Liver cancer

Introduction

Definition of liver cancer

Liver cancer is a tumour that initially forms in the tissue of the liver. Different types of liver cancer exist according to the type of cancerous cells.
Hepatocellular carcinoma is the most frequent type of liver cancer. It accounts for 90% of all liver cancers. Hepatocellular carcinoma begins in hepatocytes, the main cells of the liver.

 

Anatomy of the digestive system.

Anatomy of the liver and surrounding organs

 

Important note regarding other types of liver cancer

A rare type of liver cancer, mainly occurring in young patients, is called fibrolamellar carcinoma. This variant is usually well circumscribed, as compared to hepatocellular carcinoma, which grows more invasively. It is also characterized by a central scar when viewed using medical imaging techniques. Fibrolamellar carcinoma is mostly diagnosed and treated in the same way as hepatocellular carcinoma.

The information provided in this Guide for Patients does not apply to liver cancers that are not hepatocellular carcinoma. The main other types of cancer of the liver are:

·         Tumours developing in the liver but that originated in another organ, for instance colon, stomach or ovary. These tumours are called liver metastases or secondary liver cancers. Information on the treatment of liver metastasis is available together with the information dedicated to the cancer where the primary cancer initially occurred.

·         Cancers that start in the blood vessels of the liver are called angiosarcomas and hemangiosarcomas. For more information about angiosarcomas, and hemangiosarcomas, click here.

·         Cancers that start in the bile ducts are called bile duct cancers or cholangiocarcinomas. However, if they involve bile ducts in the liver, they are sometimes called liver cancers. For more information on bile duct cancer, click here.

·         Tumours called hepatoblastomas occur in infants and children. For more information about hepatoblastomas, click here

 

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
This guide for patients has been prepared by the Anticancer Fund as a service to patients, to help patients and their relatives better understand the nature of liver cancer and appreciate the best treatment choices available according to the subtype of liver cancer. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of disease. The medical information described in this document is based on the clinical practice guidelines of the European Society for Medical Oncology (ESMO) for the management of liver cancer. This guide for patients has been produced in collaboration with ESMO and is disseminated with the permission of ESMO. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the lead author of the clinical practice guidelines for professionals. It has also been reviewed by patients’ representatives from ESMO’s Cancer Patient Working Group.

Frequency

Is liver cancer frequent?

Liver cancer represents the sixth most common cancer worldwide. In Europe, about 10 in every 1,000 men and 2 in every 1,000 women will develop liver cancer at some point in their life. Worldwide it is much more frequent in South-East Asia and Western Africa. This is mainly due to the fact that infection with the hepatitis B virus increases the risk of developing liver cancer and is more frequent in these areas. In the USA and in Southern Europe, the hepatitis C virus is seen more frequently as a cause of liver cancer.

In 2008, about 40,000 men and about 20,000 women were diagnosed with liver cancer in Europe.
 

The median age at diagnosis is between 50 and 60 years, but in Asia and Africa it is usually between 40 and 50 years.

 

 

Causes

What causes liver cancer?

In most patients, cancers of the liver are preceded by cirrhosis of the liver. Liver cirrhosis is a consequence of a chronic liver disease, although only a limited percentage of patients with chronic liver disease will eventually develop cirrhosis. In cirrhosis, tissue of the liver is slowly modified at the expense of normal liver cells and consists more and more of fibrous tissue and scar tissue. The liver cells do not grow or function normally.

The exact mechanisms and reasons why liver cancer occurs are not fully understood. However, cirrhosis and its causes are the main risk factors of hepatocellular carcinoma, the main type of liver cancer[1].

A risk factor increases the risk of cancer occurring, but is neither necessary nor sufficient to cause cancer. It is not a cause in itself. Some people with these risks factors will never develop liver cancer and some people without any of these risk factors will nonetheless develop liver cancer.

The main risk factors are the ones causing cirrhosis, but others not related to cirrhosis exist as well.

 
  • Causes of liver cirrhosis:

o   Chronic infection with hepatitis-B virus (HBV) or hepatitis-C virus (HCV). An infection with HBV or HCV is considered chronic when the hepatitis virus remains present in the blood for more than 6 months and causes a decline in the functioning of the liver. Worldwide, hepatitis B infection is responsible for 50% and hepatitis C infection for 25% of all cases of liver cancer. Having chronic hepatitis B infection increases the risk of developing liver cancer 100-fold and having chronic hepatitis C infection increases the risk 17-fold. Up to 85% of individuals with hepatitis C infection develop a chronic infection, of these approximately 30% progress to cirrhosis and in these 1 to 2% per year develop liver cancer. Co-infection with HBV, meaning both viruses occurring at the same time, further increases the risk. Hepatitis B infection can also cause liver cancer directly, without causing cirrhosis first. The virus can mix its own DNA (deoxyribonucleic acid) with the DNA of a liver cell, causing mutations in its genes. These mutations can lead a cell to lose control over its normal functioning, reproduction and natural cell death. It is generally assumed that if these functions start to get out of control, it can lead to cancer.

It is anticipated that by introducing vaccination everywhere in the world, there would be much fewer cases of hepatitis B, and also fewer cases of liver cancer related to this virus. It is also anticipated that antiviral treatment against hepatitis B will reduce liver-related death (including liver cancer) in chronic hepatitis B infection. Also, recent studies suggest that antiviral treatment of a patient with chronic hepatitis C infections may reduce significantly his or her risk of liver cancer.

o   Long-term alcohol abuse can lead to liver cirrhosis and to liver cancer. In countries where infection by HBV is low, alcohol is the main cause of liver cancers. Alcohol intake when suffering from hepatitis increases the risk even more.

Prevention of long-term alcohol consumption can substantially reduce the risk of developing cirrhosis and liver cancer.

o   Some inherited liver conditions can also cause cirrhosis, such as haemochromatosis or alpha-1-antitrypsin deficiency. Haemochromatosis is a hereditary disease that causes higher absorption of iron from the food. The iron is then deposited in various organs, mainly in the liver. In alpha-1-antitrypsin deficiency an abnormal form of the protein alpha-1-antitrypsin is deposited in the liver cells. This can cause liver cirrhosis and increase the risk of developing liver cancer.

o   Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are two conditions affecting the liver that can also lead to cirrhosis and cancer. They are not caused by an infection or by high alcohol intake, but they seem to be linked to severe obesity and diabetes mellitus. Therefore obesity and diabetes are also seen as risk factors for liver cancer. Moreover, if a diabetic patient consumes high amounts of alcohol, the risk is a lot more increased.

