---

---

Chronic Liver Infection (Hepatitis)

Which organisms are responsible?

Certain viruses can infect the liver. The infection may be chronic. (It may not go away.) The most important risk factor for liver cancer is a chronic infection with the hepatitis B virus or the hepatitis C virus.

How does one get these infetions?

These viruses can be passed from person to person through blood (such as by sharing needles) or sexual contact. An infant may catch these viruses from an infected mother.

When does liver cancer develop after viral Infection?

Liver cancer usually develops after many years of infection with the virus. During this time these infections may or may not cause symptoms, but blood tests can show whether virus is present and how it is damaging the liver. If so, the doctor may suggest treatment, regular follow up & a screening program to pick up cancer at early stage if it occurs. Also, the doctor may discuss ways of avoiding infecting other people.

How can one avoid these infections?

In people who are not infected with hepatitis B virus, hepatitis B vaccine can prevent chronic hepatitis B infection and can protect against liver cancer. Researchers are still working to develop a vaccine to prevent hepatitis C infection.

How does chronic HBV infection cause HCC?

The role of hepatitis B virus (HBV) infection in causing HCC is well established. Patients with long-standing HBV infection, men with HBV cirrhosis (scarring of the liver) and patients with family history of HCC are at greater risk to develop HCC.

Virus causing genetic change…

In patients with chronic HBV, specific regions of the HBV genetic material (genetic code) can enter the genetic material of the liver cells. This HBV genetic material may then disrupt the normal genetic material in the liver cells, thereby causing the liver cells to become cancerous & grow uncontrollably.

Does age at which HBV infection is acquired make an impact on development of HCC?

The vast majority of HCC that is associated with chronic HBV occurs in individuals who have been infected most of their lives, exposing them to the effects of virus for a long time & have received the infection from mother before birth when immunity is not well developed.

People who get hepatitis B in adult life rarely ever become chronically infected because of good immunity and do not develop HCC commonly too. Hence community where HBV infection is not widespread (endemic), HCC is not common.

However if an adult develops chronic infection, he or she can develop HCC in due course of time. Similarly HCC can develop in individuals who acquired chronic HBV in adulthood if there are other risk factors, such as chronic alcohol use or co-infection with chronic HCV infection.

How many years does it take to develop hcc after chronic hepatitis b infection?

Patients infected with chronic hepatitis B in childhood usually start developing HCC in their 40's, and the cancer is usually more aggressive. That is, the HCC presents with severe symptoms and is inoperable (too advanced for surgery) at the time of diagnosis. It generally takes about 30 years of chronic damage to the liver before the cancer starts & grows large enough to become obvious. Also the frequency of HCC is three to four times higher in men than in women.

How does hepatitis c virus cause HCC?

The way in which HCV causes HCC is not well understood. Unlike HBV, the genetic material of HCV is not inserted directly into the genetic material of the liver cells.

However cirrhosis from any cause is a risk factor for the development of HCC & majority of HCV patients with HCC have associated cirrhosis (liver scarring). HCV, which causes cirrhosis of the liver, is probably an indirect cause of HCC.

Ironically some chronic HCV infected individuals have HCC without cirrhosis. Possibly core (central) protein of HCV is the culprit. It is thought to impede the natural process of cell death or interfere with the function of a normal tumor suppressor (inhibitor) gene (the p53 gene). The result of these actions is that the liver cells go on living and reproducing without the normal restraints, which is what happens in cancer.

In HCV infected patients, the risk for developing HCC increases in the presence of cirrhosis, older age, male gender, diabetes, metabolic syndrome, alcohol use, HCV genotype 1b and co-infection with HBV.

How many years does it take to develop HCC after chronic hepatitis c infection?

The average time to develop HCC after exposure to HCV is about 30 years & 8 to 10 years after the development of cirrhosis due to hepatitis C. Chance of developing new HCC in cirrhotic HCV patients’ ranges from 1.4 to 2.5% per year.

Alcohol

Cirrhosis caused by chronic alcohol consumption is the most common association of HCC in the developed world. Actually, many of these patients are also infected with chronic HCV.

The usual setting is an individual with alcoholic cirrhosis who has stopped drinking for ten years, and then develops HCC. It is somewhat unusual for an actively drinking alcoholic to develop HCC. What happens is that when the drinking is stopped, the liver cells try to heal by regenerating (reproducing). It is during this active regeneration that a cancer-producing genetic change (mutation) can occur.

Patients who are actively drinking are more likely to die from non-cancer related complications of alcoholic liver disease (e.g., liver failure). Indeed, patients with alcoholic cirrhosis who die of HCC are about 10 years older than patients who die of non-cancer causes. Finally, as noted above, alcohol adds to the risk of developing HCC in patients with chronic HCV or HBV infections.

Aflatoxin B1

Aflatoxin B1 is the most potent liver cancer-forming chemical known. It is a product of a mold called Aspergillus flavus, which is found in food that has been stored in a hot and humid environment. This mold is found in such foods as peanuts, rice, soybeans, corn, and wheat. It is thought to cause cancer by producing changes (mutations) in the p53 gene. These mutations work by interfering with the gene's important tumor suppressing (inhibiting) functions.

Drugs, medications, and chemicals

There are no medications that cause HCC, but female hormones (estrogens) and protein-building (anabolic) steroids are associated with the development of hepatic adenomas. These are benign liver tumors that may have the potential to become malignant (cancerous). Thus, in some individuals, hepatic adenoma can evolve into cancer.

Certain chemicals are associated with other primary liver cancers. For example, thorotrast, a previously used contrast agent for imaging, caused a cancer of the blood vessels in the liver called hepatic angiosarcoma. Also, vinyl chloride, a compound used in the plastics industry, can cause hepatic angiosarcomas that appear many years after the exposure.

Hemochromatosis

Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. This inherited or acquired liver disease.

HCC will develop in up to 30% of patients with hereditary hemochromatosis. Patients at the greatest risk are those who develop cirrhosis with their hemochromatosis. Unfortunately, once cirrhosis is established, effective removal of excess iron (the treatment for hemochromatosis) will not reduce the risk of developing HCC.

Diabetes and obesity

Over the past decade, the incidence of liver cancer has risen significantly, paralleling the rise in obesity. Although it is hard to separate the effects of diabetes from obesity on the liver, both conditions can cause chronic damage and accumulation of fat within the liver. This is a disease called NASH (non-alcoholic steatohepatitis). Fatty liver disease like this causes damage to the individual liver cells and may lead to cirrhosis in some people, thereby increasing the risk of liver cancer.

Not only is the chance of developing the cancer enhanced, but patients with diabetes who undergo surgical removal of liver cancer have a higher chance of the cancer returning than do those without diabetes.

Patients with metabolic syndrome and hepatitis C have much higher chance of developing HCC.

The more risk factors a person has, the greater the chance that liver cancer will develop. However, many people with known risk factors for liver cancer do not develop the disease. People who are at risk for developing liver cancer should have frequent regular checkups. Regardless of the cause, patients with a history of alcohol abuse as well are much sicker when they initially develop the cancer.

What are the symptoms & signs of HCC?

