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Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Incidence and Mortality
Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2012:
Hepatocellular carcinoma is a tumor that is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C infection. It is the most common cancer in some parts of the world, with more than 1 million new cases diagnosed each year. 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, percutaneous ethanol injection, radiofrequency ablation, cryotherapy, and radiolabeled antibodies, often in conjunction with surgical resection and/or radiation therapy. In some studies of these approaches, long remissions have been reported. A few patients may be candidates for liver transplantation, but the limited availability of livers for transplantation restricts the use of this approach. Hepatocellular carcinoma can coexist with bile duct cancer (cholangiocarcinoma).
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 [3,6] 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 who have both hepatitis B and hepatitis C infection may be at particularly high risk for hepatocellular cancer.[Level of evidence: 3iiiDiv] There is evidence that patients with both hepatitis B and hepatitis C infection who consume more than 80 grams of alcohol per day have an increased risk of developing cancer (odds ratio [OR] = 7.3) when compared to patients who abstain from alcohol. Additionally, having a first-degree relative with hepatitis B plus hepatocellular carcinoma is associated with an increased risk (OR = 2.41) for family members who are hepatitis B carriers.
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.[6,11] 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.
In the United States, obesity has emerged as a very important risk factor for hepatocellular carcinoma and is the main contributor of nonalcoholic steatohepatitis, which may be related to an increase in the rate of hepatocellular carcinoma.
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. (For more information on Hypercalcemia, refer to the PDQ summary of the same name.)
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 in studies such as RTOG-8301 to be prognostically important, with the median survival of AFP-negative patients significantly longer than that of AFP-positive patients.[13,14] Other prognostic variables include performance status, liver functions, and the presence or absence of cirrhosis and its severity in relation to the Child-Pugh classification.
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 angiography in most patients. Information on the arterial anatomy is helpful for the operating surgeon and may eliminate some patients from consideration for resection. The presence of tumor thrombi in the hepatic veins, the inferior vena cava, or the portal vein can significantly alter treatment approaches. 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.
Other PDQ summaries containing information related to adult primary liver cancer include the following:
Malignant tumors of the liver are primarily adenocarcinomas, with two major cell types: hepatocellular and cholangiocarcinoma.
Histologic classification is as follows:
Hepatoblastoma rarely occurs in adults.
Note: The American Joint Committee on Cancer has recently published a new edition of the AJCC Cancer Staging Manual, which includes revisions to the staging for this disease. The PDQ Adult Treatment Editorial Board, which is responsible for maintaining this summary, is currently reviewing the new staging to determine the changes that need to be made in the summary. In addition to updating this Stage Information section, additional changes may need to be made to other parts of this summary to ensure that it is up-to-date. The changes will be made as soon as possible.
Primary tumor (T)
Regional lymph nodes (N)
The regional lymph nodes are the hilar (i.e., those in the hepatoduodenal ligament, hepatic, and periportal nodes). Regional lymph nodes also include those along the inferior vena cava, hepatic artery, and portal vein. Any lymph node involvement beyond these nodes is considered distant metastasis and should be coded as M1. Involvement of the inferior phrenic lymph nodes should also be considered M1.
Distant metastasis (M)
Metastases occur most frequently in bones and lungs. Tumors may extend through the capsule to adjacent organs (adrenal glands, diaphragm, and colon) or may rupture, causing acute hemorrhage and peritoneal carcinomatosis.
The T classification is based on the results of multivariate analyses of factors affecting prognosis after resection of liver carcinomas. The classification considers the presence or absence of vascular invasion (as assessed radiographically or pathologically), the number of tumor nodules (single vs. multiple), and the size of the largest tumor (≤ 5 cm vs. > 5 cm). For pathologic classification, vascular invasion includes gross as well as microscopic involvement of vessels. Major vascular invasion (T3) is defined as invasion of the branches of the main portal vein (right or left portal vein; this does not include sectoral or segmental branches) or as invasion of one or more of the 3 hepatic veins (right, middle, or left). Multiple tumors include satellitosis, multifocal tumors, and intrahepatic metastases. Invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum is considered T4.
