Embolization Therapy with or without Chemotherapy in Controlling Liver Metastases in Patients with Neuroendocrine Tumor Metastases to the Liver That Cannot Be Removed by Surgery

This randomized phase II trial studies how well embolization therapy with or without chemotherapy works in controlling liver metastases in patients with neuroendocrine tumors which have spread to the liver and cannot be removed by surgery. Embolization therapy injects tiny particles with or without chemotherapy drugs into the arteries feeding tumors to cut off their blood supply. Embolization with chemotherapy, such as doxorubicin hydrochloride and mitomycin or doxorubicin-eluting beads, may kill more tumor cells by allowing a higher concentration of the drug to reach the tumor for a longer period of time. It is not yet known if there are differences in quality of life, side effects, or safety among these types of embolization therapy or if any one type will provide longer-lasting control of tumors in the liver.

Inclusion Criteria

• Biopsy-proven neuroendocrine tumor
• Measurable metastasis to liver with at least one dimension >= 1.0 cm
• Tumor burden dominant in the liver AND liver tumor burden less than or equal to 70% of the total liver volume by visual estimate
• Not a candidate for surgical resection based on unresectability, anatomy, anesthesia risk, patient preference
• Symptoms uncontrolled by somatostatin analogues OR morphologically progressive tumor by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in the liver OR baseline tumor burden > 25% of the liver volume
• There must be no plans for the patient to receive other concomitant therapy while on this protocol treatment (other than somatostatin analogs or bone-strengthening agents)
• Presence of hepatopetal flow
• Performance status 0-2 on Zubrod/Eastern Cooperative Oncology Group (ECOG) performance scale
• Serum creatinine =< 2.0 mg/dl
• Serum bilirubin =< 2.0
• Serum albumin >= 3.0
• Platelet count >= 50,000/ul (corrected if needed)
• International normalized ratio (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 in accordance with institutional and federal guidelines prior to study entry

Exclusion Criteria

• Pregnant or lactating women may not participate; 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 one month beyond prior chemotherapy, peptide receptor radionuclide therapy (PRRT), ablation or surgery, and 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 (history [Hx] of significant previous contrast reaction, not mitigated by appropriate pre-medication)
• 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

PRIMARY OBJECTIVES:

I. To estimate the duration of hepatic progression-free survival (HPFS) in participants treated with bland embolization (BE), transcatheter arterial lipiodol chemoembolization (TACE), and embolization by drug-eluting beads (DEB).

SECONDARY OBJECTIVES:

I. To compare the interval between cycles of embolotherapy among the arms.

II. To estimate the symptom-free interval for patients with tumor-related symptoms among the arms using the Carcinoid Symptom Severity Scale.

III. To compare patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core 30 [QLQ30] & Gastrointestinal Neuroendocrine Tumors 21 [GINET21]) among the arms.

IV. To compare toxicities and adverse events among the arms.

V. To compare progression-free survival and duration of symptom control in patients with carcinoid versus islet-cell sub types and for grade (G)1 vs. G2 histology.

VI. To identify biomarkers (imaging, serum and symptom) of treatment effect in all arms.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients undergo 1-3 lobar or segmental bland embolizations with tris-acryl gelatin microspheres depending upon the number and location of tumors every 4-8 weeks.

ARM II: Patients undergo 1-3 lobar or segmental transcatheter arterial lipiodol chemoembolizations with doxorubicin hydrochloride depending upon the number and location of tumors every 4 weeks.

ARM III: Patients undergo 1-3 lobar or segmental hepatic chemoembolizations with drug-eluting beads (DEB) loaded with doxorubicin depending upon the number and location of tumors every 4-8 weeks.

In all arms, treatment repeats every 4-8 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with intrahepatic progression may receive additional embolization therapy for another cycle or switch to another therapy.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Michael C. Soulen

• Primary ID UPCC 01215
• Secondary IDs NCI-2016-00610
• Clinicaltrials.gov ID NCT02724540