[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Role of 18F-fluoro-ethyl-tyrosine Positron Emission Tomography in Investigation and Management of Suspected Gliomas.

BACKGROUND: This study aims to investigate the utility of 18F-fluoro-ethyl-tyrosine (18F-FET) positron emission tomography in surgical decision making in suspected glioma. METHODS: A retrospective review of patients undergoing 18F-FET positron emission tomography was performed. Previously published thresholds for maximum tumor background ratios (TBRs) were used for quantitative analysis. Forty-seven patients were included in the study, of whom 15 had confirmed glioma and 7 had a confirmed alternative diagnosis. RESULTS: 18F-FET showed significantly higher uptake in high-grade glioma than in nonglioma. CONCLUSIONS: Lesions with TBRmax >2.5 should be considered suspicious for glioma and biopsy considered. Threshold TBRmax >3.0 is useful for differentiating high-grade glioma from low-grade glioma. This may be a particularly useful tool for directing management in eloquent areas, such as brainstem glioma.

FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes - A pilot study.

We aimed to determine the utility of FET PET in the management of indeterminate CNS lesions found on MRI. We performed a retrospective analysis of patients with FET PET at a single tertiary institution from 2011 to 2015. FET PET images were processed using usual methods and measurements taken including SUVmax, TBRmax, and analysis of dynamic series where available (Kipeak, Vdpeak, as well as tumor:background ratio for these variables). Correlation studies were performed using ANOVA between cohorts of high-grade histology, low-grade histology, and benign histology/stable on observation. Thirty-five patients were included, of whom 34 were suitable for analysis with median follow-up of 5 months. The positive predictive value of FET PET in this cohort was 83.3%. FET SUVmax differentiated between patients with high-grade (mean SUV 3.38, 95% CI 2.21-4.55), low-grade (1.88, 95% CI 1.33-2.43) and benign/observation (1.42, 95% CI 1.13-1.71) cohorts (p = 0.0003). Similarly, tumour to brain ratio was significant (p < 0.0001). Kipeak distinguished between high grade and observation cohorts (p = 0.036), as did KiTBR (p = 0.025). Vd peak was not significantly different in these two cohorts (p = 0.057) but Vd TBR was (p = 0.041). In conclusion, FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort.

Clinical utility of (99m Tc)-TRODAT-1 scans to differentiate Parkinsonian syndromes: case studies and commentary.

The differential diagnosis of Parkinsonian syndromes is challenging, especially in the elderly as they often have complex presentations. Nuclear imaging modalities can increase diagnostic accuracy. Single-photon emission tomography (SPECT) using the ligand (99m Tc)-TRODAT-1 is used overseas but is yet to be approved in Australia. Three pilot cases of clinically unclear Parkinsonian syndromes from the Royal North Shore Hospital Aged Care Department who underwent (99m Tc)-TRODAT-1 scans are described. From experience overseas, the (99m Tc)-TRODAT-1 scan has clinical utility in the differential diagnosis of Parkinsonian syndromes. (99m Tc)-TRODAT-1 has a lower cost and greater availability than other ligands. Our initial scan findings are largely consistent with the clinical picture, but low specific binding can affect scan interpretation. (99m Tc)-TRODAT-1 is a potential tool in the differential diagnosis of Parkinsonian syndromes. Further experience regarding its effect on patient outcomes and cost effectiveness is required before routine clinical use can be recommended.

Role of DOTATATE-PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas.

