What does the Liver Do?

The liver is an organ in the abdomen which is necessarily to live . It is mostly located behind the right ribcage, and when it becomes enlarged it protrudes below the right ribcage ("right costal margin"). It is composed of right and left "lobes", and a smaller "quadrate" lobe. The gall bladder hangs down from the bottom of the liver, collecting greenish bile from it. The liver has as a major blood supply the "hepatic artery" which comes off of the aorta. The "hepatic vein" collects nutrients and drugs from the intestines and delivers them to the liver for processing. The liver drains blood via the large "inferior vena cava", directly into the heart. There is also a system of draining "lymph glands" around the liver which help to purify the blood. These lymph glands are connected via "lymph channels" which ultimately drain back into the bloodstream via the "left thoracic duct"; they are important as they may serve as conduits for spread of infections or cancer. The liver has a "capsule" around it which contains nerve endings, accounting for pain when the liver enlarges and stretches its capsule. The damaged liver has an amazing ability to regenerate itself. The body needs only about 10% of the liver to live, and if a piece is cut out or injured, it can grow back. Sometimes, however, the liver gets chronic diseases which impair its ability to regenerate. It can become infiltrated with fat ("steatosis"), shrink from chronic alcohol or viral exposure ("cirrhosis") or grow large from infection or a blocked blood drainage ("hepatomegly") . Any inflammation of the liver, whether caused by germs, drugs, or radiation, is called hepatitis . A damaged liver may heal, or may slowly fail and require liver transplant to save the patient's life The liver is an astounding laboratory sustaining metabolism. Among its functions are purification of the blood, removing poisonous ammonia from proteins, detoxifying alcohol and drugs, controlling the body's sugar and cholesterol balance, making bile to digest fats, forming clotting factors for the blood and generating new blood cells. This myriad of functions makes clear why the liver is essential to life.

What is Liver Cancer?

The cells in the liver are meant to divide to replace those that die of injury or old age. Like all cell division in the body, this process is tightly controlled to proceed in an orderly manner, and controlled by the "genes" within each cell. Liver cancer starts within a single cell. Something changes the control mechanisms within this cell, and it starts dividing in a disorganized, uncontrolled manner. The abnormal cell makes millions of copies of itself, called "clones". They fail to perform the normal functions of liver cells, but are only intent on dividing to make more copies of themselves. Eventually these abnormal cells form a clump, or tumor. A tumor is merely a swelling, and isn't necessarily cancerous. A benign tumor just grows in its local area, and although it may become very large it doesn't spread and isn't cancer. By contrast, a malignant tumor is cancer and has a capacity to spread to any area of the body. This process of spread is called metastasis . It is this capacity to spread to other vital organs that makes cancer so dangerous.

How Common is Liver Cancer?

Liver cancer is fairly uncommon in the U.S.A. with 20,000 new cases and 15,000 deaths each year in the United States. It represents about 2% of all new cancers. About 3000 of the cases are in the liver itself, the remainder are in the Gall Bladder and bile drainage ducts. However, in Asia and Africa liver cancers are one of the most common cancers. Males are effected 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. Overall the death rate from liver cancer has dropped in the U.S.A. over the past 50 years. This is both from a decline in the number of cases, and better treatment for the disease.

What are the Types of Liver Tumors?

The most common types of benign liver tumors are hemangiomas (which are a cluster of abnormal blood vessels forming a swelling), and adenomas (which are clumps or knots of liver tissue). The most common malignant liver cancers are hepatocellular carcinoma (80% of cases) which arises from the liver cells themselves, and is also known as a hepatoma (a poor name for liver cancer, since it sounds benign). Cholangiocarcinoma (15% of cases) arises from bile ducts in the liver as they proceed down toward the gallbladder. A Klatskin tumor is a cholangiocarcinoma located at where the gall bladder meets the liver. Rare types of liver cancer include the angiosarcoma (which arises from the blood vessels in the liver), lymphomas carcinoids (from hormone making liver cells). The liver is a very common place for cancers originating in other body organs to spread to; since it offers a soft, spongy blood-rich surface for metastatic "seeds" to grow. If their are multiple areas of cancer in the liver, the chances are much higher that it began in some other organ and then spread to the liver. Bowel, lung, breast, bladder, prostate and esophagus cancers have particular propensities for liver spread. These are not considered "primary" liver cancer, and their treatment upon spread is discussed in their particular transcripts.

