Additional hepatic (166)Ho-radioembolization in patients with neuroendocrine tumours treated with (177)Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial)

BACKGROUND: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization ((166)Ho-RE) after PRRT with lutetium-177 ((177)Lu)-DOTATATE. METHODS: The HEPAR PLUS trial (“Holmium Embolization Particles for Arterial Radiotherapy Plus (177)Lu-DOTATATE in Salvage NET patients”) is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30–48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional (166)Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq (177)Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after (166)Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry. DISCUSSION: This is the first prospective study to combine PRRT with (177)Lu-DOTATATE and additional (166)Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using (166)Ho-RE may lead to an improved response rate without significant additional side-effects. TRIAL REGISTRATION: Clinicaltrials.gov NCT02067988, 13 February 2014. Protocol version: 6, 30 november 2016.