Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Patients with gastro-entero-pancreatic neuroendocrine tumours (GEP NET) who retain somatostatin receptor (SSTR) expression after initial response to [177Lu]Lu-DOTA-Octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) are amenable to re-treatment (R-PRRT) upon progression. We assessed the safety and efficacy of R-PRRT in patients with progressive metastatic GEP NET. A retrospective analysis, approved by institutional ethics board, was performed in patients with GEP NET who received R-PRRT for either symptomatically or radiologically progressive disease. Safety was assessed by renal and haematological parameters at 3 months post R-PRRT (CTCAE v5.0). Molecular imaging response was evaluated on [68Ga]Ga-DOTA-Octreotate (GaTate) PET/CT using pre-defined criteria. RECIST 1.1 responses 3 months post R-PRRT were documented when feasible. Progression-free and overall survival analysis were performed. A total of 63 patients had R1-PRRT (1–3 cycles). The majority (70

[177Lu]Lu-PSMA-617 radiopharmaceutical therapy improves survival and quality of life in patients with metastatic castration-resistant prostate cancer. We assessed whether patients who did not achieve an early prostate-specific antigen (PSA) decline after the first cycle (C1) benefited from further [177Lu]Lu-PSMA-617. Methods: We analyzed patients with metastatic castration-resistant prostate cancer participating in a registry of [177Lu]Lu-PSMA-617 (ProsTIC registry, NCT04769817). Patients with a PSA either rising (≥25% increase from baseline) or stable (30% decrease to 25% increase from baseline) within 28 d of starting treatment (C1) and consequently received a second dose (cycle 2) were included. Biochemical response was defined as a PSA decline of more than 50% from baseline (PSA-50) within 20 wk after C1. Quality of life was assessed on 2 validated scales. We evaluated the effect of PSA change and 3 imaging parameters (pretreatment PSMA PET SUVmean, pretreatment [18F]FDG PET metabolic tumor volume, and mean total tumor dosimetry on SPECT/CT after C1) with these outcomes and survival time after cycle 2. Results: Of 195 patients, 103 met inclusion criteria between January 5, 2021, and March 30, 2023, with an early PSA rise in 31 patients (30%) or stable PSA in 72 patients (70%). Of 103 patients, 45 (44%) achieved PSA-50 by 140 d after C1. Seven of 31 patients (23%) and 38 of 72 patients (53%) with early rising and stable PSA, respectively, had achieved a PSA-50 by 140 d after C1. A PSMA SUVmean of 10 or more versus an SUVmean of less than 10 conferred a higher chance of PSA-50 (59% vs. 37%; odds ratio, 2.53; 95% CI, 1.08-5.95). In total, 59 deaths were recorded with a median overall survival of 11.3 mo after cycle 2. [18F]FDG metabolic tumor volume was the only variable to have a meaningful association with overall survival. Patients with baseline pain scores of 10 or greater according to EORTC QLQ-C30 pain or 2 or greater according to BPI-SF had clinically meaningful reductions in pain in 39 of 55 patients (71%) and 17 of 37 patients (46%), respectively. Conclusion: Discontinuing [177Lu]Lu-PSMA-617 based solely on PSA response after just 1 cycle is not advisable as a substantial number of patients achieve PSA-50 or a reduction in pain. Baseline imaging parameters have prognostic utility and can assist in patient counseling and clinical decision-making.

People with malignancy of undefined primary origin (MUO) have a poor prognosis and may undergo a protracted diagnostic workup causing patient distress and high cancer related costs. Not having a primary diagnosis limits timely site-specific treatment and access to precision medicine. There is a need to improve the diagnostic process, and healthcare delivery and support for these patients. This trial aims to implement and evaluate an optimal model of care for people presenting with MUO to reduce time to diagnosis, improve patient experiences and reduce healthcare costs. This is a pragmatic stepped-wedge cluster randomised trial comparing a control phase of standard practice with an intervention phase. Patient inclusion criteria are: 1) age 18 years or older, 2) presenting with suspected metastatic malignancy without an obvious primary site on imaging, 3) clinically appropriate to undergo diagnostic work-up and 4) able to provide written or verbal consent. The intervention is a new model of care comprising four key components: standardised diagnostic workup, dedicated cancer care coordinators, virtual multidisciplinary meetings and a website resource for patients, carers and clinicians. The primary endpoint is the time to completion of minimum diagnostic workup. Secondary outcomes are whether the type of tumour is diagnosed, clinical trial participation, referral to palliative care, patient-reported physical, social and mental health, patient-reported understanding and uncertainty. Implementation outcomes include acceptability, feasibility, fidelity and adoption and health care use and costs. Intervention implementation will be supported using clinical leadership, education and reinforcement. Patients who consent to having their data collected will receive the model of care active at the site at the time of recruitment. Patients will complete a patient-reported outcomes questionnaire four months after study enrolment. A health economic analysis will be included. Across 15 hospitals, a total sample size of 240 is planned. There is a lack of intervention research for people presenting with MUO. The stepped-wedge design seeks to mitigate the potential challenge of enrolling people with a poor prognosis and high symptom burden in trials. This research will generate important evidence with scalability for future research at trial completion. ACTRN12622001504707