Prevention of obesity and type 2 diabetes by adopting a healthy lifestyle can reduce the risk of non-alcoholic fatty liver disease and liver cancer. Lifestyle change interventions in obese or type 2 diabetic people can also reduce this risk.

o   There are other, less frequent, medical conditions affecting the liver and increasing the risk of cancer. These conditions include autoimmune hepatitis, intrahepatic biliary inflammations (primary biliary cirrhosis and primary sclerosing cholangitis) and Wilson’s disease. These conditions are neither caused by an infection, nor by alcohol.

·         Gender: liver cancer is four to eight times more common in men than in women, although this is probably due to differences in behavior that affects the risk factors described before.

·         Exposure to toxic agents:

o   Anabolic steroids are hormones taken by some athletes to increase their strength and muscle mass. Long-term use of anabolic steroids increases the risk of hepatocellular adenoma, a benign tumour of the liver which can become malignant and turn into HCC.

o   Intake of aflatoxin-contaminated food: Aflatoxin is a toxic substance produced by a fungus that can grow on food (peanuts, wheat, soybeans, ground nuts, corn, and rice) when stored in warm, damp conditions. When regularly ingested, it can cause mutations in the DNA of the liver cells, causing them to become cancer cells.

Reduction of exposure to aflatoxin-contaminated food may lower the risk of liver cancer, especially in people who are infected with HBV.

Other factors like smoking have been shown to increase the risk of liver cancer but the evidence is inconsistent. More research is needed to establish these possible risk factors.

 

Diagnosis

How is liver cancer diagnosed?

Liver cancer can be suspected in different circumstances. Most patients have liver cirrhosis and/or chronic hepatitis before developing liver cancer. People with liver cirrhosis need close surveillance to detect as early as possible a potential liver tumour. The same surveillance is recommended for people infected with HBV who did not develop cirrhosis and for whom more than 10,000 copies of the virus (viral load) are found per milliliter of blood, and for people infected with HCV whose liver is in advanced stage of fibrosis. Even though a small subset of patients with non-alcoholic steatohepatitis will develop liver cancer, a similar surveillance is necessary because a cancer can develop in the absence of cirrhosis.

Therefore the circumstances of diagnosis will differ between patients with known liver cirrhosis and patients with no known liver cirrhosis.

Tumour surveillance in patients known to be at risk of developing liver cancer

 

All patients with liver cirrhosis need close surveillance, as well as some patients with no cirrhosis but with HBV and HCV infections, as described above. Every 6 months, an ultrasound of the liver should be performed, in order to screen for any new nodule, cyst or lump that could turn into cancer.

 

1.       An ultrasound test is used to detect nodules, which are usually only visible with imaging.

When a nodule is seen on ultrasound, the following steps depend on the size and the imaging characteristics of the nodule. These two features give information about the probability that a nodule might turn into liver cancer.

-               A nodule smaller than 1 cm should be followed with ultrasound at intervals of 6 months. The probability that this type of nodule is, or might turn into, liver cancer within the next months is low.

-               A nodule between 1 and 2 cm should be investigated with at least two different radiological examinations (CT-scan with contrast, ultrasound or MRI with contrast).

o   If two different techniques show a typical appearance of liver cancer, the nodule should be interpreted as such.

o   If that is not the case, the doctor needs to take a biopsy or remove the nodule for further examination in a laboratory. A biopsy is a tissue sample, which in this case is taken using a fine or a thick needle that goes through the skin of the right flank and into the liver, in order to remove a small piece of liver tissue. A sample taken with a fine needle is called fine needle aspiration. Removal of a nodule can take place during an operation.

-               Sometimes diagnosis is so likely that a biopsy will not be necessary. The following cases should be considered as proven liver cancer.

o   If an imaging technique shows that the nodule is bigger than 2 cm and has the typical look of a liver tumour.

o   If there is any nodule in the liver, and at the same time alpha-fetoprotein  level (see below) in the blood is high (400 ng/ml or more) or continues to increase.

 

2.       A blood test for a protein called alpha-fetoprotein, or AFP, can give additional information. AFP is normally present at high levels in the blood of foetuses, but its level becomes and stays very low (normal level) shortly after birth. If a higher than normal level is found in the blood of adults, it suggests they may have liver cancer.

AFP blood tests may be used to look for early tumours in people suffering from cirrhosis. However, the tests are usually not advised for screening in people without cirrhosis because they are not always accurate. In a minority of liver cancer, there is no increase of the level of AFP in the blood. The level of AFP is also not elevated in fibrolamellar carcinoma. In many cases, the level of AFP is only elevated at a late stage of liver cancer. In addition, high level of AFP can also be found in other conditions, including non-cancerous liver diseases or tumours developing in other organs like the testis or ovary. In patients with cirrhosis an altered level of AFP is often seen. Therefore this test is only found to be useful in combination with an ultrasound test.

 

Possible symptoms of liver cancer

In patients with no specific surveillance as described above, the main symptoms that could be related to liver cancer are the following:

·         Unexplainable weight loss

·         Fatigue

·         Loss of appetite or feeling very full after a small meal

·         Nausea or vomiting

·         Fever

·         An enlarged liver, felt as a mass under the ribs on the right side

·         An enlarged spleen, felt as a mass under the ribs on the left               side

·         Pain in the abdomen or near the right shoulder blade

·         Swelling or fluid build-up in the abdomen

·         Itching

·         Yellowing of the skin and eyes (jaundice)

·         Enlarged veins on the abdomen that become visible through the           skin

All these symptoms can also be caused by other conditions, or may only be noticed at an advanced stage of liver cancer. However, in case of a combination of several of the symptoms listed above, especially if they persist, further investigations should always be considered.

A deterioration of the liver function can occasionally be detected upon examination of the blood for other reasons. This can be caused by many different conditions and should therefore also lead to further investigations.