AJCC Stage Groupings
For purposes of treatment, patients with liver cancer are grouped into 1 of 3 groups: localized resectable, localized unresectable, or advanced disease. These groups are described with the following AJCC stage groupings:
Localized Resectable Adult Primary Liver Cancer
(Selected T1 and T2; N0; M0)
Localized resectable liver cancer is confined to a solitary mass in a portion of the liver, or a limited number of tumors confined to one lobe, 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 beyond Child class A or chronic hepatitis. Only a small percentage of liver cancer patients will prove to have such localized resectable disease. Preoperative assessment that includes 3-phase helical computed tomography and/or magnetic resonance 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 ideally contain a 1 cm margin of normal liver. Patients with cirrhosis and resectable tumors are also eligible for liver transplantation; if eligible, sometimes other measures are instituted until liver transplantation becomes available.
Localized and Locally Advanced Unresectable Adult Primary Liver Cancer
(Selected T1, T2, T3, and T4; N0; M0)
Localized and locally advanced unresectable liver cancer appears to be confined to the liver, but surgical resection of the entire tumor is not appropriate because of location within the liver or concomitant medical conditions (such as cirrhosis). These patients may be considered for liver transplantation.[2,3,4] For other patients, percutaneous or intraoperative radiofrequency ablation (RFA) or other forms of ablation of small (<3 cm) appropriately located tumors, or transarterial chemoembolization (TACE) may be options.
Advanced Adult Primary Liver Cancer
(Any T, N1 or M1)
Advanced liver cancer 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. Chemoembolization has been beneficial in selected patients who have no extrahepatic metastases.
For patients with selected T1 or T2; N0; M0 disease.
Standard treatment options:
Treatment options under clinical evaluation:
Adoptive immunotherapy with interleukin-2 and anti-CD3 activated autologous lymphocytes was found to have lengthened recurrence-free survival, but not overall survival, in one study.[Level of evidence: 1iiDiv] Localized recurrences in the liver may occasionally be successfully treated by re-resection.[12,13]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized resectable adult primary liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
For selected patients with T1, T2, T3, or T4; N0; M0 disease.
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 chemoembolization, cryosurgery, percutaneous ethanol injection, or radiofrequency ablation for cancers smaller than 5 cm. Survivals equivalent to resection have been reported. One randomized trial in cirrhosis patients with small hepatocellular carcinomas demonstrated improved local recurrence-free survival in patients who underwent radiofrequency ablation as compared to percutaneous ethanol injections as their only form of treatment,[Level of evidence: 1iiDiii] but overall survival was not changed.[Level of evidence: 1iiA]
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 gelatin foam powder or muscle fragments and chemotherapy, usually doxorubicin. 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. A randomized study of chemoembolization versus conservative treatment found no survival advantage for chemoembolization. This study was terminated early and was underpowered to detect any but large survival differences.
A subsequent similar trial conducted with 271 patients from 23 centers in China, South Korea, and Taiwan with a 2:1 randomization on sorafenib achieved a median overall survival rate of 6.5 months on sorafenib versus 4.2 months on placebo (HR = 0.68; 95% CI, 0.50–0.93; P = .014). Adverse events attributed to sorafenib in both of these trials included hand-foot skin reactions and diarrhea.
These studies establish a role for sorafenib in locally advanced as well as advanced hepatocellular cancers extending beyond the liver, which are not amenable to regional modalities. Studies are ongoing to evaluate the role of sorafenib after transarterial chemoembolization (TACE), with chemotherapy, or in the presence of more advanced liver disease.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with localized unresectable adult primary liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
For patients with any T, N1, M1 disease.
There is no standard therapy for patients with 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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with advanced adult primary liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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%, and 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.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult primary liver cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Adult Primary Liver Cancer
Updated statistics with estimated new cases and deaths for 2012 (cited American Cancer Society as reference 1).
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult primary liver cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Adult Primary Liver Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Adult Primary Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-02-23
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