PDQ® Treatment Health Professionals
Hepatocellular carcinoma is a tumor that is relatively uncommon in the United States, although its incidence is rising. It is the most common cancer in some other parts of the world. Hepatocellular carcinoma is potentially curable by surgical resection, but surgery is the treatment of choice for only the small fraction of patients with localized disease. Prognosis depends on the degree of local tumor replacement and the extent of liver function impairment. Therapy other than surgical resection is best administered as part of a clinical trial. Such trials evaluate the efficacy of systemic or infusional chemotherapy, hepatic artery ligation or embolization, and radiolabeled antibodies, often in conjunction with surgical resection and/or radiation therapy. In some studies of these approaches, long remissions have been reported. Hepatocellular carcinoma should be distinguished from bile duct cancer (cholangiocarcinoma) as well as from metastatic cancer that originates in another organ.
Hepatocellular carcinoma is associated with cirrhosis in 50% to 80% of patients; 5% of cirrhotic patients eventually develop hepatocellular cancer, which is often multifocal.
Hepatitis B infection [2,3] and hepatitis C infection  appear to be the most significant causes of hepatocellular carcinoma worldwide, particularly in patients with continuing antigenemia and in those who have chronic active hepatitis. A series found that male patients older than 50 years of age who have both hepatitis B and hepatitis C infection may be at particularly high risk for hepatocellular cancers.[Level of evidence:3iii]
Aflatoxin has also been implicated as a factor in the etiology of primary liver cancer in parts of the world where this mycotoxin occurs in high levels in ingested food.[3,6] Workers who were exposed to vinyl chloride before controls on vinyl chloride dust were instituted developed sarcomas in the liver, most commonly angiosarcomas. Other sarcomas of smooth muscular and vascular origin are also found.
The primary symptoms of hepatocellular carcinoma are those of a hepatic mass. Among patients with underlying cirrhotic disease, a progressive increase in alpha-fetoprotein (AFP) and/or in alkaline phosphatase or a rapid deterioration of hepatic function may be the only clue to the presence of the neoplasm. Infrequently, patients with this disease have polycythemia, hypoglycemia, hypercalcemia, or dysfibrinogenemia.
The biologic marker AFP is useful for the diagnosis of this neoplasm. By a radioimmunoassay technique, 50% to 70% of patients in the United States who have hepatocellular carcinoma have elevated levels of AFP. However, patients with other malignancies (germ cell carcinoma and, rarely, pancreatic and gastric carcinoma) also demonstrate elevated serum levels of this protein. AFP levels have been shown to be prognostically important, with the median survival of AFP-negative patients significantly longer than that of AFP-positive patients.[7,8] Other prognostic variables include performance status and liver functions.
Patients scheduled for possible resection require preoperative assessment with angiography in conjunction with helical computed tomographic (CT) scan or magnetic resonance imaging (MRI) with magnetic resonance angiography; these scans have obviated the need for most angiography. Information on the arterial anatomy is helpful for the operating surgeon and may eliminate some patients from consideration for resection. Dynamic CT and MRI scans can document the relationship of the tumor to the hepatic and portal veins (and, on occasion, involvement of these structures), delineating tumors for which the chances for surgical cure are remote. Laparoscopic evaluation may detect metastatic disease, bilobar disease, or inadequate liver remnant, and therefore obviate the need for open surgical exploration.
Malignant tumors of the liver are primarily adenocarcinomas, with 2 major cell types: hepatocellular and cholangiocarcinoma.
Histologic classification is as follows:
Note: The fibrolamellar variant is important because an increased proportion of these patients may be cured if the tumor can be resected. It is more frequent in young women.
The American Joint Committee on Cancer (AJCC) has designated TNM stages for liver cancer as follows: 
Primary tumor (T)
Regional lymph nodes (N)
Distant metastasis (M)
(T1, T2, T3, and selected T4; N0; M0)
This type of liver cancer is confined to a solitary mass in a portion of the liver that allows the possibility of complete surgical removal of the tumor with a margin of normal liver. Liver function tests are usually normal or minimally abnormal, and there should be no evidence of cirrhosis or chronic hepatitis. Only a small percentage of liver cancer patients will prove to have such localized resectable disease. Preoperative assessment that includes computed tomography and/or MR scanning should be directed toward determining the presence of extension of tumor across interlobar planes, involvement of the hepatic hilus, or encroachment on the vena cava. A resected specimen should contain a 1- to 2-centimeter margin of normal liver. Patients with chronic hepatitis and cirrhosis are at high risk when surgical resection is performed.
