240 (17%) patients. PSMA-PET prostate uptake, PSMA-PET N1/M1, and CAPRA and CAPRA-S scores were significant univariate predictors of BCR. The addition of PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly in comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64-0.75] vs 0.63 [0.57-0.69]; p < 0.001). The C-index of the postsurgical model utilizing the postsurgical CAPRA-S score alone was not significantly different from the presurgical model combining the presurgical CAPRA score and PSMA-PET N1/M1 status (p = 0.19). CONCLUSIONS: Presurgical PSMA-PET was a strong prognostic biomarker improving BCR-FS risk assessment. Its implementation in the presurgical risk assessment with the CAPRA score improved the performance and reduced the difference with the reference standard (postsurgical CAPRA-S score). PATIENT SUMMARY: The use prostate-specific membrane antigen positron emission tomography improved the assessment of biochemical recurrence risk in patients with intermediate- and high-risk prostate cancer who were treated with radical prostatectomy and pelvic lymph node dissection.

18F-FLT PET/CT as a Prognostic Imaging Biomarker of Disease-Specific Survival in Patients with Primary Soft-Tissue Sarcoma.

The purpose of this study was to evaluate 18F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival and disease-specific survival (DSS) in soft-tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This was a 10-y follow-up of a previous single-center, single-arm prospective clinical trial. Patients underwent 18F-FLT PET/CT before treatment (PET1) and after NAT (PET2). Posttreatment pathology specimens were assessed for tumor necrosis or fibrosis and for Ki-67 and thymidine kinase 1 expression. Maximally selected cutoffs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1; 16 of the 26 with primary STS underwent PET2. Thirteen deaths occurred during a median follow-up of 104 mo. In the overall cohort, overall survival was longer in patients with a low than a high PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8.5 vs. <8.5: not yet reached vs. 49.7 mo; P = 0.0064). DSS showed a trend toward significance (P = 0.096). In a subanalysis of primary STS, DSS was significantly longer in patients with a low PET1 tumor SUVmax (dichotomized by an SUVmax of ≥8 vs. <8; P = 0.034). There were no significant 18F-FLT PET response thresholds corresponding to DSS or overall survival after NAT at PET2. Conclusion:18F-FLT PET may serve as a prognostic baseline imaging biomarker for DSS in patients with primary STS.

18F-FDG PET/CT Imaging Biomarkers for Early and Late Evaluation of Response to First-Line Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma.

The purpose of this study was to evaluate 18F-FDG PET/CT as an early and late interim imaging biomarker in patients with pancreatic ductal adenocarcinoma who undergo first-line systemic therapy. Methods: This was a prospective, single-center, single-arm, open-label study (IRB12-000770). Patient receiving first-line chemotherapy were planned to undergo baseline 18F-FDG PET/CT, early interim 18F-FDG PET/CT, and late interim 18F-FDG PET/CT. Cutoffs for metabolic and radiographic tumor response assessment as selected and established by receiver-operating-characteristic analysis were applied (modified PERCIST/RECIST1.1). Patients were followed to collect data on further treatments and overall survival. Results: The study population consisted of 28 patients who underwent baseline 18F-FDG PET/CT. Twenty-three of these (82%) underwent early interim 18F-FDG PET/CT, and 21 (75%) underwent late interim 18F-FDG PET/CT. Twenty-three deaths occurred during a median follow-up period of 14 mo (maximum follow-up, 58.3 mo). The median overall survival was 36.2 mo (95% CI, 28 mo to not yet reached [NYR]) in early metabolic responders (6/23 [26%], P = 0.016) and 25.4 mo (95% CI, 19.6 mo-NYR) in early radiographic responders (7/23 [30%], P = 0.16). The median overall survival was 27.4 mo (95% CI, 21.4 mo-NYR) in late metabolic responders (10/21 [48%], P = 0.058) and 58.2 mo (95% CI, 21.4 mo-NYR) in late radiographic responders (7/21 [33%], P = 0.008). Conclusion: 18F-FDG PET may serve as an early interim imaging biomarker (at ∼4 wk) for evaluation of response to first-line chemotherapy in patients with pancreatic ductal adenocarcinoma. Radiographic changes might be sufficient for response evaluation after the completion of first-line chemotherapy.

Novel Framework for Treatment Response Evaluation Using PSMA PET/CT in Patients with Metastatic Castration-Resistant Prostate Cancer (RECIP 1.0): An International Multicenter Study.

Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). Methods: This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent 177Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Results: Patients with RECIP-PD (n = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) (n = 47; 13.1 mo; P < 0.001) or RECIP-PR (n = 38; 21.7 mo; P < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 (P = 0.028) and 0.66 versus 0.63 (P = 0.044), respectively. Conclusion: PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of 177Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study.

