Theranostic principles utilize a molecular biomarker specific for a tumor target, initially for imaging to assess target expression and, if deemed suitable, for targeted therapy. This presents an ...exciting opportunity for a highly personalized treatment strategy in the era of precision medicine. Prostate-specific membrane antigen (PSMA) theranostics has attracted increasing attention as a promising targeted treatment in metastatic prostate cancer (PC).
Lu-DOTA-PSMA-617 (
Lu-PSMA-617) is a PSMA-targeted small molecule with favorable properties and is the most extensively investigated PSMA radioligand for radionuclide therapy (RNT) in PC. Since 2014 multiple retrospective studies and more recently a phase II prospective study demonstrated safety and impressive efficacy of
Lu-PSMA RNT. The evidence generated by these trials led to two currently underway randomized trials in metastatic castrate-resistant PC: TheraP (NCT03392428) and VISION (NCT03511664). While we wait for these pivotal trials to read out, nuclear medicine physicians, medical oncologists, radiation oncologists, and urologists are facing a steep learning curve to master the intricacies and nuances of this novel therapeutic strategy. This review article aims to share and discuss the evolving experience in practical aspects of PSMA theranostics.
Purpose
We analysed quantitative biomarkers derived from both baseline whole-body imaging and blood serum to identify prognostic markers in patients treated within the lutetium-177 prostate-specific ...membrane antigen (LuPSMA) phase 2 trial.
Methods
PET image analysis was carried out using whole-body segmentation quantifying molecular tumour volume (SUV > 3 threshold for PSMA, SUV > liver+2sd for fluorodeoxyglucose (FDG) including SUVmax and SUVmean. For baseline bone scans, EXINI bone scan index (BSI) was used to calculate the percentage of involved bone. Baseline alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate specific antigen (PSA) and PSA doubling time were also used in this analysis. We used univariate cox regression analysis and log-rank comparison with optimised cut-offs to find suitable biomarkers prognostic of overall survival from time of enrolment.
Results
This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4–4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8–0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2–4.4), ALP (HR 1.1; 95% CI, 1–1.2) and LDH (HR 1.2; 95% CI, 1–1.5) as biomarkers prognostic of overall survival.
Conclusions
In addition to established biomarkers, both FDG and PSMA PET/CT parameters have prognostic significance for survival in men undergoing LuPSMA therapy.
Objective
To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177Lu‐PSMA‐617, a novel radiolabelled small molecule that binds with high affinity to ...prostate‐specific membrane antigen (PSMA), in men with metastatic castration‐resistant prostate cancer (mCRPC) who have received prior docetaxel treatment.
Patients and methods
The TheraP trial (ANZUP 1603) is an open‐label, randomized, stratified, two‐arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177Lu‐PSMA‐617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate‐specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed 68Ga‐PSMA‐11 and fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/computed tomography (CT) with no discordant FDG‐avid PSMA‐negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m2) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177Lu‐PSMA‐617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post‐therapy single‐photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression‐free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health‐related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG‐avid disease on screening 68Ga‐PSMA‐11 and Fluorine‐18 (18F)‐FDG‐PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018.
