Liver Cancer – Causes, Symptoms, Diagnosis, Treatment

Liver cancer (also known as hepatic cancer, hepatocellular carcinoma, primary hepatic cancer, or primary hepatic malignancy, and ) is a cancer that starts in the liver.[rx] Liver cancer can be primary (starts in the liver) or secondary (meaning cancer that has spread from elsewhere to the liver, known as liver metastasis). Liver metastasis is more common than that which starts in the liver.[rx] Liver cancer is increasing globally

Hepatocellular carcinoma (HCC) is a primary tumor of the liver. Hepatocellular carcinoma constitutes more than 90% of the primary tumor of the liver. This activity describes the evaluation and management of hepatocellular carcinoma and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Hepatocellular carcinoma (HCC) is a primary tumor of the liver and constitutes more than 90% of the primary tumor of the liver. Hepatocellular carcinoma occurs in approximately 85% of patients diagnosed with cirrhosis. HCC is now the fifth most common cause of cancer worldwide. The second leading cause of cancer death after lung cancer in men is HCC. Five-year survival of HCC is 18% and second to pancreatic cancer. Significant risk factors for hepatocellular carcinoma include viral hepatitis (hepatitis B and hepatitis C), alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease. HCC occurs in 80%-90% of patients with cirrhosis. The annual incidence of HCC in patients with cirrhosis is 2-4%.

Types

There are three types of primary liver cancer:

  • Hepatocellular carcinoma (HCC): This is the most common form of liver cancer, representing nearly all liver cancer cases.
  • Intrahepatic cancer (IHC): This is a form of cholangiocarcinoma. IHC is cancer in your liver’s bile ducts. It represents about 10% to 20% of all primary liver cancer cases.
  • Angiosarcoma: This type is very rare, representing about 1% of all primary liver cancer cases. This cancer begins in the lining of blood cells in your liver. (Angiosarcoma may also affect other organs.)

Overall, HCC and IHC represent about 2% of all new estimated cancer cases in the United States and 5% of all new cancer deaths. Healthcare providers often diagnose and treat HCC and IHC the same way.

Secondary Types of Liver Cancer

Hepatocellular carcinoma

Liver tumor types by relative incidence in adults in the United States (liver cancers in dark red color).[rx]

The most frequent liver cancer, accounting for approximately 75% of all primary liver cancers, is hepatocellular carcinoma (HCC).[rx] HCC is cancer formed by liver cells, known as hepatocytes, that become malignant. In terms of cancer deaths, worldwide HCC is considered the 3rd most common cause of cancer mortalities.[rx]

In terms of HCC diagnosis, it is recommended that people with risk factors (including known chronic liver disease, cirrhosis, etc.) should receive screening ultrasounds. If the ultrasound shows a focal area that is larger than 1 centimeter in size, patients should then get a triple-phase contrast-enhanced CT or MRI imaging.[rx] HCC can then be diagnosed radiologically using the Liver Imaging Reporting and Data System (LI-RADS).[rx] There is also a variant type of HCC that consists of both HCC and cholangiocarcinoma.[rx]

Intrahepatic cholangiocarcinoma

Cancer of the bile duct (cholangiocarcinoma and cholangiocellular cystadenocarcinoma) accounts for approximately 6% of primary liver cancers.[rx] Intrahepatic cholangiocarcinoma (CCA) is an epithelial cancer of the intra-hepatic biliary tree branches.[rx] Intrahepatic CCA is the second leading cause of primary liver cancer.[rx] It is more common in men and usually is diagnosed in 60-70-year-olds.[rx] Risk factors for the development of intrahepatic CCA include opisthorchus viverrini infection, Clonorchis Sinensis infection, sclerosing cholangitis, choledochal cysts, past procedures of the biliary tree, exposure to thorotrast and dioxins, and cirrhosis.[rx] This cancer is usually asymptomatic until the disease has progressed. Symptoms include abdominal pain, night sweats, weight loss, and fatigue.[rx] Liver markers that can be increased with intrahepatic CCA are carcinoembryonic antigen (CEA), CA19-9, and CA-125.[rx]

Angiosarcoma and hemangiosarcoma

These are rare and aggressive liver cancers, yet are the third most common primary liver cancer making up 0.1-2.0% of primary liver cancer.[rx] Angiosarcoma and hemangiosarcoma of the liver come from the blood vessel’s endothelial layer. These tumors have poor outcomes because they grow rapidly and metastasize easily. They are also hard to diagnose but are typically suspected on CT or MRI imaging that shows focal lesions with differing amounts of echogenicity (these tumors have a lot of bleeding or hemorrhage and subsequent dying of tissue (necrosis)).[rx] Biopsy with histopathological evaluation yields the definitive diagnosis.[rx] While the cause is often never identified (75% are idiopathic), they are associated with exposures to substances such as vinyl chloride, arsenic, and thorotrast (e.g. occupational exposure). Radiation is also a risk factor.[rx] In adults, these tumors are more common in males; however, in children, they are more common in females.[rx]

Even with surgery prognosis is poor with most individuals not living longer than six months after diagnosis. Only 3% of individuals live longer than two years.[rx]

Hepatoblastoma

Another type of cancer formed by liver cells is hepatoblastoma, which is specifically formed by immature liver cells.[rx] It is a rare malignant tumor that primarily develops in children, and accounts for approximately 1% of all cancers in children and 79% of all primary liver cancers under the age of 15.[rx][rx] Most hepatoblastomas form in the right lobe.[rx]

Metastasis to liver

Many cancers found in the liver are not true liver cancers but are cancers from other sites in the body that have spread to the liver (known as metastases). Frequently, the site of origin is the gastrointestinal tract, since the liver is close to many of these metabolically active, blood-rich organs near blood vessels and lymph nodes (such as pancreatic cancer, stomach cancer, colon cancer, and carcinoid tumors mainly of the appendix), but also from breast cancer, ovarian cancer, lung cancer, renal cancer, prostate cancer.