 

Diagnosis

In general, the diagnosis of liver cancer is based on the following examinations:

 

1.       Clinical examination

The doctor will ask about the complaints and symptoms, and examine the abdomen and the rest of the body. The doctor will look for an enlarged liver or spleen, presence of fluid in the abdomen, if there is yellowing of the skin and eyes (indicative for jaundice) or other signs indicating that the liver is not functioning properly.

2.       Blood examination

A blood test can reveal elevated levels of alpha-fetoprotein (AFP), a tumour marker, but this is seen only in 50-75% of patients with liver cancer. Therefore, if it is not elevated, this does not mean that there is no tumour present. Also, if AFP is elevated, it does not necessarily mean that there is a tumour.

3.       Radiological examination

In the first place an ultrasound of the liver will be performed to evaluate the consistency of the organ and to look for possible nodules. In 75% of the cases of liver cancer, the tumours are multifocal at the time of diagnosis. Multifocal means that several nodules (or tumours) are present in different parts of the liver.

To get a more precise image and to be able to detect smaller nodules, a CT-scan or an MRI-scan might also be performed. An MRI can be especially useful in patients who already have (benign) nodules due to their cirrhosis. These exams are sometimes performed after intravenous injection of a contrast liquid, in order to mark any nodule.

The sequence of tests used for diagnosing liver cancer will depend on the size of the lesions and on the presence of cirrhosis seen after the radiological examinations.

4.       Histopathological examination

The histopathological examination is performed on a liver tissue sample called a biopsy. The decision to perform a biopsy should be discussed with several specialists, including a surgeon specialized in liver surgery. It is the only way to assess whether a lesion seen during a radiological examination is benign or malignant. A biopsy can be taken using a fine or a thick needle that goes through the skin of the right flank and into the liver to remove a sample of liver tissue. Sometimes an ultrasound or CT-scan is used at the same time to make sure the needle goes right into a suspected nodule. A surgeon can also take a biopsy during an operation called a laparoscopy. During laparoscopy, the surgeon inserts a small camera and fine instruments through one or more small incisions in the skin of the abdomen, in order to see the inside of the abdomen and take a biopsy without having to make a big incision in the abdomen.

The tissue sample will be examined in a laboratory under a microscope by a specialist called a pathologist. He may also perform other tests to define the specific type and characteristics of the tumour. However, even if the pathologist concludes the biopsy did not contain any cancer cell, it may not be possible to rule out that the tumour is malignant.

There is a risk of bleeding due to the procedure because the liver is rich in blood vessels and blood coagulation can be impaired in patients with cirrhosis. There is also a small risk that a liver biopsy could spread the cancer along the pathway of the biopsy needle. If the cancer has not already spread, it is important to avoid this risk. However, this risk is smaller when the biopsy is taken with a fine needle. There is no risk that a tumour might explode when pierced by a needle.

However, a biopsy will not be performed in the following situations:

  • the patient is considered to be too frail to be able to tolerate any form of therapy
  • the patient has an advanced form of cirrhosis and is on the waiting for liver transplantation
  • the patient can be operated with the objective of removing the whole tumour (see paragraph on resectabilty further)

It is also possible in some patients with known cirrhosis to rely on imaging for the diagnosis. A biopsy can be avoided only when a specific radiological exam show typical vascular hallmark of liver cancer. This exam can be either a type of CT-scan (multiple-phase multidetector CT-scan) or a type of MRI (dynamic contrast-enhanced MRI).

Treatment

What is important to know to get the optimal treatment?

There is not a single best treatment that helps every patient. Doctors will need to consider many aspects of both the patient and the cancer in order to decide on the best treatment.

 

Relevant information about the patient

·         Age

·         Medical history

·         Results of clinical examination. Your doctor will especially:

o   evaluate your nutritional status

o   inspect your skin and eyes looking for any yellowing indicative of jaundice and for any dark skin spots indicative of low platelets level

o   look for indirect signs of increased blood pressure into the vein supplying the liver

o   check if the liver  and the spleen are enlarged or if there is a fluid presence in abdomen, called ascites

o   search for signs of altered mental status within a complex condition called encephalopathy.  

·         Presence of other liver diseases and current functioning of the liver, sometimes also called ‘residual liver function’. The doctor can examine the liver function through certain parameters in the blood such as prothrombin time, level of albumin, level of bilirubin and number of platelets.

·         Chronic infection with HBV or HCV, possible treatment and level of activity of the infection

·         Current alcohol consumption

·         Drug injection practices

·         Performance status, which evaluates cancer patients' general well-being and activities of daily life. The performance status evaluates the patients physical abilities by giving a score from 0, for a fully active patient, to 4 for a patient that is completely disabled due to his/her disease.

 

Through considering these elements, the doctor will decide whether the patient is in a good condition and is able to undergo resection of part of the liver or liver transplantation.

 

Relevant information about the disease

·         Staging

Doctors use staging to assess the extent of the presence of cancer and the prognosis of the patient. The stage is fundamental in order to make the right decision about the treatment. The more advanced the stage, the worse the prognosis is. Different investigations are aimed at finding out how far the cancer has grown in- and outside the liver, and whether or not it has already spread to other parts of the body. A CT-scan or an MRI-scan of the abdomen will be performed in order to evaluate the local extent of the tumour and whether it has spread to other organs. If there is any suspicion that the cancer might have spread further away, imaging of other body parts could be performed as well, in particular a chest CT scan and a bone scan.

Staging is usually performed twice: after clinical and radiological examination and after surgery. If surgery is performed, the removed tumour can be examined in the laboratory. The results of this examination may also help staging the disease.

 

Since most liver cancer occurs on underlying cirrhosis, the cancer as well as the underlying liver disease (if present) should be staged. Both determine the treatment options and the expected outcome. Several staging system exists and every system has advantages and drawbacks. Here, we will present the 2 fundamental types of staging systems namely, TNM, to stage the cancer, and Child-Pugh, to stage liver disease or cirrhosis. Another more sophisticated system widely used by specialists in liver cancer is also presented. It is called the Barcelona Clinic Liver Cancer (BCLC) staging system and its main advantage is that it identifies those patients with early cancer who may benefit from curative therapies (stage 0 and stage A), those at intermediate (stage B) or advanced stage (stage C) that may benefit from life-prolonging treatments and those with very limited life expectancy (stage D).

