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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Gastrointestinal Carcinoid Tumor, Islet Cell Tumor, Metastatic Cancer

Intervention / Treatment
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* Drug: PVA microporous hydrospheres/doxorubicin hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver metastases, metastatic gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor, islet cell carcinoma, gastrinoma, insulinoma, glucagonoma, pancreatic polypeptide tumor, somatostatinoma