CONTEXT: Diagnosis of paragangliomas (PGL) and phaeochromocytomas (PC) can be challenging particularly if the tumour is small. Detection of metastatic disease is important for comprehensive management of malignant PC/PGL. Somatostatin receptor imaging (SRI) agents have high sensitivity for these tumours, particularly the DOTA family of radiopharmaceuticals labelled with 68 Gallium. OBJECTIVE: To describe the utility of SRI in primary assessment (ie before surgery) for PC/PGL and whether measures of maximum standardized uptake (SUVmax) could be used to distinguish between adrenal adenomas and PCs. DESIGN: Retrospective analysis of patients with PC and PGL between 2012 and 2017. PATIENTS: Somatostatin receptor imaging (SRI) was performed for suspected PC (n = 46) or PGL (n = 27) of which 36 were during primary assessment and 37 during secondary assessment (follow-up after surgery). For comparison of adrenal SUVmax, scans from 30 patients without suspected PC/PGL (20 with normal adrenals; 10 with incidental adenomas) were evaluated. MEASUREMENTS: Baseline description, sensitivity, specificity, Youden's index. RESULTS: Sensitivity of DOTATATE-PET was 88% for PC and 100% for PGL. False-negative scans were seen in 2/10 PCs < 28 mm and in 1/14 PCs > 28 mm which had features of cystic degeneration. SUVmax of PCs and PGLs was more than double compared to adrenal adenomas (P > .001). CONCLUSION: Somatostatin receptor imaging (SRI) has high sensitivity in primary assessment for PC and PGL. We recommend that SRI should be performed as part of primary assessment in all suspected PGLs (due to higher risk of multifocal lesions) and in PCs suspected to be associated with hereditary syndromes or metastases.

68 Ga-PSMA-PET/CT staging prior to definitive radiation treatment for prostate cancer.

AIM: To explore the utility of prostate specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) in addition to conventional imaging prior to definitive external beam radiation treatment (EBRT) for prostate cancer. METHODS: All men undergoing PSMA-PET/CT prior to definitive EBRT for intermediate and high-risk prostate cancer were included in our ethics approved prospective database. For each patient, clinical and pathological results, in addition to scan results including site of PSMA positive disease and number of lesions, were recorded. Results of conventional imaging (bone scan, CT and multiparametric magnetic resonance imaging [MRI]) were reviewed and included. RESULTS: One hundred nine men underwent staging PSMA-PET/CT between May 2015 and June 2017; all patients had national comprehensive cancer network (NCCN) intermediate or high-risk prostate cancer and 87% had Gleason score (GS) 4 + 3 or higher. There was positive uptake corresponding to the primary in 108, equivocal in one. All patients with image detected nodal or bony lesions had GS 4 + 3 or more disease. Compared to conventional imaging with bone scan, CT and multiparametric MRI, PSMA-PET/CT upstaged an additional 7 patients (6.4%) from M0 to M1, 16 from N0M0 to N1M0 (14.7%) and downstaged 3 (2.8%) from M1 to M0 disease. CONCLUSION: PSMA-PET/CT identified the primary in 99% of patients, and altered staging in 21% of men with intermediate or high-risk prostate cancer referred for definitive EBRT compared to CT, bone scan and multiparametric MRI. Following this audit, we recommend the routine use of PSMA-PET/CT prior to EBRT in this patient group.

Survival improvements with adjuvant therapy in patients with glioblastoma.

BACKGROUND: Evaluate survival of patients diagnosed with glioblastoma multiforme (GBM) managed with adjuvant intensity modulated radiation therapy and temozolomide since the introduction of the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) protocol. METHODS: All patients with GBM managed between May 2007 and December 2014 with EORTC-NCIC protocol were entered into a prospective database. The primary endpoint was the median survival. Univariate predictors of survival were evaluated with respect to tumour resection, age and Eastern Cooperative Oncology Group (ECOG) performance status using log-rank comparisons. RESULTS: Two hundred and thirty-three patients were managed under the protocol and analysed for outcome. The median age was 57 years; the rate of gross total resection, subtotal resection and biopsy were 47.2%, 35.2% and 17.6%, respectively. At progression, 49 patients had re-resection, and in addition to second-line chemotherapy, 86 patients had Bevacizumab including 26 with re-irradiation. Median survival was 17.0 months (95% CI: 15.4-18.6). On univariate evaluation, extent of resection (P = 0.001), age, ECOG performance status and recursive partitioning analysis class III were shown to significantly improve survival (P < 0.0001). The median survival for gross total resection, age <50 years, ECOG 0-1 and recursive partitioning analysis class III were 21, 27, 20 and 47 months, respectively. CONCLUSION: This study confirms the significant improvement in median survival in GBM that has occurred in recent years since introduction of the EORTC-NCIC protocol. Further improvements have occurred presumably related to subspecialized care, improved resection rates, sophisticated radiotherapy targeting and early systemic salvage therapies. However, the burden of the disease within the community remains high and the median survival improvements over time have plateaued.

