Sir Peter MacCallum Department of Oncology - Research Publications
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ItemUtility of 68Ga-DOTA-Exendin-4 positron emission tomography-computed tomography imaging in distinguishing between insulinoma and nesidioblastosis in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia(WILEY, 2021-10)BACKGROUND: Because management is very different, it is important to differentiate between small focal insulinomas and diffuse pancreatic dysplasia (nesidioblastosis) in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia (EHH). Most insulinomas highly express glucagon-like peptide-1 receptors enabling positron emission tomography-computed tomography imaging with its radiolabelled analogue; 68 Ga-DOTA-Exendin-4 (Exendin). AIM: To determine: (i) the utility of Exendin in EHH patients in a clinical setting; and (ii) whether the degree of Exendin uptake differentiates non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) from post-gastric bypass hypoglycaemia (PGBH). METHODS: This retrospective study reviewed the clinical, biochemistry and prior imaging findings in confirmed EHH patients referred for Exendin. Accuracy of Exendin was based on surgical findings and treatment outcomes. Finally, average Exendin uptake (SUVmax) of five PGBH studies was compared with the SUVmax of a key NIPHS case report. RESULTS: Twenty of 25 consecutive patients had confirmed EHH. Exendin located insulinomas in eight of nine patients enabling successful surgical excision with rapid and durable cure. Exendin correctly identified diffuse nesidioblastosis in two of three cases requiring partial pancreatectomy for hypoglycaemia control. All three relapsed within 1.7 years with one needing completion pancreatectomy. Establishing the cause in the remainder relied on other investigations, clinical correlation and response to empirical treatment. Finally, Exendin SUVmax could not distinguish between NIPHS and PGBH. CONCLUSION: In EHH patients, Exendin accurately identifies the site of insulinoma and thereby differentiates it from nesidioblastosis but negative findings should not be ignored. Exendin is unlikely to differentiate between normal pancreatic uptake, NIPHS and PGBH.
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ItemNo Preview AvailableIs Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging Cost-effective in Prostate Cancer: An Analysis Informed by the proPSMA Trial(ELSEVIER, 2021-03)BACKGROUND: Before integrating prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) into routine care, it is important to assess if the benefits justify the differences in resource use. OBJECTIVE: To determine the cost-effectiveness of PSMA-PET/CT when compared with conventional imaging. DESIGN, SETTING, AND PARTICIPANTS: A cost-effectiveness analysis was developed using data from the proPSMA study. proPSMA included patients with high-risk prostate cancer assigned to conventional imaging or 68Ga-PSMA-11 PET/CT with planned health economics data collected. The cost-effectiveness analysis was conducted from an Australian societal perspective. INTERVENTION: 68Ga-PSMA-11 PET/CT compared with conventional imaging (CT and bone scan). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome from proPSMA was diagnostic accuracy (nodal and distant metastases). This informed a decision tree analysis of the cost per accurate diagnosis. RESULTS AND LIMITATIONS: The estimated cost per scan for PSMA PET/CT was AUD$1203, which was less than the conventional imaging cost at AUD$1412. PSMA PET/CT was thus dominant, having both better accuracy and a lower cost. This resulted in a cost of AUD$959 saved per additional accurate detection of nodal disease, and AUD$1412 saved for additional accurate detection of distant metastases. The results were most sensitive to variations in the number of men scanned for each 68Ga-PSMA-11 production run. Subsequent research is required to assess the long-term costs and benefits of PSMA PET/CT-directed care. CONCLUSIONS: PSMA PET/CT has lower direct comparative costs and greater accuracy compared to conventional imaging for initial staging of men with high-risk prostate cancer. This provides a compelling case for adopting PSMA PET/CT into clinical practice. PATIENT SUMMARY: The proPSMA study demonstrated that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) better detects disease that has spread beyond the prostate compared with conventional imaging. Our analysis shows that PSMA PET/CT is also less costly than conventional imaging for the detection of disease spread. This research was presented at the European Association of Nuclear Medicine Scientific Meeting in October 2020.
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ItemThe role of 18F-FDG PET/CT in retroperitoneal sarcomas-A multicenter retrospective study(WILEY, 2021-03)BACKGROUND: The role of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS). METHODS: Patients with the above histological subtypes in three participating institutions with preoperative 18 F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied. RESULTS: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2-33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003). CONCLUSION: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.
