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Incidence and Mortality
Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2013:
Hepatocellular carcinoma (HCC) is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C virus (HCV) infection. HCC is the most common solid tumor worldwide and the third leading cause of cancer-related deaths.[3,4]
Both local extension of tumor and extent of liver function impairment affect prognosis and guide selection of treatment. Liver transplantation, surgical resection, and ablation techniques offer high rates of complete responses, and a potential for cure in early HCC. There are no large, robust, randomized studies that compare treatments considered effective for early stage disease, nor are there studies comparing these treatments with best supportive care. Best survivals are achieved when the HCC can be surgically excised (either by a transplantation or resection).
For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (≤3 lesions, ≤3 cm), the best option is liver transplantation, but the limited availability of deceased liver donors restricts the use of this approach.
Surgical resection is usually performed in patients with localized HCC and sufficient functional hepatic reserve.
Among noncurative treatment for HCC, transarterial chemoembolization and sorafenib have been shown to improve survival.[6,7,8]
The etiology of HCC is likely multifactorial. Any chronic liver injury probably increases the risk of HCC. This risk seems elevated especially in patients who develop cirrhosis. The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30% and depends on etiology (highest in individuals with HCV infection), region or ethnicity (highest in Asians), and stage of cirrhosis.[9,10][Level of evidence: 3iii]
Hepatitis B virus (HBV) infection and HCV infection appear to be the most significant causes of HCC worldwide. Chronic HBV infection is the leading cause of HCC in Asia and Africa, and HCV infection is the leading cause of HCC in Europe, Japan, and North America.[5,11]
The annual incidence of HCC in HBV carriers is 0.5% to 1% per year in noncirrhotic patients and 2.5% per year in cirrhotic patients. The relative risk of HCC is 100 (i.e., HBV carriers are 100 times more likely to develop HCC than uninfected persons).[12,13]
In a single, prospective, population-based study that included 12,008 patients, the presence of anti-HCV positivity conferred a twentyfold increased risk of HCC compared with anti-HCV negative persons. HCC may occur in HCV-infected patients with bridging fibrosis even in the absence of overt cirrhosis. However, the risk is highest among those patients with HCV-related established cirrhosis, which has an incidence rate of HCC of 2% to 8% per year.
Several reports suggest that alcoholic cirrhosis is a risk factor for HCC. However, the true incidence of HCC in alcoholic cirrhosis is unknown because most epidemiology reports on this subject were published before the identification of hepatitis C virus.
Recently, the risk factors associated with the metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and obesity have been recognized as potential causes of nonalcoholic hepatosteatosis, cirrhosis, and HCC. However, no study to date has followed a sufficiently large group of these patients for long enough to describe an incidence rate for HCC.
Hemochromatosis is also a significant risk factor for HCC and has an increased relative risk twenty times that of the normal population.
The incidence of HCC in stage IV primary biliary cirrhosis is approximately the same as in cirrhosis resulting from hepatitis C.
Aflatoxin B1 is produced by fungi of the Aspergillus species and is a common contaminant of grain, nuts, and vegetables in some parts of Asia and Africa. Aflatoxin B1 has also been implicated as a cofactor in the etiology of primary liver cancer in HBV carriers because it enhances the neoplastic risk threefold.
(Refer to the PDQ summary on Liver (Hepatocellular) Cancer Screening for more information.)
For lesions that are smaller than 1 cm and are detected during screening in patients at high risk for HCC, no detailed investigation is required because most of these lesions will be cirrhotic nodules rather than HCC.[Level of evidence: 3iii] Close follow-up at 3-month intervals is recommended using the same technique that first documented the presence of the nodules.
For patients with liver nodules larger than 1 cm who are at risk for HCC, diagnosis should be established. The tests required to diagnose HCC may include radiology, biopsy, or both.
Alpha-fetoprotein (AFP) levels
AFP is insufficiently sensitive or specific for use as a diagnostic assay. AFP can be elevated in intrahepatic cholangiocarcinoma and in some metastases from colon cancer. The finding of a mass in a liver with an elevated AFP does not automatically indicate HCC. If the AFP level is high, it can be used to monitor for recurrence.
In patients with cirrhosis, liver disease, or other risk factors for HCC, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT]-scan or magnetic resonance imaging [MRI]) can be used to establish diagnosis of HCC for nodules larger than 1 cm.