Results and Conclusions
177Lu‐PSMA‐617 offers a potential additional life‐prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177Lu‐PSMA‐617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
Purpose Detailed data comparing the biodistribution of PSMA radioligands is still scarce, raising concerns regarding the comparability of different compounds. We investigated differences in ...normal-organ biodistribution and uptake variability between the two most commonly PSMA tracers in clinical use, .sup.68Ga-PSMA-11 and .sup.18F-DCFPyL. Methods This retrospective analysis included 34 patients with low tumor burden referred for PET/CT imaging with .sup.68Ga-PSMA-11 and subsequently .sup.18F-DCFPyL. Images were acquired with 4 cross-calibrated PET/CT systems. Volumes of interest were placed on major salivary and lacrimal glands, liver, spleen, duodenum, kidneys, bladder, blood-pool and muscle. Normal-organ biodistribution of both tracers was then quantified as SUV.sub.peak and compared using paired tests, linear regression and Bland-Altman analysis. Between-patient variability was also assessed. Clinical and protocol variables were investigated for possible interference. Results For both tracers the highest uptake was found in the kidneys and bladder and low background activity was noted across all scans. In the quantitative analysis there was significantly higher uptake of .sup.68Ga-PSMA-11 in the kidneys, spleen and major salivary glands (p < 0.001), while the liver exhibited slightly higher .sup.18F-DCFPyL uptake (p = 0.001, mean bias 0.79 + or - 1.30). The lowest solid-organ uptake variability was found in the liver (COV 21.9% for .sup.68Ga-PSMA-11, 22.5% for .sup.18F-DCFPyL). There was a weak correlation between .sup.18F-DCFPyL uptake time and liver SUV.sub.peak (r = 0.488, p = 0.003) and, accordingly, patients scanned at later time-points had a larger mean bias between the two tracers' liver uptake values (0.05 vs 1.46, p = 0.001). Conclusion Normal tissue biodistribution patterns of .sup.68Ga-PSMA-11 and .sup.18F-DCFPyL were similar, despite subtle differences in quantitative values. Liver uptake showed an acceptable intra-patient agreement and low inter-patient variability between the two tracers, allowing its use as a reference organ for thresholding scans in the qualitative comparison of PSMA expression using these different tracers. Keywords: .sup.18F-DCFPyL, .sup.68Ga-PSMA-11, PET/CT, Biodistribution, Prostate cancer
Purpose
We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor ...(combination-ICI) therapy for advanced melanoma.
Methods
We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) pre- and post-treatment FDG-PET/CT scans (pre-FDG-PET/CT and post-FDG-PET/CT) within 2 and 4 months of starting ICI, respectively; and (3) at least one lesion assessable by PET response criteria in solid tumors (PERCIST). Extracranial response was monitored by 3 monthly FDG-PET/CT. Whole-body metabolic tumor volume (wbMTV) was measured pre- and post-treatment and correlated with outcome. FDG-PET/CT manifestations of irAE were defined as new increased non-tumoral uptake on post-FDG-PET/CT and were correlated with clinical presentation.
Results
Thirty-one consecutive patients, median age 60 years (range, 30–78), were identified from 2016 to 2018. The median number of combination-ICI cycles to the first post-FDG-PET/CT response assessment was 3 (interquartile range (IQR), 2–4). The best-overall responses were complete metabolic response (CMR) in 25 (80%), partial metabolic response (PMR) in 3 (10%), and progressive metabolic disease (PMD) in 3 (10%) patients. Patients with PMD had significantly higher pre-treatment wbMTV (
p
= 0.009). At a median follow-up of 21.5 months, 26 (84%) patients were alive with median progression-free and overall survival not reached. Secondary progression occurred in 9/31 (29%) patients at a median of 8.2 months (IQR, 6.9–15.5), of those majority (78%) was detected by FDG-PET/CT. Of 36 findings on post-FDG-PET/CT suggestive of irAE, 29 (80%) had clinical confirmation. In 3 (7%), the FDG-PET/CT findings preceded clinical presentation. The most common FDG-PET/CT detectable irAEs were endocrinopathies (36%) and enterocolitis (35%).
Conclusion
FDG-PET/CT response evaluation predicts the long-term outcome of patients treated with first-line combination-ICIs. Long-term treatment response monitoring for detection of extracranial secondary progression is feasible by FDG-PET/CT. Beyond response assessment, FDG-PET/CT frequently detects clinically relevant irAEs, which may involve multiple systems contemporaneously or at various time-points and may precede clinical diagnosis.
Purpose
This study aimed to analyse the molecular imaging (MI) phenotype of typical carcinoid (TC) and atypical carcinoid (AC) by
68
Ga-DOTATATE (GaTATE) and
18
F-FDG (FDG) PET/CT with the emphasis ...on its potential theranostic implications for peptide receptor radionuclide therapy (PRRT).