The prospective multi-site trial evaluating O-(2-[18F]-fluoroethyl)-L-tyrosine Positron Emission Tomography (FET-PET) in Glioblastoma (FIG) study is currently recruiting. This abstract aims to evaluate the impact of full central Nuclear Medicine physician (NMP) review of prospective FET-PET1 delineation of the biological target volume (BTV) for radiotherapy (RT) planning. Adult GBM participants across 11 Australian sites undergo up to 3 FET-PET studies post-surgery/pre-chemo-RT [CRT] (FET-PET1), one month post CRT (FET-PET2) and at suspected progression evaluation timepoint (FET-PET3). Group 1 participants enter at timepoint 1 (FET-PET1 with MRI1), with Group 2 at timepoint 2. Adjuvant RT target volumes are derived per standard contrast MRI. These are compared to hybrid post-hoc RT volumes incorporating the FET-PET1 NM-derived BTV utilising MiM version 7.0 to evaluate the impact of FET PET on potential treatment planning. All trial sites and NMP have passed credentialling which included three benchmarking cases involving FET1-BTV delineation. Recruitment commenced in January 2021, with 253 (n=156 Group 1 and n=97 Group 2) participants enrolled to date, n=144 with evaluable FET-PET1 data. Trial credentialling demonstrated variations in FET-PET1-derived BTV in 25/72 (34.7%) -13 minor and 12 major. All n=144 prospective participant FET-PET1 with BTV delineation cases across 11 sites have undergone central NMP review, with 20/144 (13.9%) requiring resubmission. Reasons for resubmission/protocol deviation included incorrect imaging sequence selection within MiM workflow (n=3/20), static GTV overcontouring (n=12/20), dynamic volume of interest change in size/position during workflow (n=1/20) and static FET interpretation issues (n=3/20). Central radiation oncology review of hybrid BTV-derived RT volumes is underway. The importance of credentialling and full central review of all prospective FET-PET-derived BTV delineation in FIG trial participants is demonstrated. The FIG study remains the largest prospective multi-site study of its kind addressing the impact of FET-PET on radiation planning, management of pseudoprogression and prognostication.

BACKGROUND:Terbium-161 (161Tb) emits beta-radiation similar to lutetium-177 (177Lu), with additional radiation over ultra-short path lengths from Auger electrons. 161Tb has shown superior in-vitro and in-vivo efficacy compared with 177Lu. We aimed to evaluate the safety of [161Tb]Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS:VIOLET was an investigator-initiated, single-centre, phase 1/2 trial, conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia). Eligible patients were men aged 18 years or older with progressive mCRPC (histologically or cytologically confirmed adenocarcinoma of the prostate or unequivocal diagnosis of metastatic prostate cancer with an elevated serum prostate specific antigen) previously treated with an androgen receptor pathway inhibitor and taxane chemotherapy (unless medically unsuitable), Eastern Cooperative Oncology Group performance status of 0-2, and prostate-specific membrane antigen (PSMA) positivity (maximum standardised uptake value ≥20 on PSMA PET-CT) without discordance on 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT. Dose escalation (3 + 3 design) had three prespecified radioactivities (4·4 GBq, 5·5 GBq, and 7·4 GBq). Up to six cycles of [161Tb]Tb-PSMA-I&T were administered intravenously every 6 weeks, reduced by 0·4 GBq for each cycle. Primary endpoints of phase 1 were dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose, and the primary objective of phase 2 was evaluation of adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0. We present here an interim analysis, with follow-up ongoing and recruitment reopened for an additional dose level (9·5 GBq). The trial is registered at ClinicalTrials.gov (NCT05521412). FINDINGS:Between Oct 14, 2022 and Feb 15, 2024, 30 eligible patients were enrolled. Median age was 69·0 years (IQR 66·0-74·8), screening PSA 26·9 ng/mL (10·1-70·0), PSMA mean standardised uptake value 8·2 (7·4-10·8), and 20 (67%) of 30 patients had received previous docetaxel. There were no dose-limiting toxicities. The maximum administered dose and recommended phase 2 dose was 7·4 GBq. Grade 3 treatment-related adverse events (TRAEs) were limited to pain (one [3%] of 30; the only serious TRAE) and lymphopenia (one [3%] of 30). No grade 4 TRAEs or treatment-related deaths occurred. No dose reductions or treatment discontinuation occurred for toxicity. INTERPRETATION:[161Tb]Tb-PSMA-I&T is safe at the maximum administered dose of 7·4 GBq. Further investigation of this promising radionuclide is warranted in larger, randomised clinical trials. FUNDING:Prostate Cancer Foundation, Peter MacCallum Cancer Foundation, National Health and Medical Research Council Investigator Grant, Isotopia Molecular Imaging.

