Liver Cancer

Liver cancer includes two major types: hepatocellular carcinoma (HCC) and intrahepatic bile duct cancer. There is an additional, less-common variances; also refer to the Bile Duct Cancers.

Incidence and Mortality

Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2018:
• New cases: 42,220. • Deaths: 30,200.

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.
Worldwide, HCC is the sixth most prevalent cancer and the third leading cause of cancer-related deaths.

Clinical Evaluation   Staging   Treatment   Treatment Overview (ASCO)   NCCN Guidelines   Drug Rx Summary  

Risk Factors

The etiology of HCC is likely multifactorial. The following factors may increase the risk of HCC:

Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection: HBV and HCV infections appear to be the most significant causes of HCC worldwide. Chronic HBV infection is the leading cause of HCC in Asia and Africa. HCV infection is the leading cause of HCC in North America, Europe, and Japan.
The annual incidence of HCC in HBV carriers is 0.5% to 1% per year in patients without cirrhosis and 2.5% per year in patients with cirrhosis. The relative risk of HCC is 100 (i.e., carriers of HBV are 100 times more likely to develop HCC than uninfected persons).

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 persons who were anti-HCV negative. HCC may occur in HCV-infected patients with bridging fibrosis, even in the absence of overt cirrhosis. However, the risk is highest among patients with HCV-related established cirrhosis, which has an incidence rate of HCC of 2% to 8% per year.

Alcoholic cirrhosis: 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 HCV.

Metabolic syndrome: The risk factors associated with 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 the incidence of HCC caused by metabolic syndrome.

Biliary cirrhosis: The incidence of HCC in stage IV primary biliary cirrhosis is approximately the same as in cirrhosis resulting from hepatitis C.

Chronic liver injury: Chronic liver injury probably increases the risk of HCC, 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.[Level of evidence: 3iii]

Hemochromatosis: Hemochromatosis is a significant risk factor for HCC and has an increased relative risk twenty times that of the normal population.

Aflatoxin B1: 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 carriers of HBV because it increases the neoplastic risk threefold.

(Refer to the PDQ summary on Liver (Hepatocellular) Cancer Prevention for more information.)

Hepatocellular carcinoma (HCC) Risk Factors

Hepatocellular carcinoma (HCC) Risk FactorsHepatocellular carcinoma (HCC) Risk Factors



(Refer to the PDQ summary on Liver (Hepatocellular) Cancer Screening for more information.)

Diagnostic Factors

For lesions that are smaller than 1 cm and are detected during screening in patients at high risk for HCC, further diagnostic evaluation is not required because most of these lesions will be cirrhotic lesions rather than HCC.[Level of evidence: 3iii] Close follow-up at 3-month intervals is a common surveillance strategy, using the same technique that first documented the presence of the lesions.

For patients with liver lesions larger than 1 cm who are at risk for HCC, a diagnosis should be established. The tests required to diagnose HCC may include imaging, biopsy, or both.

Diagnostic imaging
In patients with cirrhosis, liver disease, or other risk factors for HCC, and with lesions greater than 1 cm, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT]-scan or magnetic resonance imaging [MRI]) can be used to establish a diagnosis of HCC.

A triple-phase CT or MRI assesses the entire liver in distinct phases of perfusion. Following the controlled administration of intravenous contrast media, the arterial and venous phases of perfusion are imaged.

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 HCC of 1 to 3 cm in diameter and virtually diagnostic of HCC.[Level of evidence: 3ii] In these cases, the diagnosis of HCC may be established without the need for a second imaging modality, even in the absence of a biopsy confirmation.[Level of evidence: 3ii]

However, if a first imaging modality, such as 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 lesion larger than 1 cm remains uncharacterized in a patient at high risk for HCC (i.e., with no or only one classic enhancement pattern), a liver biopsy can be considered.

Liver biopsy
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 lesions 1 cm or larger in high-risk patients.

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 cases in which there are metastases from colon cancer. Finding a mass in the liver of a patient with an elevated AFP does not automatically indicate HCC. However, if the AFP level is high, it can be used to monitor for recurrence.


The natural course of early tumors is poorly known because most HCC patients are treated. However, older reports have described 3-year survival rates of 13% to 21% without any specific treatment. At present, only 10% to 23% of patients with HCC may be surgical candidates for curative-intent treatment. The 5-year overall survival (OS) rate for patients with early HCC who are undergoing liver transplant is 44% to 78%; and for patients undergoing a liver resection, the OS rate is 27% to 70%.

Liver transplantation, surgical resection, and ablation offer high rates of complete responses and a potential for cure in patients with early HCC.

The natural course of advanced-stage HCC is better known. Untreated patients with advanced disease usually survive less than 6 months. The survival rate of untreated patients in 25 randomized clinical trials ranged from 10% to 72% at 1 year and 8% to 50% at 2 years.