Causes

Hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease are the etiological factors for the development of hepatocellular carcinoma.

Viral Hepatitis

Chronic hepatitis B virus and chronic hepatitis C virus are associated with more than 70% of cases of hepatocellular carcinoma.

Hepatitis B virus- Hepatitis B virus (HBV) is an enveloped virus, partially double-stranded virus, circular DNA genome, and belongs to the family HepadnavirusHepatitis B affects more than 250 million individuals worldwide and is the most common cause of chronic hepatitis worldwide. Integration of the hepatitis B virus genome into the host genome is the primary pathogenesis for oncogenesis in HBV. Insertion of viral genome in telomerase reverse transcriptase (TERT) promoter sites of the human genome resulting in mutation accounting for 60% of HCC cases. Other genetic alterations include mutations in TP53 (affecting cell cycle), beta-1 catenin (CTNNBI), axis inhibitor-1 (AXINI), AT-rich interaction domain-containing protein 1A (ARID1A), and ARID2(chromatin proliferation). The Hepatitis B virus and the Hepatitis C virus infection account for 56 % and 20% of HCC cases diagnosed worldwide, respectively. HCC can occur in the absence of cirrhosis in patients infected with the hepatitis B virus infection. More than 80% of HBV-related HCCs have underlying cirrhosis. A strong risk predictor for hepatocellular carcinoma in patients with HBV includes elevated serum HBV DNA levels (equal to or more than 10,000 copies/mL). This is independent of the hepatitis B e antigen (HBeAg) status of the patient. Also, the positivity of the hepatitis B e antigen is associated with an increased incidence of HCC. This may be an indicator of a prolonged replication phase. HBV genotype C is associated with an increased risk for HCC. Patients with low hepatitis B virus load but high levels of hepatitis B surface antigen (HBsAg) with levels of more than 1000 IU/mL are significantly associated with HCC. Viral coinfection with the hepatitis C virus and the hepatitis delta virus increases the risk for the development of HCC.

Hepatitis C virus- Hepatitis C virus (HCV) is a partially double-stranded, plus-sense RNA virus with 11 major genotypes, and 15 different subtypes. HCV genotype 1b is frequently associated with HCC. HCV does not integrate with the host genome. Cirrhosis is a significant step in viral carcinogenesis for HCC. Chronic inflammation in chronic hepatitis C virus infection with subsequent fibrosis, necrosis, and regeneration contributes to HCC development. Molecular markers noted in liver carcinogenesis include viral structural and non-structural proteins (NS3, NS4A, NS4B, NS5A, and NS5B). HCV-associated HCC mostly occurs in patients with cirrhosis or advanced stages of fibrosis. Fewer cases of HCV-related HCC have been documented in patients without cirrhosis. 20% of HCC cases diagnosed worldwide are caused by HCV. Viral coinfection with the hepatitis B virus is associated with an increased risk for HCC.

Non-Alcoholic Liver Steatohepatitis (NASH ) and Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease is excess fat in the hepatocytes in the absence of a history of alcohol. NAFLD mostly occurs in the setting of metabolic syndrome. Metabolic syndrome occurs in patients with insulin resistance, hypertension, hypertriglyceridemia, and abdominal obesity, which increases cardiovascular risk. NAFLD is now a leading cause of HCC worldwide, especially in western countries. 13% of patients noted to have HCC without background cirrhosis were noted to have NAFLD. The incidence of HCC is expected to increase by 122% in the United States due to the increase in obesity and diabetes between 2016 and 2030.

Alcohol

30% of HCC is related to a history of excessive alcohol ingestion in the United States. Alcohol can, directly and indirectly, cause HCC. Alcohol can indirectly cause HCC through cirrhosis. Alcohol leads to increased reactive oxidative stress and inflammation. Drinking more than 80 g/day of alcohol increases HCC risk by fivefold.

Aflatoxins

Aflatoxin B1 is a mycotoxin produced by Aspergillus flavus and Aspergillus parasiticus. This is mostly found in Sub-Saharan Africa and Southeast Asia, where the fungus contaminates grains. Carcinogenesis is mostly through the mutation of the tumor suppressor gene (p53). Aflatoxin B1 is associated with an increased risk for HCC in patients with chronic hepatitis B virus.

Other risk factors include iron overload, Glycogen storage disease, Wilson disease, alpha one antitrypsin disease, hypercitrullinemia, Alagille syndrome, and acute intermittent porphyrias.

Symptoms

Liver cancer may not have any symptoms, or it might be hard to spot.