 

·         The TNM staging classifies the cancer according to the combination of

o   T, size of the tumour and invasion of nearby tissue,

o   N, involvement of lymph nodes, and

o   M, metastasis or spread of the cancer to other organs of the body.

The stages based on the TNM-system are explained in the table below. The definitions are sometimes very technical so it is recommended that you ask your doctor for more detailed explanations.

 

Stage

Definition

Stage I

The tumour is unique and has neither invaded blood vessels of the liver nor spread to lymph nodes or to other parts of the body.

Stage II

Either the tumour is unique and has invaded blood vessels of the liver

 or multiple tumours are found in the liver but none is larger than 5 cm in diameter and none has spread to lymph nodes or to other parts of the body.

Stage III

Stage III is divided into the three following sub-stages. In any case, tumour cells have not spread to the lymph nodes or to organs that lie further away.

Stage IIIA

-           Multiple tumours are found in the liver and at least one is larger than 5 cm in diameter.

Stage IIIB

-           The tumour has invaded a branch of one of the major veins of the liver.

Stage IIIC

-           The tumour has spread to a nearby organ (other than the gallbladder) or to the outer covering of the liver.

Stage IV

The tumour has spread to lymph nodes or to organs that lie further away.

Stage IVA

-           Any of the above and invasion of a regional lymph node

Stage IVB

-           Any of the above and spread of the tumour to other parts of the body

 

·         The Child-Pugh score defines the prognosis as well as the need for transplantation in chronic liver disease. This score is used for any chronic liver disease and not only for liver cancer. This results in a Child-Pugh score of A, B or C. ‘A’ indicates less advanced cirrhosis and ‘C’ more advanced cirrhosis. It takes into account the accumulation of liquid in the abdomen called ascites, the level of 2 proteins (called albumin and bilirubin) in the blood, how well blood clotting is still working and the presence of encephalopathy.

The method used to attribute a Child-Pugh score is complex and is beyond the scope of this guide. It is recommended to ask your doctor for more detailed explanations.

 

·         The Barcelona Clinic Liver Cancer (BCLC) staging system

BCLC defines four stages, A to D, of liver cancer. It is based on the size and the number of (the) tumour(s) in the liver, invasion of blood vessels by the tumour, cancer spread outside the liver, blood pressure in the vein going to the liver, level of bilirubin in the blood, Child-Pugh score and performance status.

The blood pressure in the vein going to the liver (called portal vein) can be raised when the liver does not let the blood pass through easily, because of a changed consistency. Bilirubin is a protein that is normally excreted by the liver into the bile. However, when the liver function is impaired, it can be seen in the blood as well. The Child-Pugh score has been described before and takes into account the accumulation of liquid in the abdomen (ascites), the level albumin and bilirubin in the blood, how well blood clotting is working and the presence of encephalopathy. The performance status has been described in the previous section. It evaluates the patients physical abilities by giving a score from 0, for a fully active patient, to 4 for a patient that is completely disabled due to his/her disease.

Because the BCLC includes so many factors, it is found to give the best prediction of the prognosis for the patient who suffers from cirrhosis and liver cancer, and to be very useful in planning the treatment.

 

·         Results of the biopsy

The biopsy will be examined in the laboratory. This examination is called histopathology. The second histopathological examination is performed on the tumour and the lymph nodes removed by surgery. This is very important to confirm the results of the biopsy and to provide more information on the cancer. Results of the examination of the biopsy should include the following:

First of all, the pathologist will check if the tumour is actually developed in the liver i.e. a liver tumour, or a distant spread of another tumour (e.g. from the intestines), by examining the tumour cells and determining whether they present the characteristics of liver cells or other cells.

If it is a liver tumour, the pathologist will define it as a hepatocellular carcinoma or fibrolamellar carcinoma, or one of the other aforementioned types of liver cancer in the definition of liver cancer.

 

·         Resectability

The surgeons will judge a tumour as operable or resectable, meaning that it is possible to remove the complete tumour in an operation, or as not operable or unresectable, meaning that this is not possible to remove it. There is no distinct dividing line between resectable and unresectable in terms of the TNM stage of the cancer, but earlier stage cancers are more likely to be resectable. A tumour can, for example, be unresectable when it is very big or when it is close to an important blood vessel, making it hard to remove it without damaging this vessel.

 

What are the treatment options?

Planning of the treatment involves a multidisciplinary team of medical professionals. This implies a meeting of different specialists, called multidisciplinary opinion or tumour board review. During this meeting, the planning of treatment will be discussed according to the relevant information mentioned before, such as whether the patient has liver cirrhosis, what is the extent of the disease, what is the growth pattern of the tumour, how is the liver function, can the cancer be resected and how is the patient's general health status. The risks of each type of treatment are also taken into account.

The extent of the treatment will depend on the stage of the cancer, on the characteristics of the tumour and on the risks involved.

The treatments listed below have their benefits, their risks and their contraindications. It is recommended to ask doctors about the expected benefits and risks of every treatment in order to be informed of the consequences of the treatment. For some treatments, several possibilities are available and the choice should be discussed in terms of weighing up their respective benefit and risks.

 

As mentioned in the previous section, the treatment plan mainly depends on the stage according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Treatments by stages are presented in the figure below and details on therapies are given stage per stage further in the text.

Treatment of stage 0 and stage A cancer according to the BCLC classification

For patients with early stage cancers (stage 0 and stage A according to BCLC staging system), it is possible to propose a treatment with the intent of curing the cancer. This treatment can be surgical resection, liver transplantation or local ablation methods and decision will mainly depend on the level of cirrhosis, and on the size and number of tumours in the liver.

 

For these patients, several treatment options are available. The multidisciplinary opinion will decide which one is most appropriate, according to the relevant information mentioned before. The main 3 options at these stages are:

·         Resection of the tumour by surgery

·         Liver transplantation

·         Local ablation methods

 

Resection by surgery

Resection of the tumor by surgery is the preferred option for:

·         patients without cirrhosis and for whom a sufficient part of the liver can be preserved;

·         patients with BCLC stage 0 or A whose performance status allows them to undergo surgery and who have a single liver tumor that does not cause any portal hypertension.