Unlike most patients with solid tumors, the prognosis of patients with HCC is affected by the tumor stage at presentation and by the underlying liver function. The following prognostic factors guide the selection of treatment:

•Anatomic extension of the tumor (i.e., tumor size, number of lesions, presence of vascular invasion, and extrahepatic spread).
• Performance status.
• Functional hepatic reserve based on the Child-Pugh score.

Cellular Classification of Adult Primary Liver Cancer

Malignant primary tumors of the liver consist of two major cell types, which are hepatocellular (90% of cases) and cholangiocarcinoma.

Histologic classification is as follows:

• Hepatocellular carcinoma (HCC; liver cell carcinoma).
• Fibrolamellar variant of HCC.
It is important to distinguish between the fibrolamellar variant of HCC and HCC itself because an increased proportion of patients with the fibrolamellar variant may be cured if the tumor can be resected. This variant is found more frequently in young women. It also generally exhibits a slower clinical course than the more common HCC.

• Cholangiocarcinoma (intrahepatic bile duct carcinoma).
• Mixed hepatocellular cholangiocarcinoma.
• Undifferentiated.
• Hepatoblastoma. This occurs more often in children than in adults. (Refer to the PDQ summary on Childhood Liver Cancer Treatment for more information.)


Stage Information for Adult Primary Liver Cancer

Prognostic modeling in hepatocellular carcinoma (HCC) is complex because cirrhosis is 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. New classifications have been proposed in an effort to overcome the difficulties of having several staging systems.

This summary discusses the following three staging systems:

1.Barcelona Clinic Liver Cancer (BCLC) Staging System.
2.Okuda Staging System.
3.AJCC Staging System.

Barcelona Clinic Liver Cancer (BCLC) Staging System
Currently, the BCLC staging classification is the most accepted staging system for HCC and is useful in the staging of early tumors. 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:

• Tumor stage.
• Functional status of the liver.
• Physical status.
• Cancer-related symptoms.

Five stages (0 and A through D) are identified based on the variables mentioned above. The BCLC staging system links each HCC stage to appropriate treatment modalities as follows:

•Patients with early-stage HCC may benefit from curative therapies (i.e., liver transplantation, surgical resection, and radiofrequency ablation).
•Patients with intermediate-stage or advanced-stage disease may benefit from palliative treatments (i.e., transcatheter arterial chemoembolization and sorafenib).
•Patients with end-stage disease who have a very poor life expectancy are offered supportive care and palliation.

Okuda Staging System
The Okuda staging system has been extensively used in the past and includes variables related to tumor burden and liver function, such as bilirubin, albumin, and ascites. 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. As a result, Okuda staging is unable to stratify prognosis for early-stage cancers and mostly serves to recognize end-stage disease.

AJCC Staging System
Definitions of TNM The TNM (tumor, node, and metastasis) classification for staging, proposed by the AJCC, is not widely used for liver cancer. 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 tumor excision. TNM may be useful in prognostic prediction after liver resection.

The AJCC has designated staging by TNM to define liver cancer as shown here:

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 larger than 5 cm.
T3a = Multiple tumors larger than 5 cm.
T3b = Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein.
T4 = Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of 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 Metastases (M)
M0 = No distant metastasis.
M1 = Distant metastasis.

Staging by TNM (AJCC)

Stage T N M
I T1 N0 M0
II T2 N0 M0
IIIA T3a N0 M0
IIIB T3b N0 M0
IVA Any T N1 M0
IVB Any T Any N M1



Liver Cancer - Treatment Options

Treatment Option Overview for Adult Primary Liver Cancer

There is no agreement on a single treatment strategy for patients with hepatocellular carcinoma (HCC). Selection of treatment is complex due to several factors, including:
• Underlying liver function.
• Extent and location of the tumor.
• General condition of the patient.

Several treatments for HCC are associated with long-term survival, including surgical resection, liver transplantation, and ablation.
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.
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.

Best survivals are achieved when the HCC can be removed either by surgical resection or liver transplantation.
Surgical resection is usually performed in patients with localized HCC and sufficient functional hepatic reserve.

For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (≤3 lesions, ≤3 cm in diameter), the best option is liver transplantation, but the limited availability of liver donors restricts the use of this approach.

Among noncurative treatments for HCC, transarterial chemoembolization and sorafenib have been shown to improve survival.

For treatment, HCC can be divided into the following two broad categories:
• Tumors for which potentially curative treatments are available (BCLC stages 0, A, and B).
• Tumors for which curative options are not available (BCLC stages C and D).

