Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Abstract

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using 111In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of 90 Y-/ 177 Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

Targeted Radionuclide Therapy: Proceedings of a Joint Workshop Hosted by the National Cancer Institute and the Society of Nuclear Medicine and Molecular Imaging

“…Somatostatin receptors, including the 5 subtypes (1, 2a and 2b, 3, 4, and 5) have been well described in the literature, and numerous studies have reported on the characteristics and affinities of radiolabeled somatostatin analogs, including 111 In-DTPA-octreotide (Octreoscan; Mallinckrodt Pharmaceuticals), 90 (86,87). Studies have addressed response rates, outcomes, the role of imaging (particularly PET/CT with 68 Ga-DOTATOC) in guiding therapeutic management, and the relative effectiveness of different radiolabeled somatostatin receptor agents (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107). Concerns about renal toxicity were discussed, and the use of dose fractionation, amino acid infusions, radioprotectants, and other mitigating approaches were reviewed as a way to lessen adverse effects.…”

Management von Tumoren mit neuroendokriner Differenzierung

“…Ein interessanter Ansatz ist die intraarterielle Applikation der Radionuklidtherapie mit dem Ziel, am Metastasierungsort eine höhere Strahlendosis zu erzielen. Auch hier zeigen sich erste vielversprechende Ansprechraten, ohne dass die Toxizität erhöht scheint [20]. …”

Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy

“…Many strategies are being explored to try to improve on and optimise the effectiveness of PRRT: some of these strategies include intra-arterial treatments (to better target liver metastases) [11], using dosimetry to ensure adequate tumour dosing [12], combining 177 Lu-DOTA­TATE and 90 Y PRRT to target both small and large tumours [13], using chemotherapy as a PRRT radiosensitiser [14], a somatostatin receptor (SSR) antagonist PRRT (which has a higher SSR binding affinity) [15], and targeted alpha particle therapy (TAT) [16]. …”