Utilizing 18F-fluoroethyl-l-tyrosine positron emission tomography in high grade glioma for radiation treatment planning in patients with contraindications to MRI.

INTRODUCTION: Patients with high grade glioma (HGG) and contraindications to magnetic resonance imaging (MRI) are dependent on contrast-enhanced computerized tomography (CT) scan imaging for radiation therapy (RT) target volume delineation. This study reviews the experience with the utilization of 18F-fluoroethyl-l-tyrosine positron emission tomography (FET-PET) to define residual disease post craniotomy and optimize RT planning. METHODS: Patients with HGG and a contraindication to MRI managed with radiation therapy between 2007 and 2015 were identified. RT target volumes including gross tumour volume (GTV) defined by CT-alone and the biological target volume (BTV) defined by PET-CT were recorded. Clinical target volumes (CTV) were created from the GTV and BTV respectively using standard protocol volume expansion. The expanded BTV was termed clinical target volume biological (CTV-B). Union and intersection between CTV and CTV-B, conformity index, volumetric parameters and individual patient outcomes were analysed. RESULTS: Six patients fit study criteria. There was a mean increase in CTV-B from CTV by 31.6% with a conformity index of 0.78. Two out of six patients had FET-PET avid disease outside the constructed PTV when delineated by CT-alone. One patient with CT-only planning had a new contrast-enhancing mass within 1 month of completing RT, suggesting potential geographical miss. CONCLUSION: Patients with contraindication to MRI the addition of FET-PET can improve target volume delineation for RT Planning.

Delineating sites of failure following post-prostatectomy radiation treatment using 68Ga-PSMA-PET.

PURPOSE: To identify sites of failure with 68Ga-PSMA-PET (PSMA-PET) imaging in patients who have Biochemical Failure (BF) following post-prostatectomy radiotherapy. MATERIAL AND METHODS: Between June 2006 and January 2016, 409 men received post prostatectomy intensity modulated radiation treatment (IMRT) with protocolised planning. 310 patients received radiation treatment (RT) to the Prostate Fossa (PF) alone and 99 patients received RT to PF and pelvic lymphatics (PF + LN) usually in combination with androgen deprivation (AD) therapy. Any failure not detected on conventional imaging was delineated with PSMA-PET scanning. Sites of failure were characterised as in-field (PF ±â€¯LN), or out of field (nodal alone, distant metastatic alone (visceral or bone) or multi-site failure). Nodal failure was further divided into pelvic failure and/or distant failure. RESULTS: 119 men developed BF, defined as a PSA rise of >0.2 or greater, above post-RT nadir. Freedom from BF was 71% in the PF group and 70% in the PF + LN group, with median follow up of 52 and 44 months respectively. AD was used concomitantly in 13% of the PF group and 92% of the PF + LN group. 81 patients with BF (68%) had PSMA-PET imaging performed as per study intent, 67 (80%) of whom had PSMA avid disease identified. PSMA-PET delineated in-field failure occurred in 2/50 (4%) of the PF group and 1/17 (6%) in the PF + LN group. Nodal failure alone was 33/50 (66%) for the PF group vs 7/17 (41%) for the PF + LN group. For the nodal only failure patients, 18/33 (55%) had pelvic-only nodal failure in the PF group compared to 1/7 (14%) in the PF + LN group (p = 0.03). 16 (32%) of the PSMA avid failures in the PF group would have been encompassed by standard pelvic lymphatic radiotherapy volumes. CONCLUSION: Post-prostatectomy radiation treatment resulted in excellent in-field control rates. Isolated pelvic nodal failure was rare in those receiving radiotherapy to the prostatic fossa and pelvic nodes but accounted for one third of failures in those receiving PF alone treatment.

Survival Outcomes of Elderly Patients With Glioblastoma Multiforme in Their 75th Year or Older Treated With Adjuvant Therapy.