During the arterial phase of the study, HCC enhances more intensely than the surrounding liver because the arterial blood in the liver is diluted by venous blood that does not contain contrast, whereas the HCC contains only arterial blood. In the venous phase, the HCC enhances less than the surrounding liver, which is referred to as the venous washout of HCC, because the arterial blood flowing through the lesion no longer contains contrast; however, the portal blood in the liver now contains contrast.
The presence of arterial uptake followed by washout in a single dynamic study is highly specific (95%–100%) for an HCC of 1 to 3 cm in diameter and virtually diagnostic of HCC.[20,21,22][Level of evidence: 3ii] In these cases, the diagnosis of HCC may be considered established without the need for a second imaging modality, even in the absence of a biopsy confirmation.[5,22,23][Level of evidence: 3ii]
If, on the other hand, a first imaging modality, such as either a contrast-enhanced CT or MRI, is not conclusive, sequential imaging with a different modality can improve sensitivity for HCC detection (from 33% to 41% for either CT or MRI to 76% for both studies when performed sequentially) without a decrease in specificity.
If, despite the use of two imaging modalities, a nodule larger than 1 cm remains uncharacterized in a patient at high risk for HCC (i.e., with only one or no classic enhancement pattern), a liver biopsy can be considered.[5,22]
A liver biopsy may be performed when a diagnosis of HCC is not established by a dynamic imaging modality (three-phase CT or MRI) for liver nodules 1 cm or larger in high-risk patients.
Natural History and Prognostic Factors
The natural history of early tumors is poorly known because the majority of patients are treated. However, older reports have described 3-year survival rates of 13% to 21% without any specific treatment.[24,25] At present, only 10% to 23% of HCC patients may be surgical candidates for curative-intent treatment.[26,27] The 5-year overall survival rates for patients with early HCC who are undergoing liver transplant or liver resection are 44% to 78% and 27% to 70%, respectively.
The natural course of advanced-stage HCC is better known. Untreated patients with advanced disease usually survive less than 6 months. The 1-year and 2-year survival rates of untreated patients in 25 randomized clinical trials were 10% to 72% and 8% to 50%, respectively.
Unlike most patients with solid tumors, prognosis of HCC patients is affected not only by the tumor stage at presentation but also by the underlying liver function. The following are main prognostic factors for HCC patients:
Other PDQ summaries containing information related to adult primary liver cancer include the following:
Malignant primary tumors of the liver consist of two major cell types: hepatocellular, which accounts for 90% of cases, and cholangiocarcinoma.
Histologic classification is as follows:
Hepatoblastoma rarely occurs in adults.
Prognostic modeling in hepatocellular carcinoma (HCC) is complex because variables of two diseases--cirrhosis and cancer--are involved in as many as 80% of the cases. Tumor features and the factors related to functional hepatic reserve must be taken into account. The key prognostic factors are only partially known and vary at different stages of the disease. More than ten classifications are used throughout the world, but no system is accepted worldwide.
American Joint Committee on Cancer (AJCC) Staging System
Definitions of TNM
The TNM classification for staging, proposed by the AJCC, is not widely utilized. Clinical use of TNM staging is limited because liver function is not considered. It is also difficult to use this system to select treatment options because TNM staging relies on detailed histopathological examination available only after excision. TNM may be useful in prognostic prediction after liver resection.
The AJCC has designated staging by TNM to define liver cancer.
Okuda Staging System
The Okuda staging system includes variables related to tumor burden and liver function, such as bilirubin, albumin, and ascites and has been extensively used in the past. However, many significant prognostic tumor factors confirmed in both surgical and nonsurgical series (e.g., unifocal or multifocal, vascular invasion, portal venous thrombosis, or locoregional lymph node involvement) are not included.[2,3] As a result, Okuda staging is unable to stratify prognosis for early-stage cancers and mostly serves to recognize end-stage cancer patients.
Barcelona Clinic Liver Cancer (BCLC) Staging System
New classifications have been proposed in an effort to overcome the difficulties of having several staging systems. The BCLC staging classification retains its usefulness in early tumors and is currently the most accepted staging system for HCC. Recent evidence from an American cohort has shown that BCLC staging offers better prognostic stratification power than other staging systems.
The BCLC staging system attempts to overcome the limitations of previous staging systems by including variables related to the following:
Five stages (0 and A through D) are identified based on the variables mentioned above. Of note, the BCLC staging system links each HCC stage to appropriate treatment modalities. According to the BCLC, patients with early-stage HCC may benefit from curative therapies (i.e., liver transplantation, surgical resection, and radiofrequency ablation techniques); those at intermediate- or advanced-disease stage may benefit from palliative treatments(i.e., transcatheter arterial chemoembolization and sorafenib); however, those at end-stage disease who have a very poor life expectancy are offered supportive care and palliation.
