Microparticle Enhanced Cytotoxic Transarterial Embolization Therapy

Colon or rectal carcinoma that has spread to the liver is considered to be metastatic and is a Stage IV cancer. If the metastasized tumor is unresectable, the only current treatment is chemotherapy. Transarterial Chemoembolization (TACE) is considered as a palliative treatment in advanced metastatic colorectal carcinoma (mCRC), with the potential of local tumor control. TACE has evolved in the past 8 years to include drug-delivery devices that can target and deliver drugs from small microparticles (DEB-TACE). Superselective DEB-TACE has the potential to penetrate deeper into the tumor's vasculature to reach peripheral growing points. Loading these microparticles with a cytotoxic drug may improve the level of local tumor control.

The MIRACLE III study is a controlled, pilot, single center (Italy) study on 18 subjects with pretreated non-resectable mCRC.

Inclusion criteria

• Male or Female, age >18 yrs who have histologically confirmed adenocarcinoma of the colon or rectum (Stage IV)
• Presence of metastatic disease with liver as dominant disease-site defined as >80% tumor body burden confined to liver; less than 60% liver tumor replacement.
• Subject is competent and willing to provide written informed consent in order to participate in the study.
• Eastern Cooperative Oncology Group (ECOG) performance status is 0-1 or Child-Pugh classification is A or B7.
• Multinodular or single nodular tumor 4 cm, patients with bilobar disease who can be treated superselectively in a single session or both lobes able to be treated within 3 weeks. Patient must have at least one tumor lesion that meets the following criteria: lesion can be accurately measured in at least one dimension according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
• Pretreatment with two or more lines of chemotherapy containing Fluorouracil (5-FU) or analogue, oxaliplatin, irinotecan ± bevacizumab ±epidermal growth factor receptor (EGFR)-inhibitors, if indicated, for metastatic disease.
• No invasion in the blood vessel (hepatic portal, hepatic vein) or bile duct by the computerized axial tomography (CT) or Magnetic Resonance (MR) Imaging.
• Proper blood, liver, renal, heart function: testing result within 2 weeks from registry of this study as follows:

• White Blood Cell (WBC) >3,000 cells/mm3
• Absolute neutrophil count ≥1500/mm3
• International Normalized Ratio (INR) <2.0
• Partial Thromboplastin Time (PTT) <40 sec
• Platelet count >50,000/mm3
• Blood bilirubin <3.0 mg/dL
• Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) is within 5 times of normal range of each organ
• Serum creatinine <1.5 mg/dL
• Hemoglobin >8.0 g/dL
• Alkaline phosphatase <630 IU/L
• No unstable coronary artery disease or recent Myocardial Infarction(MI)
• Normal electrocardiogram (ECG) with QT interval <480 msec within the previous 12 months
• No current infections requiring antibiotic therapy
• Not on anticoagulation or suffering from a known bleeding disorder.
• Measureable disease per mRECIST.
• Expected survival more than 3 months

Exclusion criteria

• ECOG performance status >2; or Child-Pugh class>11 points or more, or American Society of Anaesthesiologists' (ASA) class 5 .
• Bilirubin levels >3 mg/dL
• mCRC within the large vessel or biliary duct invasion, diffuse hepatocellular carcinoma (HCC) or extrahepatic spread.
• Patients in which any of the following are contraindicated or present:

• The use of irinotecan
• MRI or CT scans
• Hepatic embolization procedures
• WBC <3000 cells/mm3
• neutrophil <1500 cells/mm3
• Cardiac ejection fraction <50% assessed by isotopic ventriculography, echocardiography or MRI
• Elevated serum creatinine ≥ 2.5 mg/dL
• Impaired clotting test (platelet count < 50,000/mm3, PT-INR >2.0
• AST and/or ALT >5x upper limit of normal (ULN), when greater >250 U/I
• Known hepatofugal blood flow.
• Arterio-venous shunt
• Arterio-portal shunt
• Main stem portal vein occlusion
• Women who are pregnant or nursing
• Allergy to iodinated contrast used for angiography
• Tumour burden of more than 50% of liver volume (Tumor volume by be smaller e.g. ≤30%)
• Patients with active bacterial, viral (HIV), or fungal infection.
• Other malignancies
• Any co-morbid disease or condition or event that, in the investigator's judgment, would place the patient a undue risk what would preclude the safe use of DEB-TACE.