The symptoms are the same if the liver cancer starts in the liver (primary liver cancer) or spreads from another part of the body (secondary liver cancer).

Symptoms of liver cancer can include:

  • your skin or the whites of your eyes turn yellow (jaundice), you may also have itchy skin, darker pee, and paler poo than usual
  • loss of appetite or losing weight without trying to
  • feeling tired or having no energy
  • feeling generally unwell or having symptoms like flu
  • a lump in the right side of your tummy

Other symptoms can affect your digestion, such as:

  • feeling or being sick
  • pain at the top right side of your tummy or in your right shoulder
  • symptoms of indigestion, such as feeling full very quickly when eating
  • a very swollen tummy that is not related to when you eat
  • Losing weight without trying
  • Loss of appetite
  • Upper abdominal pain
  • Nausea and vomiting
  • General weakness and fatigue
  • Abdominal swelling
  • Yellow discoloration of your skin and the whites of your eyes (jaundice)
  • White, chalky stools
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Diagnosis

Hepatocellular carcinoma is a malignant tumor of the hepatocytes. Cytological features depend on the differentiation of hepatocytes. From well-differentiated to poorly differentiated HCC. The trabecular architectural pattern is the commonest. Other patterns include pseudoscalar (acinar with proteinaceous material), compact and sarcomatoid.

Histology may show variation, according to the differentiation of the tissue:

  • Well-Differentiated: cells smaller than normal, minimal nuclear atypia, nuclear density two times of normal liver
  • Moderately Differentiated: larger tumor cells with more eosinophilic cytoplasm, pseudoglands, distinct nucleoli, bile, and giant tumor cells
  • Poorly Differentiated: large tumor cells with hyperchromatic nuclei with prominent pleomorphism may have spindle cells or small-cell areas

History and Physical

The presentation of hepatocellular carcinoma (HCC) is dependent on the stage of the tumor and background cirrhosis.

  • Non-cirrhotic related HCC may present asymptomatic in the early stage of the disease. The median age of the clinical presentation of HCC is 69 years.
  • Cirrhotic-related HCC patients may present with symptoms of decompensated liver failure, including worsening jaundice, pruritus, hepatic encephalopathy, ascites, palpable mass in the upper abdomen, fever, malaise, weight loss, early satiety, abdominal distension, and cachexia. Abdominal pain is the commonest presentation for HCC.
  • Paraneoplastic syndrome in HCC patients may present with hypoglycemia, erythrocytosis, hypercalcemia, diarrhea, and cutaneous findings such as pemphigus foliaceous, pityriasis rotunda, dermatomyositis, and Leser-Treat sign.
  • Symptomatic patients may present with variceal bleeding, intraperitoneal bleeding, obstructive jaundice, pyogenic liver abscess, and hepatic encephalopathy.
  • The most common extrahepatic metastasis of HCC is to the lung, intra-abdominal lymph node, bone, and adrenal, respectively.

Lab Test

Laboratory tests should be done as an adjunct to the overall medical status for surgical treatment. If major surgery is needed for liver cancer, multiple organs, or bone cancer your doctor may consider prescribing the following test

If the patient is older specially 50year or more hormonal imbalance tests may be included such as

Laboratory tests for the diagnosis of if the patient is 50 are:

Biochemistry

Liver function tests including bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin may be elevated during the initial evaluation. This may indicate the severity of the disease. Other abnormal laboratory findings noted in patients with decreased synthetic liver function or reserve include an elevated international normalized ratio (INR), prothrombin time (PT), thrombocytopenia, anemia, hyponatremia, or hypoglycemia. Patients with advanced HCC, chronic hepatitis, or cirrhosis-related HCC are likely to present with these findings. Patients with early non-cirrhotic-related HCC may present with normal LFTs on the initial encounter. Patients with paraneoplastic features of HCC could present with hypoglycemia, hypercalcemia, and erythrocytosis.

Other laboratory investigations to evaluate the etiology of HCC include hepatitis B surface antigen, anti-HCV antibody, alpha antitrypsin level, copper levels, and iron saturation.

Laboratory studies in patients with hepatic angiosarcoma will show elevated alanine transaminase and aspartate transaminase, as well as thrombocytopenia and anemia, as normal liver parenchyma is replaced by tumor. Tumor markers like AFP, CEA, CA19-9, and CA125 are in the normal range or only slightly elevated. Diagnosis of hepatic angiosarcoma should be made with a correlation of radiological findings and histological interpretation (as described previously). It is important to bear in mind that even with a correct diagnosis, rapid progression of the tumor yields a poor prognosis. 

Serum Alpha-Fetoprotein (AFP)

Alpha-fetoprotein is a serum glycoprotein produced by the fetal yolk sac and fetal liver during gestation. Elevated serum levels of AFP are typical for advanced HCC. This does not correlate with tumor size or vascular invasion. About 40% of small HCCs do not secrete AFP. Early non-cirrhotic HCC has normal serum AFP levels. The sensitivity of serum AFP is approximately 66% and specificity of 80% with a cut-off of 10.9 ng/ml (normal value between 10 and 20 ng/mL). Markedly elevated serum alpha-fetoprotein levels of more than 200 ng/ml are highly specific but with moderate sensitivity for detecting HCC. Detecting HCC in patients with coexisting liver disease using a cut-off point of 500 ng/mL has a specificity of more than 90%. Serum alpha-fetoprotein levels may be elevated in patients with chronic hepatitis, cirrhosis, pregnancy, and other germ and non-germ line tumors. Alpha-fetoprotein is used with ultrasound for surveillance.