Liver cancer is sometimes called a "silent disease" because in an early stage it often does not cause symptoms. But, as the cancer grows, symptoms may include:

• Pain in the upper abdomen on the right side; the pain may extend to the back and shoulder. Pain in the right upper abdominal area is caused by stretching of the liver's capsule, which is rich in nerves. The liver may then extend below the right costal margin ("hepatomegaly") and be painful to probe.
• Swollen abdomen (bloating). Swelling of the abdomen (called "ascites" pronounced a-site-ees) from the liver failing to produce the protein required to hold the blood's fluid in the blood vessels, so it migrates out to fill the abdomen, scrotum and limbs.
• Cirrhosis signs are seen e.g. breast swelling in males (from the liver failing to break down estrogens) and little spider shaped veins (angiomata) seen on the skin. Another sign of liver failure is very red palms ("palmar erythema").
• Blood clotting problems leading to intestinal bleeding and bruises on the skin. The liver normally uses vitamin K from the diet and intestinal bacteria sources to synthesize the clotting factor ("prothrombin") necessary for life.
• Fatigue and eventually coma from buildup of ammonia in the body.
• Jaundice and light stools, from blockage of the bile draining system. Also looser and smellier stools may be seen, ("steatorrhea") indicating poor breakdown of fats in the digestive tract. Jaundice normally produces itching (pruritis) when it becomes marked. The first area notable for jaundice, caused by the liver's failure to clear bilirubin, is the whites of the eyes ("scleral icterus").
• A Paraneoplastic syndrome means unusual symptoms caused by chemical alterations in the body either from the liver failing or HCC cells sometimes produce hormones that are ordinarily produced in other body systems. These hormones then can cause certain abnormalities such as a high red blood count (erythrocytosis), low blood sugar (hypoglycemia), high blood calcium (hypercalcemia) and high serum cholesterol (hypercholesterolemia).
• Signs of Distant Spread include bone pain, neurological symptoms from brain involvement, and intestinal blockage. These all indicate advanced disease.
• Weight loss, Loss of appetite and feelings of fullness, Weakness or feeling very tired, Nausea and vomiting, Fever

Some of these symptoms are not specific for liver cancer. Other liver diseases and other health problems can also cause these symptoms. Still one with these symptoms should see a doctor as soon as possible.

The tumor usually reaches an advanced stage and causes symptoms more rapidly. Tumors that progress more slowly remain without symptoms longer. Abdominal pain is the most common symptom of HCC and usually signifies a large tumor or widespread involvement of the liver. Additionally, unexplained weight loss or unexplained fever is warning signals of HCC in patients with cirrhosis.

A very common initial presentation of HCC in a patient with compensated cirrhosis (no complications of liver disease) is the sudden onset of a complication. For example, the sudden appearance of ascites (abdominal fluid and swelling), jaundice (yellow color of the skin), or muscle wasting without causative (precipitating) factors (e.g., alcohol consumption) suggests the possibility of HCC.

What's more, the cancer can invade and block the portal vein (a large vein that brings blood to the liver from the intestine and spleen). When this happens, the blood will travel paths of less resistance, such as through esophageal veins. This causes increased pressure in these veins, which results in dilated (widened) veins called esophageal varices. The patient then is at risk for hemorrhage from the rupture of the varices into the gastrointestinal tract.

In advanced HCC, tumor can invade the veins that drain the liver (hepatic veins). The tumor can then block these veins, which results in congestion of the liver. The congestion occurs because the blocked veins cannot drain the blood out of the liver. (Normally, the blood in the hepatic veins leaving the liver flows through the inferior vena cava, which is the largest vein that drains into the heart.) Blockage of either the hepatic veins or the inferior vena cava results in a very swollen liver and massive formation of ascites and swelling of legs.

Whenever the overall health of a patient with cirrhosis deteriorates, every effort should be made to look for HCC.

Rarely, the cancer itself can rupture and bleed into the abdominal cavity, resulting in bloody ascites.

HCC frequently spreads to the lungs and rarely to bone or brain. by way of the blood stream. Usually, patients do not have symptoms from the lung metastases.

Quite often patients do not have any symptoms and are diagnosed during routine health check up.

Thorough physical examination may not reveal any finding if the patient is having a fairly small silent tumor. However patient may have an enlarged, sometimes tender liver or signs of cirrhosis like jaundice, enlarged spleen, dilated abdominal wall veins, ascites and abdominal distension, muscle wasting etcetera. Any sign of advanced liver disease (e.g., ascites, jaundice, or muscle wasting) means a poor prognosis. Rarely, a patient with HCC can become suddenly jaundiced when the tumor erodes into the bile duct. The jaundice occurs in this situation because both sloughing of the tumor into the duct and bleeding that clots in the duct can block the duct.

If tumor is large it may be palpable. HCCs are very vascular (containing many blood vessels) tumors. Thus, increased amounts of blood feed into the hepatic artery (artery to the liver) and cause turbulent blood flow in the artery. The turbulence results in a distinct sound in the liver (hepatic bruit) that can be heard with a stethoscope in about one quarter to one half of patients with HCC.

Males are affected slightly more commonly than females, and the average patient is 50 years old. By contrast, benign liver tumors are more common in females and tend to occur at a younger age.

How is HCC diagnosed?

Liver cancer is not diagnosed by routine blood tests, including a standard panel of liver tests. Usually a liver cancer is picked up as a mass in liver during ultrasonography of abdomen. You may have done it for symptoms related to it or completely unrelated. USG may be part of a routine health check up or screening examination if you are a cirrhosis patient or part of work up in a cirrhotic patient with high serum level of AFP.

Once there is suspicion of a liver cancer more tests are done to confirm the nature of disease. These include blood test for tumor markers alpha-fetoprotein (AFP) if not done already, CA 19.9 & CEA. High AFP levels could be a sign of primary liver cancer. This will be followed up with a triple phase IV contrast CT scan or MRI of liver & abdomen.

LFT of these patients is performed routinely. Most patients with HCC have associated liver disease (cirrhosis) & their liver blood tests may not be normal to begin with. If these blood tests become abnormal or worsen due to HCC, this usually signifies extensive cancerous involvement of the liver. At that time, any medical or surgical treatment would be too late.

What is AFP & is it a good screening test for HCC?

Sadly there is no reliable or accurate screening blood test for HCC. The most widely used biochemical blood test is AFP which is a protein normally made by the immature liver cells in the fetus. In adults, high blood levels (over 500 nanograms/milliliter) of AFP are seen in only three situations i.e. HCC, Germ cell tumors (cancer of the testes and ovaries) & some metastatic cancer in the liver (originating in other organs). Normal levels of AFP are below 10 ng/ml. Moderate levels of AFP (even almost up to 500 ng/ml) can be seen in patients with chronic hepatitis. Moreover, many patients with various types of acute and chronic liver diseases without documentable HCC can have mild or even moderate elevations of AFP.

The sensitivity of AFP for HCC is about 60%. In other words, an elevated AFP blood test is seen in about 60% of HCC patients. That leaves 40% of patients with HCC who have normal AFP levels. Therefore, a normal AFP does not exclude HCC. Also, as noted above, an abnormal AFP does not mean that a patient has HCC. It is important to note, however, that patients with cirrhosis and an abnormal AFP, despite having no documentable HCC, still are at very high risk of developing HCC. Thus, any patient with cirrhosis and an elevated AFP, particularly with steadily rising blood levels, will either most likely develop HCC or actually already have an undiscovered HCC.

An AFP greater than 500 ng/ml is very suggestive of HCC. In fact, the blood level of AFP loosely relates to (correlates with) the size of the HCC. Finally, in patients with HCC and abnormal AFP levels, the AFP may be used as a marker of response to treatment. For example, an elevated AFP is expected to fall to normal in a patient whose HCC is successfully removed surgically (resected).

Are there other screening blood tests for HCC?