Standard Treatment Options for HCC

Stage Standard Treatment Options
Stages 0, A, and B Surgical Resection
Liver Transplantation
Stages C and D Transarterial Embolization and
Transcatheter Arterial Chemoembolization
Targeted Therapy
Radiation Therapy
Recurrent Stage Liver Transplantation
Surgical Resection
Palliative Therapy



Stages 0, A, and B Adult Primary Liver Cancer Treatment

Localized hepatocellular carcinomas (HCCs) that present as a solitary mass in a portion of the liver or as a limited number of tumors (≤3 lesions, ≤3 cm in diameter) without major vascular invasion constitute approximately 30% of the HCC cases.

There are three potentially curative therapies that are acceptable treatment options for small, single-lesion HCC in patients with well-preserved liver function.

Standard treatment options for stages 0, A, and B adult primary liver cancer include the following:
1. Surgical resection.
2. Liver transplantation.
3. Ablation.
Resection and transplantation achieve the best outcomes in well-selected candidates and are usually considered to be the first option for curative intent.

Surgical Resection
Surgery is the mainstay of HCC treatment.

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.

Surgical resection can be considered for patients who meet the following criteria:
• A solitary mass.
• Good performance status.
• Normal or minimally abnormal liver function tests.
• No evidence of portal hypertension.
• No evidence of cirrhosis beyond Child-Pugh class A.

After considering the location and number of tumors, and the hepatic function of the patient, only 5% to 10% of patients with liver cancer will prove to have localized disease amenable to resection.

The principles of surgical resection involve obtaining a clear margin around the tumor, which may require any of the following:
• Segmental resection.
• Hormone-lymphatic lobectomy.
• Extended lobectomy.

The 5-year overall survival (OS) rate after curative resection ranges between 27% and 70% and depends on tumor stage and underlying liver function.
In patients with limited multifocal disease, hepatic resection is controversial.

Liver Transplantation
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.

According to the Milan criteria, patients with a single HCC lesion smaller than 5 cm, or 2 to 3 lesions smaller than 3 cm are eligible for liver transplantation.
Expansion of the accepted transplantation criteria for HCC is not supported by consistent data.
Liver transplantation is considered if resection is precluded as a result of multiple, small, tumor lesions (≤3 lesions, each <3 cm), or if the liver function is impaired (Child-Pugh class B and class C). In patients who meet the criteria, transplantation is associated with a 5-year OS rate of approximately 70%.[Level of evidence: 3iiiA]

When tumor excision, either by transplant or resection, is not feasible or advisable, ablation may be used if the tumor can be accessed percutaneously or, if necessary, through minimally invasive or open surgery. Ablation may be particularly useful for patients with early-stage HCC that is centrally located in the liver and cannot be surgically removed without excessive sacrifice of functional parenchyma.

Ablation can be achieved in the following ways:
• Change in temperature (e.g., radiofrequency ablation [RFA], microwave, or cryoablation).
• Exposure to a chemical substance (e.g., percutaneous ethanol injection [PEI]).
• Direct damage of the cellular membrane (definitive electroporation).

With ablation, a margin of normal liver around the tumor should be considered. 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 procedure.
Furthermore, when tumors are located adjacent to major vessels, the blood flow in the vessels may keep thermal ablation techniques, such as RFA, from reaching optimal temperatures. This is known as the heat-sink effect, which may preclude complete tumor necrosis.

RFA 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.[7,8] Local control success progressively diminishes as the tumor size increases beyond 3 cm.

PEI obtains good results in patients with Child-Pugh class A cirrhosis and a single tumor smaller than 3 cm in diameter. In those cases, the 5-year OS rate is expected to be as high as 40% to 59%.[Level of evidence: 3iiiD]

In the few randomized, controlled trials that included patients with Child-Pugh class A cirrhosis, RFA proved superior to PEI in 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 outcomes.

Of note, RFA may have higher complication rates than PEI, but both techniques are associated with lower complication rates than excision procedures. RFA is a well-established technique in the treatment of HCC.

Treatment Options Under Clinical Evaluation for Stages 0, A, and B adult primary liver cancer include the following:
• Definitive electroporation.



Stages C and D Adult Primary Liver Cancer Treatment

Standard treatment options for stages C and D adult primary liver cancer include the following:

1.Transarterial embolization (TAE) and transcatheter arterial chemoembolization (TACE).
2.Targeted therapy.
3.Radiation therapy.

Transarterial Embolization (TAE) and Transcatheter Arterial Chemoembolization (TACE)
TAE is the most widely used primary treatment for hepatocellular carcinoma (HCC) 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, whereas blood flow to the tumor 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 HCC who are not amenable to surgery or 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. No standardized approach for TAE has been determined (e.g., embolizing agent, chemotherapy agent and dose, and treatment schedule). However, a meta-analysis has shown that TAE-TACE improves survival more than supportive treatment.

