Hepatobiliary (Liver and Bile Ducts) Cancer

The liver is one of the largest organs in the body, filling the upper right side of the abdomen inside the rib cage. It has two parts, a right lobe and a smaller left lobe. The liver's role is to filter harmful substances from the blood so they can be passed from the body in stool and urine and convert nutrients into ready-to-use chemicals. It produces key proteins that control blood clotting, makes bile to help digest fats from food and stores glycogen (sugar), which the body uses for energy. Conditions such as cirrhosis, Hepatitis B or C, and hemochromatosis can increase the risk of developing liver cancer.

Mayo Clinic researchers are studying novel therapies for the diagnosis, treatment and prevention of liver and biliary cancers. Clinical trials typically involve the study of new drugs that show promise in slowing the growth of tumors. GI Program researchers are conducting studies of liver cancer patients with the goal of identifying the natural history of liver cancer and the best treatment protocols, as well as testing new medications for viral hepatitis and other chronic liver diseases.

Mayo Clinic's research in the area of liver cancer is multi-faceted. Our scientists are investigating the causes of liver cancer, ways to detect it early, prevent it, and improve treatment. Some key areas of research include:

Prevention and Detection
Researchers are looking at ways to prevent or treat hepatitis before it causes liver cancer. Progress is being made in treating chronic hepatitis with drugs that make the patient's immune system stronger. Scientists are studying new blood tests that will reveal liver cancer earlier. Investigators Lewis Roberts, M.D., and Denise Harnois, D.O., are participating in a National Cancer Institute study to evaluate a new biomarker called des-γ-carboxy prothrombin as a diagnostic marker for liver cancer.

Treatment
New methods of surgery to remove the cancer from the liver are also being studied. Shrinking the cancer before surgery has shown some promising results, as has laparoscopic surgery to treat liver cancer. One exciting area of research led by Ricardo Paz-Fumagalli, M.D., involves putting radioactive microspheres into the artery that goes to the liver. This way the treatment goes directly to the tumors.

Newer forms of chemotherapy are being combined with new drugs that target specific growth pathways in the cancer cell and kill it. Another way researchers are trying to improve the effectiveness of therapy is by administering chemotherapy agents straight into the hepatic artery, which supplies most tumors. The healthy liver then removes most of the remaining drug before it can reach the rest of the body.

Scientists are learning more about many of the genes that are damaged when normal cells become cancerous. Clinical trials are in progress to study this type of treatment as well as the side effects and short and long-term results.

Ongoing Research
Radioemobilization using the TheraSphere protocol, which involves infusion of glass microspheres impregnated with the radioisotope yt- trium-90, is being used as a treatment for intermediate stage hepatocellular cancer at Mayo Clinic Rochester and Mayo Clinic Jacksonville. Investigators, including Greg Wiseman, M.D.; James Andrews, M.D.; and Lewis Roberts, M.D.; are studying the relative effectiveness of radioemobilization compared to the current standard treatment for intermediate disease, chemoembolization.

Recent studies have shown a survival advantage using photodynamic therapy (PDT) in patients with unresectable cholangiocarcinoma. The presence of a visible mass on imaging studies (hazard ratio, 3.55; 95 percent confidence interval, 1.21-10.38), and increasing time between diagnosis and PDT (hazard ratio, 1.13; 95 percent confidence interval, 1.02-1.25) predicted a poorer survival rate after PDT. A higher serum albumin level (hazard ratio, 0.16; 95 percent confidence interval, 0.04-0.59) predicted a lower mortality rate after PDT (Clinical Gastroenterology and Hepatology; 5(6):743-8, 2007).

Investigator Gregory Gores, M.D., focuses his laboratory-based research program on the mechanisms by which cholangiocarcinoma cells evade apoptosis. Through this effort, his team has generated considerable data demonstrating that these cancers over-express the potent anti-apoptotic protein, Mcl-1. Strategies to down-regulate Mcl-1 and restore sensitivity to apoptosis include inhibiting IL-6 signaling, increasing cellular concentrations of mi29B (a micro-RNA) and the employment of various kinase inhibitors, especially AKT inhibitors. In particular, down-regulation and/or inhibition of Mcl-1 function sensitizes the cancer cells to cell death by tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). This death ligand specifically induces apoptosis of susceptible cancer cells but is nontoxic to normal cells. Given its differential ability to attack cancer cells, it is under development for the treatment of human cancer. Their work on this topic with reputable publications (including in 2007 Gastroenterology, 132(1):384-96; Oncogene, 2 APR 07 epub ahead of print; and Journal of Biological Chemistry, 282(25):18407-17) has attracted the attention of the pharmaceutical industry. Dr. Gores hopes to co-develop a clinical trial employing TRAIL agonists for the treatment of human hepatobiliary cancers.

Research Advances
Sulfastase 1 has been known to inhibit growth factor sequencing in liver cancer. A recurrent unique finding is that Sulfatase 1 regulates gene expression through effects on nuclear histone acetylation. The new class of anti-cancer agents and the histone deacetylase inhibitors have shown to act together with sulfatase 1 to inhibit growth of liver cancer cells (Gastroenterology; 130(7):2130-44, 2006).

Fluorescence in situ hybridization and digital image analysis are new tests developed at Mayo that have significantly improved the ability to diagnose malignancy in biliary strictures (Gastroenterology; 131(4):1064-72, 2006).