Other biomarkers include des-gamma-carboxyprothrombin (DCP) and lectin-bound alpha-fetoprotein, which may be elevated in HCC.

Imaging

HCC may be diagnosed with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).

Ultrasound: Ultrasound (US) is a non-invasive, widely used screening test for HCC and surveillance. Sensitivity and specificity range from 51%-87% and 80-%100% respectively. Non-contrast US determines the size, morphology, location, and vascular invasion of HCC. HCC can be hypoechoic or hyperechoic depending on the background of fatty infiltration or fibrosis. HCC demonstrates increased blood flow and neovascularity. USG is limited to the detection of tumors less than 2 cm.

Contrast-enhanced ultrasound (CEUS) is used for the characterization of lesions detected on non-contrast ultrasound. CEUS has specificity greater than 97% and sensitivity and sensitivity of 90% in diagnosing lesions previously demonstrated on the non-contrast US as HCC.

Ultrasound with or without serum alpha-fetoprotein is recommended every six months for HCC surveillance in high-risk patients.

Computed Tomography (CT): Diagnostic imaging criteria for detecting HCC with triphasic CT scan include hyperenhancement in the arterial phase and rapid washout during the portal venous phase relative to the liver background. Contrast CT has sensitivity and specificity per lesion of 65% and 96%, respectively. Sensitivity decreases to 40% for lesions less than 2cm. The positive predictive value increases to more than 92% for lesions greater than or equal to 2cm.

MRI: T1-weighted images may be isointense to hyperintense depending on the degree of fibrosis, fat, and necrosis. Hyperintense images on T1 are mostly well-differentiated tumors and appear as isointense on T2 images. Poorly or moderately differentiated tumors appear as isointense on T1 images and hyperintense on T2 images. Contrast MRI has a sensitivity of 77%-90% and a specificity of 84-97%.

American radiology Association (ARA) has developed a liver imaging reporting and data system (LI-RADS) for classifying hepatic nodules and has been adopted by several societies including the American association for the study of liver disease (AASLD) in 2018. The lesion should demonstrate a non-peripheral washout appearance in the portal venous or delayed phase, non-rim arterial phase hyperenhancement about the background liver parenchyma, smooth enhancing capsule appearance, and growth of more than 50% increase in size in less than 6 months. High-risk patients include patients with chronic hepatitis B virus infection, cirrhosis, concurrent or prior diagnosis of HCC, and lesions identified on a surveillance US for HCC.

Liver Biopsy

Liver biopsy is not routinely done for HCC as the procedure is associated with the risk of tumor seeding and bleeding, and false negative on failure to obtain tissue from the appropriate site. Liver biopsy has a sensitivity of 66%-93% depending on the size of the tumor, positive predictive value, and specificity of 100%.

AASLD recommends biopsy in lesions not typical for HCC on contrast-enhanced imaging and categorized as LI-RADS-M or LI-RADS-4. Several biomarkers to increase the accuracy of the diagnosis of HCC from high-grade dysplastic nodules include heat shock protein 70 (HSP70), glypican-3 (GPC3), and glutamine synthetase (GS).

Your healthcare provider may do the following tests if they think you may have IHC:

  • Endoscopic retrograde cholangiopancreatography (ERCP): ERCP uses an endoscope and a catheter (thin, flexible tubes) to examine your bile ducts.
  • Percutaneous transhepatic cholangiography (PTC): A PTC creates X-rays of your bile ducts like an ERCP. Instead of an endoscope and catheter, your healthcare provider delivers contrast dye by inserting a needle directly into your bile ducts and liver. A PTC is usually only for people who can’t have an ERCP.

Treatment

Non-Pharmacological

It also includes determining prognosis and the need for liver support including possible liver cancer. All patients should be hospitalized preferably at a center that has facilities and expertise for a liver transplant.

Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation

  • To have a high degree of suspicion, evaluate and treat any infection as early as possible.
  • Attain sustained viral suppression of HBV and HCV
  • Intravenous administration of albumin in patients with diagnosed spontaneous bacterial peritonitis to prevent accelerated renal dysfunction characterized by hepatorenal physiology. Intravenous albumin has no proven benefit in other bacterial infections
  • Prophylactic antibiotics for low ascetic albumin
  • In patients with severe acute alcoholic hepatitis, early initiation of both Pentoxifylline or a combination of prednisolone and intravenous N-acetylcysteine has been shown to reduce the incidence of type-1 hepatorenal syndrome.
  • In patients with severe sepsis, a combination of granulocyte colony-stimulating factor (C-CSF) and Darbepoetin has been shown to have improved 1-year survival in decompensated cirrhotics.

