Integrated Imaging Strategy to Phenotype Progression of Liver Tumors During and After Chemoembolization

Background

• TACE is the standard therapy for inoperable primary liver cancers or tumor control prior to transplantation. The mechanisms for TACE s failure remains poorly understood.
• Although acute hypoxia and significant tumor necrosis occurs following TACE, the tumor adaptive response and localization for such have not been well characterized.
• Imaging tools using a hypoxia-specific tracer [(18)F] FMISO may help identify the pattern and distribution of acute post-TACE tumor hypoxia relative to demonstrated tumor progression.
• The primary hypothesis of this study states that tumor progression post-TACE arises from changes in tumor phenotype induced by treatment-related hypoxia superimposed on the dynamic process of underlying tumor hypoxia.

Objectives

-To determine the feasibility of hypoxic tumor identification despite relatively high liver background signal, and describe patterns of tumor hypoxia in the immediate post-TACE treatment period using PET imaging [(18)F] MISO uptake registered with cross-sectional imaging.

Eligibility

• Patients greater than or equal to 18 years with inoperable primary hepatic malignancy or hepatic-dominant metastatic-disease and be otherwise eligible to receive TACE treatment. Patients with hepatocellular carcinoma should have intermediate stage disease according to the BCLC staging system (Stage A4 or B).
• Patients must not have had chemotherapy- or radiation therapy to liver for at least 2 weeks prior to starting study treatments.
• Patients must not have an acute, critical illness.
• Patients must not be pregnant
• Able to understand and be willing to sign a written informed consent

Design

• Fifteen patients with primary or metastatic liver malignancy will be enrolled into this pilot, non-randomized, open study of the feasibility of using (18)F-fluoromisonidazole PET scanning to determine hypoxic tumor identification and localization, and to identify the pattern and distribution of acute post-TACE tumor hypoxia relative to demonstrated tumor progression.
• Twenty-four to seventy-two hours after standard of care TACE, patients will undergo

PET scanning using 0.1mCi/kg (maximum 10mCi) of (18)F-fluoromisonidazole [(18)F] MISO).

• INCLUSION CRITERIA:
• Patients must have confirmed inoperable primary hepatic malignancy or hepatic dominant metastatic - neoplastic disease evidenced by histology or cytology, or characteristic enhancement pattern on CT or MRI together with an abnormal serum alpha-fetoprotein >200mg/dl in the case of hepatocellular carcinoma.
• Patients with hepatocellular carcinoma should conform to intermediate stage disease according to the BCLC(16) staging system (Stage A4 or B) and be otherwise eligible to receive TACE treatment.
• Patients must have had no chemotherapy or radiotherapy to the liver therapy for, their malignancy for at least 2 weeks (or until response can be adequately assessed) prior to treatment and must have recovered from all clinically significant side effects of therapeutic and diagnostic interventions.
• Serum creatinine less than or equal to 2.0 mg/dl unless the measured creatinine clearance is greater than 60ml/min
• Age greater than or equal to18 years
• Ability of subject to understand and willingness to sign a written informed consent document
• Patient must be able to lie still for the procedure
• ECOG status less than or equal to 2
• In addition, for patients receiving TACE outside NIH:

• Patient must have physician willing to collaborate with NIH PI by providing required medical record and digital MR/ CT scan documentation pre and post TACE procedure.
• Patient must be willing to sign an Authorization for the Release of Medical Information form

Exclusion criteria

• Patients who have received prior TACE treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to misonidazole or other agents used in study.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients of childbearing age must not be pregnant. The effects of [(18)F]FMISO on the developing human fetus are unknown. Pregnancy is a contraindication for TACE.