There are a number of other HCC tumor markers that currently are research tools and not generally available. These include des-gamma-carboxyprothrombin (DCP) produced by normal liver cells. Potentially, these blood tests, used in conjunction with AFP, could be very helpful in diagnosing more cases of HCC than with AFP alone.

Which is the best imaging study for HCC?

There is no simple answer. Many factors need to be taken into consideration. For example, is the diagnosis of HCC known or is the scan being done for screening? What is the expertise of doctors in the patient's area? What is the quality of the different scanners at a particular facility? Are there economic considerations? Does the patient have any other conditions that need to be considered, such as claustrophobia or kidney impairment? Does the patient have any hardware, e.g., a pacemaker or metal prosthetic device? (The hardware would make doing an MRI impossible.)

Imaging studies play a very important role in the diagnosis of HCC. A good study can provide information as to the size of the tumor, the number of tumors, and whether the tumor has involved major blood vessels locally or spread outside of the liver. Each has its merits and disadvantages. In practice, several studies combined often complement each other.

---

Ultrasonography

USG is usually the first study ordered if HCC is suspected in a patient. Ultrasound is also the most practical (easier and cheaper) study for regular screening (surveillance). In select centers ultrasonography is done with simultaneous intravenous contrast medium injection. If there is a tumor it will usually pick up the contrast and the enhancement will be detected by USG. It works on the same principles of contrast enhanced CT or MRI scan but is much cheaper. It is quite sensitive too.

CT Scan or MRI?

CT or MRI is done for diagnosis or work-up of tumors in the liver. The ideal CT study is a multi-phase, spiral CT scan using oral and intravenous contrast material. Pictures are taken in three phases; without intravenous contrast, with intravenous contrast (enhanced imaging) that highlights the arterial system (arterial phase) & when the contrast is in the venous phase. The pictures are taken at very frequent intervals (thin slices) as the body is moved through the scanner.

CT requires the use of contrast material, which has the potential risks of an allergic reaction and adverse effects on kidney function. Hence, for patients with impaired renal function or who have access to a state-of-the-art MRI scanner, MRI may be the diagnostic scan of choice

There are several variations to CT scanning. For example, in a CT angiogram intravenous contrast is selectively infused through the hepatic artery (artery to the liver). The purpose is to highlight the vessels for better visualization of them by the CT scan. Sometimes an oily contrast material called lipiodol, which is selectively taken up by HCC cells, has been used with CT. The purpose of this approach is to improve the sensitivity of the scan. That is to say, the goal is to increase the percentage of abnormal CT scans in patients who have HCC.

Advantage of MRI over CT is that MRI can provide sectional views of the body in different planes. The technology has evolved to the point that the newer MRIs can actually reconstruct images of the biliary tree (bile ducts and gallbladder) and of the arteries and veins of the liver. (The biliary tree transports bile from the liver to the duodenum, the first part of the intestine.) MRI studies can be made even more sensitive by using intravenous contrast material (e.g., gadolinium). MRI can find lesions that are smaller than can be seen on a CT scan

It is important to realize here that some patients require all these investigations to reach the diagnosis or sometimes on multiple occasions before the conclusion is made or sometimes it is impossible to conclusively prove the cancerous nature on imaging

Will I need a conventional angiography?

Advances in ultrasound, CT, and MRI technology have almost eliminated the need for conventional angiography. An angiography procedure involves inserting a catheter into the femoral artery (in the groin) through the aorta, and into the hepatic artery, the artery that supplies blood to the liver. Contrast material is then injected, and X-ray pictures of the arterial blood supply to the liver are taken. Very rarely when all investigations fail, angiography with lipiodol injection followed by a CT scan is done to diagnose a HCC.

When will you do a biopsy?

The physician always asks two questions before deciding on doing a liver biopsy:

1. Is this tumor most likely to be a cancer & in this case HCC?
2. Will the biopsy findings change the management of the patient?

If the answer to both questions is yes, then the biopsy is done.

In many instances, there is probably no need for a tissue diagnosis by biopsy or aspiration. If a patient has a risk factor for HCC (e.g., cirrhosis, chronic hepatitis B, or chronic hepatitis C) and a significantly elevated alphafetoprotein blood level & CT or MRI shows typical picture; then it is almost certain that the patient has HCC without doing a biopsy and it is safe to undergo a surgery too without a biopsy. Moreover, recent advances in CT & MRI interpretation can identify small liver cancers as such with an extremely high degree of probability.

However, there are few situations related to HCC in which a biopsy may be considered. The first is to characterize a liver abnormality (e.g., a possible tumor) seen by imaging in the absence of risk factors for HCC or elevated alpha-fetoprotein. The second is when there are multiple areas of abnormalities (possibly tumors)

seen by imaging in the liver. The third is prior to starting palliative therapies.

What is FNAC & biopsy?

Tissue can be sampled with a very thin needle. This technique is called fine needle aspiration. With this only few cluster of cells are removed, hence called Fine Needle Aspiration Cytology (FNAC).

When a larger needle is used to obtain a core of tissue, the technique is called a biopsy. Generally, radiologists, using ultrasound or CT scans to guide the placement of the needle, perform the biopsies or fine needle aspirations.

What are risks or possible complications?

The most common risk of the aspiration or biopsy is bleeding, especially because HCC is a tumor that is very vascular (contains many blood vessels). Rarely, new foci (small areas) of tumor can be seeded (planted) from the tumor by the needle into the liver along the needle track.

Which is better & preferred, biopsy or FNAC?

The aspiration procedure is safer than a biopsy with less risk for bleeding. However, interpretation of the specimen obtained by aspiration is more difficult because often only a cluster of cells is available for evaluation. Thus, a fine needle aspiration requires a highly skilled pathologist. Moreover, a core of tissue obtained with a biopsy needle is more ideal for a definitive diagnosis because the architecture of the tissue is preserved.

Overall, no blanket recommendation can be given regarding the need for liver biopsy or aspiration. The decision has to be made on an individual basis, depending on the treatment options and the expertise of the medical and surgical teams. The truth is, biopsies are not always definitive; people with cirrhosis have many small nodules in their livers, and while one might be cancerous, others are not. Occasionally, people have to undergo several biopsies over many months before a definite diagnosis can be made

Is biopsy fullproof?

A definitive diagnosis of HCC is not always possible after microscopic (histological) examination. Some liver cancers are well differentiated, which means they are made up of nearly fully developed, mature liver cells (hepatocytes). Therefore, these cancers can look very similar to non-cancerous liver tissue under a microscope. Moreover, not all pathologists are trained to recognize the subtle differences between well-differentiated HCC and normal liver tissue. Also, some pathologists can mistake HCC for adenocarcinoma in the liver. An adenocarcinoma is a different type of cancer, and, as previously mentioned, it originates from outside of the liver. Most importantly, a metastatic adenocarcinoma would be treated differently from a primary liver cancer (HCC). Therefore, all of this considered, it is important that an expert liver pathologist review the tissue slides of liver tumors in questionable situations.

How long will it take?

The procedure usually takes 15 to 30 minutes and is performed under local anesthesia. Patient is awake during the procedure. Patient is sometimes admitted for this in the hospital and observed for 24 hours postprocedure to rule out complications.

How soon will I know the results?

The results of FNAC are usually available in 48 to 72 hours, however occasionally can take longer. Biopsy results may take 3-7 days depending on the underlying pathology. Rarely special studies with special stains and immunohistochemistry study will be necessary and results will be delayed.

If I do have cancer, who will talk with me about treatment? When?

The results will be discussed with you by your doctor on the round in the ward in the next few days or you should meet your doctor with the result in his chamber.

