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. 2019 Mar;46(3):704-717.
doi: 10.1007/s00259-018-4158-1. Epub 2018 Sep 28.

Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours

W A van der Zwan  1 , T Brabander  2 , B L R Kam  2 , J J M Teunissen  2 , R A Feelders  3 , J Hofland  3 , E P Krenning  4 , W W de Herder  3
Affiliations

Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours

W A van der Zwan et al. Eur J Nucl Med Mol Imaging. 2019 Mar.

Abstract

Purpose: Therapy with [177Lu-DOTA,Tyr3]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [177Lu-DOTA,Tyr3]octreotate.

Methods: Patients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).

Results: The safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0-98.2). Median cumulative doses were 44.7 GBq (range 26.3-46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2-≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0-95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.

Conclusion: A cumulative dose of up to 60.5 GBq salvage PRRT with [177Lu-DOTA,Tyr3]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [177Lu-DOTA,Tyr3]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.

Keywords: Efficacy; Gastroenteropancreatic; Neuroendocrine; PRRT; Safety; Salvage.

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Conflict of interest statement

Conflicts of interest

E.P. Krenning is an advisor to Advanced Accelerator Applications, S.A., Saint-Genis Pouilly, France.

All other authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not describe any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Flow chart showing selection of the retreatment and (nonrandomized) control groups. Boxes with dashed lines indicate reasons and numbers of patients excluded from analysis. Boxes with bold lines indicate total numbers of patients available for safety/efficacy analysis and comparison. See text for reasons of final exclusion
Fig. 2
Fig. 2
Planar scintigraphy in a patient with metastasized well-differentiated pancreatic NET. a Images obtained 24 h after administration of 7.4 GBq of [177Lu-DOTA0,Tyr3]octreotate during the initial four cycles (I-PRRT) and two additional cycles (R-PRRT) after PD in the first half of 2015 show high uptake by somatostatin receptor-positive tumours. b Course of the tumour marker chromogranin A (CgA) during and after treatment with PRRT
Fig. 3
Fig. 3
PFS and OS in patients with bronchial NET and GEP-NET, midgut NET and pancreatic NET and in patients in the respective control groups. The PFS of the R-PRRT group, for comparison with the PFS in the control group, was obtained after I-PRRT, and thus does not include the additional PFS due to R-PRRT or RR-PRRT. The two groups had comparable PFS. The OS of the control group was obtained after I-PRRT plus unknown other treatment(s) and is compared with the cumulative OS in patients receiving I-PRRT, R-PRRT, RR-PRRT and unknown other treatment(s) obtained after the last salvage PRRT
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