The use of drug-eluting beads for TACE (DEB-TACE) has the potential of reducing systemic side effects of chemotherapy and may increase objective tumor response. Only one study has suggested that DEB-TACE may offer an advantage in overall survival (OS).

Targeted Therapy
■ Sorafenib
Sorafenib is an oral multikinase inhibitor that prolongs survival in patients with advanced HCC and well-compensated liver function.

Evidence (sorafenib):
1. 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 Child-Pugh class 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).
2. A subsequent, similar trial conducted in 23 centers in China, South Korea, and Taiwan included 226 patients (97% with Child-Pugh class A liver function) with twice as many patients randomly assigned to sorafenib as to 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 reaction and diarrhea.

These studies established a role for sorafenib in locally advanced HCC and advanced hepatocellular cancers extending beyond the liver, which are not amenable to regional modalities.

Little is known about the efficacy of sorafenib for patients with Child-Pugh class B or C liver function. Further studies are needed to determine whether sorafenib is an appropriate treatment option for these patients.
Studies are also ongoing to evaluate the role of sorafenib after TACE, with chemotherapy, or in the presence of more-advanced liver disease.

Radiation Therapy
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 of radiation therapy in local control and OS compared with historical controls for patients with locally advanced HCC unsuitable for standard locoregional therapies.[Level of evidence: 3iiDiii]

Systemic Chemotherapy
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.

Treatment Options Under Clinical Evaluation for Stages C and D Adult Primary Liver Cancer
The efficacy of other targeted therapy agents (e.g., sunitinib and brivanib) is currently being investigated.
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 in the treatment of locally advanced HCC.



Recurrent Adult Primary Cancer Treatment

Intrahepatic recurrence is the most common pattern of failure after curative treatment. Intrahepatic recurrence of hepatocellular carcinoma (HCC) may be the result of either intrahepatic metastasis or metachronous de novo tumor.
Theoretically, intrahepatic metastasis may be associated with less favorable outcomes because it is most likely the result of concurrent hematogenous metastases. However, in clinical practice, the two causes of recurrence cannot be differentiated from each other.

Treatment options for recurrent adult primary liver cancer include the following:
1. Liver transplantation.
2. Surgical resection.
3. Ablation.
4. Palliative therapy (transcatheter arterial chemoembolization [TACE] and sorafenib).

In regard to primary HCC, the treatment strategy for recurrent intrahepatic HCC is determined by the function of the liver and the macroscopic tumor features (e.g., number of lesions, site of recurrence, and invasion of major vessels). Using the same selection criteria that are used for primary HCC, either curative (i.e., salvage liver transplant, surgical resection, and ablation) or palliative treatments (e.g., TACE and sorafenib) can be offered for recurrent HCC.

1. Liver transplantation. 2. Surgical resection. 3. Ablation.

Evidence (salvage liver transplant, resection, and ablation):
1.In a retrospective study of 183 patients with intrahepatic recurrence, only 87 of the patients could be treated with curative intent (transplantation, resection, and ablation).[Level of evidence: 1A]
• The 5-year tumor-free survival rate was 57.9% for liver transplantation, 49.3% for resection, and 10.6% for radiofrequency ablation. Subgroup analysis showed that transplantation and resection led to comparable survival and that both treatments led to significantly better outcomes than did ablation (P < .001); however, selection bias was a major pitfall of this retrospective study.
• Other than the use of ablation for secondary treatment, risk factors for shorter disease-free survival were identified as alpha-fetoprotein blood levels above 400 ng/mL and recurrence within 1 year of treatment (47.5% vs. 6.7% at 5 years, P < .001).

Other studies have also suggested that most of the recurrences that appear early during follow-up are caused by tumor dissemination and have a more aggressive biological pattern than primary tumors.

Clinical trials are appropriate and should be offered to patients with recurrent HCC whenever possible.




Liver Cancer - Treatment Options

Treatment overview
Treatment options and recommendations depend on several factors:
• How much of the liver is affected by the cancer
• Whether the cancer has spread
• The patient’s preferences and overall health
• The damage to the remaining cancer-free area of the liver

When a tumor is found at an early stage and the patient’s liver is working well, treatment is aimed at trying to eliminate the cancer. The care plan may also include treatment for symptoms and side effects, an important part of cancer care. When liver cancer is found at a later stage, or the patient’s liver is not working well, the patient and doctor should talk about the goals of each treatment recommendation. At this point, the goals of treatment may focus on slowing growth of the cancer and relieving symptoms to improve quality of life.

The various disease-directed treatment options can be grouped according to whether they may cure the cancer or will improve survival but will most likely not eliminate the cancer. Descriptions of the most common treatment options, both disease-directed and those aimed at managing side effects and symptoms, are listed below. Take time to learn about your treatment options and be sure to ask questions about things that are unclear. Talk with your doctor about the goals of each treatment and what you can expect while receiving the treatment. Learn more about making treatment decisions.