In individual cases, more lesions can be safely resected, but since surgery of the liver carries some risks, the risk of the surgery per patient has to be taken into account before making any decision.

Depending on the extent of the tumor and the degree of liver cirrhosis a part of the liver containing the tumor, or the complete liver, can be removed.

 

The resection of the tumour consists in removing the part of the liver which contains the tumour. This type of surgery is called a partial hepatectomy. This type of surgery can only be performed in patients without cirrhosis or limited cirrhosis (BCLC stage 0 and stage A), since the liver still functions correctly in these patients. The remaining part of the liver will take over the liver function. After surgery, the resected part will be examined by a pathologist in the laboratory. The pathologist will check whether the whole tumour has been removed by analyzing if the tumour is totally surrounded by normal tissue. This is reported either as negative margins of resection, meaning that it is very likely that the whole tumour has been removed or as positive margins of resection, meaning that it is very likely that the whole tumour has not been removed. If margins are negative, it is a sign of a better prognosis.

 

Liver transplantation

When a resection of the tumour is not possible, a liver transplantation should be considered either when there is a single tumour of less than 5 cm in diameter, or when there are 2 to 3 tumours, each measuring less than 3 cm in diameter. Those requirements are called the Milan criteria.

 

·         Criteria to register as a candidate for liver transplantation in patients with liver cancer

Transplantation is only possible under very strict conditions because of the scarcity of available donor livers. The first condition is that the patient meets the aforementioned Milan criteria regarding number and size of liver tumours. Regulations on liver donors and transplantations differ from country to country. Country-specific information can be obtained by asking doctor(s) or other professionals involved in liver transplantation. Usually, donor livers come from other patients who recently died, or who are diagnosed ‘brain-dead’. Brain-dead means the brain has suffered from oxygen-deficit and therefore will never function again, and breathing and blood circulation can only be maintained by medical equipment. Again, when and how someone can be considered as brain-dead is defined precisely by laws specific to individual countries.

Since these situations are scarce and not every patient can get a donor liver, the patient first has to be judged fit enough for the surgery. Also his or her overall prognosis should be good enough to be registered on the waiting list.

Patients who suffer from liver cirrhosis caused by alcohol abuse and are still using alcohol, or patients who have a poor prognosis due the characteristics of their cancer or due to other concurrent diseases, will not be considered for transplantation. Some centers with a lot of experience are able to perform split-liver transplants (in which several patients get a part of one donor liver), transplants with marginal grafts (livers that are not perfectly healthy) or live donor liver transplantation (meaning a part of the liver of a healthy living donor is transplanted to the patient). Since these are exceptional situations, the possibility for each patient has to be evaluated by the ethics committee as well as by the transplant advisory board of the hospital.

 

·         Procedure of a liver transplantation

A liver transplantation is an operation under general anaesthetic that usually takes 6 to 10 hours. During this time the surgeons will first make an incision shaped like a boomerang on the upper part of the abdomen and remove the patient's old liver, leaving portions of the major recipient blood vessels in place. The new liver will then be inserted and attached to these blood vessels and to the patient's bile ducts.

 

·         Therapies for patients awaiting liver transplantation

Owing to organ shortage, liver transplant candidates are confronted with long waiting times, which must not delay the discussion about an alternative effective treatment. In the case of a long anticipated waiting time (>6 months), patients may be offered resection, local ablation or trans-arterial chemoembolization in order to minimize the risk of tumour progression and to offer a ‘bridge’ to transplant. Details on techniques of local ablation and trans-arterial chemoembolization are provided further in this guide.

 

Local ablation methods

The goal of local ablation is to destroy cancer cells by targeting them with chemical or physical means. The two main local ablation methods are radiofrequency ablation and percutaneous ethanol injection, which will be described further. While these techniques are effective in destroying small tumours, they unfortunately do not prevent the occurrence of new lesions in the surrounding cirrhotic liver tissue.

They have been put forward as alternatives for surgery. In patients with BCLC stage 0 and who cannot undergo surgical resection or liver transplantation, these techniques are recommended. They are also recommended in the case of a long anticipated waiting time (>6 months) for liver transplantation.

These two techniques show similar results for BCLC stage 0 tumours, i.e. a single nodule of less than 2 cm in diameter, and they can be considered alternatives to resection. However, radiofrequency ablation gives better results in terms of control of the tumour growth in tumours larger than 2 cm in diameter.

 

Radiofrequency ablation

Radiofrequency ablation uses high-energy radio waves to destroy cancer cells. A thin, needle-like probe is inserted through the skin and into the tumour. A high-frequency current is then passed through the tip of the probe. This heats the tumour and in this way destroys the cancer cells. At the same time, heat from radiofrequency energy closes small blood vessels and decreases the risk of bleeding. The dead tumour cells are gradually replaced by scar tissue that shrinks over time. An ultrasound or a CT-scan may be used to guide the ablation. The procedure usually takes place under local anaesthetic, but sometimes it is also performed during open surgery or during laparoscopy, and thus under general anaesthetic. During laparoscopy, the surgeon inserts a small camera and fine instruments through one or more small incisions in the skin of the abdomen. This helps to see the inside of the abdomen and perform interventions without having to make a big incision in the abdomen.

Radiofrequency ablation is most effective in cancers with up to five nodules and a diameter of no more than 5 cm. In bigger tumours, it is unlikely that they can be completely destroyed by this technique. When a tumour is close to major blood vessels there might be a risk of bleeding and radiofrequency ablation is therefore not advised.

 

Percutaneous ethanol injection

Percutaneous ethanol injection uses ethanol (concentrated alcohol) to scorch the tumour. The ethanol is injected through the skin directly into the tumour. Sometimes an ultrasound or CT-scan is used to guide the needle right into the tumour. Percutaneous ethanol injection has been shown to be less effective than RFA in nodules larger than 2 cm in diameter.

 

Treatment of stage B cancer according to the BCLC classification

For patients with intermediate stage cancer (stage B according to BCLC staging system), the treatment consists in injecting an anticancer drug and a coil or small degradable particles directly in the artery that supplies the liver with blood. This type of treatment is called transarterial chemoembolization.

