Table 1 RETNET trial inclusion and exclusion criteria

• Participants aged 18 years and older

• Biopsy-proven neuroendocrine tumor with tumor burden dominant in the liver

• Measurable metastasis to liver with at least one dimension ≥1.0 cm. Known extrahepatic disease should be limited to lymph nodes of < 2 cm and/or any bone metastases.

• Liver tumor burden ≤ 70% of the total liver volume by visual estimate

• Not a candidate for surgical resection owing to unresectability, anatomy, anesthesia risk, patient preference

• Symptoms uncontrolled by somatostatin analogues OR morphologically progressive tumor by RECIST 1.1 criteria in the liver OR baseline tumor burden > 25% of the liver volume

• No plans for the patient to receive other concomitant therapy while on this protocol treatment (other than octreotide or bisphosphonate therapy)

• Performance status 0–2 on Zubrod performance scale

• Serum creatinine ≤ 2.0 mg/dl

• Serum bilirubin ≤2.0 mg/dl

• Serum albumin ≥3.0 g/dl

• Platelet count ≥ 50,000/μl (corrected if needed)

• INR ≤ 1.5 (corrected if needed)

• All patients must be informed of the investigational nature of this study and must sign a study-specific informed consent form in accordance with institutional and federal guidelines prior to study entry.

• Pregnant or lactating women may not participate, owing to the embryotoxic effects of protocol treatment.

• Women/men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

• Prior hepatic arterial therapy or hepatic radiation therapy. Prior surgical resection or ablation of liver metastases is acceptable. Patients must be at least 1 month beyond prior chemotherapy, PRRT, ablation, or surgery and must have recovered from all therapy-associated toxicities.

• Active infection (symptomatic bacterial and fungal infection, newly diagnosed and/or requiring treatment)

• Choledochoenteric anastomosis, transpapillary biliary stent, or sphincterotomy of duodenal papilla

• Absolute contraindication to intravenous iodinated contrast agent (history of significant previous contrast agent reaction not mitigated by appropriate premedication)

• Allergy to doxorubicin

• Contraindications to arteriography and selective visceral catheterization:

 ○ Severe allergy or intolerance to contrast media, narcotics, sedatives, or atropine

 ○ Bleeding diathesis not correctable by usual forms of therapy

 ○ Severe peripheral vascular disease precluding catheterization

• Contraindications to hepatic artery embolization:

 ○ Portal vein occlusion without hepatopedal collateral flow demonstrated by angiography or portal hypertension with hepatofugal flow

 ○ Hepatic encephalopathy