What is the expected survival?

The survival of patients with HCC depends on the stage of the tumor and the severity of associated liver disease (e.g., cirrhosis) at the time of diagnosis.

Staging is an attempt to find out the size of the tumor, whether the disease has spread, and if so, to what parts of the body. Careful staging shows whether the tumor can be removed with surgery. This is very important because many liver cancers cannot be removed with surgery. The doctor may determine the stage of liver cancer at the time of diagnosis, or the patient may need more tests. These tests may include imaging tests, such as a CT scan, MRI, angiogram, or ultrasound. The doctor also may use a laparoscope to look directly at the liver and nearby organs.

Points going against a long life expectancy are male gender, old age, alcohol consumption, weight loss, signs of poor liver function like jaundice, ascites (water in the abdomen) or encephalopathy (altered mental state), blood tests showing elevated bilirubin or liver enzymes (transaminase), reduced albumin, elevated AFP, elevated blood urea nitrogen (BUN), or low serum sodium and staging of tumor on imaging studies shows more than one tumor, tumor size over 5cm (almost 1¼ inches), tumor growth in local blood vessels (portal and/or hepatic vein), tumor spread outside of the liver (to lymph nodes or other organs).

The doubling time for a cancer is the time it takes for the tumor to double in size. For liver cancer, the doubling time is quite variable, ranging from one month to eighteen months. This kind of variability tells us that every patient with HCC is unique. Therefore, an assessment of the natural history and the evaluation of different treatments are very difficult. Nevertheless, in patients with a solitary HCC that is less than 3 cm, with no treatment, we can expect that 90% of the patients will survive (live) for one year, 50% for three years, and 20% for five years. In patients with more advanced disease, we can expect that 30% will survive for one year, 8% for three years, and none for five years.

What are the treatment options for HCC?

At this time, liver cancer can be cured only when it is found at an early stage (before it has spread) and only if the patient is healthy enough to have an operation. However, treatments other than surgery may be able to control the disease and help patients live longer and feel better. When a cure or control of the disease is not possible, some patients and their doctors choose palliative therapy. Palliative therapy aims to improve the quality of a person's life by controlling pain and other problems caused by the disease.

Cancer of the liver is very hard to control with current treatments. For that reason, many doctors encourage patients with liver cancer to consider taking part in a clinical trial. Clinical trials are research studies testing new treatments. They are an important option for people with all stages of liver cancer

The choice of treatment depends on the condition of the liver; the number, size, and location of tumors; and whether the cancer has spread outside the liver. Other factors to consider include the patient's age, general health, concerns about the treatments and their possible side effects, and personal values.

If the tumor cannot be operated upon, other treatments are done. These treatments may decrease your pain or decrease the size of your tumor for surgery at a later date.

Localized resectable cancer

Localized resectable liver cancer is cancer that can be removed completely by surgery. There is no evidence that the cancer has spread to the nearby lymph nodes or to other parts of the body.

If lab tests show that the liver is working well and adequate liver can be left behind after removing tumor, surgery to remove part of the liver is called partial hepatectomy, is suggested.

Liver resection involves complete removal of the tumor and the appropriate surrounding liver tissue without leaving any tumor behind. (R0 resection in surgeon’s language, which is necessary for cancer cure) This option is best suited to patients with one or two small (3cm or less) tumors and excellent liver function, ideally without associated cirrhosis. However patients with large liver tumors with preserved liver function or an otherwise normal liver can also undergo surgery. As a result of these strict guidelines, in practice, very few patients with HCC can undergo liver resection.

How much liver is removed?

The extent of the surgery depends on the size, number, and location of the tumors. It also depends on how well the liver is working. The doctor may remove a wedge of tissue that contains the liver tumor, a single segment, a sector (2 segments), an entire lobe (3 or more segments), or an even larger portion of the liver. In a partial hepatectomy, the surgeon leaves a margin of normal liver tissue. This remaining healthy tissue takes over the functions of the liver.

Will it be tolerated well?

In patient with normal liver even 70% or more of liver removal is well tolerated by patient. However in patients with cirrhosis, hepatitis or fatty liver barely 60% or lesser may be tolerated. In severe liver disease resection of even small portion is not tolerated.

The biggest concern about resection is that following the operation, the patient can develop liver failure. The liver failure can occur if the remaining portion of the liver is inadequate to provide the necessary support for life. Even in carefully selected patients, about 10% of them are expected to die shortly after surgery, usually as a result of liver failure.

Does remaining liver regenerate?

The remaining liver can regenerate or regrow to a significant extent. If underlying liver is absolutely normal then it can regenerate to almost 80% of original size by the end of 3 weeks of surgery. However if underlying liver is diseased then capacity to regenerate is reduced and a cirrhotic, fibrotic or very fatty liver cannot show regeneration. Therefore, before resection is performed for HCC, the non-tumor portion of the liver should be biopsied to determine whether there is associated cirrhosis.

What is portal vein embolisation?

Portal Vein Embolization is a vascular intervention procedure done transhepatically usually by an interventional radiologist to block the right branch of portal vein supplying the liver. This causes reduced blood supply to right lobe of liver (one to be resected) thereby shrinking it and at the same time diverting all the nutrients and growth factors to the left lobe (one to be preserved) thereby enlarging it. This is done in patients with otherwise small left lobe of liver. It allows the patient to tolerate a large right liver resection. However patients with bad cirrhosis, hepatitis and severe fatty liver may not show any growth after PVE and thereby will not be suitable candidates for surgery.

Which anesthesia is used?

PVE is usually done under local anesthesia with mild sedation if necessary. A formal general anesthesia is not necessary. Procedure is performed either in radiology suite or cardiac catheterization lab.

Will I be in icu? How many days will i be in hospital?

After the procedure patient is shifted back in the room for observation. Patients do not require observation in ICU. Patients are observed over next 2-3 days for derangement in liver function. Patient is usually discharged after 2-3 days.

Will there be complications?

PVE is a safe procedure in experienced hands. Still there is a slim chance of problems like bleeding from liver surface, fever, abdominal pain, and leukocytosis after the procedure. It is not a surgery and will not usually require blood transfusion.

What if remaining liver is insufficient or fails?

Usually patients do not develop liver insufficiency following PVE. However if he or she does develop signs of liver failure or remaining lobe doesn’t show enlargement it is a bad sign for patient and signal that surgery is not possible. This liver failure can be managed medically.

What is the survival after resection?

For patients whose tumors are successfully resected, the five-year survival is about 30 to 40% or more if there is no cirrhosis and tumor related factors are favorable. (small size, single well-differentiated tumor, no vascular invasion) This means that 30 to 40 % of patients who actually undergo liver resection for HCC are expected to live five years. Many of these patients, however, will have a recurrence of HCC elsewhere in the liver. Still, this is the procedure of choice for patients without cirrhosis and a solitary tumor who are felt to be medically able to undergo surgery.

Some studies from Europe and Japan have shown that survival rates with alcohol injection or radiofrequency ablation procedures are comparable to the survival rates of those patients who underwent resection. But again, the reader should be cautioned that there are no head-to-head comparisons of these procedures versus resection.

Is liver transplantation an option?

Liver transplantation has become an accepted treatment for patients with end-stage (advanced) liver disease (ESLD) of various types (e.g., chronic hepatitis B and C, alcoholic cirrhosis). Survival rates for these patients without HCC are 90% at one year, 80% at three years, and 75% at five years.