 

Transarterial chemoembolization (TACE)

In addition to patients with BCLC stage B cancer, patients awaiting liver transplantation can benefit from transarterial chemoembolization or TACE, to bridge the waiting time if this exceeds 6 months.

TACE is the injection of an anticancer drug directly in the artery that supplies the liver with blood (hepatic artery). This requires introducing a catheter into the artery in the groin and leading it into the hepatic artery. This procedure is done while using an X-ray to make sure the catheter is in the vessel(s) supplying the tumour with blood. The drug used is a chemotherapy, meaning it aims to kill cancer cells and/or limit their growth. Through the blood vessels the drug reaches the cancer cells and the normal liver cells, but the latter break down the drug before it reaches the rest of the body. Anticancer drugs that can be used are doxorubicin, cisplatin and/or mitomycin. Lipiodol can also be mixed with the chemotherapeutic drugs before they are injected. Tumour cells preferentially absorb lipiodol and will at the same time absorb the drugs.

After injection of this drug, either gel foam or small degradable balls are injected to block the small arteries providing blood to the tumour and to cut the tumour’s provision of nutrients and oxygen.

TACE can also be used to relieve symptoms experienced by patients with hepatocellular cancer and cirrhosis. The goal is not to cure the cancer, but to make the patient feel more comfortable. However, as the size and number of tumours in the liver increase, results of TACE are less favorable.

TACE should not be used in patients with

·         liver cirrhosis grade C according to Child-Pugh,

·         spread of the tumour in 2 lobes of the liver or to other body               parts,

·         portal-vein thrombosis, or

·         an exceptional connection between the artery and the main               vein that are going to the liver.

Portal vein thrombosis is the formation of blood clots in the main vein going to the liver. This is to avoid the toxic drugs being injected ending up somewhere other than the location of the tumour.

 

Other transarterial techniques

Transarterial techniques have evolved during the last years. Several alternatives to the typical TACE described before are emerging.

The use of small beads loaded with doxorubicin (chemotherapy) instead of the classical TACE aims at embolizing the vessels supplying the tumour(s) and delivering doxorubicin to the tumour at the same time. These beads have demonstrated less diffusion of chemotherapy outside of the liver, resulting in fewer side effects and at least the same activity than classical TACE.

Internal radiation with Iodine 131 or Yttrium 90 particles aims to embolize as well as to bring radiation therapy very close to the tumour. This type of treatment is experimental and must be performed in a clinical trial. A small tube is placed in the main artery going to the liver (hepatic artery), through which microscopic balls are released. These balls reach the tumour through the blood vessels of the liver and contain a radioactive substance called Iodine 131 or Yttrium 90. They block the supply of blood to the tumour, and at the same time emit radiation that destroys the tumour cells surrounding them. Due to the precise targeting of this approach, it can deliver a much more potent dose of radiation than the usual external radiation therapy. The radioactivity of the balls is gone after 2 weeks. An advantage is that it can be used regardless of how numerous or how big the nodules in the liver are, and it can also be used to treat tumours possibly undetected. It can be used in some patients who cannot receive TACE or who already received TACE, but not in patients with cancer which has spread outside the liver.

 

Sorafenib in case of progression of the disease despite TACE

In patients whose disease is progressing (development of new tumours or growth of existing tumours), a treatment with drug called sorafenib is recommended.

 

Treatment of stage C cancer according to the BCLC classification

The standard treatment at this stage is sorafenib, a drug taken orally. If sorafenib is not well tolerated or if the cancer progresses despite treatment with sorafenib, supportive care and participation to clinical trials are recommended.

Because the tumour has spread away from the liver, either to lymph nodes or to distant organs, the treatment will aim at targeting cancer cells all over the body. This is called systemic therapy. The main option is sorafenib. If sorafenib is not well tolerated or is not able to affect the growth of the tumour, the treatment will aim at relieving the symptoms caused by the disease. It is also possible to participate to a clinical trial. In clinical trial, new treatments or new combinations of treatments are tested. It is advised to ask the doctor if there are trials going on that are appropriate for the stage of tumour and the specific situation of the patient. In this way the patient can get access to new therapies, and at the same time help scientific progress in relation to developing better cancer treatments.

 

Systemic therapy

Sorafenib is a drug that has shown to prolong overall survival in patients with advanced liver cancer. For example, it extended survival for an average of 2.8 months for patients with Child–Pugh grade A liver disease in a randomized clinical trial. It is taken orally and reaches the whole body through the blood stream after absorption by the intestines. Sorafenib is called a targeted therapy since it has been made with the goal of specifically targeting tumour cells.

Other targeted therapies are under investigation but should not be given outside of clinical trials.

 

Chemotherapy that is given systemically, meaning either orally or in an intravenous manner and thus not by injection into the artery of the liver, can also be considered. However, none of the chemotherapy drugs used for liver cancer have shown to prolong the patient’s life expectancy, but some chemotherapy regimens like XELOX (consisting of a combination of capecitabine and oxaliplatin) and GEMOX (combination of gemcitabine and oxaliplatin) have shown that they could stop or slow the growth of tumour in some patients. Systemic chemotherapy should not be included in standards of care, but may be discussed with and offered to selected candidates for systemic treatment if no other options are available in the hospital where the patient is treated.

 

Radiotherapy

Radiotherapy uses radiation to kill cancer cells. It is under investigation for patients with liver cancer whose tumour has invaded the portal vein or the inferior vena cava. Radiotherapy can be used in case of one large tumour with a few satellites (smaller tumours around it) and a sufficient amount of healthy liver to be spared. Possible techniques are the following:

 

·         Radioembolization with yttrium-90 microspheres for patients who suffer from blood clots blocking a branch of one of the main veins of the liver, called portal vein thrombosis. This treatment has been described before.

External radiotherapy by three-dimensional conformal radiotherapy (3D-CRT). Radiations are produced by a device outside of the body and are then directed towards the tumour. It is called 3D-conformational because, unlike with classic external radiotherapy technique, a computer calculates the exact direction and shape of the radiation beams. This helps to direct them very precisely to the tumour and to leave as many normal liver cells as possible unharmed. This promising strategy needs however further validation before it can be recommended.

 

Treatment of stage D cancer according to the BCLC classification

The standard treatment at this stage is to relieve the symptoms caused by the disease.

