Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival

S Rudisile,F J Gildehaus,G Böning,H Ilhan,M Unterrainer,C Spitzweg,P Bartenstein,C J Auernhammer,W P Fendler,A Gosewisch,A Todica,V Wenter

doi:10.1186/s12885-019-6000-y

Abstract

BackgroundNETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression.MethodsThirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method.ResultsThe median PFS after initial PRRT was 33 months (95% CI: 30–36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5–47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0–16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92–119) and 51 months (95% CI: 41–61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively.ConclusionsSalvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.

Highlights

NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized Neuroendocrine tumors (NET)
In the prospective Phase 3 trial NETTER-1 the combination of 177LuDOTATATE and 30 mg octreotoide LAR demonstrated longer Progression free survival (PFS) and Overall survival (OS) in midgut NET patients compared to 60 mg octreotide LAR alone [9], which led to the approval of Lutathera® (177Lu-DOTA-D-Phe-Tyr3-octreotate) by the U.S Food and Drug Administration (FDA) and the European Medicines Agency (EMA)
All patients fulfilled the inclusion criteria for PRRT according to current guidelines [10, 11]. 68Ga-DOTATATE positron emission tomography / computed tomography (PET/CT) was performed in each patient to determine sufficient uptake of somatostatin-analogs prior to PRRT

Summary

Introduction

NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. In the prospective Phase 3 trial NETTER-1 the combination of 177LuDOTATATE and 30 mg octreotoide LAR demonstrated longer PFS and OS in midgut NET patients compared to 60 mg octreotide LAR alone [9], which led to the approval of Lutathera® (177Lu-DOTA-D-Phe-Tyr3-octreotate) by the U.S Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Several studies indicate that additional PRRT cycles using 177Lu-DOTATATE in the so called salvage therapy setting are feasible, safe and effective [12,13,14,15]

Methods

Results

Discussion

Conclusion