Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Ulrike Garske-Román,Hans Lundqvist,Katarzyna Fröss Baron,Staffan Welin,Silvia Johansson,Per Hellman,Barbro Eriksson,Lars Lundin,Dan Granberg,Mattias Sandström,Anders Sundin,Tanweera Khan

doi:10.1007/s00259-018-3945-z

Abstract

PurposePeptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.MethodsThe study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3–20% in 121 (60.5%) and >20% in 16 (8%).ResultsIn 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22–30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39–53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.ConclusionsDosimetry-based therapy with 177Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Highlights

When Peptide receptor radionuclide therapy (PRRT) became available in Sweden, the legal demand for individualized planning of radiotherapy necessitated the development of dosimetry procedures suitable for use under clinical conditions [15,16,17,18,19,20]
One patient with pancreatic neuroendocrine tumours (NETs) received a tenth cycle upon reaching the 23 Gy level after a favourable response in order to reach a tumour burden qualifying him for surgery of his primary tumour, which was performed several months after the last cycle
To prescribe tumour doses in PRRT, as in external beam radiation, is not possible, but the present results indicate that the absorbed dose to the kidneys can serve as a substitute for tumour dose and the tolerance of the individual patient

Summary

Introduction

Peptide receptor radionuclide therapy (PRRT) has been used successfully in patients with neuroendocrine tumours (NETs) for two decades [1,2,3,4,5]. 177Lu-DOTA-octreotate [5,6,7,8,9], different 90Y–labelled peptides [10,11,12,13,14] and combinations of both have been used. 177Lu-DOTA-octreotate has usually been administered according to a standard protocol with four cycles of 7.4 GBq [5, 8, 9]. Peptide receptor radionuclide therapy (PRRT) has been used successfully in patients with neuroendocrine tumours (NETs) for two decades [1,2,3,4,5]. The organs at risk are the kidneys and bone marrow, with a growing body of data demonstrating higher nephrotoxicity with 90Y–labelled peptides using several schedules [11, 14, 21] than with 177Lu-DOTA-octreotate [5, 22,23,24]. From dosimetry data compiled in our department we concluded that about 50% of patients might be undertreated and able to receive more than 4 × 7.4 GBq of 177Lu-DOTA-octreotate before reaching either 23 Gy to the kidneys or 2 Gy to the bone marrow [17]

Methods

Results

Discussion

Conclusion