For patients with stage D cancer according to the BCLC classification, best supportive care is offered. The goal of best supportive care is not to cure the cancer or to prolong survival. It aims to reduce symptoms and maximize the patient’s comfort.

Effective medications exist to control pain, nausea and other symptoms. It is important to tell the doctor or nurse about any discomfort in order to adapt the medication according to their needs.

Jaundice is the yellow discoloration of skin and eyes. It is caused by an excess of bilirubin that is no longer excreted by the liver because it is blocked by the tumour. It is a very frequent problem for patients with advanced liver cancer. It can be treated by inserting a stent into the biliary duct, either during a surgical intervention or during an endoscopy. A stent is a small hollow tube that ensures a free passage of the excess of bilirubin into the intestines.

External radiotherapy may be used to control pain caused by bone metastases.

 

How is the effect of the treatment measured?

In patients with advanced cancer, it can be difficult to measure the effect of the treatment, especially when the cancer is composed of several tumours. The best way to evaluate if the treatment has a positive effect is to evaluate:

·         How the tumour responds to the treatment by using imaging techniques, such as  CT-scan or MRI. Dynamic techniques of CT-scan or MRI, requiring the injection of a contrast agent, are recommended since they allow observing a decreased activity of the tumour even in the absence of reduction of the size of the tumour. Many of the therapies used to treat liver cancer can actually kill cancer cells or reduce blood supply to the tumour without necessarily causing reduction in tumour size.

·         How the patient feels during and after the therapy.

·         How the level of alpha-fetoprotein in the blood evolves over time. This can be particularly useful in patients for whom imaging techniques do not give much information on the tumour response.   

 

What are the possible side effects of treatment?

 

Risks and side effects of surgical removal of part of the liver

Removal of a part of the liver is a high-risk surgical procedure. There are several risks and it can cause unwanted health problems, called complications. Complications can usually be treated, but are sometimes difficult to treat and can even be fatal.

Some risks are shared by all surgical interventions performed under general anaesthesia. These complications are infrequent and include deep vein thrombosis, heart or breathing problems, infection, or reaction to the anaesthesia. Although there are risks, doctors will take the most appropriate steps to minimize them.

Excessive bleeding is the main risk of surgery of the liver in patients with liver cancer. The liver normally controls blood clotting and any damage done to the liver before or during surgery can increase bleeding. Liver failure is another complication of liver surgery, especially in patients whose liver function is not optimal because of a chronic liver disease.

 

Risks and side effects of liver transplantation

A liver transplantation is major surgery and there is risk of serious complications. The risks of the surgery include excessive bleeding, infections or complications from the anaesthesia. Bleeding can occur because the liver normally controls blood clotting and may not be able to do so during the first days after it has been transplanted.

After the transplantation, the immune system might start fighting the new ‘unknown’ organ. This reaction is called rejection and should be avoided if possible, as it can harm the new liver. Signs of a rejection can be fever, fatigue, breathlessness, itchy feeling and jaundice, which is a yellow discoloration of the skin and the eyes.

The patient will have to take drugs that suppress his or her immune system for the remainder of his/her life so as to avoid a rejection. The most common anti-rejection drugs are:

The most important side effect of this suppression is that the patient is very susceptible to infections. It is important to take some precautions to decrease the risk of infection. Hands should be washed regularly and contact with people who might be sick or have a cold should be avoided. The patient should avoid staying in enclosed spaces with a lot of people or consider wearing a mouth mask. Anti-rejection drugs also increase the risk of a new cancer occurring. This is because they also suppress the action of the immune system against malignant cells that can develop anywhere in the body. Other side effects include high blood pressure, high cholesterol, diabetes, and weakening of the bones and kidneys. For this reason, and also to detect a rejection as soon as possible, the blood will be examined regularly. When a rejection occurs, an increase of anti-rejection medications can usually help the patient recover. Doctors will also propose a close follow-up to monitor liver function and to detect any new tumours as soon as possible.

 

Side effects of local ablation methods

Possible side effects after radiofrequency ablation therapy include abdominal pain, infection in the liver, and bleeding into the chest cavity or abdomen.

The most common adverse effects of percutaneous ethanol injection are pain and fever. Pain most often is localized to the injection site but can occasionally be experienced elsewhere in the abdomen related to leakage of alcohol onto the surface of the liver and into the abdominal cavity.

 

Side effects of transarterial chemoembolization (TACE)

Transarterial chemoembolization can cause some nausea, pain or fever after the treatment. Because the drugs do not reach the rest of the body in high concentrations, the other side effects are less severe than in classic chemotherapy. They can, however, still cause some fatigue, hair loss, diarrhea and decreasing blood cell counts.

 

Side effects of sorafenib

The most common side effects (seen in more than 1 patient in 10) of sorafenib include:

o   fatigue

o   diarrhea

o   redness, tenderness, swelling, blistering on the palms of the hands or soles of the feet (called hand-foot syndrome)

o   skin rash and skin redness

o   nausea and vomiting

o   loss of appetite

o   high blood pressure

o   pain

o   swelling

o   bleeding

o   hair loss

o   increased levels of some enzymes produced by the pancreas (amylase and lipase)

o   low level of lymphocytes (a type of white blood cell) in the blood

o   low level of phosphate in the blood

Other less common side effects can occur. Any symptom experienced during the treatment with sorafenib should be reported to your doctors.

 

Side effects of chemotherapy

Common side effects of chemotherapy include fatigue, hair loss, mouth sores, loss of appetite, nausea, vomiting and diarrhea. The drugs can also cause low blood cell counts, leading to an increased chance of infections (due to low white blood cell counts), easy bruising or bleeding (due to low blood platelet counts) and fatigue (due to low red blood cell counts). Chemotherapy can be harmful for a baby, so it is important not to be pregnant during the treatment. Beside these, doxorubicin may cause a temporary red color of the urine, sensitivity to sunlight, watery eyes and in some patients even a permanent loss of fertility. Cisplatin can damage the kidneys, therefore it is important to drink a lot of water during the treatment. It can also cause some hearing loss.

However, most of these side effects are treatable and temporary.