If your liver has severe disease (ESLD), partial hepatectomy is not possible. The diseased liver needs removal and replacement with a healthy donated liver. Liver Transplantation can also be done in patients with HCC without ESLD.

This option is useful in only those handful patients who have small tumors, preferably smaller than 5cms. Moreover, In fact, patients with small cancers (less than 3 cm) and no involvement of the blood vessels have a less than 10% risk of recurrent HCC after transplant. On the other hand, there is a very high risk of recurrence in patients with tumors greater than 5 cm or with involvement of blood vessels.

What should a patient do while waiting for an organ?

There is a severe shortage of organ donors. As a result, in many HCC patients, while they are on the waiting list, the tumor may become too large for the patient to benefit from liver transplantation.

Doing palliative treatments, such as TACE or Ablation, while the patient is on the waiting list for liver transplantation is an option. The use of a partial liver from a healthy, live donor may provide a few patients with HCC an opportunity to undergo liver transplantation before the tumor becomes too large. This innovation is a very exciting development in the field of liver transplantation.

What precautions should be taken in a candidate for liver transplanatation?

As a precaution, doing a biopsy or aspiration of HCC should be avoided in patients considering liver transplantation. There is about a 1 to 4% risk of seeding (planting) cancer cells from the tumor by the needle into the liver along the needle track. You see, after liver transplantation, patients take powerful anti-rejection medications to prevent the patient's immune system from rejecting the new liver. However, the suppressed immune system can allow new foci (small areas) of cancer cells to multiply rapidly. These new foci of cancer cells would normally be kept at bay by the immune cells of an intact immune system.

People who do undergo transplantation for liver cancer have a lower chance of having the cancer return if they are first treated with a local method such as chemoembolization. This also helps them to be treated while they are spending time on the transplant waiting list, so that the cancer does not grow while they are waiting.

What is done in liver transplantation?

In liver transplantation, the transplant surgeon removes the patient's entire liver (total hepatectomy) and replaces it with a healthy liver from a donor. A liver transplant is an option only if the disease has not spread outside the liver and only if a suitable donated liver can be found. The replacement liver can come either from a brain dead or cadaver donor or a living related person donating a portion of his or her liver. While the patient waits for a suitable donated liver to become available, the health care team monitors the patient's health and provides other treatments, as necessary. These include protecting the diseased liver or treatments directed towards halting progress of primary tumor.

What if patient is suitable for both resection and transplantation?

Often a patient is suitable for both resection and transplantation. Moreover, one and three year survival rates for resection are perhaps comparable to those for liver transplantation for same stage. This has caused a debate amongst clinicians treating HCC over the years over which form of therapy to choose. This question is not answered fully yet and patients should take their decision after understanding both procedures, risks involved, cost and availability of transplantation facility and a donor.

However, most patients with HCC also have cirrhosis of the liver and would not tolerate liver resection surgery. But, they probably would tolerate the transplantation operation, Furthermore; many patients who undergo hepatic resections will develop a recurrence of HCC elsewhere in the liver within several years. In fact, some experts believe that once a liver develops HCC, there is a tendency for that liver to develop other tumors at the same time (synchronous multicentric occurrence) or at a later time (metachronous multicentric occurrence)

Can I go for transplantation after resection?

Yes, you can opt for liver transplantation after resection if there is a recurrence. Often doctors suggest this form of sequential measure in some patients who cannot tolerate major resection but would tolerate a minor resection, which can buy you time when you are on waiting list for a transplant.

Localized inoperable cancer

Localized inoperable liver cancer cannot be removed by surgery even though it has not spread to the nearby lymph nodes or to distant parts of the body. Surgery to remove the tumor is not possible because of cirrhosis (or other conditions that cause poor liver function), the location of the tumor within the liver, or other health problems. Liver transplantation is an option for some of these patients. If localized liver cancer is unresectable because of poor liver function, some patients may be able to have a liver transplant. While the patient waits for a donated liver to become available, the health care team monitors the patient's health and provides other treatments, as necessary. However majority of patients may receive other treatments to control the disease and extend life. These include

Ablation techniques

Ablation refers to any method that physically destroys a tumor, and is generally only applicable to situations in which there are only one, two, or sometimes three individual cancers in a liver. When there are more than that, it is not possible to reach every one on its own, so a different method such as systemic or transarterial chemotherapy must be used

Radiofrequency ablation (RFA)

How does it destroy tumor?

In RFA, heat is generated locally by a high frequency, alternating current that flows from the electrodes. A probe is inserted into the center of the tumor and the non-insulated electrodes, which are shaped like prongs, are projected into the tumor. The local heat that is generated melts the tissue (coagulative necrosis) that is adjacent to the probe. The probe is left in place for about 10 to 15 minutes. The whole procedure is monitored visually by ultrasound scanning.

Does it require anesthesia?

The doctor can insert the probe directly through the skin under local anesthesia. In other cases, the doctor may insert the probe under the guidance of laparoscope through a small incision in the abdomen or may make a wider incision to open the abdomen. These procedures are done in the hospital with general anesthesia.

Which tumors are suitable for RFA?

The ideal size of an HCC tumor for RFA is less than 3 cm. Larger tumors may require more than one session. This treatment should be viewed as palliative (providing some relief), not curative.

Will I be in ICU?

After the procedure patient is shifted back to the ward. Usually no special monitoring except pulse, BP & temperature is required.

How many days will I be in hospital?

You will be discharged in 2-3 days or at times in 1 day. If many tumors or larger tumor is ablated then you may have to stay little longer.

Will there be complications?

Complications are uncommon but known and include bleeding, biliary injury, bowel perforation, liver abscess, and high fever.

Other therapies that use heat to destroy liver tumors include laser or microwave therapy.

Cryosurgery

What is cryoablation?

Cryoablation is similar to RFA, however, instead of using heat, cryoablation uses a probe filled with liquid nitrogen to freeze the tumor and kill it that way. This is probably as effective as RFA but can be used in some tumor locations where heat might accidentally damage adjacent organs (like when the gallbladder or colon is too close to the tumor).

How is it done?

A single tumor is identified and then targeted by a radiologist with a needle inserted through the skin directly into the cancer. Sometimes the doctor makes an incision into the abdomen and inserts a metal probe to freeze and kill cancer cells. The doctor may use ultrasound to help guide the probe. Because a smaller incision is needed for cryosurgery than for traditional surgery, recovery after cryosurgery is generally faster and less painful. Also, infection and bleeding are not as likely.

Percutaneous ethanol (alcohol) injection

How is it done?

Pure alcohol is injected into the tumor through a very thin needle under ultrasound or CT guidance. The procedure may be performed once or twice a week. Usually local anesthesia is used, but if the patient has many tumors in the liver, general anesthesia may be needed.

How does it work?

Alcohol induces tumor destruction by drawing water out of tumor cells (dehydrating them) and thereby destroying cellular proteins. It may take up to five or six sessions of injections to completely destroy the cancer.

Who are better suited for this therapy?

Patient should have fewer than three tumors, with distinct margins, less than 3cm in diameter surrounded by a shell consisting of scar tissue (fibrous capsule) and is not near the surface of the liver.

Who is not suitable for alcohol injection?

Patients with signs of chronic liver failure, such as ascites or jaundice would not be able to tolerate the alcohol injections.

What are the side effects & complications?

The most common side effect of alcohol injection is leakage of alcohol onto the surface of the liver and into the abdominal cavity, thereby causing pain and fever. The doctor can suggest medicines to relieve these problems. Rarely bleeding, bile duct inflammation, or bile leakage can occur.