PURPOSE: To assess the outcomes of the most elderly cohort of patients with a diagnosis of glioblastoma multiforme (GBM) after intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: The data of patients with GBM who had underwent IMRT from May 2007 to December 2015 were entered into a prospective database. Analysis was performed on the data from patients diagnosed during or after 75 years of age. The primary endpoint was the median survival. Univariate and multivariate analyses were performed with respect to survival for patients aged 74 to 80 versus >80 years, Eastern Cooperative Oncology Group performance status of 0 to 1 versus 2 to 3, extent of resection, a high radiation dose (60 Gy) versus any hypofractionated schedule, MGMT methylation status, planning target volume, and the use of temozolomide (TMZ) versus no TMZ. RESULTS: Of the 108 patients, 35 received best supportive care, 1 received TMZ alone, 40 received RT alone, and 32 received combined RT and TMZ. IMRT was delivered with a hypofractionated technique (40 Gy) in 58 patients or long-course RT (60 Gy) in 11 patients. The median age was 79 years, with 61.6% of patients aged 74 to 80 years and 38.4% aged >80 years. Of the 108 patients, 64 died during the follow-up period, with a median survival of 10 months (95% confidence interval 7.1-11.9), projected 12-month survival rate of 35.6%, and 24-month survival rate of 7.9%. On univariate analysis, the independent predictors of survival included younger age (P=.02), better performance status (P=.014), greater resection extent (P=.002), and TMZ use (P<.001). MGMT methylation status, RT dose, and planning target volume showed no significant differences between the groups. Only chemotherapy use remained statistically significant (P=.035) on multivariate analysis. CONCLUSION: The current data underrepresent elderly patients aged >75 years with GBM. Despite elderly patients having a worse prognosis, the results of the present study suggest the presence of survival benefits with IMRT for selected patients that can be further extended with addition of TMZ. Further study of this cohort and an understanding of the appropriate selection criteria are warranted.

Delineating biochemical failure with 68Ga-PSMA-PET following definitive external beam radiation treatment for prostate cancer.

BACKGROUND AND PURPOSE: We investigated the role of 68Ga-PSMA-PET (PSMA) to determine the location of disease recurrence in those with a rising PSA following definitive external beam radiation treatment (EBRT). MATERIALS AND METHODS: 538men were treated with image guided EBRT to a dose of 78 or 82Gy between 2007 and 2014. Patients at least 24months post EBRT with biochemical failure (nadir+2) underwent PSMA scanning. Local recurrence (LR) was defined as increased uptake within the prostate or seminal vesicles. Distant disease included lymph node (LN), bone or visceral metastases. RESULTS: 419men formed the study cohort. Median follow-up was 50months, 70 patients (17%) had biochemical failure (BF), 13 of whom have died. Of the 57 survivors, 5 had metastases detected on conventional scans; 2 were lost to follow up. 48men (of 50 candidates) underwent PSMA; in all cases, the PSMA was unequivocally positive. Of the 48 positive scans, 25 patients (52%) failed beyond the prostate - 5 in bones, 16LN, 3 in both, and 1 in the lungs. Fifteen men (31%) failed within the gland and in either LN (11), bones (3), or both (1). Eight (17%) had an isolated LR, which represents 2% of patients managed with definitive EBRT and followed for at least 2years. CONCLUSIONS: PSMA was positive in all patients with BF. Site of failure following dose-escalated EBRT was generally distant. Isolated LR (on PSMA) occurred in only 8 of 419 patients post-EBRT.

Follicular Thyroid Adenoma Showing Avid Uptake on 68Ga PSMA-HBED-CC PET/CT.

68Ga-prostate-specific membrane antigen (PSMA) PET/CT imaging is a relatively new imaging technique used to evaluate the extent of disease in prostate carcinoma. Various other neoplasms may also express PSMA and show uptake on PSMA PET/CT scan. We report a case of a 62-year-old man who had a PSMA PET/CT scan for restaging of prostate carcinoma. A PSMA-avid thyroid lesion was identified, and subsequent tissue sampling confirmed the diagnosis of follicular thyroid adenoma. It is important to be aware of this possibility to avoid scan misinterpretation. Tissue biopsy of PSMA-avid thyroid lesions should be considered to exclude a primary thyroid neoplasm.