Supportive Care

  • Access hemodynamic stability and the need for intravenous fluids and maintenance of acid-base levels and normal electrolytes. Vasopressors are indicated to maintain a mean arterial pressure of greater than or equal to 75 mm Hg to ensure adequate renal and cerebral perfusion.
  • Monitor hematocrit for any bleeding, as the patients have coagulopathy and poor platelet functions. Blood products of platelets and fresh frozen plasma for coagulopathy is only indicated in patients with active bleeding or before an invasive procedure. Patients should be empirically started on proton pump inhibitors for prophylaxis of gastrointestinal bleed.
  • Monitor hepatic encephalopathy and protect the airway (aspiration risk) should the patient show signs of worsening encephalopathy. This patient should be intubated and should be on a protocol to avoid cerebral edema.
  • Adequate nutrition with 1.0 to 1.5 gm of protein per kilogram per day should be administered
  • Monitor for hypoglycemia and maintain blood glucose between 160 to 200.
  • Discontinue all home medications except the ones we identify essential to continue.

Specific Treatment when Etiology is Known   

  • Patients with hepatitis A and E-associated ACLF should receive supportive care as no specific anti-virals are known to be effective.
  • Patients with acute or reactivation of hepatitis C should receive appropriate anti-virals based on the prior treatment administered
  • Patients with acute or reactivation of hepatitis B should receive nucleos(t)ide analogs.
  • Patients with acute decompensation in known Wilson’s disease or development of hepatic vein thrombosis as the etiology for ACLF should be considered for a liver transplant.

Some simple strategies that can reduce the risk of liver disease and help the liver rid the body of toxins include

  • Limiting alcohol intake – Excessive alcohol consumption is a risk factor for liver disease. People with an addiction to alcohol should consider treatment.
  • Avoiding unnecessary over-the-counter medications – Never exceed the recommended dose, particularly of drugs such as acetaminophen that can harm the liver. Do not mix alcohol and over-the-counter drugs.
  • Choosing reputable tattoo and piercing salons – Choose a salon that sterilizes their equipment. Unsafe body modifications can transmit hepatitis C.
  • Getting vaccinated – A person should get vaccinated for hepatitis A and B, and make sure they get appropriate vaccinations before traveling overseas.
  • Practicing safe sex – This can reduce the risk of transmitting conditions that affect the liver. People should also get tested regularly for sexually transmitted infections (STIs).
  • Avoiding potentially dangerous chemicals – When painting or using pesticides, wear a mask and ensure the area is well-ventilated.
  • Drinking plenty of water.
  • Rinsing fruit and vegetables – This can help ensure they are free of pesticides.
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What To Eat and What to avoid

Eat Nutritiously During Your Recovery from Liver disease

All bones and tissues in the body need certain micronutrients to heal appropriately and promptly. Eating a nutritious and balanced diet that includes lots of minerals and vitamins is proven to help heal from liver cancer. Therefore, focus on eating lots of fresh food (fruits and veggies), whole grains, cereal, beans, lean meats, seafood, and fish to give your body the building collagen needed to destroy cancer cells in the liver correctly. In addition, drink plenty of purified water, milk, and other dairy-based non-alcoholic beverages to augment what you eat.

Surgery

Surgical Resection

Patients with Barcelona-clinic liver cancer (BCLC) classification of very early (0) and early-stage (A) are ideal candidates for surgical resection. The very early (0) stage has preserved liver function, European cooperative oncologic group performance status (ECOG-PS) score of 0, and a solitary nodule of 2 cm. Patients with early-stage (A) with preserved liver function and ECOG-PS score of 0 and with a solitary nodule of more than 2 cm are appropriate surgical resection candidates.

Patients with Child–Turcotte–Pugh A and without clinically significant portal hypertension have favorable surgical resection outcomes. Patients with small HCC (tumors less than 5 cm) and Child-Pugh A have survival rates of 70% and 35% at 5 and 10 years, respectively, and recurrence-free survival rates of 36% and 22%. Predictors of HCC recurrence after surgical resection include micro-and macrovascular invasion, tumor differentiation, and the presence of satellite nodules. Five years’ risk of recurrence is up to 70%. Adjuvant therapies have not been shown to reduce the risk of recurrence.

Liver Transplantation

Liver transplantation is associated with the removal of tumors and the potential for cure. Milan criteria for liver transplantation is a single nodule less than or equal to 5 cm in diameter or not more than three nodules, with none large than 3 cm in diameter without macrovascular invasion and extrahepatic spread. A patient who meets Milan criteria for liver transplantation is associated with a 60%-80% and 50% survival at 5 and 10 years, respectively. Posttransplantation recurrence of HCC is less than 15%. Milan criteria have been the benchmark for liver transplantation in patients with HCC and embraced by the united network for organ sharing (UNOS). Adjuvant therapy has been shown to be cost-effective in patients with HCC awaiting liver transplantation. There is a moderate gain in life expectancy whiles waiting for liver transplantation.

Tumor Ablation

Patients with BCLC classification of very early (0) and early-stage (A) who do not meet surgical resection criteria are appropriate for ablation. Ablation is by modifying the local tumor temperature by using either radiofrequency ablation (RFA), cryotherapy, microwave, or laser therapy or injection of chemical substances, including ethanol, boiling saline, and acetic acid. Radiofrequency ablation has been shown to have superior ablative therapy in patients with tumors greater than 2 cm as compared to percutaneous ethanol and acetic acid injection.  Fewer complications have been associated with ablation as compared to surgical resection.