Hepatic arterial infusion of chemotherapy

What is the logic behind this form of chemotherapy?

The normal liver gets its blood supply from two sources; the portal vein (about 75%) and the hepatic artery (25%). However, HCC gets its blood exclusively from the hepatic artery. Making use of this fact, chemotherapy agents are delivered selectively through the hepatic artery directly to the tumor. The theoretical advantage is that higher concentrations of the agents can be delivered to the tumors without subjecting rest of the organs to the toxicity of the agents.

So will there be side effects?

Some of the chemotherapeutic agents do end up in the rest of the body. Therefore, selective intra-arterial chemotherapy can cause the usual systemic (body-wide) side effects in milder form.

In addition, this treatment can result in some regional side effects, such as inflammation of the gallbladder (cholecystitis), intestinal and stomach ulcers, and inflammation of the pancreas (pancreatitis).

HCC patients with advanced cirrhosis may develop liver failure after this treatment.

Well then, what is the benefit of intraarterial chemotherapy?

The bottom line is that fewer than 50% of patients will experience a reduction in tumor size. Some of these patients may be able to undergo a surgery (resection or transplantation) later too.

How is it done?

An interventional radiologist (one who does therapeutic procedures) usually carries out this procedure. The radiologist must work closely with the oncologist (cancer specialist), who determines the amount of chemotherapy that the patient receives at each session, hepatobiliary surgeon and hepatologist. Some patients may undergo repeat sessions at 6 to 12 week intervals.

This procedure is done in fluoroscopy suite or cardiac cathlab. A catheter (long, narrow tube) is inserted into the femoral artery in the groin and is threaded into the aorta (the main artery of the body). From the aorta, the catheter is advanced into the hepatic artery. Once the branches of the hepatic artery that feed the liver cancer are identified, the chemotherapy drug is infused. The whole procedure takes one to two hours, and then the catheter is removed.

The patient generally stays in the hospital overnight for observation. A sandbag is placed over the groin to compress the area where the catheter was inserted into the femoral artery. The nurses periodically check for signs of bleeding from the femoral artery puncture. They also check for the pulse in the foot on the side of the catheter insertion to be sure that the femoral artery is not blocked as a result of the procedure. (Blockage would be signaled by the absence of a pulse.)

What are the postprocedure problems?

Generally, the liver tests increase (get worse) during the two to three days after the procedure. This worsening of the liver tests is actually due to death of the tumor (and some non-tumor) cells. The patient may experience some post-procedure abdominal pain and low-grade fever. However, severe abdominal pain and vomiting suggest that a more serious complication has developed.

Imaging studies of the liver are repeated in 6 to 12 weeks to assess the size of the tumor in response to the treatment.

Hepatic arterial infusion also can be done with a small pump. The doctor implants the pump into the body during surgery. The pump continuously sends the drug to the liver. Side effects include infection and problems with the pump device. Sometimes the device may have to be removed.

Chemoembolization

(Trans-Arterial ChemoEmbolization or TACE)

What is the logic behind thia therapy?

This technique like infusion chemotherapy takes advantage of the fact that HCC is a very vascular (contains many blood vessels) tumor and gets its blood This technique like infusion chemotherapy takes advantage of the fact that HCC is a very vascular (contains many blood vessels) tumor and gets its blood.

Sometimes the chemotherapeutic agents are mixed with a special compound, lipiodol. The idea is that since the tumor cells preferentially take up lipiodol, they would likewise take up the chemotherapy.

The potential disadvantage of TACE is that blocking the feeding vessels to the tumor(s) may make future attempts at intra-arterial infusions impossible.

What are the benefits of TACE?

TACE shows maximum benefits in patients with small tumors especially less than 3 cms. In case of large tumors treated patients may show tumor shrinkage, sometimes enough to lower (improve) the stage of the cancer. From the practical point of view, shrinking the tumor creates the option for surgery in some of these patients. Otherwise, these tumors were not operable (eligible for operation) because of the initial large size of their tumors. More importantly, there is an improvement in survival in patients whose tumors become considerably smaller.

Is TACE curative or palliative?

It is safe to say that TACE or intra-arterial chemoinfusion are palliative treatment options for HCC. This means that these procedures can provide relief or make the disease less severe. However, they are not curative (do not result in a cure). Fewer than 50% of patients will have some shrinkage in tumor size.

What are the limitations?

TACE can be used only in patients with relatively preserved liver function. The reason for this is that these procedures can lead to liver failure in individuals with poor liver function.

By relying upon blocking blood flow to the tumor, TACE will also cause some damage to the surrounding liver, and this is its primary limitation.

Whar are the side effects?

Liver damage can cause pain, fever, nausea, infection, fluid accumulation, and rarely, death. The doctor can give medications to help lessen these problems. Some patients may feel very tired for several weeks after the treatment.

---

What are the newer techniques?

The newer techniques for delivering chemotherapy intraarterially and blocking the blood vessels at the same time are microscopic drug-eluting beads. While the side effects seem to be less, it is not clear whether this method is more effective.

Radioembolization

Radioembolization (also known as SIRT, or selective internal radiotherapy) involves attaching a radioactive molecule (called Yttrium) to tiny glass beads. These are then injected directly into the blood vessels feeding the cancers (as in TACE). The radiation particles can then kill tumor cells within a distance of 2.5 mm from them, so that any part of the cancer fed by tiny blood vessels will be exposed to the radiation. It seems to have fewer complications than TACE, although severe liver damage is still possible. The effectiveness is probably comparable to chemoembolization. It is much more expensive than TACE and requires special set up.

Stereotactic radiosurgery / cyberknife?

Stereotactic radiosurgery (SRS) is a new technique directing radiation (high-powered X-ray beams) directly to the tumor. Previously, radiation could not generally be used for liver cancer, because the normal liver was more sensitive to dying from radiation than the cancer was. SRS uses computer planning and CT scans to model the exact size, shape, and location of the cancer. It then directs the radiation machine, which can move around the patient in all three dimensions, to give many individual beams of radiation designed to converge just on the tumor, thus sparing much of the normal liver from the cumulative high doses. This appears to be very effective against solitary tumors.

Proton beam therapy

This technique is able to deliver high doses of radiation to a defined local area. Proton beam therapy is used in the treatment of other solid tumors as well. There are not much data yet regarding the efficacy of this treatment in HCC. The ideal patient is one with only a small (<5 cm) solitary lesion. To have this procedure done, the patient actually is fitted with a body cast so that he or she can be placed in the identical position for each session. Therapy is conducted daily for 15 days. It is not known, however, whether this type of radiation treatment prolongs the life of the patient.

Many patients actually need combinations of these procedures (e.g., proton beam and TACE).

---

Advanced cancer

Advanced cancer is cancer that is found in both lobes of the liver or that has spread to other parts of the body. Although advanced liver cancer cannot be cured, some patients opt for anticancer therapy to try to slow the progress of the disease. Others discuss the possible benefits and side effects and decide they do not want to have anticancer therapy. In either case, patients receive palliative care to reduce their pain and control other symptoms. Treatment for advanced liver cancer may involve chemotherapy, radiation therapy, or both

Systemic (entire body) chemotherapy

What is systemic chemotherapy?

Systemic therapy, means the drugs are injected into a vein and flow through the bloodstream to nearly every part of the body. The doctor may call this intravenous (IV) chemotherapy.

Will i need hopsitalisation?

Usually chemotherapy is an outpatient treatment given at the hospital, clinic, or at the doctor's office. However, depending on which drugs are given and the patient's general health, the patient may need to stay in the hospital.