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ItemPSMA targeting in metastatic castration-resistant prostate cancer: where are we and where are we going?(SAGE PUBLICATIONS LTD, 2021-10)Prostate-specific membrane antigen (PSMA) is highly expressed on the membrane of most prostate cancer cells and to a lesser extent in normal tissues. Many vectors targeting this protein have been created over the past decade and numerous clinical studies have positively demonstrated the tolerance and efficacy of radiolabeled prostate-specific membrane antigen ligands for PSMA radioligand therapy (PRLT). Preliminary results are encouraging that PRLT will become an important addition to the current therapeutic options in a number of settings. Improvement in radiopharmaceutical targeting and combination with other oncological agents are under investigation to further improve its therapeutic efficacy. These encouraging results have led to the development of other therapies using PSMA as a target, such as PSMA-targeted chimeric antigen receptor T-cells, PSMA-targeted antibody drug conjugates, and PSMA-targeted bi-specific T-cell-directed therapy. This narrative review details the current state and advancements in prostate-specific membrane antigen targeting in prostate cancer treatment.
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ItemNo Preview AvailableNomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study(ELSEVIER SCIENCE INC, 2021-08)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.
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ItemNo Preview AvailableAdvanced prostate cancer experimental radioactive treatment-clinical trial decision making: patient experiences(BMJ PUBLISHING GROUP, 2021-08-09)OBJECTIVES: Nested qualitative studies within clinical trials provide the opportunity to better understand participant experiences of participation and identify areas where improved support is required. The purpose of this qualitative study is to describe the lived experiences of men with advanced prostate cancer participating in the TheraP trial; a randomised trial of 177Lu-PSMA-617 compared with cabazitaxel chemotherapy. METHODS: Fifteen men with advanced prostate cancer were recruited from the TheraP clinical trial and interviewed at three time points during the trial. Interviews were inductively analysed using thematic analysis. This research paper reports the results from the baseline interview at commencement of the trial, focusing specifically on participants' enrolment experiences. RESULTS: Four themes were identified representing the lived experiences of men with advanced prostate cancer deciding to participate in the TheraP trial: (1) hoping to survive; (2) needing to feel informed; (3) choosing to participate and (4) being randomised. The process of deciding to enrol in a clinical trial is filled with indecision, emotional difficulties and focused on a desire to live. CONCLUSIONS: For men with advanced prostate cancer, the experience of deciding to enrol in a clinical trial is principally driven by a desire to survive but interlinked with the need to make an informed decision as participants in this study expressed a preference for allocation to the experimental arm. Men seeking to enrol in clinical trials of new prostate cancer treatments would benefit from improved informational and decision support. TRIAL REGISTRATION NUMBER: NCT03392428, ANZUP1603.
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ItemMeeting report from the prostate cancer foundation PSMA theranostics state of the science meeting(WILEY, 2020-11)INTRODUCTION: The Prostate Cancer Foundation (PCF) convened a PCF prostate-specific membrane antigen (PSMA) Theranostics State of the Science Meeting on 18 November 2019, at Weill Cornell Medicine, New York, NY. METHODS: The meeting was attended by 22 basic, translational, and clinical researchers from around the globe, with expertise in PSMA biology, development and use of PSMA theranostics agents, and clinical trials. The goal of this meeting was to discuss the current state of knowledge, the most important biological and clinical questions, and critical next steps for the clinical development of PSMA positron emission tomography (PET) imaging agents and PSMA-targeted radionuclide agents for patients with prostate cancer. RESULTS: Several major topic areas were discussed including the biology of PSMA, the role of PSMA-targeted PET imaging in prostate cancer, the physics and performance of different PSMA-targeted PET imaging agents, the current state of clinical development of PSMA-targeted radionuclide therapy (RNT) agents, the role of dosimetry in PSMA RNT treatment planning, barriers and challenges in PSMA RNT clinical development, optimization of patient selection for PSMA RNT trials, and promising combination treatment approaches with PSMA RNT. DISCUSSION: This article summarizes the presentations from the meeting for the purpose of globally disseminating this knowledge to advance the use of PSMA-targeted theranostic agents for imaging and treatment of patients with prostate cancer.
