Review of commonly used prostate specific PET tracers used in prostate cancer imaging in current clinical practice.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) underperforms in detecting prostate cancer (PCa) due to inherent characteristics of primary and metastatic tumors, including relatively low rate of glucose utilization. Consequently, alternate PCa PET imaging agents targeting other aspects of PCa cell biology have been developed for clinical practice. The most common dedicated PET imaging tracers include 68Ga/18F prostate-specific membrane antigen (PSMA), 11C-Choline, and 18F-fluciclovine (Axumin™). This review will describe how these agents target specific inherent characteristics of PCa and explore the current literature for these agents for both primary and recurrent PCa, comparing the advantages and limitations of each tracer. Both 11C-Choline and 18F-Fluciclovine PET have been shown to detect nodal and osseous disease at higher rates compared to FDG-PET but offer no additional benefit in detecting prostate disease, especially in primary staging. As a result, PSMA PET, specifically 68Ga-PSMA-11, has emerged as a key imaging option for both primary and recurrent cancer. PSMA PET may be more sensitive than MRI at the local level and more sensitive than 11C-Choline and 18F-Fluciclovine PET for distant disease. Furthermore, compared to 11C-Choline and 18F-Fluciclovine PET, 68Ga-PSMA-11 PET has higher detection rates at low PSA levels (<2 ng/dL). With improved delineation of disease, PSMA imaging has influenced treatment planning; radiation fields can be narrowed, and patients with isolated or oligo-metastatic disease can be spared systemic therapy. The retrospective nature of many of the studies describing these PCa imaging modalities complicates their assessment and comparison.

Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapies for Prostate Cancer.

PURPOSE OF REVIEW: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) is a promising investigational treatment for metastatic castration-resistant prostate cancer (mCRPC). This review describes the available data with PSMA TRT. RECENT FINDINGS: Conjugates used for PSMA TRT include antibodies or small molecules PSMA-radiolabeled with beta (most commonly 177Lu) or alpha emitters (commonly 225Ac). 177Lu-J591 demonstrated accurate targeting of known metastatic sites, based on post-treatment scintigraphy, in study populations that were not selected for PSMA expression, with evidence of dose-response and dose-limiting myelosuppression. Early phase studies of 177Lu-PSMA-617 have demonstrated favorable adverse event profiles and signs of clinical activity as evidenced by PSA responses and other short-term outcomes. A phase II randomized study of 177Lu-PSMA-617 showed a superior PSA50 response rate (66 vs 37%) over cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC selected by PSMA and FDG PET/CT scans. PSMA TRT is emerging as a promising investigational therapy for mCRPC. The first randomized data with 177Lu-PSMA-617 (phase 2) have been presented, and the first phase 3 trial has completed accrual with radiographic progression-free and overall survival as dual primary endpoints. Multiple additional phase 3 trials of PSMA-TRT are starting and studies investigating optimal patient selection and combination therapy continue.

Prostate-Specific Membrane Antigen Uptake and Survival in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) imaging has been suggested as highly sensitive modality for detection of metastases in patients with biochemically recurrent or advanced prostate cancer (PCa). PSMA expression is associated with grade and stage and has a relationship with androgen receptor signaling. The aim of this study was to evaluate the prognostic utility of radiographic PSMA expression in men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Patients with mCRPC and available baseline PSMA imaging were studied. Images by planar/single-photon emission computed tomography (SPECT) or positron emission tomography (PET)/CT were reviewed. Planar/SPECT images were scored semi-quantitatively and PET/CT scored quantitatively with comparison of tumor uptake to liver uptake on a scale of 0-4 in order to determine an imaging score (IS). The IS (high: 2-4 versus low: 0-1), subsequent receipt of life-prolonging systemic therapies (taxane chemotherapy, potent androgen receptor pathway inhibitors, sipuleucel-T, and radium-223), and the CALGB prognostic risk stratification of patients were analyzed according to overall survival (OS) in univariate and multivariate Cox's proportional hazards models. RESULTS: High PSMA expression (IS 2-4) was found in 179 (75.21%) patients, and 59 (24.79%) patients had low PSMA uptake. The median OS of the entire cohort was 16.8 (95%CI: 14.9-19.3) months. Patients with a high IS had a significantly shorter OS of 15.8 (95%CI 13.0-18.1) months compared to those with low expression [22.7 (95%CI: 17.7-30.7) months, p = 0.002]. After accounting for use of life-prolonging therapies (p<0.001) and CALGB prognostic groups (p = 0.001), high PSMA IS emerged as an independent prognostic factor for OS [HR(95%CI): 1.7 (1.2-2.2); p = 0.003]. CONCLUSION: Presence of high radiographic PSMA expression on SPECT or PET/CT may portend a poor prognosis in patients with mCRPC treated with standard systemic therapies. This provides implications for therapeutic targeting of PSMA-avid disease as a means to improve outcomes.

