Interreader and intrareader reproducibility of 18F-flotufolastat PET/CT scans in newly diagnosed and recurrent prostate cancer patients was assessed from masked image evaluations from two phase 3 studies. Methods: 18F-flotufolastat PET/CT images of newly diagnosed (n = 352) or recurrent (n = 389) patients were evaluated by 3 masked readers. Cohen κ was used to assess pairwise patient- and region-level interreader agreement. Agreement among all readers was assessed using Fleiss κ. Intrareader agreement between the first and repeat read (20% of images, ≥4 wk later) was assessed using Cohen κ. Results: Pairwise interreader agreement was 95% or better (newly diagnosed) and 75% or better (recurrent). The κ coefficients were impacted by the high-agreement-low-κ paradox: Cohen κ ranged from not estimable to 0.55, whereas Fleiss κ was 0.50 (newly diagnosed) and 0.41 (recurrent). Agreement was highest in the prostate of newly diagnosed patients (≥95%) and in the pelvic lymph nodes in recurrent patients (≥87%). Intrareader agreement was 86% or better across both populations. Conclusion: 18F-flotufolastat PET/CT images can be reliably interpreted, with a high degree of inter- and intrareader agreement.

Background: This study evaluated tracer uptake and lesion detectability with the novel radiopharmaceutical 18F-radiohybrid (rh)PSMA-7.3 in patients with prostate cancer (PCa). Materials and Methods: Ten patients (three with high-risk primary localized PCa [Cohort A], three with hormone-sensitive metastatic PCa [Cohort B], and four with castration-resistant metastatic PCa [Cohort C]) underwent whole-body 18F-rhPSMA-7.3 positron emission tomography (PET)/computed tomography (CT) and findings were correlated with standard-of-care imaging. 18F-rhPSMA-7.3 maximum standardized uptake value (SUVmax) and its possible association with Gleason score (GS)/International Society of Urological Pathology (ISUP) grade group (GG) and serum PSA levels were evaluated. Cohort A 18F-rhPSMA-7.3 findings were also correlated with histopathology, including prostate-specific membrane antigen (PSMA) staining. Results: 18F-rhPSMA-7.3 identified the primary tumor in 3/3 Cohort A patients and lymph node (LN) and/or bone lesions in 7/7 metastatic patients. All prostate lesions with GS ≥4 + 3/GG ≥3 were identified, but only 1/4 GS ≤3 + 4/GG ≤2 lesions. Prostate lesion SUVmax appeared positively associated with GS/GGs. Among metastatic patients, 18F-rhPSMA-7.3 identified all known pelvic and extrapelvic LN metastases and all known bone lesions. 18F-rhPSMA-7.3 detected possible additional nodal and bone lesions not reported in standard-of-care imaging in all metastatic patients. No association existed between bone or LN uptake and either GS/GG or PSA. Conclusions: 18F-rhPSMA-7.3 PET/CT showed good detection of primary and metastatic PCa lesions. In this small patient population, 18F-rhPSMA-7.3 identified intraprostatic lesions with GS ≥4 + 3/GG ≥3 with good accuracy.

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of 18F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of 18F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results:18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution, and internal radiation dosimetry of 18F-rhPSMA-7.3 are considered favorable for PET imaging.

This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, 18F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer. Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq 18F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35–45, 60–88 and 90–118 min. Net influx rates (Ki) were calculated using Patlak plots. Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The 18F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. Ki, SUV and lesion-to-reference ratio estimates showed good agreement. 18F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, 18F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer. NCT03995888 (24 June 2019).

Purpose Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. Methods and Materials Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. Results 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA=0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). Conclusions 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