There is no worldwide agreement on a common treatment strategy for patients with hepatocellular carcinoma (HCC). Several treatments for HCC are available that are associated with long-term survival, including liver transplantation, surgical resection, and ablation techniques.
Selection of treatment is complex because several factors related to the underlying liver function, the extent and location of the tumor, and the general condition of the patient must be considered. Often, patients with HCC are evaluated by a multidisciplinary team including hepatologists, radiologists, interventional radiologists, radiation oncologists, transplant surgeons, surgical oncologists, pathologists, and medical oncologists.
From a treatment perspective, HCC can be divided into the following two broad categories:
Localized hepatocellular carcinomas (HCCs) that present either as a solitary mass in a portion of the liver or as a limited number of tumors (three nodules, each <3 cm in diameter) without major vascular invasion constitute approximately 30% of the HCC cases. The three potentially curative therapies (i.e., liver transplantation, surgical resection, and ablation techniques) are acceptable treatment options for small, single-nodule HCC in patients with well-preserved liver function. Surgery is the mainstay of HCC treatment. Resection and transplantation achieve the best outcomes in well-selected candidates and are usually considered to be the first option for curative intent.
Liver transplantation is a potentially curative therapy for HCC and has the benefit of treating the underlying cirrhosis, but the scarcity of organ donors limits the availability of this treatment modality.
Liver transplantation is determined by the Milan criteria, which is defined as a single HCC lesion smaller than 5 cm, or 2 to 3 nodules smaller than 3 cm. Expansion of the accepted transplantation for HCC is not supported by consistent data. Liver transplantation is considered if resection is precluded as a result of multiple, small, tumor nodules (≤3 nodules, each <3 cm), or if the liver function is impaired (Child-Pugh B and C class). In those patients, transplantation is associated with a 5-year overall survival (OS) rate of approximately 70%.[Level of evidence: 3iii]
Surgical resection can be considered for patients who present with the following:
The principles of surgical resection involve obtaining a clear margin around a tumor, which may require any of the following:
Hepatic resection is controversial in patients with limited multifocal disease.
Preoperative assessment includes three-phase helical computed tomography, magnetic resonance imaging, or both to determine the presence of an extension of a tumor across interlobar planes and potential involvement of the hepatic hilus, hepatic veins, and inferior vena cava. Tumors can be resected only if a sufficient amount of liver parenchyma can be spared with adequate vascular and biliary inflow and outflow. Patients with well-compensated cirrhosis can generally tolerate resection of up to 50% of their liver parenchyma. After considering the location and number of tumors, and the patient's hepatic function, only 5% to 10% of liver cancer patients will prove to have localized disease amenable to resection. The 5-year OS rates following curative resection range between 27% and 70% and depend on tumor stage and underlying liver function.[1,3,4,5,6]
When tumor excision, either by transplant or resection, is not feasible or advisable, ablation techniques may be used if the tumor can be accessed percutaneously or, if necessary, through minimally invasive or open surgery. Ablation can be achieved in the following ways:
Ablation may be particularly useful for patients with early HCC that is centrally located in the liver and cannot be surgically removed without excessive sacrifice of functional parenchyma.
Ablation should include a margin of normal liver around the tumor. Ablation is relatively contraindicated for lesions in close proximity to bile ducts, the diaphragm, or other intra-abdominal organs that might be injured during the ablation. Furthermore, when tumors are located adjacent to major vessels, the blood flow in the vessels may decrease the temperature reached when thermal ablation techniques such as RFA are used. This is known as the heat sink effect, which may preclude a complete tumor necrosis.
Percutaneous ethanol injection (PEI) obtains good results in patients with Child-Pugh class A cirrhosis and a single tumor less than 3 cm in diameter. In those cases, the 5-year OS rate is expected to be as high as 40% to 59%.[7,8][Level of evidence: 3iiiD]
RFA also achieves best results in patients with tumors smaller than 3 cm. In this subpopulation of patients, 5-year OS rates may be as high as 59%, and the recurrence-free survival rates may not differ significantly from treatment with hepatic resection.[9,10] Local control success progressively diminishes as the tumor size increases beyond 3 cm.
In the few randomized, controlled trials that included patients with Child-Pugh A cirrhosis, RFA proved superior to PEI in terms of rates of complete response and local recurrences; some of those studies have also shown improved OS with RFA. Furthermore, RFA requires fewer treatment sessions than PEI to achieve comparable effects.[11,12,13,14]
Of note, RFA may have higher complication rates than PEI, but both techniques are associated with lower complication rates than excision procedures.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with 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.