Which are the common drugs used?

The most commonly used systemic chemotherapeutic agents are doxorubicin (Adriamycin) and 5-fluorouracil (5 FU). These drugs are used together or in combination with new agents. These drugs are quite toxic and results have been disappointing. The new agent SORAFENIB has shown some good results & is the current standard of care in patients who cannot be operated. It is very expensive and there is no end point for treatment. Additionally it cannot be used in patients with compromised liver function. Advantage is that it is given orally.

One of the most important recent advances in the filed of treating liver cancer has been the understanding of the genetic makeup of these tumors, as well as the cancer cells' reliance upon blood vessels and molecules produced in the body that can help them grow. Many cancers grow by causing the development and recruitment of tiny new blood vessels to feed the tumor and enable it to spread to other parts of the body. This is called angiogenesis. One drug, bevacizumab, which controls angiogenesis has been approved for use in many cancers such as colon, lung, and breast, and is known to help standard chemotherapy shrink and control other types of cancer. It might be helpful in liver cancer as well, and similar drugs are still being investigated.

What are the side effects of systemic chemotherapy?

The side effects of chemotherapy depend mainly on the drugs and the doses the patient receives. As with other types of treatment, side effects are different for each patient. Systemic chemotherapy affects rapidly dividing cells throughout the body, including blood cells. Blood cells fight infection, help the blood to clot, and carry oxygen to all parts of the body. When anticancer drugs damage blood cells, patients are more likely to get infections, may bruise or bleed easily, and may have less energy. Cells in hair roots and cells that line the digestive tract also divide rapidly. As a result, patients may lose their hair and may have other side effects such as poor appetite, nausea and vomiting, or mouth sores. Usually, these side effects go away gradually during the recovery periods between treatments or after treatment is complete. The health care team can suggest ways to relieve side effects.

Radiation therapy

Also called radiotherapy, uses high-energy rays to kill cancer cells. Radiation therapy is local therapy, meaning that it affects cancer cells only in the treated area. A large machine outside the body directs radiation to the tumor area.

The side effects of radiation therapy depend mainly on the treatment dose and the part of the body that is treated. Patients are likely to become very tired during radiation therapy, especially in the later weeks of treatment. It may cause nausea, vomiting, diarrhea, or urinary discomfort. Radiation therapy also may cause a decrease in the number of healthy white blood cells, cells that help protect the body against infection. Although the side effects of radiation therapy can be distressing, the doctor can usually treat or control them.

Pain control

Pain is a common problem for people with liver cancer. The tumor can cause pain by pressing against nerves and other organs. Also, therapies for liver cancer may cause discomfort. The patient's doctor or a specialist in pain control can relieve or reduce pain in several ways.

• Pain medicine
  Medicines often can relieve pain (These medicines may make people drowsy and constipated, but resting and taking laxatives can help.)
• Radiation
  High-energy rays can help relieve pain by shrinking the tumor.
• Nerve block
  The doctor may inject alcohol into the area around certain nerves in the abdomen to block the pain.

Nutrition

People with liver cancer may not feel like eating, especially if they are uncomfortable or tired. Also, the side effects of treatment can make eating difficult. Foods may smell or taste different. Nevertheless, patients should try to eat enough calories and protein to control weight loss, maintain strength, and promote healing. Also, eating well often helps people with cancer feel better and have more energy.

The doctor, dietitian, or other health care provider can advise patients about ways to have a healthy diet during treatment.

Continuing care

Continuing care for patients with liver cancer depends on the stage of their disease and the treatments they have received. Follow up is very important after surgery to remove cancer from the liver. This is because the cancer can return in the liver or in another part of the body.

Follow up care may include blood tests, x-rays, ultrasound tests, CT scans, angiograms, or other tests. For people who have had a liver transplant, the doctor will test how well the new liver is working. The doctor also will watch the patient closely to make sure the new liver is not being rejected. People who have had a liver transplant may want to discuss with the doctor the type and schedule of follow up tests that will be needed.

For patients with advanced disease, the health care team will focus on keeping the patient as comfortable as possible. Medicines and other measures can help with digestion, reduce pain, or relieve other symptoms.

---

Support for people with liver cancer

Having a serious disease such as liver cancer is not easy. Some people find they need help coping with the emotional and practical aspects of their disease. Support groups can help. In these groups, patients or their family members get together to share what they have learned about coping with the disease and the effects of treatment. Patients may want to talk with a member of their health care team about finding a support group. Groups may offer support in person, over the telephone, or on the Internet. Patients may worry about caring for their families, holding on to their jobs, or keeping up with daily activities. Concerns about treatments and managing side effects, hospital stays, and medical bills are also common. Doctors, nurses, and other members of the health care team will answer questions about treatment, working, or other activities. Meeting with a social worker, counselor, or member of the clergy can be helpful to those who want to talk about their feelings or discuss their concerns. Often, a social worker can suggest resources for emotional support, financial aid, transportation, or home care.

Cancer research

Laboratory scientists are studying the liver to learn more about what may cause liver cancer and how liver cancer cells work. They are looking for new therapies to kill cancer cells. Doctors in hospitals and clinics are conducting many types of clinical trials. These are research studies in which people take part voluntarily. In these trials, researchers are studying ways to treat liver cancer that have shown promise in laboratory studies. Research has led to advances in treatment methods, but controlling liver cancer remains a challenge. Scientists continue to search for more effective ways to treat this disease. Patients who join clinical trials have the first chance to benefit from new treatments. They also make an important contribution to medical science. Although clinical trials may pose some risks, researchers take very careful steps to protect people. Currently, clinical trials involve chemotherapy, chemoembolization, and radiofrequency ablation for the treatment of liver cancer. Another approach under study is biological therapy, which uses the body's natural ability (immune system) to fight cancer. Biological therapy is being studied in combination with chemotherapy.

How do we know if a particular nonsurgical

Treatment worked for a particular patient?

Well, hopefully, the patient will feel better. However, a clinical response to treatment is usually defined more objectively. Thus, a response is defined as a decrease in the size of the tumor on imaging studies along with a reduction of the alpha-fetoprotein in the blood, if the level was elevated prior to treatment.

One thing to keep in mind is that in a relatively healthy patient there is never just one answer to this question. Usually, people go through multiple different treatments sequentially. Something is chosen as the best place to start, and then other treatments are tried once the previous one stops working. The idea is to make sure someone is healthy enough to be able to try another therapy if they still desire it.

How do these various medical treatment procedures compare to each other?

We really don't know. Selection of a treatment option for a particular patient will depend primarily on the expertise of the doctors in the patient's area. Decisions are generally made by a multidisciplinary team of liver cancer specialists who are knowledgeable and expert in all of these techniques, so that the team can choose the best method for an individual patient depending upon overall health and liver function as well as the size, number, and location of the tumors.

Based on evidence, liver resection and elective liver transplantation should be reserved for patients with small tumors and normal liver function (no evidence of cirrhosis) or preserved liver function. Patients with multiple or large tumors should receive palliative therapy with intra-arterial chemotherapy or TACE, provided they do not have signs of severe liver failure. Patients with an early stage of cancer and signs of chronic liver disease should receive palliative treatment with RFA or TACE and undergo evaluation for liver transplantation and undergo transplantation if possible.

---

How to prevent liver cancer?

Majority of liver cancer is associated with chronic hepatitis B virus infection. Vaccination of newborns against hepatitis B is the best way to prevent HCC due to HBV.

