Cancer Treatment Information by Disease
Adult Primary Liver Cancer - Information for Health professionals
- General Information
- Cellular Classification
- Stage Information
- Treatment Option Overview
- Localized Resectable Adult Primary Liver Cancer
- Localized and Locally Advanced Unresectable Adult Primary Liver Cancer
- Advanced Adult Primary Liver Cancer
- Recurrent Adult Primary Liver Cancer
- Changes to This Summary (07/18/2007)
- More Information
General Information
Note: A separate PDQ summary on Screening for Hepatocellular Cancer is also available.
Note: Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2007:[1]
- New cases: 19,160.
- Deaths: 16,780.
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.)
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.[2] 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.[3] 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.[3] A few patients may be candidates for liver transplantation, but the limited availability of livers for transplantation restricts the use of this approach.[4] Hepatocellular carcinoma can coexist with bile duct cancer (cholangiocarcinoma).[5]
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 [7] 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.[8][Level of evidence: 3iiiDiii] 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.[9] 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.[10]
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.
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.[12][13] Other prognostic variables include performance status, liver functions,[14] and the presence or absence of cirrhosis and its severity in relation to the Child-Pugh classification.[15]
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.[16] Laparoscopic evaluation may detect metastatic disease, bilobar disease, or inadequate liver remnant, and therefore obviate the need for open surgical exploration.[17]
References:
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American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed September 7, 2007.
Cellular Classification
Malignant tumors of the liver are primarily adenocarcinomas, with two major cell types: hepatocellular and cholangiocarcinoma.
Histologic classification is as follows:
- Hepatocellular carcinoma (liver cell carcinoma).
- Hepatocellular carcinoma (fibrolamellar variant). 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. It also generally exhibits a slower clinical course than the more common hepatocellular carcinoma.
- Cholangiocarcinoma (intrahepatic bile duct carcinoma).
- Mixed hepatocellular cholangiocarcinoma.
- Undifferentiated.
Hepatoblastoma rarely occurs in adults.
Stage Information
The American Joint Committee on Cancer (AJCC) has designated TNM stages for liver cancer as follows:[1]
TNM Definitions
Primary tumor (T)
- TX: Primary tumor cannot be assessed
- T0: No evidence of primary tumor
- T1: Solitary tumor without vascular invasion
- T2: Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
- T3: Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
- T4: Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum
Regional lymph nodes (N)
- NX: Regional lymph nodes cannot be assessed
- N0: No regional lymph node metastasis
- N1: Regional lymph node metastasis
Distant metastasis (M)
- MX: Distant metastasis cannot be assessed
- M0: No distant metastasis
- M1: Distant metastasis
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
Stage I
- T1, N0, M0
Stage II
- T2, N0, M0
Stage IIIA
- T3, N0, M0
Stage IIIB
- T4, N0, M0
Stage IIIC
- Any T, N1, M0
Stage IV
- Any T, any N, M1
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
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.
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][5] For other patients, percutaneous ethanol injection, radiofrequency ablation, or chemoembolization may be options.[6]
Advanced Adult Primary Liver Cancer
Advanced liver cancer is present in both lobes of the liveror 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.[6]
References:
Treatment Option Overview
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Localized Resectable Adult Primary Liver Cancer
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.)
For patients with selected T1 or T2; N0; M0 disease.
