Peptide receptor radionuclide therapy in grade 3 neuroendocrine neoplasms: Safety and survival analysis in 69 patients

Abstract

To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of greater than 20%. The purpose of this study was to analyze the long-term outcome, efficacy, and safety of PRRT in patients with somatostatin receptor (SSTR)–expressing G3 NENs. Methods: A total of 69 patients (41 men; age, 28–81 y) received PRRT with 177 Lu- or 90 Y-labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitizing chemotherapy. Kaplan–Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT, including a subgroup analysis for patients with a Ki-67 index of less than or equal to 55% and a Ki-67 index of greater than 55%. Treatment response was evaluated according to RECIST 1.1 as well as molecular imaging criteria (European Organization for Research and Treatment of Cancer). Short- and long-term toxicity was documented (Common Terminology Criteria for Adverse Events, v 5.0) using a structured database (comprising .250 items per patient) and retrospectively analyzed. Results: Forty-six patients had pancreatic NENs, 11 had unknown primary cancer, 6 had midgut NENs, 3 had gastric NENs, and 3 had rectal NENs. The median follow-up was 94.3 mo. The median PFS was 9.6 mo, and the median OS was 19.9 mo. For G3 NENs with a Ki-67 index of less than or equal to 55% (n 5 53), the median PFS was 11 mo and the median OS was 22 mo. Patients with a Ki-67 index of greater than 55% (n 5 11) had a median PFS of 4 mo and a median OS of 7 mo. For patients with positive SSTR imaging but no 18 F-FDG uptake, the median PFS was 24 mo and the median OS was 42 mo. A significant difference was found for both PFS and OS, with median PFS of 16 mo and 5 mo and median OS of 27 mo and 9 mo for an SUV max of greater than 15.0 and an SUV max of less than or equal to 15.0, respectively, on SSTR PET. In the group with 18 F-FDG uptake scored as 3 or 4, the median PFS was 7.1 mo and the median OS was 17.2 mo. In the group with 18 F-FDG uptake scored as 0–2, the median PFS was 24.3 mo and the median OS was 41.6 mo. PRRT was well tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred, and no clinically significant decline in renal function was observed. There was no hepatotoxicity. Conclusion: PRRT was tolerated well, without significant adverse effects, and was efficacious in G3 NENs; the clinical outcome was promising, especially in patients with a Ki-67 index of less than or equal to 55% and even in patients for whom chemotherapy had failed. Baseline 18 F-FDG along with SSTR molecular imaging was useful for stratifying G3 NEN patients with high uptake on SSTR PET/CT and no or minor 18 F-FDG avidity—a mismatch pattern that was associated with a better long-term prognosis.