Abstract
BackgroundNeuroendocrine 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 (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE.MethodsThe HEPAR PLUS trial (“HolmiumEmbolizationParticles forArterialRadiotherapyPlus177Lu-DOTATATE inSalvage 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 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-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 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry.DiscussionThis is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects.Trial registrationClinicaltrials.gov NCT02067988, 13 February 2014. Protocol version: 6, 30 november 2016.
Highlights
Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin
The beneficial effect of additional 166Holmium isotope (166Ho)-RE within 12 weeks after systemic 177Lutetium isotope (177Lu)-DOTATATE will be investigated. Combining these treatments may lead to an improved response rate for liver metastases, with acceptable and suppressible side effects, which may eventually lead to prolonged survival
A cumulative liver dose of 2– 12 Gy was described after peptide receptor radionuclide therapy (PRRT)
Summary
In accordance with the most recent WHO/ENETS criteria, grade 1 and 2 neuroendocrine tumours (G1-/G2NET) are regarded as well- to moderately-differentiated tumours and grade 3 NET (G3NET) as poorly-differentiated NET or neuroendocrine carcinomas (NEC) [1, 2]. Rectal NET has a slim chance of distant metastasis (5%) compared with pancreatic or colonic NET (respectively 64% and 53–86%) [3, 5] Considering these numbers, many patients will be ineligible for curative treatment, which currently only includes surgical resection of the primary tumour. Most systemic therapies have a limited objective response rate This indicates a need for improved treatment of extensive liver disease. It is hypothesized that improved outcome can be obtained by escalating the treatment of liver metastases, the most significant prognostic factor for NET patients, additional to treatment of all extrahepatic disease in G1-/ G2NET patients, by combining systemic PRRT with RE.
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