The European Association of Urology (EAU) prostate cancer guidelines panel recommends risk groups for biochemical recurrence (BCR) of prostate cancer to identify men at high risk of progression or metastatic disease. The rapidly growing availability of PSMA-directed PET imaging will impact prostate cancer staging. We determined the rates of local and metastatic disease in BCR and biochemical persistence (BCP) of prostate cancer stratified by EAU BCR risk groups and BCP. Methods: Patients with BCR or BCP were enrolled under the same prospective clinical trial protocol conducted at 3 sites (n = 1,777 [91%]: UCLA, n = 662 [NCT02940262]; University of California San Francisco, n = 508 [NCT03353740]; University of Michigan, n = 607 [NCT03396874]); 183 patients with BCP from the Universities of Essen, Bologna, and Munich were included retrospectively. Patients with BCR had to have sufficient data to determine the EAU risk score. Multivariate, binomial logistic regression models were applied to assess independent predictors of M1 disease. Results: In total, 1,960 patients were included. Post-radical prostatectomy EAU BCR low-risk, EAU BCR high-risk, and BCP groups yielded distant metastatic (M1) detection in 43 of 176 (24%), 342 of 931 (37%), and 154 of 386 (40%) patients. For postradiotherapy EAU BCR low-risk and EAU BCR high-risk groups, the M1 detection rate was 113 of 309 (37%) and 110 of 158 (70%), respectively. BCP, high-risk BCR, and higher levels of serum prostate-specific antigen were significantly associated with PSMA PET M1 disease in multivariate regression analysis. PSMA PET revealed no disease in 25% and locoregional-only disease in 33% of patients with post-radical prostatectomy or postradiotherapy EAU BCR high risk. Conclusion: Our findings support the new EAU classification; EAU BCR high-risk groups have higher rates of metastatic disease on PSMA PET than do the low-risk groups. Discordant subgroups, including metastatic disease in low-risk patients and no disease in high-risk patients, warrant inclusion of PSMA PET stage to refine risk assessment.

Head-to-Head Comparison of 68Ga-PSMA-11 PET/CT and mpMRI with a Histopathology Gold Standard in the Detection, Intraprostatic Localization, and Determination of Local Extension of Primary Prostate Cancer: Results from a Prospective Single-Center Imaging Trial.

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.

A Comprehensive Assessment of 68Ga-PSMA-11 PET in Biochemically Recurrent Prostate Cancer: Results from a Prospective Multicenter Study on 2,005 Patients.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated levels of prostate-specific antigen (PSA) after initial therapy. Methods:68Ga-PSMA-11 hybrid PET was performed on 2,005 patients at the time of biochemically recurrent prostate cancer after radical prostatectomy (RP) (50.8%), definitive radiation therapy (RT) (19.7%), or RP with postoperative RT (PORT) (29.6%). The presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis, creating a disease burden estimate from the presence or absence of local (prostate/prostate bed), nodal (N1: pelvis), and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of 68Ga-PSMA-11 PET/CT confirmed by histopathology. Results: After RP, the scan detection rate increased significantly with rising PSA level (44.8% at PSA < 0.25%-96.2% at PSA > 10 ng/mL; P < 0.001). The detection rate significantly increased with rising PSA level in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from the RP specimen (P < 0.001). After RT, the detection rate for in-gland prostate recurrence was 64.0%, compared with 20.6% prostate bed recurrence after RP and 13.3% after PORT. PSMA-positive pelvic nodal disease was detected in 42.7% after RP, 40.8% after PORT, and 38.8% after RT. In patients with histopathologic validation, the PPV per patient was 0.82 (146/179). The SUVmax of histologically proven true-positive lesions was significantly higher than that of false-positive lesions (median, 11.0 [interquartile range, 6.3-22.2] vs. 5.1 [interquartile range, 2.2-7.4]; P < 0.001). Conclusion: We confirmed a high PPV for 68Ga-PSMA-11 PET in biochemical recurrence and the PSA level as the main predictor of scan positivity.

Tumor Sink Effect in 68Ga-PSMA-11 PET: Myth or Reality?

We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25-189 cm3), moderate (quintile 3, 189-532 cm3), high (quintile 4, 532-1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range [IQR], 47-1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7-11.8), 26.0 (IQR, 20.0-33.4), 3.7 (IQR, 3.0-4.7), and 5.3 (IQR, 4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = -0.44, P < 0.001), kidneys (r = -0.34, P < 0.001), and liver (r = -0.30, P < 0.001) and a weak negative correlation with the spleen SUVmean (r = -0.16, P = 0.002). Patients with a very high PSMA-VOL (quintile 5, ≥1,355 cm3) had a significantly lower PSMA uptake in the salivary glands, kidneys, liver, and spleen than did the control group, with an average difference of -38.1%, -40.0%, -43.2%, and -34.9%, respectively (P < 0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with a very high tumor load showed a significantly lower uptake of 68Ga-PSMA in normal organs, confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.

The Impact of Monosodium Glutamate on 68Ga-PSMA-11 Biodistribution in Men with Prostate Cancer: A Prospective Randomized, Controlled Imaging Study.

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT because of the high salivary gland uptake of PSMA radioligands. Here, we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68Ga-PSMA-11 PET imaging. Methods: Sixteen men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ("swishing") arms. Each subject underwent 2 68Ga-PSMA-11 PET/CT scans within 14 d under baseline and MSG conditions. The salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via SUVmean and SUVmax and compared parameters within each patient. Results: For the oral ingestion arm, salivary gland SUVmean and SUVmax decreased on average from the control scan to the MSG scan by 45% ± 15% (P = 0.004) and 53% ± 11% (P < 0.001), respectively. Tumor lesion SUVmean and SUVmax also decreased by 38% (interquartile range, -67% to -33%) and -52% (interquartile range, -70% to -49%), respectively (P = 0.018). Swishing had no significant effect on 68Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion: Oral ingestion but not topical application of MSG reduced 68Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined; therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.

Update from PSMA-SRT Trial NCT03582774: A Randomized Phase 3 Imaging Trial of Prostate-specific Membrane Antigen Positron Emission Tomography for Salvage Radiation Therapy for Prostate Cancer Recurrence Powered for Clinical Outcome.

The purpose of this randomized trial is to evaluate the success rate of salvage radiation therapy for recurrence of prostate cancer after radical prostatectomy, with and without planning based on prostate-specific membrane antigen positron emission tomography/computed tomography. Enrollment has been completed and patients are being followed for 5yr.