394 Objectives: Gliomas are the most common primary brain tumor in the US and account for approximately 25% of all brain tumors, and 80% of all malignant brain tumors.1 The amino acid positron emission tomography (PET) tracer, 18F-fluciclovine, has Orphan Drug designation in the US and Europe for imaging glioma and has the potential to address the limited utility of the current standard of care, magnetic resonance imaging (MRI).2 However, in order to facilitate the successful migration of this technology from expert sites into general clinical use an understanding of the reproducibility of interpretation of 18F-fluciclovine images by naive users is required. Here, we explore 3D Volumes of Interest (VOI) derived from 18F-fluciclovine imaging of suspected glioma and report the reproducibility of 18F-fluciclovine PET image interpretation among naive users. Data were captured as part of a Phase 3, blinded image evaluation of the diagnostic performance and reproducibility of interpretation of 18F-fluciclovine images when interpreted in combination with contrast-enhanced T1-weighted (CE-T1W) MRI for suspected glioma (abbreviated as 18F-fluciclovine + CE-T1W). Methods: Thirty-five 18F-fluciclovine PET and MRI (CE-T1W and fluid-attenuated inversion recovery [FLAIR] [or T2W]) datasets with corresponding histopathological truth standards collected as part of a previous prospective Phase 2 trial (JapicCTI-132289) were evaluated. A neuroradiologist read the MRI images and 3 blinded nuclear medicine physicians who were naive to 18F-fluciclovine PET independently read each 18F-fluciclovine image in combination with CE-T1W MRI. Diagnostic performance parameters were determined for 18F-fluciclovine + CE-T1W and compared with those determined for CE-T1W and FLAIR (or T2W) alone. Readers delineated the extent of any malignancy, recording the VOI. Inter- and intra-reader reproducibility were assessed for both the diagnostic performance parameters and the VOI (using intersections and similarity metrics such as dice coefficient [DC] and concordance index [CI]). Results: The positive predictive value for 18F-fluciclovine PET + CE-T1W MRI was > 90% for all 3 readers, similar to CE-T1W MRI alone (94%), but higher than that of FLAIR (85%). The sensitivity of 18F-fluciclovine PET + CE-T1W MRI (66-71%) was higher than that of CE-T1W MRI alone (42%) and the specificity (89%) was higher than that of FLAIR (or T2W) MRI alone (33%). Inter‑reader concordance based on the binary interpretation of the data between the 3 readers for 18F-fluciclovine PET + CE‑T1W was 89% (Fleiss’ Kappa, 0.86). Inter‑reader VOI agreement was also high (median DC, 0.78−0.89; median CI, 0.64−0.80 between comparisons). Intra‑reader concordance was 83.3−100% (Cohen’s Kappa, 0.66−1.00) for the three readers interpreting an image for the second time, with the DC for second VOI recordings ranging from 0.90 to 0.91 and the median CI ranging from 0.81 to 0.84 across the 3 readers. When compared with the VOI identified on CE-T1W MRI alone, a median increase in VOI of 28−60% was recorded with 18F-Fluciclovine PET + CE-T1W MRI. Comparisons with FLAIR imaging showed a median additional volume identified on FLAIR (or T2W) MRI, but not on 18F-fluciclovine PET + CE-T1W MRI, of 67−68% of the total volume identified by FLAIR (or T2W) MRI. Conclusions: 18F-Fluciclovine PET + CE-T1W MRI shows good diagnostic performance, with consistent image interpretation demonstrated across 3 naive readers. 18F-Fluciclovine PET + CE-T1W MRI accurately identified higher tumor volumes than CE-T1W MRI alone and showed greater specificity than FLAIR (or T2W) MRI. The addition of 18F-fluciclovine PET to MRI has potential clinical value in delineating which part of the additional volume of abnormality shown on FLAIR is not malignant, thus more accurately identifying the extent of glioma prior to surgery or radiotherapy.

