2005

Mayo Clinic to Study Early Marker for Liver Cancer

Points to Remember

• Hepatocellular carcinoma (HCC) is one of the 10 leading causes of cancer death in the United States and the third leading cause of cancer death worldwide.
• In the past 25 years, the incidence of HCC in the United States has doubled. An accurate biomarker that detects liver cancers early when they are most treatable would improve patient prognoses.
• Mayo Clinic and 5 other US institutions have been selected to participate in a National Institutes of Health-sponsored clinical trial of the diagnostic utility of the biomarker des-y-carboxy prothrombin (DCP) in the early detection of HCC. Mayo Clinic is currently enrolling patients in this study.

Scope of Problem

Hepatocellular carcinoma (HCC) is one of the 10 leading causes of cancer death in the United States and the third leading cause of cancer death worldwide. Mortality attributable to HCC has not improved during the past 20 years. One explanation for the poor survival in patients is the poor performance of available tumor markers, which leads to delays in diagnosis. Eighty percent of patients initially present with advanced disease, and of these, only 2% to 6% survive 5 years. About 17,550 new cases of HCC have been diagnosed in the United States in 2005. It is one of the few cancers in the United States with an increasing number of cases, and the number of cases is expected to continue to increase during the next 2 decades, due in large part to the steady increase of cases caused by hepatitis C virus infection. The rise in obesity and associated hepatic steatosis that can lead to cirrhosis also appears to contribute to the increase of primary liver cancer. In 80% to 90% of patients, HCC is associated with cirrhosis.

Patients with HCC, as those with other cancers, have a better prognosis when they present with early disease. The 10% to 20% of patients who have early disease at the time of diagnosis have a 5-year survival rate higher than 50%, yet current screening methods have low sensitivity. This is especially true for detecting the small cancers that are most responsive to treatment. Treatment options for early disease consist of liver transplantation, surgical resection, percutaneous ethanol injection, radiofrequency ablation, and hepatic artery chemoembolization or radioembolization. Systemic or infusional chemotherapy is generally not effective. Treatments targeted at molecular pathways that support tumor growth are currently under investigation.

Current Diagnostic Approaches and Limitations

The α-fetoprotein (AFP) is the most widely used biochemical blood test for surveillance of liver cancer. AFP is a protein normally made by immature liver cells in the fetus. In adults, AFP levels higher than 200 ng/mL usually indicate HCC; increased AFP levels of up to 200 ng/mL are often indicative of chronic hepatitis or other forms of liver damage. A notable drawback to the utility of AFP as a screening test for HCC is that it has limited sensitivity for small cancers -- about 20% to 30%. Thus, 70% to 80% of patients with small HCCs have normal or indeterminate AFP levels (false-negative test results). The upshot is that a person can have early HCC and a falsely normal or indeterminate AFP reading. A person also can have an elevated AFP but not have liver cancer. Because of these issues, new international guidelines do not support the use of AFP in HCC screening. Liver ultrasonography can be helpful in early detection of HCC, but its efficacy depends on the skills and knowledge of the technician and the patient's anatomy, which also can lead to falsenegative results.

A New Approach

An accurate and sensitive biomarker that could reliably detect primary liver cancer at an early stage would be an important advance in patient care. One promising substance is des-y-carboxy prothrombin (DCP). DCP is a protein precursor of prothrombin, one of the clotting factors produced by the liver. In patients with liver cancer, this protein seems to be elevated compared with levels in patients without liver cancer. Early studies have shown that DCP is more specific and sensitive than AFP for predicting the diagnosis of liver cancer and has close to 90% accuracy. Its potential now needs to be validated with further studies, and Mayo Clinic is one of 6 US medical centers evaluating the clinical utility of DCP as part of a 2-year National Cancer Institute (NCI) study.

Nationwide, the validation study will enroll 450 patients with a diagnosis of HCC; of these, at least 170 will have early-stage liver cancer. An additional 450 patients with cirrhosis, but no cancer, will serve as controls. Of the total number of patients, Mayo Clinic will enroll about 100 study subjects and 100 controls. Validation — proving that the measurement of a substance accurately signifies the risk for or presence of cancer — is the critical step to creating a truly useful test. The 5 other medical centers involved in the DCP validation study are the University of Michigan, Ann Arbor; Mount Sinai University Hospital, New York; University of Pennsylvania, Philadelphia; Saint Louis University, St. Louis, Missouri; and Stanford University, Stanford, California.

About DCP

DCP has been documented in several studies to be more sensitive and specific than AFP as a marker for the diagnosis of HCC. A 2003 University of Michigan case-control study looked at 207 patients to determine whether DCP is more sensitive and specific than AFP for differentiating HCC from nonmalignant liver disease. Four groups were studied: normal healthy subjects,patients with noncirrhotic chronic hepatitis,patients with compensated cirrhosis, and patients with histologically proven HCC. Results showed that DCP was more sensitive and specific than AFP for differentiating HCC from nonmalignant chronic liver disease.

Enrollment Inclusion Criteria

For inclusion in the DCP early biomarker study, HCC patients must be at least 18 years old. The diagnosis of HCC is based on either histologic evidence (required if the patient has only 1 lesion smaller than 2 cm) or 2 imaging tests, with at least 1 test (CT, MRI, or angiography) within the past 3 months showing evidence of arterial hypervascularization and the other within the past 6 months (ultrasonography, CT, or MR angiography) indicating a mass in the liver.