Methods
Retrospective review of patients with biopsy-proven TC or AC undergoing both GaTATE and FDG PET/CT at presentation. Based on correlative CT or MRI, positive lesions on either scan were defined by uptake above liver parenchyma. Per patient MI phenotypic pattern was classified as score 1, if all lesions were negative on both scans; score 2, if all were GaTATE positive/FDG negative; score 3, if all lesions were GaTATE positive but some or all were also FDG positive and score 4, if there were any GaTATE negative/FDG positive lesions. Scores 1 and 4 were deemed unsuitable for PRRT.
Results
Of 56 patients (median age 66.5 years, 32 female), 22 had TC, and 34 had AC. Distant metastases were seen in 32% of TC and 94% of AC. At a median follow-up of 37 months for TC and 38 months for AC, 100% and 63% were alive, respectively. Median OS for AC was 56 months (95% CI 43, not reached NR), and TC was NR. On inter-patient dual-tracer analysis, scores 1, 2, 3 and 4 were 23%, 18%, 36% and 23% in TC and 3%, 15%, 32% and 50% in AC, respectively. In 16 patients (score 2,
N
= 3; score 3,
N
= 12; score 4,
N
= 1) who were treated with PRRT, disease control rate at 3 months and OS were, 85% and 54.6 months (95% CI 44–70), respectively.
Conclusions
TC and AC showed a wide inter-patient phenotypic heterogeneity on GaTATE and FDG with around half of patients (46% TC and 53% AC) having an unsuitable phenotype for PRRT. Dual-tracer MI phenotype can be used to select the most suitable patients for PRRT.
Prostate cancer remains the commonest cancer diagnosed in males and a leading cause of cancer-related death. Men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on ...chemotherapy and androgen receptor pathway inhibitors (ARPI) have limited treatment options, significant morbidity, and poor outcomes. Prostate-specific membrane antigen (PSMA)-directed radionuclide therapy (RNT) is emerging as an efficacious and well-tolerated therapy; however, disease progression is universal. Several ongoing RNT trials focus on combination strategies to improve efficacy and durability of treatment response, including combinations with ARPIs, chemotherapy, immunotherapy, and targeted therapies. Further, efforts are underway to expand the role of PSMA-directed RNT to earlier stages of disease including hormone-sensitive and localized prostate cancer. In this review, we discuss the rationale and ongoing RNT combination therapeutic trials in prostate cancer and summarize the efficacy and toxicity associated with RNT.
Neuroendocrine neoplasia (NEN) is an umbrella term that includes a widely heterogeneous disease group including well-differentiated neuroendocrine tumours (NETs), and aggressive neuroendocrine ...carcinomas (NECs). The site of origin of the NENs is linked to the intrinsic tumour biology and is predictive of the disease course. It is understood that NENs demonstrate significant biologic heterogeneity which ultimately translates to widely varying clinical presentations, disease course and prognosis. Thus, significant emphasis is laid on the pre-therapy evaluation of markers that can help predict tumour behavior and dynamically monitors the response during and after treatment. Most well-differentiated NENs express somatostatin receptors (SSTRs) which make them appropriate for peptide receptor radionuclide therapy (PRRT). However, the treatment outcomes of PRRT depend heavily on the adequacy of patient selection by molecular imaging phenotyping not only utilizing pre-treatment SSTR PET but
F-Fluorodeoxyglucose (
F-FDG) PET to provide insights into the intra- or inter-tumoural heterogeneity of the metastatic disease. Molecular imaging phenotyping may go beyond patient selection and provide useful information during and post-treatment for monitoring of temporal heterogeneity of the disease and dynamically risk-stratify patients. In addition, advances in the understanding of genomic-phenotypic classifications of pheochromocytomas and paragangliomas led to an archetypical example in precision medicine by utilizing molecular imaging phenotyping to guide radioligand therapy. Novel non-SSTR based peptide receptors have also been explored diagnostically and therapeutically to overcome the tumour heterogeneity. In this paper, we review the current molecular imaging modalities that are being utilized for the characterization of the NENs with special emphasis on their role in patient selection for radioligand therapy.
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