Positron emission tomography (PET) with amino acid analogs is a useful tool in the diagnostics and therapy planning of gliomas. PET-based delineation of the tumor volume enables delivery of a more targeted radiation dose and sparing of normal brain tissue, with potential consequences for patient survival. PET tracer, 18F-fluciclovine, has Orphan Drug designation in the US and Europe for imaging gliomas. Here, we explored its diagnostic performance and reproducibility in high- and low-grade gliomas when interpreted in combination with contrast-enhanced T1-weighted MRI (hereafter referred to as "18F-fluciclovine + CE-T1W"). In a previous prospective study, 18F-fluciclovine PET and MRI (CE-T1W and fluid-attenuated inversion recovery [FLAIR]) were performed in patients with suspected gliomas (Anaplastic astrocytoma (7), Anaplastic oligodendroglioma (1), Diffuse astrocytoma (7), Glioblastoma (14), Oligoastrocytoma (2), Oligodendroglioma (3), other: Anaplastic ependymoma (1)) Imaging data from thirty five individuals with a histopathologically confirmed diagnosis of glioma were analyzed. A neuroradiologist read the MRI images, while three blinded, 18F-fluciclovine-naïve, experienced nuclear medicine physicians interpreted 18F-fluciclovine + CE-T1W. Diagnostic performance was determined for CE-T1W, FLAIR and 18F-fluciclovine + CE-T1W. Inter- and intra-reader reproducibility (via a re-read of a random 20% of images) were assessed using Cohen's kappa and Fleiss' kappa statistics. Results were stratified by tumor grade, i.e. high and low. Across the three readers, the positive predictive value (PPV) for 18F-fluciclovine + CE-T1W was 96%, the negative predictive value (NPV) was 38-42%, the sensitivity was 66−71%, and specificity was 89%. For high-grade tumors (n = 15), the PPV, NPV, sensitivity and specificity for 18F-fluciclovine + CE-T1W for the three readers overall were 100.0%, 40.0%, 83.3% and 100.0%, respectively. In low-grade tumors (n = 11), these were 100.0%, 45.5%, 50.0% and 100.0%, respectively. The biopsy samples for the remainder (n=9) demonstrated malignancy but the neuro-pathologist could not confidently assign a grade. Inter-reader concordance was 89% (Fleiss' Kappa = 0.86) overall, 100% (Fleiss' Kappa=1.00) for high-grade, and 82.4% (Fleiss' Kappa = 0.74) for low-grade gliomas. All pair-wise inter-reader comparisons showed 100% agreement (Cohen's Kappa = 1.0) for high-grade gliomas and ranged from 82.4−94.1% (Cohen's Kappa = 0.6−0.87) for low-grade. Intra-reader concordance was 83.3−100% (Cohen's Kappa =0.66−1.00) with no discernible differences when stratifying by high- or low-grade gliomas. 18F-Fluciclovine PET + CE-T1W MRI show reproducible results and good diagnostic performance for imaging gliomas, a prerequisite for accurate PET-guided radiotherapy planning.

Aim: To demonstrate the clinical capability of ultra-fast whole body PET acquisition enabled by digital photon counting PET (dPET) and to assess and compare its diagnostic and quantitative characteristics to current clinical PET acquisition.Methods: Twenty-five patients scheduled for FDG whole body PET/ CT were imaged using three separate acquisitions as part of intraindividual comparison study with a pre-commercial release dPET/CT (Vereos) and cPET/CT (Gemini, Philips, Cleveland).Standard cPET imaging was performed at ~75 min p.i. of ~450 MBq FDG with investigational dPET imaged at ~55 min p.i.The first dPET acquisition was performed using 90s/bed position, immediately followed by a 9s/bed position.Acquisition which lead to average table times of ~15 and ~2 min.These were compared with standard-of-care 90s/bed position cPET.The 9s/bed dPET listmode data were reconstructed using a previously optimized methodology.All other aspects of image acquisition were kept identical.Three blinded reviewers evaluated the data sets regarding visual characteristics, diagnostic confidence and semiquantitative readouts.Results: Visual assessment scores were significantly higher for 90s/bed dPET whole body (p<0.01) with no difference between 9s/bed dPET and 90s/bed cPET.Quantitatively, the 9s/bed dPET images presented slightly increased background noise, however there was no significant impact on diagnostic confidence or SUV measures of FDG-avid lesions.Conclusion: Next generation digital photon counting PET detector technology enables a new capability of Ultra-Fast (~2min) wholebody acquisition with comparable diagnostic confidence and quantitative precision to current generation cPET acquisitions taking 10 times longer.This allows for new PET workflow concepts, improved patient comfort, minimized patient motion and whole-body pseudo-dynamic imaging of tracer uptake.