 

Side effects of external radiotherapy

Side effects of external radiation therapy (like 3D-CRT) include sunburn-like skin problems where the radiation enters the body, nausea, vomiting, and, most often, fatigue. 

 

What happens after treatment?

 

It is not unusual to experience treatment-related symptoms once the treatment is over.

• It is not rare that anxiety, sleeping problems, or depression are experienced in the post-treatment phase. Patients who exhibit these symptoms may benefit from psychological support.
• Fatigue can last for months after treatment. Most patients find their energy levels are back to normal within 6 months to a year.
• Memory deficiencies and difficulties in concentrating are common side effects of chemotherapy and are generally reversible within a few months.

After transplantation, the patient will have to take drugs that suppress the immune system, in order to prevent the immune system from starting to reject the new ‘unknown’ organ. The most important side effect of this suppression is that the patient is very susceptible to infections. It is advised to take certain precautions so that the risk of infections is always minimal. These precautions include washing hands regularly, avoiding contact with people who are sick or even have a simple cold, and wearing a mouth mask when close contact with other people cannot be avoided.

Follow-up with doctors

After the treatment has been completed, doctors will propose a follow-up aiming to:

• evaluate adverse effects of the treatment and treat them
• provide psychological support and information to enhance returning to normal life
• detect possible recurrence as soon as possible
• after a transplantation
o detect rejection as soon as possible
o adjust the dosage of the anti-rejection drugs
o detect and treat any infection as soon as possible
o evaluate the functioning of the new liver
o detect a new tumour (due to the effect of anti-rejection drugs) as soon as possible

Following partial hepatectomy or radiofrequency ablation or percutaneous ethanol injection, the patient will be proposed to return to the doctor every 3 months for the first two years and every 6 months afterwards.
Following transplantation, follow-up visits will be scheduled in a specialized transplantation centre with the frequency of once monthly for up to 6 months, then once every 3 months for up to 1 year, then twice a year up to 2 years and once a year every year thereafter.
Following transarterial chemoembolization or sorafenib or chemotherapy, a visit to the doctor is recommended every 2 months to guide further therapy decision.

During the follow-up visits the doctor will

• ask for signs and symptoms
• perform a physical examination and look for signs of gradual loss of function of the liver (liver decompensation)
• draw blood to examine the function of the liver and the level of AFP
• arrange appointments for a CT-scan, or MRI to check the effect of the treatments and to detect any sign of the cancer coming back in the liver or elsewhere in the body.

After a liver transplant, regular blood tests are also important to identify signs of the body rejecting the new liver. Sometimes liver biopsies are taken to see if rejection is occurring and if changes are needed in the anti-rejection medicines.

In some patients suffering from hepatitis B or C, a treatment with antiviral drugs and/or interferon can be useful to slow down the evolution of cirrhosis and to maintain the current liver function. If they were already on antiviral treatment before the cancer, this should be resumed if possible.
Close monitoring of the liver function, also in patients without hepatitis, can guide doctors in their efforts to keep the liver working as well as possible.

Return to normal life

It can be hard to live with the idea that the cancer can come back. Today we do not know any specific way of decreasing the risk of recurrence, which is the medical term for the cancer’s coming back. Especially if the cancer was caused by a disease (cirrhosis due to Hepatitis B or C or alcohol abuse), the underlying disease will not be cured by the cancer treatment and will continue to be a risk for recurrence.

As a consequence of the cancer itself and of the treatment, return to normal life may not be easy for some people. Questions related to body-image, fatigue, work, emotions or lifestyle may come up. Discussing these questions with relatives, friends or doctors may be helpful. Some people may also want to find support from ex-patients’ groups or telephone information lines.

What if the cancer comes back?

If the cancer comes back, it is called a recurrence and the treatment depends on the extent of the recurrence.
After treatment by surgery, it is not uncommon that the cancer will come back. It is estimated that half to two thirds of the patients operated will experience a recurrence within 5 years after surgery.  New lesions are either metastases in the liver from the first cancer (often within 2 years following surgery) or a new liver cancer in the remaining liver (occurring beyond 2 years after surgery).
If the cancer comes back locally (meaning only in the liver) the doctors will again decide whether the tumour is resectable or not.

If the tumour is resectable, surgery will be considered.
Sometimes, after a partial liver resection for liver cancer, the tumour might come back on different spots in the remaining part of the liver. In specialized centers, the possibility of liver transplantation might be discussed in these cases. When a cancer comes back inside the new liver after transplantation, the doctors will consider liver resection, re-transplantation or medical treatment, according to the extent of the recurrence and the other relevant information mentioned above.

If the tumour is not resectable, ablative treatments alone or sorafenib may be applied.
If there is no cirrhosis and the surgeons decide the tumour to be unresectable, TACE, or sorafenib may be applied.

If the tumour comes back after transplantation and spreads outside the liver, sorafenib is the treatment of choice for selected patients.

Synonyms

Liver cancer

Primary liver cancer

Primary liver tumour

Primary liver tumor

Liver tumor

Liver tumour

Cancer of the liver

Tumor of the liver

Tumour of the liver

Hepatoma

Hepatic cancer

Hepatic tumour

Hepatic tumor

Hepatocellular carcinoma

HCC

Primary cancer of the liver

Primary tumour of the liver

Primary tumor of the liver

Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Surgical interventions

Procedures involving instrumental means to investigate or treat a cancer, or to improve the body’s functions or appearance. Generally, a surgical intervention involves an incision. More

Radiotherapy

Medical use of high-energy radiation to kill cancer cells and reduce tumor size. More

Registered drugs

Anti-cancer drugs with market authorization in the USA or in countries of the European Union. More

Cell-based therapies

Administration to patients of their own or someone else’s manipulated human cells. More

Synthetic products (excluding registered drugs)

Synthetically produced substances or modified natural products that are not registered as anti-cancer drugs.

Natural products (excluding registered drugs)

Substances found in nature that usually have a pharmacological or biological activity. More

Diets

Controlled consumption of carefully selected foods and beverages with the intent to influence disease outcome.

Energy based therapies

Use of electromagnetic energy including electricity, magnetic fields, radio waves, microwaves, infrared rays and light to diagnose or treat disease.

Body-based & Manipulative therapies

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.

The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for primary liver cancer is available here.