What Causes or Increases Risk for Liver Cancer?

As for any cancer, the exact reason why any one person gets liver cancer and another doesn't remains unknown . However, several things have been noted which increase the risk, called"risk factors":

Chronic Hepatitis can lead to changes in the liver cells associated with the most common type of liver cancer, hepatocellular carcinoma (HCC).
a) Hepatitis B -- evidence of prior infection is found in 75% of liver cancer patients worldwide. It can lead to cirrhosis, below. The more common Hepatitis A (spread by feces) isn't associated with liver cancer.
b) Carcinogens (chemicals inducing cancer) such as aflatoxin food contamination (used by Iraq on the Kurds) and nitrosamines.

Cirrhosis of the liver (the liver can shrink up and become fibrous and fatty in response to chronic irritation). Causes of cirrhosis include:
a) Alcoholism-- alcoholic cirrhosis leads to 5% of liver cancer.
b) Hemochromatosis is an overload of iron in the liver. 20% of patients who get cirrhosis from the overload may develop HCC.
c) Alpha1- antitrypsin deficiency is a rare condition where a necessary enzyme is lacking to break down waste products in the liver and lung. HCC can develop in 40% of patients who get this type of cirrhosis.

Miscellaneous irritants to the liver including:
a) Polyvinyl Chloride (PVC) is linked to angiosarcoma.
b) Liver flukes are linked with bile duct cancer in China.
c) Thorotrast is a contrast dye for radiology studies no longer used after being linked to angiosarcoma.
d) Radiation Exposure can lead to liver sarcomas, sometimes as long as 5 decades after the exposure.
The common thread to liver cancer risk factors is chronic irritation, which causes the liver cells to divide more quickly than they ordinarily would to repair perceived damage. The more often cells divide, the more the chance for a genetically abnormal one to arise, with the gene changes leading to its becoming cancerous.

What are the symptoms of Liver Cancer?

The most common symptoms of liver cancer are from a massive tumor growing in the liver, or even liver failure. A very early cancer will have no symptoms, since it is too small to cause any. As it enlarges, common symptoms include:

Pain in the right upper abdominal area 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.

Weight Loss and loss of appetite; the liver is a digestive organ.

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 like 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").

Paraneoplastic syndromes means unusual symptoms caused by chemical alterations in the body either from the liver failing or secretions from the tumor cells themselves. These include elevated blood calcium, low blood sugar, anemias, precocious puberty in children, intense flushing, and other metabolic
disturbances. These syndromes often will be alleviated with cancer shrinkage.

Signs of Distant Spread include bone pain, neurological symptoms from brain involvement, and intestinal blockage. These all indicate advanced disease.

How is Liver Cancer Diagnosed and Evaluated?

Since liver cancer is unusual, and its symptoms mimic many other conditions, there is commonly a delay in making the diagnosis while the cancer grows larger. Unfortunately, most patients have advanced disease by the time the diagnosis is made. Important steps to diagnosing liver cancer include:

A high "index of suspicion" in patients with a history of chronic hepatitis, alcoholic cirrhosis, toxin exposure, or the rare genetic diseases which increase risk.

A Complete Physical Exam especially looking for signs of a tumor in the upper right abdomen and signs of liver failure like body swelling and bruising. Other organs (i.e. rectum, prostate, breast) are examined to see if a primary tumor has arisen there, and possibly spread to the liver.

Blood Tests including a complete blood count (CBC) to look for anemia or infection, and a blood chemistry panel(SMA) which tells about liver function and general metabolism. The most commonly elevated blood tests with liver damage are AST, ALT, GGT and alkaline phosphatase . These are all enzymes that are released into the bloodstream when liver cells die. Also, a hepatitis panel is appropriate. Blood clotting studies (PT/PTT) are gotten both to assess liver function and a part of a pre-surgical screen if surgery is a possibility. There is a "tumor marker" to help diagnosis liver cancer. In HCC patients, especially younger ones, the "alpha-fetoprotein" (AFP) blood test is elevated in over 50% but it may represent some other malignancy besides liver cancer. If it is elevated, it will usually return to normal with successful treatment.

