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	Cancer of the Liver Alan P. Venook, MD, Sabrina Selim, MD

Primary liver cancer also called hepatocellular carcinoma or hepatoma may be the most common cancer worldwide. It occurs with great frequency in Asia and Africa and is becoming more common in the United States as a complication of chronic Hepatitis C viral infection. Because only about 30,000 cases are diagnosed yearly in the U.S, liver cancer is generally not suspected until it is at an advanced stage.

Because the liver plays a vital role in removing toxins and medications from the blood, liver cancer can severely disrupt metabolic pathways and make drug or chemotherapy administration/regulation particularly difficult. Even when it is identified in its early stages, the co-existent liver damage, which is almost always present, may thus limit treatment options. The treatment now available for advanced liver cancer is not particularly effective, and the principal goal of therapy is to relieve the symptoms related to the disease.

Types
Primary liver cancer originates in the liver. It includes hepatocellular carcinoma which is cancer of the liver cells, and, more rarely, blood vessels in the liver (hemangioendothelioma), other glands in the liver (adenocarcinoma) or connective tissue in the liver (sarcoma, angiosarcoma). Most commonly, liver cancer is secondary: the tumor cells originated in another organ (breast, lung, gallbladder) and spread (metastasized) to the liver.

How It Spreads
Liver cancers can spread to other areas through either the lymph system or the blood. Most often the cancer first moves into the lymph nodes in the region of the liver (porta hepatis), then goes to other lymph nodes or into the lung or bones. Tumor cells can also spread into adjacent blood vessels, into the abdominal cavity causing the accumulation of fluid (ascites) or masses elsewhere in the abdomen

What Causes It
Hepatocellular carcinoma most often develops in damaged livers. Long-standing infection with either the hepatitis B or hepatitis C virus often precedes it and is therefore seen as a significant risk factor. Worldwide, men are twice as likely as women to develop liver cancer. Cirrhosis of the liver (from, for example, a viral infection, alcohol, toxin exposure or a genetic defect) also increases the likelihood of hepatocellular carcinoma, presumably because of chronic inflammation in the liver. In fact, an estimated 5 percent of people with cirrhosis will eventually develop liver cancer. Fifty to 80 percent of all people with liver cancer have cirrhosis. Common Signs and Symptoms Common symptoms include bloating, abdominal pain, fever, weight loss, decreased appetite and nausea. But because liver cancer is so rare, its symptoms are usually attributed to more common, benign conditions. Frequently, the diagnosis of cancer is not considered until these symptoms persist or until a person develops an enlarging abdominal mass or fluid in the abdomen. Jaundice (the skin turning yellow) and swelling in the legs are usually associated with more advanced tumors. Sometimes, people with liver cancer feel entirely well.

Staging
Although a TNM staging system exists for hepatocellular carcinoma, for purposes of deciding about therapeutic options, there are only three stages - localized resectable, localized unresectable and advanced disease.

Stage	Signs and Symptoms	Diagnostic Procedures	Treatments	Survival
Localized Resectable The tumor is confined to a portion of the liver that allows for its complete surgical removal.	There are no findings specific to liver cancer. They may include the following, all of which may have other explanations: Fever Enlarged liver and spleen Enlarged, hard lymph nodes	Abdominal ultrasound: can distinguish a solid mass from a non-cancerous (benign) accumulation of fluid Blood count may be normal or show decrease or increase in red blood cells Liver function tests may be abnormal, but may also be normal even in advanced stages of liver cancer Clotting tests (PT and PTT) may be abnormal	Surgery: Unfortunately, only a small percentage of patients are candidates for surgery and many experience tumor recurrence. The relative health of the patient and the remaining liver (cirrhosis involvement) must be taken into account Chemotherapy: The role for chemo after surgery is unknown. Although Adriamycin is often recommended, no systematic studies have been done to see if it increases the cure rate. Often, side effects of therapy outweigh the benefits Radiation Therapy: Radiation is often applied to the liver after surgery but has never been proven to be beneficial	5 year: 10 to 30%
Localized Unresectable Despite being a localized mass, the tumor may be unresectable because crucial blood vessel structures are involved or because the liver is impaired	Same as above plus Swelling of the abdomen (ascites) Jaundice (skin turning yellow) Swelling of the legs (edema) Serum alpha-fetoprotein (AFP) is elevated in 30-50% of people with primary liver cancer	CT and MRI scans help determine the extent of tumor within the liver and possible extension into lymph nodes or other abdominal structures Arteriography involves injection of dye into the artery going to the liver then taking an x-ray picture. This helps the surgeon determine the blood supply to the tumor	There is no standard therapy, so clinical trials should be considered. These include: Liver Transplantation: this may benefit patients with few (<3) small tumors (< 5 cm) and without hepatitis B Cryosurgery (freezing the tumor using a cold probe) and radiofrequency ablation (inserting a heated probe into the tumor): these may hold some promise to allow for removal of otherwise unresectable tumors, but only a few specialized physicians perform these techniques	2 year:less than 5%
Advanced Disease The tumor involves all lobes of the liver and/or has spread to involve other organs (lung, lymph nodes, bone)	Same as above	Biopsy: either fine needle (FNA) or regular needle biopsy allows a pathologist to distinguish between a primary liver cancer or if it has spread from another organ	No standard therapy is known to prolong survival. The usual approach is single-agent chemotherapy such as Adriamycin or 5-FU and combinations include cisplatin and alpha-interferon. These, however, have painful side-effects. Radiation: along with chemotherapy this may relieve the pain of large liver masses, and radiation to painful bone or other metastases may be also appropriate Investigational methods: combination chemo or new drugs including derivatives of Adriamycin and 5-FU may prove beneficial. Chemoembolization (administering a combination of chemotherapy and colloid particles directly into the liver tumor via its main (hepatic) artery) may improve symptoms even when there is metastatic disease	2 year: less than 5%

Supportive Therapy

Pain relievers are sometimes called for in liberal doses. Narcotics may have excessive side effects because they are metabolized by the liver, which may not be functioning properly.
Non-steroidal anti-inflammatory drugs may be surprisingly effective even against the severe pain associated with liver cancer and may also be helpful if patients are having fevers and sweats related to the cancer.
Frequent small meals may be necessary to provide enough nutrition, since an enlarged liver might reduce the capacity of the stomach.
The loss of appetite that frequently accompanies liver cancer may be relieved with a medication called Megace.
Water pills (diuretics) to relieve fluid in the abdomen or legs may cause significant imbalance in kidney function if not carefully monitored.
Nausea can be treated with standard medications, including suppositories.
Sleep disturbances are common. Most sleeping pills are metabolized by the liver, however, so they should be used carefully.

The Most Important Questions to Ask Your Doctor

Should I see another physician to confirm that this tumor can or cannot be removed for cure?
Could I benefit from an investigational therapy available at another institution?
How sick will the proposed chemotherapy or radiation treatment make me relative to the potential benefit?
Should any tests be done on my spouse or children to see if they are at risk for developing this cancer?
Is a liver transplant an option for me?

Reference
Everyone's Guide to Cancer Therapy by Malin Dollinger, Ernest H. Rosenbaum, Margaret Tempero and Sean Mulvihill. Andrews McMeel. 4th edition, 2001

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