BACKGROUND:Lutetium-177 [177Lu]Lu-PSMA-I&T (177Lu-PSMA-I&T) and the bone-seeking α-emitter radium-223 (223Ra) are established life-extending therapies for patients with metastatic castration-resistant prostate cancer; however, resistance and progression are inevitable. We aimed to evaluate the safety and preliminary antitumour activity of 177Lu-PSMA-I&T combined with 223Ra in this patient group. METHODS:We conducted an investigator-initiated, single-centre, single-arm, phase 1/2 trial (AlphaBet) at the Peter MacCallum Cancer Centre in Melbourne, Australia. Adults (aged ≥18 years) with a diagnosis of progressive, metastatic castration-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0-2, at least two visible bone metastases not treated with radiotherapy, previous exposure to an androgen receptor pathway inhibitor, prostate-specific membrane antigen (PSMA)-positive disease (defined by maximum standardised uptake value ≥20 at a site of disease), and no discordant sites (ie, avid on 2-[18F]fluoro-2-deoxy-D-glucose-PET-CT with minimal PSMA expression and no uptake on bone scintigraphy) were eligible for inclusion. Phase 1 dose-escalation assessed two dose levels of 223Ra (27·5 kBq/kg and 55·0 kBq/kg) combined with 7·4 GBq 177Lu-PSMA-I&T, administered intravenously every 6 weeks for up to six cycles. Phase 2 dose expansion continued with the recommended phase 2 dose. Co-primary endpoints were the maximum tolerated or administered dose and the recommended phase 2 dose (phase 1), and the PSA response rate (phase 2), analysed in all patients treated at the maximum tolerated or administered dose in either phase. Safety was assessed in all patients who received at least one dose of either protocol treatment in phase 1 or 2. Herein, we report the results of an interim analysis, which was added to the protocol following an amendment on May 30, 2024. This trial is registered at ClinicalTrials.gov (NCT05383079) and follow-up is ongoing. FINDINGS:Between Nov 3, 2022, and Nov 5, 2024, 37 patients were enrolled, of whom 36 (97%; median age 72·5 years [IQR 67·0-78·0]) were included in the safety analysis and 33 (89%) were included in the preliminary activity analysis. No dose-limiting toxicities were observed. The recommended phase 2 dose of 223Ra was 55·0 KBq/kg combined with 7·4 GBq 177Lu-PSMA-I&T, administered every 6 weeks. With a median follow-up of 13·3 months (IQR 8·7-17·1), 11 (31%) patients completed all six cycles of both treatments. 18 (50%) patients discontinued treatment early, primarily due to unequivocal disease progression (11 [61%]) or adverse events (three [17%]). A reduction in PSA of at least 50% was observed in 18 (55%; 95% CI 36-72) patients. Grade 3 or higher treatment-related adverse events occurred in five (14%) of 36 patients, including anaemia (four [11%]) and neutropenia (three [8%]), with no treatment-related deaths. Non-clinically significant grade 3 lymphopenia occurred in ten (28%) patients. INTERPRETATION:The combination of 177Lu-PSMA-I&T and 223Ra is safe and feasible in patients with metastatic castration-resistant prostate cancer and bone metastases. These findings warrant further evaluation of combined α-emitting and β-emitting approaches. FUNDING:Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council.

BACKGROUND:During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging.METHODS:Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection.RESULTS:Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated.CONCLUSION:Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients.TRIAL REGISTRATION:This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 .

