The management of liver metastases in neuroendocrine neoplasms is challenging. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs (SSA) is one of the most promising therapeutic options. As liver is the most frequent site of metastatic disease, our project proposes to compare administration of radiolabeled SSA by arterial intrahepatic infusion (experimental approach) vs intravenous administration (conventional). Evaluation will be made by (i) comparing 68Ga-DOTA-peptides uptake after intra-hepatic versus intravenous route (imaging), (ii) by evaluating the safety of an additional intra-hepatic administration of therapeutic radiolabeled SSA (therapy).

Liver metastases of neuroendocrine tumors of gastro-entero-pancreatic origin are one of the most limiting factors of patient survival. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs (SSA) such as LUTATHERA® represents now a major therapeutic option. As far as these metastases are mainly perfused by the hepatic artery, it could be relevant to deliver the treatment by intra-hepatic route, in order to achieve a maximized dose to the tumour when compared with a systemic conventional administration, while also reducing kidney and bone marrow toxicity. By using radiolabeled SSA for imaging and therapy, the present project aims to compare the uptake of 68Ga-DOTA-peptides after intra-hepatic versus intravenous injections for targeted liver metastases, as well as for dose limiting organs (kidney, spleen, healthy liver, bone marrow) and extra-hepatic lesions if present. The investigators will also evaluate whether the intra-hepatic infusion of one treatment dose of LUTATHERA® after conventional treatment by 4 intravenous administrations, is safe.

Following 4 intravenous administrations of LUTATHERA® in GEP-NET with dominant liver metastases, patients who gave informed consent will be enrolled for 2 PET-scans, the first one after intra-hepatic injection of 68Ga-DOTA-peptides and the second one after intravenous injection for purpose of uptake comparison by 5 liver metastases chosen by radiologists on MRI.

In 10 patients who meet a predefined enhancement ratio of 3, a 5th dose of LUTATHERA® will be administered by intra-arterial hepatic injection. An average enhancement ratio of 3.75 is expected from intra-arterial injection compared to intravenous results. Those 10 patients will be evaluated for 177Lu-DOTA-peptide activity and residence time by SPECT/CT imaging.

Follow-up through 18 months will include clinical examination, MRI and CT scan, as usually performed in these clinical settings and progression

Inclusion Criteria:

• Histologically proven well differentiated neuroendocrine tumor (NET) of gastrointestinal or pancreatic origin (GEP).
• Patients are progressive after treatment with cold somatostatin analog (within 12 months according to RECIST), or as soon as the diagnosis is made in case of hepatic invasion > 50% without waiting for tumour progression
• Patient has received 4 standard of care LUTATHERA® cycles
• Liver Metastatic disease dominant or exclusive and assessable by RECIST 1.1, and not amenable to surgical resection after the last cycle
• ECOG performance status 0-2
• Adequate kidney and liver function: creatinine clearance ≥ 50 mL/min, ALT/AST ≤ 2,5x the upper limit of normal
• With no evidence of hematologic alteration after 4 LUTATHERA® cycles: hemoglobin ≥ 8 g/dL, neutrophils ≥ 1500/ mm3, platelets ≥ 75.000/mm3
• Age ≥ 18 years, no superior limit
• Contraception required in pre-menopausal female (Intrauterine device, Progestin Pills, Combined Oral Contraceptives, Monthly Injectables, Progestin Injectables, Combined Patch, Combined Vaginal Ring, Female Sterilization, Vasectomy, Implants) and men for at least 6 months after the last LUTATHERA ® injection.
• Patient´s signed written informed consent
• Patient affiliated to a social security system

Exclusion Criteria:

• Patients with complete response defined by the absence of lesion according to RECIST 1.1 realized during morphological imaging at inclusion (chest-abdomen-pelvis CT scan and hepatic MRI)
• No residual uptake according to standard 177-Lu scintigraphy performed in the clinical routine 24 hours after each LUTATHERA IV treatment
• Carcinoid heart disease (LVEF < 40%)
• Dominant or threatening extrahepatic metastases or that may affect vital prognosis
• Contraindications to intra-hepatic arterial infusion (coagulation disorders, portal thrombosis, intra-hepatic biliary tract dilatation, digestive or biliary anastomosis or fistula, cirrhosis (Child Pugh B8 or C…)
• Serum albumin <30 g/L unless prothrombin time is within the normal range.
• Heart failure, myocardial infarction, stroke, uncontrolled arterial hypertension under optimal treatment (≥ 160/95 mmHg), pulmonary embolism or revascularization procedure, unstable angina pectoris, uncontrolled cardiac arrhythmia, and clinically significant bradycardia during the last 12 months.
• Individuals under legal protection or unable of giving their informed consent
• Pregnancy or breast feeding
• Currently participating to another clinical research protocol
• Individuals under legal protection or unable of giving their informed consent
• MRI scan contraindicated
• LUTATHERA® contraindicated or toxicity during one of the IV administrations leading to a reduction or cancellation of the following dose