Transarterial Therapies

Transarterial therapies are considered for patients with BCLC intermediate stage (B). Intermediate stage (B) has preserved liver function, ECOG-PS 0, and multinodular without macrovascular invasion or extrahepatic spread. Transarterial chemoembolization (TACE) is the intraarterial infusion of cytotoxic agents and subsequent embolization of the feeding artery to the tumor. TACE is contraindicated in patients with decompensated cirrhosis. Metanalysis revealed an objective response rate of 52.5% and overall survival of 70.3%, 40.4%, and 32.4% at 1, 3, and 5 years respectively. Selective internal radiation therapy (SIRT) is an intraarterial infusion of radioisotope yttrium-90 microspheres. This is considered for patients with BCLC intermediate stage (B). No benefit has been shown with patients with BCLC advanced stage (C).

Systemic Chemotherapy

Sorafenib is the first-line treatment for the patient with BCLC advanced stage (C) with preserved liver function, ECOG-PS score of 1-2, and macrovascular invasion or extrahepatic spread. Sorafenib is a multikinase inhibitor. Sorafenib hepatocellular carcinoma assessment randomized protocol (SHARP) trial demonstrated a median survival of 10.7 months for patients receiving sorafenib as compared to 7.9 months in the placebo group. In addition, sorafenib was shown to be effective in the Asia-Pacific region with patients having advanced HCC. Common side effects of sorafenib include palmar-plantar erythrodysesthesia, diarrhea, weight loss, and hypertension. Lenvatinib was demonstrated noninferiority, but not superior to sorafenib. Lenvatinib has been approved as the second agent for the first-line treatment of advanced HCC by the food and drug authority (FDA). Lenvatinib is associated with significant weight loss but less palmar-plantar erythrodysesthesia when compared to sorafenib. Patients who are intolerant or have tumor progression on sorafenib are started on the second line of treatment. Regorafenib, which is a multikinase inhibitor, has been approved by the FDA as the second line of treatment for advanced HCC. Other second-line medications include cabozantinib, ramucirumab, and nivolumab, which is a programmed cell death 1 (PD-1) immune checkpoint inhibitor.

Systemic therapy for hepatocellular carcinoma patients with advanced disease is a single-agent multikinase inhibitor which is sorafenib and no role for chemotherapy.

The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study, a multicenter, phase 3, double-blind, placebo-controlled trial with 602 patients with unresectable hepatocellular carcinoma compared sorafenib (at a dose of 400 mg twice per day) to placebo and results revealed the time to progression of 5.5 months versus 2.8 months and mOS of 10.7 months versus 7.9 months, in favor of sorafenib and statistically significant for both outcomes. Of note, the SHARP study only included hepatocellular carcinoma patients with Child-Pugh A, and subgroup analysis showed HCV-positive patients had a longer median survival of 14 months. Sorafenib was for long the only approved hepatocellular carcinoma option in the advanced disease setting until the Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESOURCE) study with regorafenib (a multikinase inhibitor) revealed positive results. This was a randomized, double-blind, placebo-controlled, multicenter phase 3, that enrolled 573 patients with Hepatocellular carcinoma whose disease has progressed after treatment with sorafenib greater than 400 mg/day and CP-A (97%). The trial compared 160 mg regorafenib once daily for 3 weeks on and 1 week off, or best supportive care plus placebo, with 28 days cycles. The results revealed a statistically significant median of survival of 10.6 months in the regorafenib group when compared with 7.8 months in the control arm. The Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESOURCE) study included 87% of patients with hepatocellular carcinoma and a Barcelona Clinic Liver Cancer system stage C. Another option for patients with hepatocellular carcinoma whose disease progressed on sorafenib therapy is ramucirumab (a recombinant monoclonal antibody that inhibits vascular endothelial growth factor receptor 2). In the REACH study, the median of survival was improved with ramucirumab (9.2 months) compared with placebo (7.6 months) but did not reach statistical significance (p = 0.1391). Nonetheless, a sub-analysis demonstrated a significant median of survival benefit for patients with an AFP level of 400 ng/mL or greater and Child-Pugh A for 7.8 months for ramucirumab compared with 4.2 months for placebo (HR, 0.67; 95% CI; 0.51, 0.90). REACH-2 study of ramucirumab in patients with advanced hepatocellular carcinoma with underlying Child-Pugh A cirrhosis and baseline AFP levels of 400 ng/mL or more is currently recruiting to evaluate this hypothesis. Ongoing clinical trials and future therapies are focused on immunotherapy (nivolumab and durvalumab) and small molecule tyrosine kinase inhibitors (cabozantinib).

Ifosfamide, a chemotherapy drug used to treat testicular cancer, soft tissue sarcoma, osteogenic sarcoma, urinary bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer, is given in combination with cisplatin and doxorubicin in a combination termed “IPA”. Cisplatin is a chemotherapy drug that interferes with DNA replication using chloride ions to displace water to give the aquo-complex cis-[PtCl(NH3)2(H2O)]+, while doxorubicin acts to stop the growth of cancer cells by blocking topoisomerase 2. IPA was initially present as a chemotherapeutic combination in HB89, but in HB94 carboplatin and etoposide are added to the IPA combination (). However, the results were not satisfactory, with disease-free survival of only 32% in HB94. Currently, high-dose carboplatin and etoposide are given for nonresectable HCC. The rationale is to achieve tumor regression to allow for surgical resection. A microscopic residual tumor (termed an R1 resection in relation to TNM classification) may be observed and requires careful histological examination. New targeted therapies for pediatric HCC are being explored and are proving to be promising.