Background: Metastatic gastroenteropancreatic neuroendocrine neoplasms (GEPNEN) can cause ectopic Cushing’s syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. Aim: To describe the characteristics and outcomes of patients with ECS treated with PRRT. Methods: Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006 to 2023. Results: Patients were aged 17–75 (female n = 6). The primary site was the pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one had a previous BA). A median of 34.4 GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) were also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within 1 week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5–6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), and one had a partial metabolic response. PFS was 3–208 months. Two patients progressed at the first follow-up. The longest ECS remission and CMR continues at >17 years. Conclusion: PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

PURPOSE:18F-fluorothymidine (FLT) positron emission tomography (PET) enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/computed tomography scans before and during chemoradiation therapy (CRT) for non-small cell lung cancer were repurposed to investigate the dose-response effects of radiation on BM proliferation. METHODS AND MATERIALS:Twenty-six non-small cell lung cancer patients underwent platinum-based CRT to 60 Gy in 30 fractions with FLT-PET/computed tomography scans at baseline, week 2 (20 Gy), and week 4 (40 Gy). FLT uptake in BM was isolated using Medical Image Merge software. Weeks 2 and 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (highest standardized uptake values within the volume and visual parameters) were analyzed using generalized linear and restricted cubic spline models. Percentage volumes of total BM without appreciable FLT uptake ("ablated") on weeks 2 and 4 FLT-PET scans were calculated by comparisons with baseline scans. RESULTS:Thoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3 Gy by week 2. In all cases, BM FLT's highest standardized uptake values within the volume declined rapidly as the radiation dose increased. BM proliferation significantly decreased by >95% after ≥3 to 4 Gy at 2 weeks and ≥4 to 5 Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. The median percentage of total BM ablated was 13.1% (range, 5.6%-20.3%) at 2 weeks and 15.7% (range, 9.2%-24.1%) at 4 weeks. Mean lymphocyte counts fell from a baseline of 2.01 × 109/L to 0.77 at week 2 and 0.60 at week 4. Lymphocyte decline strongly correlated with the percentage of total BM ablated by week 4 (y = -46 to 1.64x; R2adj = 0.34; P = .001). CONCLUSIONS:BM ablation associated with low-dose radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ at risk, and reducing the BM volume exposed to ≥3 Gy may help preserve lymphocytes, which is essential for effective adjuvant immunotherapy.

Abstract BACKGROUND To provide an update from the multi-site trial evaluating O-(2-[18F]-fluoroethyl)-L-tyrosine Positron Emission Tomography (FET-PET) in Glioblastoma (FIG) study and 2) assess the impact of central Nuclear Medicine physician (NMP) review of prospective FET-PET1 delineation of the biological target volume (BTV) for radiotherapy (RT) planning. Material and methods Up to 210 adult GBM participants across 11 Australian sites will undergo FET-PET post-surgery/pre-chemo-RT [CRT] (FET-PET1), one month post CRT (FET-PET2) and at suspected progression (FET-PET3). Group 1 participants enter at timepoint 1 (FET-PET1 with MRI1), with Group 2 entering at timepoint 2. Adjuvant RT target volumes are derived per standard contrast MRI with hybrid post-hoc RT volumes then incorporating the FET-PET1 NM-derived BTV utilising MiM version 7.0. All trial sites and NMP have passed credentialling which included three benchmarking cases involving BTV delineation. RESULTS Trial recruitment commenced in January 2021, with 189 (n=126 Group 1 and n=63 Group 2) participants enrolled to date, with a target of 140 Group 1 participants. During trial credentialling, results demonstrated variations in FET-PET1-derived BTV in 25/72 (34.7%) - 13 minor and 12 major.Currently, 42 of 112 participant FET-PET1 with BTV delineation cases across 10 sites have undergone central review, with 7/42 (16.7%) requiring resubmission. Reasons for resubmission/protocol deviation included incorrect imaging sequence selection within the MiM workflow (n=3), Static GTV overcontouring (n=3) and dynamic volume of interest change in size/position during MiM workflow use (n=1). CONCLUSION The FIG trial will complete recruitment in 2024 with analyses planned at one year post CRT completion. Despite improvements in resubmission rates compared to the credentialling phase, central review of prospective FET-PET1-derived BTV delineation remains important in ensuring protocol adherence. The FIG study is the largest prospective multi-site study of its kind addressing FET-PET’s impact on adjuvant radiation planning and its role in management of pseudoprogression and prognostication.