(67)Ga SPECT/CT accurately localized recurrent hepatic cyst infection in patients with autosomal dominant polycystic kidney disease.

Hepatic pyocyst is a rare but potentially life-threatening complication of autosomal dominant polycystic kidney disease. With extensive hepatic cystic disease, localization of a pyocyst and targeted aspiration or drainage is often a diagnostic challenge. Two patients with autosomal dominant polycystic kidney disease and recurrent gram-negative sepsis were imaged with Ga SPECT/CT for investigation of an infective source. In both patients, imaging accurately localized infected pyocysts and guided percutaneous drainage and further management.

CT-based quantitative SPECT for the radionuclide ²°¹Tl: experimental validation and a standardized uptake value for brain tumour patients.

We have previously reported on a method for reconstructing quantitative data from 99mTc single photon emission computed tomography (SPECT) images based on corrections derived from X-ray computed tomography, producing accurate results in both experimental and clinical studies. This has been extended for use with the radionuclide ²°¹Tl. Accuracy was evaluated with experimental phantom studies, including corrections for partial volume effects where necessary. The quantitative technique was used to derive standardized uptake values (SUVs) for ²°¹Tl evaluation of brain tumours. A preliminary study was performed on 26 patients using ²°¹Tl SPECT scans to assess residual tumor after surgery and then to monitor response to treatment, with a follow-up time of 18 months. Measures of SUVmax were made following quantitative processing of the data and using a threshold grown volume of interest around the tumour. Phantom studies resulted in the calculation of concentration values consistently within 4% of true values. No continuous relation was found between SUVmax (post-resection) and patient survival. Choosing an SUVmax cut-off of 1.5 demonstrated a difference in survival between the 2 groups of patients after surgery. Patients with an SUVmax<1.5 had a 70% survival rate over the first 10 months, compared with a 47% survival rate for those with SUVmax>1.5. This difference did not achieve significance, most likely due to the small study numbers. By 18 months follow-up this difference had reduced, with corresponding survival rates of 40% and 27%, respectively. Although this study involves only a small cohort, it has succeeded in demonstrating the possibility of an SUV measure for SPECT to help monitor response to treatment of brain tumours and predict survival.

The utility of metaiodobenzylguanidine single photon emission computed tomography/computed tomography (MIBG SPECT/CT) for the diagnosis of pheochromocytoma.

BACKGROUND: The enhancement of metaiodobenzylguanidine single photon emission computed tomography (MIBG SPECT) imaging through the addition of CT images fused with SPECT data (coregistered MIBG SPECT/CT imaging) is new technology that allows direct correlation of anatomical and functional information. We hypothesized that MIBG SPECT/CT imaging would provide additional information and improve diagnostic confidence for the radiological localization of a pheochromocytoma, in particular for patients at high risk of multifocal or recurrent disease. METHODS: A retrospective study of all patients investigated by MIBG SPECT/CT at our institution from 2006 to 2008 for a suspected pheochromocytoma was performed. Each case was compared with conventional radiological investigations to determine whether MIBG SPECT/CT was able to improve diagnostic confidence and provide additional diagnostic information compared with conventional imaging alone. RESULTS: Twenty-two patients had MIBG SPECT/CT imaging for a suspected pheochromocytoma. Fourteen patients had positive MIBG SPECT/CT imaging results correlating with imaging by CT or magnetic resonance imaging in all cases. In six cases, MIBG SPECT/CT provided additional information that altered the original radiological diagnosis. Five patients with a pheochromocytoma-associated germline mutation had multifocal disease excluded by MIBG SPECT/CT. Patients without a germline mutation that had positive biochemistry and a solitary lesion with conventional imaging had no diagnostic improvement with MIBG SPECT/CT imaging. CONCLUSIONS: MIBG SPECT/CT fusion imaging is a sensitive and specific radiological imaging tool for patients suspected to have pheochromocytoma. The particular strengths of MIBG SPECT/CT are detection of local recurrence, small extra-adrenal pheochromocytomas, multifocal tumors, or the presence of metastatic disease.