Sorafenib, a multikinase inhibitor that targets vascular endothelial growth factor, in combination with doxorubicin has been demonstrated to be advantageous in advanced adult HCC (). This study showed improved progression-free survival time and tumor shrinkage. Moreover, GPOH showed that in 50% (6 of 12) of pediatric patients receiving PLADO (cisplatin/doxorubicin) and sorafenib as first-line therapy for HCC, there was complete remission at a median follow-up of 20 months. Of these six children, four received PLADO/sorafenib and had a liver resection, whereas two children underwent OLT after a localized relapse. Alternate approaches with first- and second-line chemotherapy regimens include gemcitabine/oxaliplatin (GemOx), 5-fluorouracil (FU)/cisplatin, capecitabine/cisplatin, 5-FU/mitomycin, 5-FU/oxaliplatin, gemcitabine/cisplatin, 5-FU/interferon, and monotherapy with sorafenib (, ). These approaches are derived from studies on adult patients because pediatric experience is limited. Some chemotherapy protocols have been investigated in pediatrics in small, single-institution trials. They include: (i) the combination of irinotecan, vincristine, temozolomide, and bevacizumab; (ii) the combination of oxaliplatin, irinotecan, and gemcitabine; and (iii) the combination of gemcitabine and oxaliplatin (). Experience in adult HCC suggests that GemOX is both efficient and well-tolerated in relapsed/refractory neoplastic disease ().

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Complete hepatic resection or radical resection of the tumor is the most effective form of treatment for single lesions; however, it is not always feasible in metastatic disease. A liver transplant is not recommended in these cases due to the high rate of recurrence and the rapid progression of the disease. Survival after a liver transplant is less than seven months. Unfortunately, no effective chemotherapy has been established. There has been one report that showed the efficacy of using 5-FU-carboplatin with doxorubicin or ifosfamide in patients with unresectable hepatic angiosarcoma and distant metastasis. A study with a large patient population showed a significant survival benefit of surgical treatment for stage I hepatic angiosarcoma and the prognosis of patients that underwent surgical treatment were better than patients who received non-operative treatment. Transcatheter arterial chemoembolization (TACE) can also be used with palliative intention or to control bleeding. Unfortunately, there are no established guidelines on optimal treatment modalities regarding surgery, chemotherapy, and radiation, as there are different outcomes that have been studied.

Chemotherapy

Chemotherapy uses medicines to kill cancer cells.

For liver cancer, chemotherapy medicine is usually given to the blood vessels of cancer. It aims to stop cancer from growing. This is called chemoembolization. You’ll usually have chemoembolization to help make cancer smaller or to control and improve the symptoms. This is done if you are not able to have surgery because you are very unwell, or cancer cannot be removed by surgery.

Using heat to destroy cancer (thermal ablation)

Thermal ablation uses an electric current or microwaves to destroy cancer. You may have thermal ablation to treat liver cancer if you’re not able to have surgery because you are very unwell, or cancer cannot be removed by surgery.

Localized treatments

Localized treatments for liver cancer are those that are administered directly to the cancer cells or the area surrounding the cancer cells. Localized treatment options for liver cancer include:

  • Heating cancer cells. Radiofrequency ablation uses electric current to heat and destroy cancer cells. Using an imaging test as a guide, such as an ultrasound, the doctor inserts one or more thin needles into small incisions in your abdomen. When the needles reach the tumor, they’re heated with an electric current, destroying the cancer cells. Other procedures to heat the cancer cells might use microwaves or lasers.
  • Freezing cancer cells. Cryoablation uses extreme cold to destroy cancer cells. During the procedure, your doctor places an instrument (cryoprobe) containing liquid nitrogen directly onto liver tumors. Ultrasound images are used to guide the cryoprobe and monitor the freezing of the cells.
  • Injecting alcohol into the tumor. During alcohol injection, pure alcohol is injected directly into tumors, either through the skin or during an operation. Alcohol causes the tumor cells to die.
  • Injecting chemotherapy drugs into the liver. Chemoembolization is a type of chemotherapy treatment that supplies strong anti-cancer drugs directly to the liver.
  • Placing beads filled with radiation in the liver. Tiny spheres that contain radiation may be placed directly in the liver where they can deliver radiation directly to the tumor.

Treatment with targeted medicines

Targeted cancer medicines aim to stop cancer from growing.

You may have treatment with targeted medicines for liver cancer if:

  • you cannot have surgery because you are very unwell, or cancer cannot be removed by surgery
  • cancer has spread to another part of the bod

Palliative care is specialized medical care that focuses on providing relief from pain and other symptoms of a serious illness. Palliative care specialists work with you, your family and your other doctors to provide an extra layer of support that complements your ongoing care. Palliative care can be used while undergoing other aggressive treatments, such as surgery, chemotherapy or radiation therapy.

When palliative care is used along with all of the other appropriate treatments, people with cancer may feel better and live longer.