Disease-directed treatments to eliminate and potentially cure HCC

These treatments are generally recommended when the tumor has been found at an early stage. They may not be recommended to treat patients with later stages of disease. These treatments are 1. surgery, 2. radiofrequency ablation, 3. percutaneous ethanol injection, and 4. radiation therapy.

1. Surgery
Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. It is likely to be the most successful disease-directed treatment, particularly for patients with good liver function and tumors that can be safely removed from a limited portion of the liver. Surgery may not be an option if the tumor takes up too much of the liver, the liver is too damaged, the tumor has spread outside the liver, or the patient has other serious illnesses. A surgical oncologist is a doctor who specializes in treating cancer using surgery. A hepatobiliary surgeon also has specialized training in surgery on the liver and pancreas. Sometimes, liver transplant surgeons are involved in these operations. Before surgery, talk with your health care team about the possible side effects from the specific surgery you will have. Learn more about the basics of cancer surgery.

Two types of surgery are used to treat HCC:
• Hepatectomy. When a portion of the liver is removed, the surgery is called a hepatectomy. A hepatectomy can be done only if the cancer is in 1 part of the liver and the liver is working well. The remaining section of liver takes over the functions of the entire liver. The liver may grow back to its normal size within a few weeks. A hepatectomy may not be possible if the patient has advanced cirrhosis, even if the tumor is small.

The side effects of a hepatectomy may include pain, weakness, fatigue, and temporary liver failure. The health care team will watch for signs of bleeding, infection, liver failure, or other problems that need immediate treatment.

• Liver transplantation. Sometimes, a liver transplantation can be done. This procedure is possible only when the cancer has not spread outside the liver, a suitable donor is found, and very specific criteria are met in terms of tumor size and number. These criteria usually are a single tumor that is 5 cm or smaller or 3 or fewer tumors, all of which are smaller than 3 cm. It is important to understand that the number of available donor livers is very limited, so transplantation is not always an option.

After a transplant, the patient will be watched closely for signs that the body might be rejecting the new liver or that the tumor has come back. The patient must take medication to prevent rejection. These drugs can cause side effects, such as puffiness in the face, high blood pressure, or increased body hair. Liver transplant has significant risks of serious complications, including death from infection or rejection of the donor liver.

Liver transplantation is a particularly effective treatment for people with a small tumor because transplantation removes the tumor and the damaged liver. However, there are few donors, and people waiting for a liver transplant may have to wait for a long time before a liver becomes available. During this time, the disease may get worse. The transplant center will advise you on how long the wait is likely to be and what rules are used to prioritize people on the waiting list.

2. Radiofrequency ablation (RFA)
RFA and microwave therapy both use heat to destroy cancer cells. They may be given through the skin, through laparoscopy, or during a surgical operation while a patient is sedated. Sedation is giving medication to become more relaxed, calm, or sleepy. This treatment is also called thermal ablation.

3. Percutaneous ethanol injection
Percutaneous ethanol injection is when alcohol is injected directly into the liver tumor to destroy it. Side effects include fever and pain after the procedure. In general, the procedure is simple, safe, and particularly effective for a tumor smaller than 3 cm. However, if the alcohol escapes from the liver, a person may have brief but severe pain. This option is rarely used and has been largely replaced by RFA (see above).

4. Radiation therapy

Radiation therapy is the use of high-energy x-rays or other particles to destroy cancer cells.

• Stereotactic body radiation therapy (SBRT). SBRT is a term that describes several methods of delivering high doses of radiation to a tumor while limiting the amount of radiation to which healthy tissues are exposed. This is important because healthy liver tissue can be damaged by radiation. SBRT effectively treats tumors that are about 5 cm or smaller. However, it is still considered investigational compared to RFA (see above) because there is not much available information about its long-term effectiveness.

Side effects may include damage to the stomach and lungs. However, these side effects can often be prevented. Talk with your health care team about avoiding and managing possible side effects. Learn more about the basics of radiation therapy.

Disease-directed treatments to help patients live longer

If the doctor feels the cancer cannot be cured using the treatments listed above, he or she may recommend 1 of the following options to shrink the tumor and/or slow tumor growth. While these treatments will most likely not eliminate the cancer, they have been shown to improve how long patients can live.

Chemoembolization and radioembolization
Chemoembolization is a type of chemotherapy treatment that is similar to hepatic arterial infusion (see below). Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide. During this procedure, drugs are injected into the hepatic artery, and the flow of blood through the artery is blocked for a short time so the chemotherapy stays in the tumor longer. Blocking the blood supply to the tumor also destroys cancer cells.