- Surgery: Resection of localized hepatocellular cancer varies from segmental resection to trisegmental (80% of liver) resection. In series of carefully selected patients, partial hepatectomy has resulted in a 5-year survival of 30% to 40%, with median survivals approaching 3 years.[1] In a retrospective study of patients with intrahepatic cholangiocarcinoma, hepatic resection demonstrated a 5-year survival of 23% and a tumor-free survival of 11%.[2][Level of evidence: 3iiiDi] Hepatic carcinoma is frequently multifocal and may involve multiple sites throughout the liver at the time of exploration, even when a dominant mass is found on preoperative assessment. Preoperative assessment should also include a search for extrahepatic metastases, since this condition will also preclude the planned hepatic resection. Intraoperative ultrasound assessment of the liver often finds satellite or second lesions.[3] Resection that involves more than a nonanatomic wedge of liver is poorly tolerated and leads to a high mortality rate in patients with severe cirrhosis. Severe cirrhosis may be a contraindication to major hepatic resection but may not contraindicate hepatic transplantation.[4][5][6][7] Hepatic transplantation for hemangioendothelioma, fibrolamellar hepatocellular carcinoma, and small (<5 cm) hepatocellular carcinoma in patients with or without cirrhosis has been associated with 5-year survivals of 20% to 30%.[8][Level of evidence: 3iiiA];[9]
Treatment options under clinical evaluation:
-
Chemotherapy or biologic therapy: Because of the high proportion of patients who experience relapse following
surgery for localized hepatic cancer, adjuvant approaches have been employed
using chemoembolization, regional arterial infusion of the liver or systemic therapy with
chemotherapeutic agents. One randomized trial of 43 patients suggested
improved survival with adjuvant injection of a single dose (1,850 MBq) of I-131
lipiodol via the hepatic artery. Median disease-free survival in the treatment
group was 57 months compared to 13.6 months in the group that did not receive
treatment beyond resection (P = .037).[10][Level of evidence: 1iiA,1iiB] Lipiodol
was nontoxic, but required thyroid suppression before and after surgery.
Enrollment in this trial was prematurely terminated because of early
differences in survival between the treatment and control arms. Therefore, the
results must be considered preliminary and will require confirmation.
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.[11][Level of evidence: 1iiDiii] Localized recurrences in the liver may occasionally be successfully treated by re-resection.[12][13]
References:
Localized and Locally Advanced Unresectable Adult Primary Liver Cancer
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.)
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.[1] 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,[2][Level of evidence: 1iiDii] but overall survival was not changed.[2][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 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. A randomized study of chemoembolization versus conservative treatment found no survival advantage for chemoembolization.[3] This study was terminated early and was underpowered to detect any but large survival differences.
- Radiofrequency ablation, chemoembolization, cryosurgery, or percutaneous ethanol injection: These techniques may be used in patients with small (<5 cm), localized, unresectable tumors.[1][4][5][6][7][8]
- Liver transplantation: For selected patients with localized unresectable hepatoma, particularly patients with fibrolamellar hepatomas, liver transplantation may offer a potentially curative treatment option.[9]
- 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 (i.e., biodegradable microspheres) have been evaluated in pilot trials,[10][11][12] as has regional chemotherapy with external-beam radiation therapy.[13] Many patients are not candidates for these approaches, which often require surgical intervention.
- Systemic chemotherapy: Durable remissions have rarely been reported, and no significant survival benefits have been conclusively demonstrated.
- 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, radiofrequency ablation, 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.[1] Chemotherapy plus radiation has also been used to shrink tumors prior to resection.[14] However, the whole liver is not tolerant of large doses of radiation therapy.
- 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.[15]
References:
Advanced Adult Primary Liver Cancer
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.
Recurrent Adult Primary Liver Cancer
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.)
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.[1] 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.[2] 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.[2][Level of evidence: 3iiA] Clinical trials are appropriate and should be considered whenever possible.
References:
Changes to This Summary (07/18/2007)
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.
Editorial changes were made to this summary.
More Information
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PDQ® - NCI's Comprehensive Cancer Database.
- Full description of the NCI PDQ database.
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PDQ® Cancer Information Summaries: Adult Treatment
- Treatment options for adult cancers.
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PDQ® Cancer Information Summaries: Pediatric Treatment
- Treatment options for childhood cancers.
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PDQ® Cancer Information Summaries: Supportive Care
- Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
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PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
- Tests or procedures that detect specific types of cancer.
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PDQ® Cancer Information Summaries: Prevention
- Risk factors and methods to increase chances of preventing specific types of cancer.
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PDQ® Cancer Information Summaries: Genetics
- Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
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PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
- Information about complementary and alternative forms of treatment for patients with cancer.
This information was last updated on July 18, 2007