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ItemNo Preview AvailablePreclinical Evidence of the Efficacy of Lewis Y Car T Cells in Patient-Derived Models of Prostate Cancer(The Endocrine Society, 2021-05-03)Abstract Chimeric antigen receptor T (CAR T) cell therapy is an adoptive immunotherapy that has led to new treatments for lymphoma, leukemia, and other blood cancers; however, its efficacy for prostate cancer remains unproven. Here we report pre-clinical evidence of the efficacy of CAR T cell therapy against the Lewis Y antigen (LeY) using patient-derived models of prostate cancer. To assess the expression of LeY on prostate tumours, we performed immunohistochemistry on a cohort of 41 patient-derived xenografts (PDXs). Cytoplasmic and membrane expression were separately assessed and quantified, for each patient. Overall, 61% (25/41) of PDXs were positive for membrane LeY expression, of which 18 PDXs had greater than 50% membrane-positive cells, and considered most suitable to detection and stable binding by anti-LeY CAR T’s. To determine the in vitro sensitivity to CAR T cytotoxicity, we selected 4 PDXs with high and 2 PDXs with low LeY expression using 3 androgen receptor (AR)-positive adenocarcinomas and 3 AR-negative tumors expressing neuroendocrine markers. Next we established organoids for in vitro co-culture assays where organoids were co-incubated with an equal number of anti-LeY+ CAR T cells or Empty vector control CAR T cells (Ev CAR T). Using time-lapse microscopy we reported destruction of organoids by LeY+ CAR T cells as indicated by their morphological collapse and uptake of propidium iodide from the culture medium; control Ev CAR T cells produced no cytotoxicity. Over the 48h assay, the level of target cell death of the LeY+ organoids was correlated to the intensity LeY surface expression. Target cell death mediated by the CAR T cells required perforin and granzyme B, as potent and highly specific small molecule inhibitors of perforin (SN34960) and granzyme B (C20) applied alone or in combination greatly decreased PI uptake, indicating organoid survival. Neither inhibitor adversely affected CAR T cell viability as measured by PI and Annexin V staining. This demonstrated canonical activation of granule exocytosis pathway by the CAR T cells, leading to organoid cell death. To assess CAR T cell efficacy in vivo, we selected one PDX with high LeY expression. Monotherapy with CAR T cells failed to decrease tumour volume compared to vehicle control. However, CAR T cells given after a single dose of the chemotherapeutic agent carboplatin greatly and durably reduced tumour burden, with residual tumour mass being less than 1% of their original size (0.56 ± 0.23% of tumour volume at the start of treatment). Overall, these data provide preclinical evidence that: i) high membrane expression of LeY correlates with in vitro and in vivo CAR T cell-induced tumour cell death via the canonical perforin/granzyme B mechanism; and, ii) membrane LeY can be used as a biomarker for patient selection.
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ItemE-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET(SPRINGER, 2021-05)RATIONALE: The development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions. METHODS: A panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process. RESULTS: According to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET. CONCLUSIONS: The E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.
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ItemIntra-patient comparison of physiologic 68Ga-PSMA-11 and 18F-DCFPyL PET/CT uptake in ganglia in prostate cancer patients: a pictorial essay(BMC, 2021-04-16)BACKGROUND: Recent studies reported metabolic uptake in at least one of the evaluated ganglia in 98.5% of patients undergoing 68Ga -PSMA-11 and in 96.9% of patients undergoing 18F-DCFPyL PET/CT examination. We have observed different patterns of ganglion visualization with 18F-DCFPyL compared to 68Ga-PSMA-11. This includes more frequent visualization of cervical and sacral ganglia, which may be attributable to better imaging characteristics with 18F PET imaging. CASE PRESENTATION: This pictorial essay is to illustrate and compare, in the same patient, various representative cases of 68Ga-PSMA-11 and 18F-DCFPyL PET/CT uptake in ganglia at different anatomic locations, with different patterns and distribution of metabolic activity. CONCLUSION: Reading physicians should be aware of the frequently encountered and occasionally different physiologic uptake of 68Ga-PSMA-11 and 18F DCFPyL in different ganglia.