177Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors: Data From the Prospective Phase 2 LUMEN Study.

PURPOSE: The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177Lu-DOTATATE. PATIENTS AND METHODS: Thirty-seven patients with GEP-NETs underwent 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. RESULTS: The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% (P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. CONCLUSIONS: This study confirms the safety profile of 177Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.

Prediction of 177Lu-DOTATATE PRRT Outcome Using Multimodality Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Results from a Prospective Phase II LUMEN Study.

Our objective was to predict the outcome of peptide receptor radionuclide therapy (PRRT) using multimodality imaging and tumor dosimetry on gastroenteropancreatic neuroendocrine tumor (GEP-NET) lesions and patients. Methods: This prospective study included patients with progressive GEP-NETs. Treatment consisted of 4 cycles of 7.4 GBq of 177Lu-DOTATATE. Imaging parameters were measured on 68Ga-DOTATATE PET/CT (SUVmax/mean, somatostatin receptor [SSTR] tumor volume [TV], total lesion SSTR expression, and tumor-to-blood and tumor-to-spleen ratios), 18F-FDG PET/CT (SUVmax/mean, metabolically active TV, and total lesion glycolysis), and diffusion-weighted MRI (apparent diffusion coefficient) in a maximum of 5 target lesions per patient at approximately 10 wk after each injection. Tumor dosimetry was performed using SPECT/CT at 3 time points for every cycle. Baseline imaging parameters, their relative changes after PRRT cycle 1 (C1), and the tumor-absorbed dose at C1 were correlated with lesion morphologic outcome. The average values of the imaging parameters and the minimal, maximal, and mean C1 tumor-absorbed dose in each patient were tested for association with progression-free survival (PFS) and best objective response (RECIST 1.1). Results: In the 37 patients, the median PFS was 28 mo. Eleven of the 37 (30%) achieved a partial response (RECIST 1.1). After a median follow-up of 57 mo, the median time to lesion progression had not been reached in 84 morphologically evaluable lesions, with only 12 (14%) progressing (size increase ≥ 20% from baseline). Patients receiving a minimal C1 dose of 35 Gy in all target lesions exhibited a significantly longer PFS (48.1 vs. 26.2 mo; hazard ratio, 0.37; 95% CI, 0.17-0.82; P = 0.02). Volumetric 68Ga-DOTATATE PET parameters correlated with lesion and patient outcome: patients with an SSTR TV decrease of more than 10% after C1 had a longer PFS (51.3 vs. 22.8 mo; hazard ratio, 0.35; 95% CI, 0.16-0.75; P = 0.003). There was no statistical evidence of an association between other dosimetric or imaging parameters and the lesion or patient outcome. Conclusion: Minimal tumor-absorbed dose at C1 is predictive of outcome in patients with GEP-NETs treated with PRRT, providing a basis for personalized dosimetry-guided treatment strategies. An SSTR TV decrease after C1 could be used for early therapy response assessment as a predictor of PRRT outcome.

Prognostic value of a three-scale grading system based on combining molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias.

We investigated on the added prognostic value of a three-scale combined molecular imaging with 68Ga-DOTATATE and 18F-FDG PET/CT, (compared to Ki-67 based histological grading), in gastroenteropancreatic neuroendocrine neoplasia patients. 85 patients with histologically proven metastatic gastroenteropancreatic neuroendocrine neoplasias, who underwent combined PET/CT imaging were retrospectively evaluated. Highest Ki-67 value available at time of 18F-FDG PET/CT was recorded. Patients were classified according to World Health Organization/European Neuroendocrine Tumor Society histological grades (G1, G2, G3) and into three distinct imaging categories (C1: all lesions are 18F-FDG negative/68Ga-DOTATATE positive, C2: patients with one or more 18F-FDG positive lesions, all of them 68Ga-DOTATATE positive, C3: patients with one or more 18F-FDG positive lesions, at least one of them 68Ga-DOTATATE negative). The primary endpoint of the study was Progression-Free Survival, assessed from the date of 18F-FDG PET/CT to the date of radiological progression according to Response Evaluation Criteria In Solid Tumors version 1.1. Classification according to histological grade did not show significant statistical difference in median Progression-Free Survival between G1 and G2 but was significant between G2 and G3 patients. In contrast, median Progression-Free Survival was significantly higher in C1 compared to C2 and in C2 compared to C3 patients, revealing three distinctive imaging categories, each with highly distinctive prognosis. Our three-scale combined 68Ga-DOTATATE/18F-FDG PET imaging classification holds high prognostic value in patients with metastatic gastroenteropancreatic neuroendocrine neoplasias.