Imaging expression of prostate-specific membrane antigen and response to PSMA-targeted ß-emitting radionuclide therapies in metastatic castration-resistant prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) has demonstrated efficacy and tolerability with a dose-response effect in phase I/II trials in men with metastatic castration-resistant prostate cancer (mCRPC). The need for positive PSMA imaging before PSMA-TRT to select patients is largely practiced, but its utility is not proven. Given target heterogeneity, developing a biomarker to identify the optimal patient population remains an unmet need. The aim of this study was to assess PSMA uptake by imaging and response to PSMA-TRT. METHODS: We performed an analysis of men with mCRPC enrolled in sequential prospective phase I/II trials of PSMA-TRT. Each patient had baseline PSMA imaging by planar 111 In and/or 177 Lu SPECT (N = 171) or 68 Ga-PSMA-11 PET/CT (N = 44), but the results were not used to include/exclude treatment. Semiquantitative imaging scores (IS) on a 0-4 scale were assigned based on PSMA uptake in tumors compared to liver uptake. We compared the ≥50% PSA decline response proportions between low (0-1) and high (2-4) PSMA IS using the χ2 -test. We used multivariable logistic regression analysis to understand the relationship between independent and dependent variables, including IS, radionuclide activity (dose) administered, CALGB (Halabi) prognostic risk score, prior taxane use. RESULTS: 215 men with progressive mCRPC received PSMA-TRT as follows: 177 Lu-J591 (n = 137), 177 Lu-PSMA-617 (n = 44), 90 Y-J591 (n = 28), 177 Lu-J591 + 177 Lu-PSMA-617 (n = 6). High PSMA expression (IS 2-4) was found in 160 (74.4%) patients and was significantly associated with more frequent ≥ 50% PSA reduction (26.2 vs. 7.3%, p = .006). On multivariate logistic regression analysis, higher IS was associated with a ≥50% decrease in PSA, even after accounting for CALGB (Halabi) prognostic score, the dose administered, and previous taxane use (OR, 4.72; 95% CI, 1.71-16.85; p = .006). Patients with low PSMA expression (N = 55, 24.7%) were less likely to respond. Thirteen of 26 (50%) with no PSMA uptake (IS = 0) had post-PSMA-TRT PSA decline with 2 (7.7%) having ≥ 50% PSA declines. CONCLUSION: Collectively, the data provide evidence in favor of the hypothesis that patients with high PSMA uptake and high administered radionuclide dose correlate with a higher chance of response.