Palliative care is provided by a team of doctors, nurses and other specially trained professionals. Palliative care teams aim to improve the quality of life for people with cancer and their families. This form of care is offered alongside curative or other treatments you may be receiving.

Radiotherapy

Radiotherapy is where radiation is used to kill cancer cells.

A type of radiotherapy called selective internal radiation therapy (SIRT) is sometimes used to treat liver cancer. This is where radioactive beads are injected into your liver’s blood supply to stop cancer from growing.

You may have SIRT for liver cancer if you’re an adult and:

  • your liver has not been too badly damaged
  • cancer cannot be removed by surgery

Immunotherapy

Immunotherapy uses your immune system to fight cancer. Your body’s disease-fighting immune system may not attack your cancer because the cancer cells produce proteins that blind the immune system cells. Immunotherapy works by interfering with that process.

Biological therapy

A range of treatments work against cancer cells by either stopping their growth or function or by helping the body’s immune system destroys them. Used for both primary and secondary cancers in the liver, it can be used in conjunction with, or after other treatments for cancer.

Selective internal radiation therapy (SIRT)

Also known as radioembolization, this treatment targets liver tumors directly with high doses of internal radiation in tiny beads. It is used for both primary and secondary cancers in the liver when the tumors can’t be removed with surgery. It is not available in all areas, so talk to your doctor about the availability and the costs involved.

Endoscopic stent placement

If cancer in the liver has obstructed the bile duct and bile has then built up in the liver, it may be recommended that a stent (thin tube) is placed in your liver to drain the bile and ease symptoms.

Palliative care

In some cases of liver cancer, your medical team may talk to you about palliative care. Palliative care aims to improve your quality of life by alleviating symptoms of cancer.

As well as slowing the spread of liver cancer, palliative treatment can relieve pain and help manage other symptoms. Treatment may include radiation therapy, chemotherapy or other drug therapies.

FAQ about Liver Cancer

How can I prevent liver cancer?

While you can’t completely prevent liver cancer, you can do the following to lower your chances of getting liver cancer:

  • Avoid behaviors that lead to cirrhosis.
  • Reach or maintain a healthy weight.
  • Get a hepatitis B vaccine. This vaccine is safe for nearly everyone. Ask your doctor about the hepatitis A vaccine.
  • Avoid hepatitis C.
  • If you have any liver disease, have diabetes, obesity or are a heavy drinker, ask your healthcare provider about liver cancer screenings.

What’s involved in liver cancer screening?

You can have very early-stage liver cancer without symptoms. Liver cancer screening is how healthcare providers monitor your liver’s health for signs of liver cancer. While there aren’t any standard liver cancer screening tests, your healthcare provider may recommend you have ultrasounds and blood tests every six months.

Is liver cancer curable?

Successful liver transplants can cure liver cancer, but not everyone who needs a liver transplant will be healthy enough to go through a transplant or able to find a donor. Studies show people who have surgery to remove part of their liver tend to live longer than people whose illness prevents surgery. When that happens, healthcare providers focus on treatments to help people live with quality of life for as long as possible.

What is the life expectancy of liver cancer?

Healthcare providers are making progress on liver cancer treatment so people can live longer. But liver cancer remains a life-threatening disease.

Data show that 35% of people treated for early-stage hepatocellular carcinoma (HCC) liver are alive five years after diagnosis. About 12% of people treated for HCC that has spread to nearby tissues organs or lymph nodes are alive five years after diagnosis. About 3% of people treated for HCC that has spread further are alive five years after diagnosis.

The five-year survival rates for intrahepatic bile (IHC) duct cancer are 24% for bile duct that hasn’t spread outside of your liver, 9% for cancer that’s spread to nearby lymph nodes and 2% for cancer that’s spread further.

I have liver cancer. How do I take care of myself?

Liver cancer and liver cancer treatments take a toll on your body. Some people have liver transplants or surgery to remove part of their liver. Other people may need treatment for as long as they live. Either way, you should plan on regular appointments with your healthcare provider so they can monitor your progress and watch for signs of recurring liver cancer (cancer that comes back). For example, people who don’t have signs of liver cancer after treatment should plan on follow-up imaging and blood tests every three to six months for the first two years after treatment.

If you’ve been treated for liver cancer, here are some steps you can take that may reduce your risk for recurrent liver cancer:

  • Protect yourself from hepatitis B and hepatitis C viruses.
  • If you smoke, try to stop. If you need help, ask your healthcare provider about smoking cessation programs.
  • If you drink alcohol, either cut back or try to stop. Again, if you need help, your healthcare provider can recommend programs and services.
  • Eat a healthy diet. Liver cancer and liver cancer treatment may affect your appetite just when your body needs nutrition to heal and stay strong. If you’re having trouble eating, talk to a nutritionist. They’ll suggest ways you can get the nutrition you need.
  • Get some exercise. Ask your healthcare provider what exercise makes sense given your situation. Cancer is stressful. Exercise can relieve some of that stress.
  • Get enough rest. Fatigue is a common side effect of liver cancer and treatment.
  • Living with liver cancer can be lonely. You may not feel comfortable talking about your illness with others. If that happens, ask your healthcare provider to recommend support groups where you’ll find people who know what you’re going through. Their support and understanding can make a difference.

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