Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is mostly administered using a fixed injected activity (IA) per cycle. This empiric regime results in highly variable absorbed doses to the critical organs and undertreatment of the majority of patients. We conceived a personalized PRRT protocol in which the IA is adjusted to deliver a prescribed absorbed dose to the kidney, with the aim to safely increase tumour irradiation. We herein report on the initial results of our prospective study of personalized PRRT, the P-PRRT Trial (NCT02754297). METHODS: PRRT-naïve patients with progressive and/or symptomatic neuroendocrine tumour (NET) were scheduled to receive a four-cycle induction course of 177Lu-octreotate with quantitative SPECT/CT-based dosimetry. The IA was personalized according to the glomerular filtration rate and the body surface area for the first cycle, and according to the prior renal Gy/GBq for the subsequent cycles. The prescribed renal absorbed dose of 23 Gy was reduced by 25-50% in case of significant renal or haematological impairment. Responders were allowed to receive consolidation or maintenance cycles, for each of which 6 Gy to the kidney were prescribed. We simulated the empiric PRRT regime by fixing the IA at 7.4 GBq per cycle, with the same percentage reductions as above. Radiological, molecular imaging, biochemical, and quality of life responses, as well as safety, were assessed. RESULTS: Fifty-two patients underwent 171 cycles. In 34 patients who completed the induction course, a median cumulative IA of 36.1 (range, 6.3-78.6) GBq was administered, and the median cumulative kidney and maximum tumour absorbed doses were 22.1 (range, 8.3-24.3) Gy and 185.7 (range: 15.2-443.1) Gy respectively. Compared with the simulated fixed-IA induction regime, there was a median 1.26-fold increase (range, 0.47-2.12 fold) in the cumulative maximum tumour absorbed dose, which was higher in 85.3% of patients. In 39 assessable patients, the best objective response was partial response in nine (23.1%), minor response in 14 (35.9%), stable disease in 13 (33.3%) and progressive disease in three patients (7.7%). In particular, 11 of 13 patients (84.6%) with pancreatic NET had partial or minor response. The global health status/quality of life score significantly increased in 50% of patients. Acute and subacute side-effects were all of grade 1 or 2, and the most common were nausea (in 32.7% of patients) and fatigue (in 30.8% of patients) respectively. Subacute grade 3 or 4 toxicities occurred in less than 10% of patients, with the exception of lymphocytopenia in 51.9% of patients, without any clinical consequences however. No patient experienced severe renal toxicity. CONCLUSIONS: Personalized PRRT makes it possible to safely increase tumour irradiation in the majority of patients. Our first results indicate a favourable tolerance profile, which appears similar to that of the empiric regime. The response rates are promising, in particular in patients with NET of pancreatic origin.

Highly Symptomatic Progressing Cardiac Paraganglioma With Intracardiac Extension Treated With 177Lu-DOTATATE: A Case Report.

Introduction: Primary cardiac paragangliomas are rare tumors. Metastatic disease is even rarer. Surgical management is technically challenging, and sometimes even impossible. Available therapeutic modalities for metastatic disease include external beam radiation therapy as well as systemic treatments, namely 131I-MIBG and more recently, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. To our knowledge, this is the first case of progressive unresectable cardiac paraganglioma with intracardiac extension treated with dosimetry based personalized PRRT to be reported. This case is of particular interest since it documents for the first time the efficacy, and especially the safety of the 177Lu-DOTATATE PRRT in this precarious context for which therapeutic options are limited. Case Presentation: A 47-year-old man with no medical history consulted for rapidly decreasing exercise tolerance. The investigation demonstrated an unresectable progressing metastatic cardiac paraganglioma with intracardiac extension. The patient was treated with personalized 177Lu-DOTATATE PRRT and showed complete symptomatic and partial anatomical responses, with a progression-free survival of 13 months. Conclusions: PRRT with 177Lu-DOTATATE should be considered for inoperable cardiac paraganglioma. No major hemodynamic complications were experienced. Therapy resulted in safety and substantially improved quality of life.

Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of 177Lu-PSMA-617 Theranostics in Metastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted ß-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177Lu-PSMA radioligand therapy. On progression, rechallenge 177Lu-PSMA demonstrated higher response rates than other systemic therapies.

What 18F-FDG PET Response-Assessment Method Best Predicts Survival After Curative-Intent Chemoradiation in Non-Small Cell Lung Cancer: EORTC, PERCIST, Peter Mac Criteria, 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.

How we read FCH-PET/CT for prostate cancer.

Over the last decade, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) has gained in popularity for the staging and restaging of patients with prostate cancer (PCa). However, despite abundant literature on the topic, there is a lack of publications on how to actually interpret FCH-PET/CT in a clinical setting. Here we propose a practical, TNM-oriented approach to read FCH-PET/CT, with notes on procedure technique, image display, review sequence and report structure. The purpose of this article is to provide guidance to radiologists, nuclear medicine physicians and residents who are new to FCH-PET/CT, as well as to propose an alternate approach to more experienced physicians.