(selected T2, T3, and T4; N0; M0)
This type of cancer appears to be confined to the liver, but surgical resection of the entire tumor is not possible despite a localized mass because of location within the liver or concomitant medical conditions (such as cirrhosis). Patients with locally unresectable fibrolamellar variant hepatomas may be considered for liver transplantation.[2-5]
(any T, N1 or M1)
Advanced liver cancer is cancer that is present in both lobes of the liver or has metastasized to distant sites. Median survival is usually 2 to 4 months. The most common metastatic sites of hepatocellular cancer are the lungs and bone. Multifocal disease in the liver is common, particularly when cirrhosis or chronic hepatitis is present.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Patients whose tumors are localized but unresectable due to location in the liver, concomitant medical considerations (such as cirrhosis), or even limited bilateral tumors, may be candidates for cryosurgery, percutaneous ethanol injection, or radiofrequency ablation for cancers smaller than 5 centimeters. Survivals equivalent to resection have been reported.
Clinical trials that use systemic chemotherapy, regional chemotherapy, and/or labeled or radiolabeled antibodies have demonstrated remission of unresectable hepatoma. Other approaches include embolization of the hepatic artery with gelfoam powder or muscle fragments and chemotherapy, usually adriamycin. These approaches often produce central tumor necrosis, reduction in tumor size, and relief of pain, but the benefits are usually transient. Any interference with arterial blood supply (including infusion chemotherapy) may be associated with significant morbidity and is contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice.
3. Chemotherapy (regional infusion of the liver): Chemotherapeutic agents may be infused with a subcutaneous portal or implantable pump via a catheter placed in the hepatic artery. Older studies that use standard agents have demonstrated responses in 15% to 30% of such cases, but newer agents and techniques (that is, biodegradable microspheres) have been evaluated in pilot trials,[8-10] as has regional chemotherapy with external-beam radiation therapy. Many patients are not candidates for these approaches, which often require surgical intervention.
4. Systemic chemotherapy: Durable remissions have rarely been reported, and no significant survival benefits have been conclusively demonstrated.
5. Surgery, chemotherapy, and radiation therapy: These modalities may be combined in clinical trials for patients with a dominant hepatic mass and multifocal involvement with small amounts of tumor; surgical resection or cryosurgery of the mass may be followed by hepatic infusion of the remaining liver with chemotherapeutic agents alone or in combination with hyperthermia, radiation, or radiation with radiosensitizers. Chemotherapy plus radiation has also been used to shrink tumors prior to resection.
7. Other approaches include the use of radiosensitizers and external-beam radiation therapy without chemotherapy. The relative radiosensitivity of normal liver tissue compared with tumor tissue must always be considered when radiation therapy is contemplated.
8. Radiofrequency tissue ablation.
There is no standard therapy for advanced metastatic liver cancer. Such patients should be considered candidates for clinical trials exploring the usefulness of new biologicals or antitumor drugs (phase I and II studies) or combinations of existing drugs, radiosensitizers, and radiation therapy. Palliation may sometimes be achieved in such studies.
External-beam radiation therapy and chemotherapy followed by radiolabeled polyclonal antiferritin antibody produces objective response in up to 50% of patients, but it is a localized treatment and does not address the question of systemic disease.
The prognosis for any treated primary liver cancer patient with progressing, recurring, or relapsing disease is poor. The question and selection of further treatment depends on many factors, including prior treatment, site of recurrence, presence of cirrhosis, and hepatic function as well as individual patient considerations. Re-resection should be considered when feasible, but most patients experience recurrence, typically in the liver. When re- resection is not possible, treatment options for patients with recurrent hepatocellular cancer may include the use of transarterial oily chemoembolization (TOCE), percutaneous ethanol injection therapy (PEIT), chemotherapy, or liver transplantation. At a single institution in Hong Kong, 244 consecutive patients treated with curative resection were followed for intrahepatic recurrence. Of the 244 patients followed, 139 patients did not develop intrahepatic recurrence and had 1-, 3-, and 5-year survival rates of 87%, 79%, and 74%, respectively. Of the 105 patients who developed subsequent intrahepatic recurrences, 11 patients were treated with re-resection and had 1-, 3-, and 5-year survival rates of 81%, 70%, and 69%, respectively; 71 patients were treated with TOCE and had 1-, 3-, and 5-year survival rates of 72%, 38%, and 20%, respectively; 6 patients were treated with PEIT and had 1-, 3-, 5-year survival rates of 67%, 22%, 0%, respectively; the remaining 17 patients had either systemic chemotherapy or conservative treatment, and had no survivors at 3 years.[Level of evidence: 3iiA] Clinical trials are appropriate and should be considered whenever possible.
Date Last Modified: 11/1999