Transarterial Embolization (TAE) and Transcatheter Arterial Chemoembolization (TACE)
TAE is the most widely used primary treatment for hepatocellular carcinoma (HCC) when HCC is not amenable to curative treatment by excision or ablation. The majority of the blood supply to the normal liver parenchyma comes from the portal vein, while blood flow to the HCC comes mainly from the hepatic artery. Furthermore, HCC tumors are generally hypervascular compared with the surrounding normal parenchyma. The obstruction of the arterial branch(es) feeding the tumor may reduce the blood flow to the tumor and result in tumor ischemia and necrosis.
Embolization agents, such as microspheres and particles, may also be administered along with concentrated doses of chemotherapeutic agents (generally doxorubicin or cisplatin) mixed with lipiodol or other emulsifying agents during chemoembolization, arterial chemoembolization, usually via percutaneous access; and TACE. TAE-TACE is considered for patients with nonsurgical HCC, who are also not amenable to percutaneous ablation in the absence of extrahepatic disease. In patients with cirrhosis, any interference with arterial blood supply may be associated with significant morbidity and is relatively contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice. In patients with liver decompensation, TAE-TACE could increase the risk of liver failure.
A number of randomized, controlled trials have compared TAE and TACE with supportive care. Those trials have been heterogeneous in terms of patient baseline demographics and treatment. The survival advantage of TAE-TACE over supportive care has been demonstrated by two trials.[1,2,3] No standardized treatment for a TAE approach has been determined (e.g., embolizing agent, chemotherapy agent and dose, treatment schedule). However, a meta-analysis has shown that TAE-TACE improves survival more than supportive treatment.
The use of drug-eluting beads (DEB) for TACE has the potential of reducing systemic side effects of chemotherapy and may increase objective tumor response.[4,5,6,7] Only one study has suggested that DEB-TACE may offer an advantage in overall survival (OS).
At this time, there is no evidence supporting a survival benefit for patients with advanced HCC receiving systemic cytotoxic chemotherapy when compared with no treatment or best supportive care.
Sorafenib is an oral multikinase inhibitor that prolongs survival in patients with advanced HCC and well-compensated liver function.
The SHARP trial (NCT00105443), randomly assigned 602 patients with advanced HCC to receive either sorafenib 400 mg twice daily or a placebo. All but 20 of the patients had a Childs-Pugh A liver disease score; 13% were women. After 321 deaths, the median survival was significantly longer in the sorafenib group (10.7 months vs. 7.9 months on placebo; hazard ratio [HR] favoring sorafenib, 0.69; 95% confidence interval [CI], 0.55–0.87; P < .001).
A subsequent, similar trial conducted in 23 centers in China, South Korea, and Taiwan included 226 patients (97% with Child-Pugh A liver function) with a 2:1 randomized assignment to sorafenib versus placebo. The median OS rate was 6.5 months for the sorafenib group versus 4.2 months for the placebo group (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 established a role for sorafenib in locally advanced and advanced hepatocellular cancers extending beyond the liver, which are not amenable to regional modalities.
Little is known about the efficacy of sorafenib for the patient with Child B or C liver function. At this time, further studies are needed before sorafenib can be recommended for a patient with Child B or C cirrhosis.
Studies are also ongoing to evaluate the role of sorafenib after TACE, with chemotherapy, or in the presence of more-advanced liver disease.
The efficacy of other targeted therapy agents (e.g., sunitinib and brivanib) is currently being investigated.
The role of radiation therapy for HCC has traditionally been limited by the low dose tolerance of the liver to radiation. However, recent technological developments in radiation therapy, including breathing motion management and image-guided radiation therapy, have allowed for more precise and targeted radiation therapy delivery to the liver. As a result of these advances, conformal liver irradiation has become feasible in the treatment of focal HCC. Several phase II studies have suggested a benefit in local control and OS compared with historical controls for patients with locally advanced HCC unsuitable for standard locoregional therapies.[12,13][Level of evidence: 3iiDiii] An ongoing, multi-institutional, randomized, phase III study (RTOG 1112 [NCT01730937]) evaluating sorafenib versus stereotactic body radiation therapy followed by sorafenib in HCC is currently open for patient accrual. This study aims to definitively evaluate the role of radiation therapy for locally advanced HCC.
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.
This summary was extensively revised and comprehensively reviewed.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
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://www.cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-09-23
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