165 Background: Detection of the extent of local recurrence and of metastases in biochemical recurrence (BCR) of prostate cancer facilitates selection of appropriate treatment. The FALCON trial (NCT02578940) assessed the impact of 18F-fluciclovine PET/CT on the clinical management of men with BCR of prostate cancer following initial radical therapy. Methods: Men being considered for curative-intent salvage therapy following first BCR were recruited at 6 UK sites. Management plans were documented prior to and following 18F-fluciclovine PET/CT imaging. Post-scan changes to treatment modality such as salvage radiotherapy [RT] to systemic therapy were classed as ‘major’, while changes within a modality (e.g. modified RT fields) were classed as ‘other’. A pre-planned interim analysis of the first 85 patients was conducted; recruitment was to be stopped for efficacy if the number of treatment changes was > 45 (52.9%; 97.5% CI: 40.3–62.3%), or for futility if ≤ 8 (9.4%, 97.5% CI: 3.6–18.9%). Results: The 85 enrolled patients were a mean 4.8 y post-initial diagnosis, with a median age of 67 y and median PSA of 0.63ng/mL. Twelve (14.1%) had a Gleason score ≤ 6, 60 (70.6%) had a score of 7 and 13 (15.3%) had a score ≥ 8. Most (56; 65.9%) had previously undergone radical prostatectomy (RP), with 27 having received RT (± other therapy). The majority of those imaged (52; 61.2%) had a change in management (CIM) post-scan (Table). Recruitment was subsequently stopped as the pre-specified condition defining overwhelming efficacy was met. Conclusions: This prospective trial shows 18F-fluciclovine PET/CT has substantial impact on clinical decisions for men with a first BCR of prostate cancer after curative-intent primary therapy. Clinical trial information: NCT02578940. [Table: see text]

When biochemical recurrence (BCR) of prostate cancer is suspected, early and accurate localization of metastases facilitates treatment when tumors are small and most amenable to localized therapy, and may guide clinicians in making management plans regarding salvage therapy. Here, we present results of a preplanned analysis of the FALCON trial (NCT02578940), which assessed the impact of PET/CT imaging with 18F-fluciclovine on clinical management choices for men with BCR of prostate cancer.

Integrins are upregulated on both tumor cells and associated vasculature, where they play an important role in angiogenesis and metastasis. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for alpha(v)beta(3)/alpha(v)beta(5) integrin, which can be radio-labeled for PET imaging of angiogenesis. Thus, F-18-fluciclatide is a potential biomarker of therapeutic response to antiangiogenic inhibitors. The aim of this study was to evaluate the reproducibility of F-18-fluciclatide in multiple solid-tumor types. Methods: Thirty-nine patients underwent PET/CT scanning at 40, 65, and 90 min after injection of F-18-fluciclatide (maximum, 370 MBq) on 2 separate days (2-9 d apart). Patients did not receive any therapy between PET/CT scans. F-18-fluciclatide images were reported and quantitative measures of uptake were extracted using the PERCIST methodology. Intrasubject reproducibility of PET uptake in all measurable lesions was evaluated by calculating relative differences in SUV between PET scans for each lesion during the 2 imaging sessions. Results: Thirty-nine measurable lesions were detected in 26 patients. Lesion uptake correlated strongly across imaging sessions (r = 0.92, P < 0.05, at 40 min; r = 0.94, P < 0.05, at 65 min; r = 0.94, P, 0.05, at 90 min) with a mean relative difference and SD of the relative difference of 0.006 +/- 0.18 at 40 min, 0.003 +/- 0.19 at 65 min, and 0.025 +/- 0.20 at 90 min. This reflects 95% limits of repeatability of 35%-39% for the difference between the 2 SUV measurements or a variability of 18%-20% in agreement from that observed in well-calibrated multicenter F-18-FDG studies. Conclusion: The test-retest reproducibility of F-18-fluciclatide across multiple tumor types has been measured and shown to be acceptable. This is an important step in the development of this in vivo biomarker to identify and quantify response to antiangiogenic therapy in cancer patients.

[18F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvβ3 and αvβ5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [18F]fluciclatide (formerly known as [18F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression.

We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, F-18-AH111585, a peptide with a high affinity for the alpha(v)beta(3) integrin receptor involved in angiogenesis. Methods: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of F-18-AH111585. F-18 activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo F-18 activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose. Results: Injection of F-18-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of F-18 excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11 %); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 mu Gy/MBq), kidneys (102 mu Gy/MBq), and cardiac wall (59 mu Gy/MBq). The effective dose was 26 mu Gy/MBq. Conclusion: F-18-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common F-18 PET tracers.

The integrin αvβ3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. Methods: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. Conclusion:18F-AH111585 designed to bind the αvβ3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.