In addition to being used as a primary treatment for HCC, chemoembolization may be used to slow tumor growth for people who are on the waiting list for liver transplantation.

Radioembolization is similar to chemoembolization, except that during radioembolization, a doctor places radioactive beads into the artery that supplies the tumor with blood. The beads deliver radiation directly into the tumor when they become trapped in the small blood vessels of the tumor.

Targeted therapy
Targeted therapy is drug treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.

Recent studies show that not all tumors have the same targets. To find the most effective treatment, your doctor may run tests to identify the genes, proteins, and other factors in your tumor. This helps doctors better match each patient with the most effective treatment whenever possible. In addition, many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them. Learn more about the basics of targeted treatments.

For HCC, anti-angiogenesis drugs are the most common type of targeted therapy. Anti-angiogenesis therapy is focused on stopping angiogenesis, which is the process of making new blood vessels. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapies is to “starve” the tumor. Sorafenib (Nexavar) is believed to work through this process. Sorafenib is used to treat advanced HCC that cannot be completely removed with surgery. It is taken as pill that is swallowed (orally). The side effects of sorafenib include diarrhea and certain skin problems.

In April 2017, the U.S. Food and Drug Administration (FDA) approved the use of another targeted therapy, regorafenib (Stivarga), to treat people with HCC that was previously treated with sorafenib. Regorafenib also inhibits angiogenesis, and it is already used to treat colorectal cancer and gastrointestinal stromal tumors.

Talk with your doctor about the possible side effects for a specific medication and how they can be managed.

Other treatment options

Immunotherapy (updated 09/2017)
Immunotherapy, also called biologic therapy, is designed to boost the body's natural defenses to fight the cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function. In September 2017, the FDA approved an immunotherapy called nivolumab (Opdivo) for the treatment of HCC. Nivolumab can be used to treat people who have already been treated with sorafenib. Other immunotherapy drugs are still being studied in clinical trials.

Side effects of immunotherapy can range from very few side effects in many patients to dangerous autoimmune conditions in some patients. In autoimmune conditions, the immune system attacks normal parts of the body, such as the colon or lungs. Talk with your health care team about possible side effects for the immunotherapy recommended for you. Learn more about the basics of immunotherapy.

Getting care for symptoms and side effects

Cancer and its treatment often cause side effects. In addition to treatments intended to slow, stop, or eliminate the cancer, an important part of cancer care is relieving a person’s symptoms and side effects. This approach is called palliative or supportive care, and it includes supporting the patient with his or her physical, emotional, and social needs.

Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care. It works best when palliative care is started as early as needed in the cancer treatment process. People often receive treatment for the cancer at the same time that they receive treatment to ease side effects. In fact, patients who receive both at the same time often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional support, and other therapies. You may also receive palliative treatments similar to those meant to eliminate the cancer, such as chemotherapy, surgery, or radiation therapy. Talk with your doctor about the goals of each treatment in your treatment plan.

Before treatment begins, talk with your health care team about the possible side effects of your specific treatment plan and palliative care options. During and after treatment, be sure to tell your doctor or another health care team member if you are experiencing a problem so it can be addressed as quickly as possible. Learn more about palliative care.

Metastatic HCC

If HCC has spread to another location in the body, it is called metastatic cancer. People with this diagnosis are encouraged to talk with doctors who are experienced in treating this stage of cancer because there can be different opinions about the best treatment plan. Learn more about getting a second opinion before starting treatment, so you are comfortable with your chosen treatment plan. This discussion may include clinical trials studying new treatments.

Your treatment plan may include a combination of chemotherapy, targeted therapy, radiation therapy, and/or other options. At this stage, the goal of treatment is typically to slow the cancer’s growth. Palliative care will also be important to help relieve symptoms and side effects.

For most patients, a diagnosis of metastatic cancer is very stressful and, at times, difficult to bear. Patients and their families are encouraged to talk about the way they are feeling with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

Remission and the chance of recurrence

A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having “no evidence of disease” or NED.

A remission may be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. While many remissions are permanent, it’s important to talk with your doctor about the possibility of the cancer returning. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.

If the cancer does return after the original treatment, it is called recurrent cancer. It may come back in the same place (called a local recurrence), nearby (regional recurrence), or in another place (distant recurrence).

When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence. After this testing is done, you and your doctor will talk about your treatment options. Often the treatment plan will include the treatments described above, such as surgery and radiation therapy, but they may be used in a different combination or given at a different pace. Your doctor may suggest clinical trials that are studying new ways to treat this type of recurrent cancer. Whichever treatment plan you choose, palliative care will be important for relieving symptoms and side effects.

People with recurrent cancer often experience emotions such as disbelief or fear. Patients are encouraged to talk with their health care team about these feelings and ask about support services to help them cope. Learn more about dealing with cancer recurrence.

