Doxorubicin Beads in Treating Patients With Unresectable Liver Metastases From Neuroendocrine Tumors

Treatment of Patients With Hepatic Neuroendocrine Metastases Using Drug-Eluting Bead Embolization

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Infusing doxorubicin beads into the liver, and blocking blood flow to the tumor, may keep doxorubicin near the tumor and kill more tumor cells.

PURPOSE: This clinical trial is studying the side effects of doxorubicin beads and to see how well they work in treating patients with unresectable liver metastases from neuroendocrine tumors.

Study Overview

• Status: Terminated
• Conditions: Metastatic Cancer; Islet Cell Tumor; Gastrointestinal Carcinoid Tumor
• Intervention / Treatment: Drug: PVA microporous hydrospheres/doxorubicin hydrochloride

Detailed Description

OBJECTIVES:

Primary

• To gather preliminary data and determine the feasibility of a randomized study of patients with unresectable hepatic neuroendocrine metastases using PVA microporous hydrospheres/doxorubicin hydrochloride.

OUTLINE: A catheter is placed into the right or left hepatic artery. Patients with unifocal tumors will have the catheter or microcatheter placed more selectively into the 2nd or 3rd order branch off the right or left hepatic artery in closer proximity to the tumor. Polyvinyl alcohol (PVA) microporous hydrospheres/doxorubicin hydrochloride mixture is injected into the delivery area.

Patients with less than 75% necrosis at 1 month undergo a second (and possibly a third a month later) chemoembolization.

After completion of study therapy, patients are followed at 1 month, every 2 months for 1 year, and then every 3 months for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

Inclusion criteria:

• Diagnosis of hepatic neuroendocrine metastases not suitable for radical therapies (e.g., resection or liver transplantation)

  • Histologically proven neuroendocrine tumor
  • Tumors are hypervascular based on visual estimation by investigator

• Predominant to the liver disease, but extrahepatic disease is not an exclusion

  • No predominant extrahepatic liver disease
  • No significant life-threatening extrahepatic disease, in the judgment of the physician
• Recent-interval progression of hepatic liver metastases
• No diffuse hepatic neuroendocrine metastases defined as massive ill-defined tumor involvement measuring > 90% tumor burden

Exclusion criteria:

• Clinically evident ascites (a radiographic finding of trace ascites on imaging is acceptable)
• Complete occlusion of the entire portal venous system
• Evidence of cirrhosis or portal hypertension
• Vascular resistance peripheral to the feeding arteries precluding passage of PVA microporous hydrospheres/doxorubicin hydrochloride

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Must have preserved liver function (Child-Pugh class A-B) without significant liver decompensation

  • No advanced liver disease (e.g., Child-Pugh C class or active gastrointestinal bleeding, encephalopathy, or ascites [trace ascites is acceptable]), meeting the following criteria:

    • Bilirubin > 3 mg/dL
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase > 5 times upper limit of normal
    • Serum creatinine > 2.0 mg/dL
    • Albumin ≤ 2.0 g/dL
• No vascular anatomy or blood that precludes catheter placement or emboli injection
• No presence of arteries supplying the lesion not large enough to accept PVA microporous hydrospheres/doxorubicin hydrochloride
• No collateral vessel pathways potentially endangering normal territories during embolization
• No feeding arteries smaller than distal branches from which they emerge
• Not pregnant

Exclusion criteria:

• See Disease Characteristics
• Another active primary tumor

• Any contraindication for hepatic embolization procedures, including any of the following:

  • Porto-systemic shunt
  • Hepatofugal blood flow
  • Impaired clotting tests (i.e., platelet count < 50,000/mm³, international normalized ratio (INR) ≥ 1.8, or partial thromboplastin time (PTT) ≥ 39 seconds)
  • Renal failure
  • Severe peripheral vascular disease precluding catheterization
• Any contraindication for doxorubicin hydrochloride administration (i.e., serum bilirubin > 5 mg/dL or leukocyte count < 1,500 cells/mm³)
• Allergy to contrast media
• Intolerant to occlusion procedures
• Presence of end arteries leading directly to cranial nerves
• Presence or likely onset of hemorrhage
• Presence of severe atheromatous disease

PRIOR CONCURRENT THERAPY:

Exclusion criteria:

• Prior anticancer therapy for hepatic neuroendocrine metastases, except previous surgical therapy
• Any continuing complication or prior cancer therapy that has not improved or resolved prior to 21 days before start of treatment, if the investigator determines that the continuing complication will compromise the safety of the patient after treatment with PVA microporous hydrospheres/doxorubicin hydrochloride
• Presence of patent extra-to-intracranial anastomoses or shunts

• Use of PVA microporous hydrospheres/doxorubicin hydrochloride in the following applications:

  • Embolization of large-diameter arteriovenous shunts
  • Pulmonary arterial vasculature
  • Any vasculature where the use of PVA microporous hydrospheres/doxorubicin hydrochloride could pass directly into the internal carotid artery or the above-listed vessels
• Concurrent enrollment in another clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DEB-TACE; PVA microporous hydrospheres loaded with doxorubicin hydrochloride used for the treatment of unresectable liver metastases from neuroendocrine tumors.	Drug: PVA microporous hydrospheres/doxorubicin hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Number of CTCAE v3.0 Events 1 Month Post DEB-TACE	Safety was assessed at each DEB-TACE procedure and at every follow-up thereafter according to National Cancer Institute Common Toxicity Criteria (CTCAE) v3.0. The study was prematurely terminated due to high incidence of biloma and liver abscess. Safety data below is based off of 13 patients enrolled on protocol at 1 month post initial treatment.	1 month after initial DEB-TACE treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response (Efficacy) - by Response Evaluation Criteria in Solid Tumors (RECIST) and the European Association for the Study of the Liver (EASL) Criteria	Study was terminated and full outcome not assessed. The results below are based on 13 patients at 1 month post DEB-TACE, 10 patients at 6 months, and 6 patients at 12 months. RECIST: Complete Response (CR): Disappearance of all targeted lesions Partial Response (PR): At least 30% decrease in the sum of longest diameter (LD) of targeted lesions Progressive Disease (PD): At least 20% increase in the sum of LD of targeted lesions Stable Disease (SD): Cases that are not applicable for PD or PR. EASL: CR: Absence of any enhancement in target lesion PR: Greater than 50% decrease from baseline enhancement in target lesion PD: Greater than 25% increase in target lesion SD: All other cases	12 months
Survival	Survival outcomes not assessed due to premature termination of study.	overall survival
Biochemical Response - Time to Progression	Biochemical response not assessed due to premature termination of study.	Time to progression, 12 months
Symptomatic Response by Assessing Symptom Severity in Patients	Symptomatic response not assessed due to premature termination of study. Scoring system for assessing symptom severity in patients with neuroendocrine/carcinoid syndrome was as follows: - No symptoms - Patient completely asymptomatic; - Mild symptoms - Patient with symptoms of diarrhea, flushing, or asthma up to 4 times weekly; - Symptoms impact daily living - symptoms of diarrhea, flushing, or asthma up 5-7 weekly; - Severe symptoms - multiple daily symptoms of diarrhea, flushing, or asthma; symptoms require significant reorganization of daily activities; - Disabling symptoms - Patient disabled by multiple attacks and severe symptoms; unable to leave home or requires hospitalization	Duration of study participation, average of 12 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jeffrey F. Geschwind, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• Bhagat N, Reyes DK, Lin M, Kamel I, Pawlik TM, Frangakis C, Geschwind JF. Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. Cardiovasc Intervent Radiol. 2013 Apr;36(2):449-59. doi: 10.1007/s00270-012-0424-y. Epub 2012 Jun 22.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (ACTUAL): June 1, 2014
• Study Completion (ACTUAL): June 1, 2014

Study Registration Dates

• First Submitted: August 7, 2008
• First Submitted That Met QC Criteria: August 7, 2008
• First Posted (ESTIMATE): August 8, 2008

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2017
• Last Update Submitted That Met QC Criteria: July 24, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: liver metastases; metastatic gastrointestinal carcinoid tumor; regional gastrointestinal carcinoid tumor; gastrinoma; insulinoma; glucagonoma; pancreatic polypeptide tumor; somatostatinoma; islet cell carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Pancreatic Diseases; Neuroendocrine Tumors; Adenoma; Pancreatic Neoplasms; Neoplasms; Neoplasm Metastasis; Gastrointestinal Neoplasms; Carcinoid Tumor; Adenoma, Islet Cell; Malignant Carcinoid Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: J0739 CDR0000601054; JHOC-J7039; JHOC-NA_000010736; JHOC-SKCCC-J7039