Some studies suggest that patients with chronic hepatitis C treated with interferon were less likely to develop liver cancer than patients who were not treated. Interestingly, in these studies, interferon treatment seemed to provide this benefit, even to patients who had less than an optimal antiviral response to interferon. Still, it remains to be seen whether the risk of developing cirrhosis and liver cancer is significantly decreased in prospectively (looking ahead) followed patients who responded to interferon.

Theoretically, we know that liver cancer should be an almost totally preventable disease. Most of it is caused by infection with hepatitis; this can be reduced (if not eliminated) by treating infected mothers before they give birth, vaccinating all children regardless of where they live, screening the blood supply to avoid infected transfusion, and always using clean needles for any injections. (Many cases of hepatitis C infection are thought to have been from doctors or schools using the same needles for many patients or classroom vaccinations!) Aflatoxin contamination can be eradicated by proper storing of foodstuffs and, in fact, is not a measurable problem in developed countries. Alcohol abuse is difficult to eliminate, but at an individual level, this is a totally avoidable risk factor for liver cancer. Even more difficult is obesity and diabetes, but as with alcohol, personal lifestyle choices will directly lead to the development of this cancer. Therefore, a combination of societal, financial, and political changes around the world could lead to a very substantial decrease in the incidence of this cancer over the next two to three decades.

What is the role for routine screening for HCC?

It makes sense to screen for HCC just as we do for colon, cervical, breast, and prostate cancer. However, the difference is that there is, as yet, no cost-effective way of screening for HCC.

Blood levels of alpha-fetoprotein are normal in up to 50% of patients with small HCC. The importance and value of the test improves with higher cut off values. A level greater than 400 invariably indicates HCC, unless proven otherwise.

Ultrasound scanning, which is non-invasive and very safe, is, as mentioned before, operator-dependent. Therefore, the effectiveness of a screening ultrasound that is done at a small facility can be very suspect.

Patients found with small tumors on screening live longer than patients with larger tumors only because of what is called a "lead time bias." In other words, they seem to liver longer (the bias) only because the cancer was discovered earlier (the lead time), not because of any treatment given.

Nevertheless, strong arguments can be made for routine screening. For example, the discovery of an HCC in the early stages allows for the most options for treatment, including liver resection and liver transplantation. Therefore, all patients with cirrhosis, particularly cirrhosis caused by chronic hepatitis B or C, hemochromatosis, and alcohol, should be screened at 6 to 12 month intervals with a blood alpha-fetoprotein and an imaging study, alternating between an ultrasound and CT scan or MRI. Patients with chronically (long duration) elevated alpha-fetoprotein levels warrant more frequent imaging since these patients are at even higher risk of developing HCC.

Patients with liver cirrhosis due to viral hepatitis and those with elevated AFP levels (>200) need 3 monthly USG and AFP level done for monitoring the trend and development of SOLs. CT scans have a higher pick up rate of liver cancer but due to radiation risk and cost, it cannot be used with the same frequency as an ultrasound test for screening high risk patients. Sometimes contrast enhanced ultrasound examination is done for screening or follow up of high risk individuals.

In general in low risk category a six monthly frequency of screening with AFP and USG is considered acceptable interval for early detection.

---

Liver Cancer at a glance

• Liver cancer is the third most common cancer in the world, and the majority of patients with liver cancer will die within one year as a result of the cancer.
• Most patients will have associated cirrhosis caused by chronic hepatitis B or C infections, alcohol, obesity or diabetes.
• Patients with chronic liver disease (for example, hepatitis C virus, hepatitis B virus, or hemochromatosis) should avoid drinking alcohol, which can further increase their risk of developing cirrhosis and liver cancer.
• Many patients with liver cancer do not develop symptoms until the advanced stages of the tumor. When the patient does develop symptoms, the prognosis is usually poor
• A combination of USG & measurement of serum levels of Alpha-fetoprotein is the cheapest and effective screening method possible for patients with chronic liver disease to pick up early HCC.
• The combination of an imaging study (ultrasound, CT, or MRI scans) and an elevated blood level of alpha-fetoprotein most effectively diagnoses liver cancer.
• A liver biopsy can make a definitive diagnosis of liver cancer, but the procedure requires an expert liver pathologist and is not necessary for all patients.
• The natural history of liver cancer is quite variable and depends on the histology & stage of the tumor and the severity of the associated cirrhosis.
• Medical treatments for liver cancer such as chemotherapy are slowly becoming more effective, although still disappointing. The new drug sorafenib has shown that survival can be prolonged.
• Ablative and local techniques such as chemoembolization, radioembolization, radiofrequency or cryoablation, and stereotactic radiosurgery can by very useful in controlling individual cancers for an extended time.
• Surgical resection (removal) of the tumor may be curative for a select group of individuals with liver cancer, specifically for those with small tumors and healthy liver function.
• For patients with small liver cancer and significant associated liver disease, liver transplantation offers the only chance for cure.

How can I decrease my risk of getting liver cancer?

• Do not drink too much alcohol. How often you drink is as important as how much you drink. If you drink alcohol, discuss your drinking with your caregiver.
• Get checked for a disease called hemochromatosis. Do this especially if you have a close family member with this disease.
• Prevent liver cancer caused by hepatitis B and C. These viruses are spread through blood transfusions, dirty IV needles of drug abusers, and by unprotected sex. Do the following to prevent hepatitis B and C:
• Avoid body piercing and tattooing.
• Do not have unprotected sex (sex without a condom) unless you know that your partner is not infected.
• Get vaccinated against hepatitis B virus.
• Do not use injectable street drugs. If you have a problem with drug abuse, get help by talking to your caregiver. Use only sterile needles when needed to inject medicine, and safely discard the needles. Ask your caregiver how to discard needles safely

Where can I find support and more information?

Liver cancer is a life-changing disease for you and your family. Accepting that you have liver cancer is hard. You and those close to you may feel angry, sad, or frightened. These feelings are normal. Talk to your caregivers, family, or friends about your feelings. You may also want to join a cancer support group. This is a group of people who also have liver cancer.

Above information will help you to make an informed decision but it cannot replace the professional advice and expertise of a doctor who is familiar with your condition. You may have questions that are not covered; you should discuss these with your surgeon. You must remember every individual is different.

Doctors dealing with liver disease that you may meet

Endoscopist: This may be a gastroenterologist or a surgeon who is able to undertake endoscopy (examination of the stomach or bowel using a flexible telescope). A few endoscopists can also perform ERCP and EUS, which are special forms of endoscopy that examine the biliary and pancreatic ducts and the pancreas

Gastroenterologist: A physician who is highly specialized in ‘gut’ problems.

General physician: A consultant medical doctor who works in a hospital and who is broadly specialized including ‘gut’ problems.

General surgeon: A consultant surgeon who works in a hospital and who is broadly specialized including ‘gut’ problems.

HepatoPancreatoBiliary surgeon: A surgeon who is highly specialized in pancreato-biliary & liver operations.

Glossary

• MRI - Magnetic Resonance Imaging.
  A type of scanning performed to diagnose problems not picked up by regular investigations
• CT SCAN - Computerized Tomography
  A type of scanning performed to diagnose problems not picked up by regular investigations
• ERCP - Endoscopic Retrograde Cholangiography
  An endoscopic procedure performed to visualize bile & pancreatic ducts & treat the disease endoscopically whenever possible
• EUS - Endoscopic UltraSound.
  An endoscopic procedure performed to visualize pancreas & biliary tract from very close, diagnose problems, obtain biopsies and at times treat the disease too.
• MRCP - Magnetic Resonance
  
• CholangioPancreatography