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 (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)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 (111)In-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.

Figure 1

Complete remission. Maximum intensity projections of initial and follow-up examinations with ⁶⁸Ga-DOTATOC (DOTA⁰-d-Phe¹-Tyr³-octreotide) positron emission tomography (PET). A patient presented with 12 neuroendocrine liver metastases as diagnosed with magnetic resonance imaging (MRI) and ⁶⁸Ga-DOTATOC-PET. (a) After each cycle of intra-arterial radiopeptide therapy regression of the metastases was observed (b and c). After three cycles complete remission was demonstrated both in MRI and DOTATOC-PET (d). A fourth cycle was performed for consolidation and the complete remission is still present with 27 months of follow-up.

Figure 2

Partial remission. Patient with multiple neuroendocrine liver metastases before (upper row) and after (lower row) one cycle of intra-arterial therapy with 4 GBq ⁹⁰Y- and 4 GBq ¹⁷⁷Lu-labeled DOTATOC. DOTATOC-PET is presented as maximum intensity projections (left) and with contrast enhanced MRI follow-up studies. Serum chromogranin A decreased by 90%.

Figure 3

Waterfall graph demonstrating the radiologic response. Treatment induced changes in sum of the diameter of up to five liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 criteria of 15 patients (patient numbering corresponding to Table 1). Overall response (complete and partial remission) was observed in nine of the 15 patients (60%).

Figure 4

Pharmacokinetics. Tumoral time-activity-curves for 20 min intra-arterial versus i.v. infusion of ¹¹¹In-DOTATOC. Arterial infusion leads to a higher slope in the initial phase, but after 10 min the slope decreases due to saturating effects and is followed by a washout phase. In contrast, the i.v. infusion uptake demonstrates a nearly linear slope and continues to increase after the infusion is stopped.