Amir Iravani

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study

BACKGROUND Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [177Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [177Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. METHODS In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours [RECIST] or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous [177Lu]-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583. FINDINGS Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37-75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to [177Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1-2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [177Lu]-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment. INTERPRETATION Our findings show that radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care. FUNDING None.

Gallium-68 Prostate-Specific Membrane Antigen PET Imaging

The role of gallium-68 (68Ga) prostate-specific membrane antigen (PSMA) PET imaging is evolving and finding its place in the imaging armamentarium for prostate cancer (PCa). Despite the progress of conventional imaging strategies, significant limitations remain, including identification of small-volume disease and assessment of bone. Clinical studies have demonstrated that 68Ga-PSMA is a promising tracer for detection of PCa metastases, even in patients with low prostate-specific antigen. To provide an accurate interpretation of 68Ga-PSMA PET/computed tomography, nuclear medicine specialists and radiologists should be familiar with physiologic 68Ga-PSMA uptake, common variants, patterns of locoregional and distant spread of PCa, and inherent pitfalls.

Detection of Synchronous Primary Malignancies with 68Ga-PSMA PET/CT in Patients with Prostate Cancer: Frequency in 764 Patients

We evaluated the incidence of synchronous primary malignancies in patients undergoing 68Ga-labeled prostate-specific membrane antigen PET/CT for prostate cancer (PC). Methods: Reports for 764 PC patients were reviewed. Incidental lesions atypical for PC metastases and suggestive of a synchronous primary malignancy were identified. Follow-up was obtained to confirm etiology. Results: Lesions atypical for PC metastases were found in 49 (6.4%) of 764 patients, and a synchronous primary malignancy was confirmed in 5 patients (0.7%; 2 lung, 1 lymphoma, 1 thyroid, and 1 base of tongue). In 8 patients (1.0%), lesions were proven to be atypical metastases from PC. In 24 patients (3.1%), lesions had a benign etiology. Follow-up was not available in 12 patients (1.6%). Conclusion: Synchronous 68Ga-labeled prostate-specific membrane antigen–avid malignancies were rare (0.7%) in PC patients; atypical lesions were more commonly unusual PC metastases (1.0%) or benign (3.1%).

Advances in Urologic Imaging: Prostate-Specific Membrane Antigen Ligand PET Imaging

Radiolabeled prostate-specific membrane antigen PET (PSMA PET) is emerging as an important modality for imaging prostate cancer (PCa). Promising clinical experience has led to increasing number of studies exploring the role of PSMA PET in different aspects of PCa including primary detection, risk stratification, targeted biopsy, initial staging, restaging at biochemical recurrence, biologic characterization, treatment response assessment and prognostication. PSMA PET may prove an important disease biomarker, expand our understanding of the pathogenesis and pave the way for personalized management of PCa.

What FDG-PET response-assessment method best predicts survival after curative-intent chemoradiation in non-small cell lung cancer (NSCLC): EORTC, PERCIST, Peter Mac or Deauville criteria?

The optimal methodology for defining response with 18F-FDG PET after curative-intent chemoradiation for non–small cell lung cancer (NSCLC) is unknown. We compared survival outcomes according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC), PERCIST 1.0, the Peter Mac metabolic visual criteria, and the Deauville criteria, respectively. Methods: Three prospective trials of chemoradiation for NSCLC, involving baseline and posttreatment 18F-FDG PET/CT imaging, were conducted between 2004 and 2016. Responses were categorized as complete metabolic response (CMR), partial metabolic response, stable metabolic disease, or progressive metabolic disease. Cox proportional-hazards models and log-rank tests assessed the impact of each response on overall survival (OS). Results: Eighty-seven patients underwent 18F-FDG PET/CT before and after radical chemoradiation for NSCLC. Follow-up 18F-FDG PET/CT scans were performed at a median of 89 d (interquartile range, 79–93 d) after radiotherapy. Median follow-up and OS after PET response imaging were 49 and 28 mo, respectively. Interobserver agreements for EORTC, PERCIST, Peter Mac, and Deauville had κ values of 0.76, 0.76, 0.87, and 0.84, respectively. All 4 response criteria were significantly associated with OS. Peter Mac and Deauville showed better fit than EORTC and PERCIST and distinguished better between CMR and non-CMR. Conclusion: All 4 response criteria were highly predictive of OS, but visual criteria showed greater interobserver agreement and stronger discrimination between CMR and non-CMR, highlighting the importance of visual assessment to recognize radiation pneumonitis, changes in lung configuration, and patterns of response.

Dosimetry of Lu-177 PSMA-617 in metastatic castration-resistant prostate cancer: correlations between pre-therapeutic imaging and “whole body” tumor dosimetry with treatment outcomes

177Lu-prostate-specific membrane antigen (PSMA)–617 enables targeted delivery of β-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pretherapeutic imaging and outcomes. Methods: Thirty patients with prostate cancer receiving 177Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening 68Ga-PSMA-11 PET/CT demonstrated high PSMA expression in all patients. After therapy, patients underwent quantitative SPECT/CT at 4, 24, and 96 h. Pharmacokinetic uptake and clearance at a voxel level were calculated and translated into absorbed dose using voxel S values. Volumes of interest were drawn on normal tissues and tumor to assess radiation dose, and a whole-body tumor dose was defined. Correlations between PSMA PET/CT parameters, dosimetry, and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. Results: Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. On screening PSMA PET, whole-body tumor SUVmean correlated with mean absorbed dose (r = 0.62), and SUVmax of the parotids correlated with absorbed dose (r = 0.67). There was an inverse correlation between tumor volume and mean dose to the parotids (r = −0.41) and kidneys (r = −0.43). The mean parotid dose was also reduced with increasing body mass (r = −0.41) and body surface area (r = −0.37). Conclusion: 177Lu-PSMA-617 delivers high absorbed doses to tumor, with a significant correlation between whole-body tumor dose and PSA response. Patients receiving less than 10 Gy were unlikely to achieve a fall in PSA of at least 50%. Significant correlations between aspects of screening 68Ga-PET/CT and tumor and normal tissue dose were observed, providing a rationale for patient-specific dosing. Reduced salivary and kidney doses were observed in patients with a higher tumor burden. The parotid dose also reduced with increasing body mass and body surface area.