If treatment doesn’t work

Recovery from cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.

This diagnosis is stressful, and for many people, advanced cancer is difficult to discuss. However, it is important to have open and honest conversations with your doctor and health care team to express your feelings, preferences, and concerns. The health care team is there to help, and many team members have special skills, experience, and knowledge to support patients and their families. Making sure a person is physically comfortable and free from pain is extremely important.

Patients who have advanced cancer and who are expected to live less than 6 months may want to consider a type of palliative care called hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment can make staying at home a workable option for many families. Learn more about advanced cancer care planning.

After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss.



NCCN Guidelines for Hepatobiliary Cancers


Hepatobiliary cancers are associated with a poor prognosis. Many patients with HCC are diagnosed at an advanced stage, and patients with biliary tract cancers commonly present with advanced disease. In the past few years, several advances have been made in the therapeutic approaches for patients with hepatobiliary cancers.

Complete resection of well-selected patients is currently the best available potentially curative treatment. Liver transplantation is a curative option for select resectable patients. Bridge therapy can be considered for patients with HCC to decrease tumor progression and the dropout rate from the liver transplantation waiting list.

Locoregional therapies (ablation, arterially directed therapies, and RT) are often the initial approach for patients with HCC who are not candidates for surgery or liver transplantation. Ablation should be considered as definitive treatment in the context of a multidisciplinary review in well-selected patients with small properly located tumors. Arterially directed therapies (TACE, DEB-TACE, or TARE with yttrium-90 microspheres) are appropriate for patients with unresectable or inoperable tumors that are not amenable to ablation therapy. SBRT can be considered as an alternative to ablation and/or embolization techniques (especially for patients with 1–3 tumors and minimal or no extrahepatic disease) or when these therapies have failed or are contraindicated. Though it is currently rarely used, there are emerging data supporting its usefulness. PBT may also be used in select settings. Locoregional therapy is also included as an option for patients with unresectable or metastatic intrahepatic cholangiocarcinoma. RTwith EBRT and SBRT may be used in patients with unresectable gallbladder cancer or extrahepatic cholangiocarcinoma, though there is little evidence to support this treatment option without concurrent chemotherapy and in patients with unresected disease.

Regarding systemic therapy, the safety and efficacy of sorafenib as front-line therapy for patients with advanced HCC and Child-Pugh class A liver function was demonstrated in two phase III randomized placebo-controlled studies, though the survival differences between groups were small. Sorafenib is recommended as a category 1 option for this group of patients and is included as a category 2A option for selected patients with Child-Pugh class B liver function. Systemic therapy for patients with HCC that has failed on or after sorafenib is an active area of research, with options currently recommended by the panel including regorafenib and nivolumab. The results of the randomized phase III ABC-02 study demonstrated a survival advantage for the combination of gemcitabine and cisplatin over gemcitabine alone in patients with advanced or metastatic biliary tract cancers. The combination of gemcitabine and cisplatin is included as a category 1 recommendation for this group of patients.

It is essential that all patients should be evaluated prior to initiation of treatment. Careful patient selection for treatment and active multidisciplinary cooperation are essential. There are relatively few high-quality randomized clinical trials of patients with hepatobiliary cancers, and patient participation in prospective clinical trials is the preferred option for the treatment of patients with all stages of disease.

Child Pugh Score

Child Pugh Score

Second-line Therapy Following Sorafenib

Therapeutic agents are being assessed in patients with advanced HCC, particularly in those who had disease progression following treatment with sorafenib. The randomized, double-blind, placebo-controlled, international phase III RESORCE trial assessed the efficacy and safety of regorafenib in 573 patients with HCC and Child-Pugh A liver function who progressed on sorafenib. Compared to the placebo (median survival of 7.8 months), regorafenib (median survival of 10.6 months)improved OS (HR, 0.63; 95% CI, 0.50–0.79; P < .001), PFS (HR, 0.46; 95% CI, 0.37–0.56; P < .001), TTP (HR, 0.44; 95% CI, 0.36–0.55; P < .001), objective response (11% vs. 4%; P = .005), and disease control (65% vs. 36%; P < .001). Adverse events were universal among patients randomized to receive regorafenib (n = 374), with the most frequent grade 3 or 4 treatment-related events being hypertension (15%), hand-foot skin reaction (13%), fatigue (9%), and diarrhea (3%). Seven deaths that occurred were considered by the investigators to have been related to treatment with regorafenib. Based on the results of this trial, the FDA approved use of regorafenib in 2017 for patients with HCC who progressed on or after sorafenib, and the panel recommends regorafenib as a category 1 option for this setting in patients with Child-Pugh A liver function.

