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.