Study Comparing Radio Frequency Ablation Plus Chemotherapy and Chemotherapy Alone in Patients With Secondary Liver Metastases

A Prospective, Randomized, Active-Control, Multi-Center Study Assessing Overall Survival Using Chemotherapy With or Without Impedance-Based Radiofrequency Ablation for Subjects With Colorectal Cancer and Incurable Metastatic Liver Disease, Failing at Least First-Line Chemotherapy

The purpose of this study is to determine whether patients treated with Radiofrequency Ablation (RFA) in conjunction with chemotherapy have a better overall survival rate than patients treated with chemotherapy alone.

The American Cancer Society has estimated that colorectal cancer is the second leading cause of cancer related deaths, with 106,370 new cases diagnosed in 2004. Due to the unique nature of the hepatic circulatory system, with preferential portal venous drainage of the gastrointestinal tract, the liver is the most common site for metastatic tumor growth from a colorectal carcinoma. It is estimated that approximately 20% of patients diagnosed with colorectal cancer will present with liver involvement at the time of diagnosis, and 50% of patients will manifest metastatic involvement of the liver following resection of the primary colorectal cancer. Over one half of patients who die of colorectal cancer have liver metastases at autopsy.

The current "gold standard" in the treatment of isolated metastatic liver disease is curative hepatic resection. Only within the last 20 years has surgical resection become a viable option, as in the past it was considered unjustified due to high morbidity and mortality rates. The primary drawback to hepatic resection is the sheer number of patients for whom it is contraindicated. Only 10-20% of patients liver metastases are candidates for surgical resection, owing to factors such as tumor locations, size, extent of disease, and other medical co-morbidities.

Historically, in cases where hepatic resection was contraindicated, systemic chemotherapy was the only alternative treatment. In the last several years an increasing number of hepatic directed therapies have become available such as hepatic artery ligation, radiation, hepatic artery infusion of chemotherapy, chemoembolization, and mechanical ablation of the tumor(s).

One mechanical method of ablation involves the use of radiofrequency thermal technology, also called radiofrequency ablation (RFA). The RFA procedure involves inserting an RF electrode into the center of a hepatic tumor mass under ultrasonic or CT guidance. Radiofrequency energy is then applied through the electrode, causing a thermal injury to the surrounding tumor tissue. Currently there are two basic designs for monitoring inter-procedural progress during RFA; temperature monitoring of set points within the target tissue with thermocouples, or assessing the system-wide impedance of tissue adjacent to the deployed electrode tines. Radiofrequency ablation systems are comprised of three components: a radiofrequency generator, an active electrode, and dispersive electrodes.

To date no prospective multi-center trials have been completed which would conclusively demonstrate whether RFA is an effective adjunct to systemic chemotherapy with respect to advantages in median overall survival compared with chemotherapy alone. The primary objective of this trial is to determine overall survival for subjects with colorectal cancer and incurable metastatic liver disease who fail at least first line chemotherapy and are treated with radiofrequency ablation plus additional chemotherapy, compared to subjects receiving additional chemotherapy only.

Inclusion Criteria:

All subjects must meet the following criteria:

• Subject must have incurable metastatic colorectal cancer with metastatic disease to the liver
• Subject must have extrahepatic metastatic disease, as confirmed by radiographic evidence or surgical/other documentation that cannot be treated by surgery or image guided therapy to an endpoint of no evidence of residual disease by imaging criteria
• Subject has received and, in the opinion of the treating physician, progressed through at least one prior chemotherapy regimen for metastatic disease, or has developed recurrent disease on or within 6 months of completing adjuvant therapy
• At least 50% of the total tumor burden is in the liver, as determined by the treating investigator, and prior to any study specified intervention (resection or ablation).
• Subject must have no more than 10 hepatic tumors remaining after surgical resection, with no tumor exhibiting a unidimensional size greater than 5cm
• Subject is medically eligible to receive RFA, as determined by the treating investigator
• Subject is naïve to, and medically eligible (as defined by the treating investigator) to receive, at least one of the following:
• an oxaliplatin containing regimen
• an irinotecan containing regimen
• an anti-EGFR monoclonal antibody-containing regimen (subject must be naïve to both cetuximab and panitumumab)
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Age > 18 years
• Subject life expectancy > 3 months
• International Normalized Ratio (INR) < 2.0
• Platelets > 100 x103/mm3
• Total Bilirubin <1.5mg/dl
• Creatinine level < 2.0 mg/dl
• Must sign an Informed Consent form

Exclusion Criteria:

All subjects who meet any of the following criteria will not be enrolled into the study:

• Subjects's extrahepatic disease is amenable to curative surgical or image guided therapy
• Subject has known brain metastases
• Uncorrectable coagulopathy
• Subject is pregnant, nursing, or wishes to become pregnant during the study
• Other serious medical condition(s) (e.g. uncontrolled infection, uncontrolled cardiac disease) that, in the opinion of the treating investigator, would preclude study treatment or impact survival.
• Current or planned treatment with any experimental chemotherapy or biological agents