Nivolumab, an anti-programmed death receptor-1 (PD-1) antibody, was assessed in the phase I/II nonrandomized multi-institution CheckMate 040 trial including 48 patients with advanced HCC in a dose-escalation phase and 214 patients in a dose-expansion phase. In patients treated with nivolumab 3 mg/kg, the objective response rate was 20% for patients in the dose-expansion phase and 15% for patients in the dose-escalation phase. The disease control rates were 64% and 58% for patients in these phases, respectively. Nine-month OS for patients in the dose-expansion phase was 74%. In the dose-escalation phase, 25% of patients had grade 3 or 4 treatment-related adverse events. In the dose-expansion phase, analyses of 57 patients without viral hepatitis who progressed following sorafenib showed a disease control rate of 61%. Median OS and 6-month OS rates for these patients were 13.2 months and 75%, respectively. Additional analyses from this trial showed a median duration of response of 17 months in sorafenib-naïve patients (n = 80) and 19 months in patients who had been previously treated with sorafenib (n = 182). Eighteen-month OS rates for these patients were 57% and 44%, respectively. Based on the results from the CheckMate 040 trial, the FDA approved use of nivolumab in 2017 for patients with HCC who progressed on or after sorafenib, and the panel recommends nivolumab for this setting in patients with Child-Pugh A or B7 liver function. CheckMate 459, a phase III RCT in which nivolumab is being compared to sorafenib as definitive treatment in patients with advanced HCC, is currently in process (NCT02576509).

Cabozantinib, a tyrosine kinase inhibitor, was assessed in the phase III randomized CELESTIAL trial including 707 patients with incurable HCC who have progressed on or after sorafenib, with 7.6% of the sample having received more than one line of previous treatment. Median OS and PFS rates were significantly greater in patients randomized to receive cabozantinib (10.2 months and 5.2 months, respectively), compared to patients randomized to receive a placebo (8.0 and 1.9months, respectively) (HR, 0.76; 95% CI, 0.63–0.92; P = .005 for OS; HR, 0.44; 95% CI, 0.36–0.52; P < .001 for PFS). Though the objective response rate was better in the cabozantinib arm than in the placebo arm (P = .009), this value was low, with a PR having been reported in only 4% of patients who received cabozantinib (vs. 0.4% in patients who received a placebo).

In a phase III RCT, the effects of the VEGF receptor inhibitor ramucirumab were assessed as second-line therapy following sorafenib in patients with advanced HCC (N = 565).392,393 Though this regimen did not improve OS, median PFS (HR, 0.63; 95% CI, 0.52–0.75; P < .001) and time to tumor progression (HR, 0.59; 95% CI, 0.49–0.72; P < .001) were improved, relative to the placebo group. Analyses of patient-focused outcomes showed that deterioration of symptoms was not significantly different in patients randomized to receive ramucirumab, compared to the placebo group. Data from a phase II trial has demonstrated potential activity of axitinib and tolerability for patients with intermediate/advanced Child Pugh class A disease as a second-line therapy.



Therapy for Unresectable Hepatocellular carcinoma (HCC)

Therapy for Unresectable Hepatocellular carcinoma (HCC)

Therapy for Inoperable or Metastatic Hepatocellular carcinoma (HCC)

Therapy for Inoperable or Metastatic Hepatocellular carcinoma (HCC)

Summary - Drug therapy for Hepatocellular carcinoma (HCC)

Systemic Chemotherapy

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.
Chemotherapy should be used preferably in the context of a clinical trial.

Targeted Therapy

        ◦ sorafenib (Nexavar) - Multi-Kinase Inhibitor - Anti-angiogenesis drugs

        ◦ regorafenib (Stivarga) - Multi-Kinase Inhibitor - Anti-angiogenesis drugs
        ◦ Nivolumab (Opdivo) - Immune checkpoint inhibitors

BCLC Staging and Treatment and Treatment Algorithm

Therapy for Inoperable or Metastatic Hepatocellular carcinoma (HCC)

BCLC = Barcelona Clinic Liver Cancer


• First-line systemic therapy
        ◊Sorafenib (Child-Pugh Class A [category 1] or B7)
        ◊Lenvatinib (Child-Pugh Class A only)
    Other Recommended
        ◊Systemic Chemotherapy (category 2B)

• Subsequent-line therapyd if disease progression:
    Regorafenib (Child-Pugh Class A only) (category 1)
    Cabozantinib (Child- Pugh Class A only) (category 1)
    Ramucirumab (AFP ≥ 400 ng/mL only) (category 1)
    Nivolumab (Child-Pugh Class A or B7)
    Sorafenib (Child-Pugh Class A or B7) (after first-line lenvatinib)
    Pembrolizumab (Child-Pugh Class A only) (category 2B)