Phase I trial of docetaxel plus lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 (177Lu-J591) for metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of 177Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to determine the safety, DLT, and maximum tolerated dose of fractionated 177Lu-J591 administered concurrently with standard docetaxel. METHODS: Men with progressive mCRPC received docetaxel 75 mg/m2 every 3 weeks with escalating 2 fractionated doses of 177Lu-J591 (1.48 GBq/m2 up to max of 2.96 GBq/m2) with cycle 3. Cycle 4 of docetaxel was planned 6 weeks after cycle 3 to allow for recovery from 177Lu-J591-associated hematologic toxicity. DLT was defined as delay in docetaxel >3 weeks, prolonged myelosuppression or need for >2 platelet transfusions, febrile neutropenia, or grade ≥3 nonhematological toxicity following 177Lu-J591. PSA was assessed prior to each cycle and serial computed tomography (CT) and bone scan were performed. RESULTS: Fifteen men with progressive mCRPC received dose-escalated targeted radionuclide therapy in 4 cohorts up to the highest planned dose (2.96 GBq/m2). No DLT was seen at any dose level. Grade 4 neutropenia without fever occurred in 8 (53.5%) and thromboytopenia in 2 (13.3%), with 2 receiving prophylactic platelet transfusion. No grade ≥3 nonhematological toxicity was observed. 11 (73.3%) had >50% PSA decline, with 78.6% having favorable circulating tumor cell counts after 177Lu-J591. All patients had targeting of known sites of disease by planar 177Lu-J591 imaging. CONCLUSION: The combination of 177Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC. Without preselection for prostate-specific membrane antigen, accurate targeting of known sites of disease and a strong preliminary efficacy signal was observed.

Pilot Study of Hyperfractionated Dosing of Lutetium-177-Labeled Antiprostate-Specific Membrane Antigen Monoclonal Antibody J591 (177 Lu-J591) for Metastatic Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Hyperfractionation of lutetium-177 (177 Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177 Lu-J591 or fractionated two-dose 177 Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177 Lu-J591 (also known as TLX591) is planned and will use the two-dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). BACKGROUND: Phase I and II single-dose studies of lutetium-177 (177 Lu)-J591, a radio-labeled antibody binding prostate-specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177 Lu-J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. METHODS: Men with progressive metastatic castration-resistant prostate cancer and adequate organ function were enrolled. 177 Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177 Lu-J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. RESULTS: Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75-150 mCi/m2 ). Two (33%) patients had >30% prostate-specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. CONCLUSION: Hyperfractionation of 177 Lu-J591 is feasible but does not seem to have significant advantages over the two-dose fractionation regimen.

Functional Outcome After Decompressive Craniectomy in Patients with Dominant or Non-Dominant Malignant Middle Cerebral Infarcts.

BACKGROUND:  The use of decompressive craniectomy (DC) has been studied in the setting of different conditions, including traumatic brain injury, subarachnoid hemorrhage, and malignant middle cerebral artery (MCA) infarction. The rationale of this study is to determine the functional outcome after DC in patients with malignant MCA infarcts. METHODS:  A longitudinal cohort study was performed based on patients diagnosed with malignant MCA territory infarction admitted to the Neurosurgery Department of a tertiary care hospital in Islamabad, Pakistan between July 2015 and November 2016. All patients had a clinical diagnosis of stroke according to the World Health Organization (WHO) stroke criteria. RESULTS:  A total of 34 patients participated in this study, out of which 20/31 (64.5%) were males while 11/31 (35.5%) were females with a mean age of 51.61 ± 13.96 years. The mean time from diagnosis to surgery was 60.61 ± 49.83 hours. Out of 31 patients, 18 (58.1%) had a right middle cerebral artery infarct (RMCAI) and 13 (41.9%) had a left middle cerebral artery infarct (LCAI). Logistic regression was applied to assess the association between the type of MCA infarct with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), modified Barthel Index (mBI) scores, and upper and lower limb motor power. However, the logistic regression model was not statistically significant χ2 (4) = 3.896, p = 0.866. There was a statistically significant mild improvement of neurological scores and upper and lower motor power over a course of six months, but the overall functional outcome was poor with mBI < 60 and mRS > 4 (p < 0.001) with total mortality of 8.7%. CONCLUSION:  Decompressive craniectomy is a life-saving surgery that appears to benefit patients with malignant MCA infarcts of either the dominant or non-dominant cerebral hemisphere. Decompressive craniectomy results in mild improvements in neurological scores but still poor functional outcome after six months.