Radiologic Tests , include standard Chest X-ray to look for infection or tumor in the lungs. Ultrasound (US) remains useful for looking at the shape of the liver, identifying a tumor, and tracking the progress of therapy. Ultrasound doesn't use any radiation (just sound waves) and is very safe in children and pregnant women. However, the results are very dependent upon the skill of the technician performing the test, and if something is found then a CT scan will be ordered anyway. A CT scan is very accurate for detecting tumors larger than 1 cm, it does use radiation like a series of multiple X-rays which are joined together. If contrast is injected into an arm vein for a CT scan, the blood vessel of the liver will be more clearly visible. It is best to ask for "omnipaque" or equivalent contrast, which is more expensive but less likely to cause an allergic reaction. The CT scan isn't technician dependent, and is very good for showing extension of the tumor into nearby organs and enlarged lymph glands in the vicinity of the tumor, which can represent spread to them. Other tests to visualize cancer are arteriography, where some contrast dye is injected and special X-rays are taken that show the shape of the tumor's blood vessels. Another test is the MRI scan which uses no radiation, shows the organs in the abdomen very clearly and is excellent for showing local spread and imaging nearby lymph glands. The MRI can also be given with contrast ("gadolinium") to better show the blood vessels. However, it is expensive ($1000) and requires the patient to lie almost perfectly still for an hour to be accurate. These tests are gotten to evaluate a patient for possible surgery or check their response to therapy. Other more exotic tests, such as bone scans, liver-spleen scans, or CT scans of the brain are only gotten if their are symptoms is these particular areas, and the therapy will be changed depending upon the results of these tests.

Biopsy is the only way to absolutely diagnose any cancer by getting a piece of it for analysis. This biopsy may be obtained by a fine needle under local anesthesia, in the radiology department using ultrasound or CAT scan to guide the needle into the tumor. Several samples are usually taken for accuracy. Risks of biopsy include spilling the tumor or bleeding the from puncturing blood vessels in the tumor, this may require an emergency operation to stop bleeding. Overall fine-needle biopsy is safe and effective; it is a very common procedure in hospital Interventional Radiology Departments. The biopsy material is examined by a pathologist, a physician who specializes in diagnosing diseases from tissue samples. If cancer is detected, he will specify the particular type, and the grade (I,II or III) which tells how aggressive the cancer is likely to be. Higher grade cancers ( III ) look more "malignant" under the microscope, with numerous cell divisions and cells scantly resembling normal liver tissue. They tend to be more aggressive (likely to grow very quickly and spread). On the other hand, low grade (I ) tumors have fewer cell divisions and look much like the normal liver tissue they arose from. They are considered more "indolent" (slow growing) and less likely for early spread. Grade II tumors are considered intermediate in appearance and behavior.

There can be more than one grade (or even type) of cancer in a given specimen, this is called a "mixed tumor" . If there is any doubt, more than one pathologist should review the biopsy material, since pathologists do not always agree on the diagnosis. Pathologist's themselves (obviously) know this and
will normally request a review upon any biopsy they are unsure of. It is also obviously important for the pathologist to state whether the tumor has arisen from the liver primarily, or has spread there from some other organ. Occasionally it is strongly felt the tumor did not arise in the liver, since it does not have a resemblance to liver tissue. On the other hand, it may be difficult or impossible to say just where it originated. This is called "cancer of unknown primary" and is thoroughly investigated with emphasis on re-examining the liver biopsy.

How is the Extent of Liver Cancer Gauged?

Like all cancers, the extent of liver cancer is given by the"stage". The commonest staging system used is from the American Joint Cancer Committee("AJCC"):

"Stage I" means the cancer is smaller than 2 cm (about 1 inch) and doesn't invade local blood vessels.
"Stage II" means the cancer is smaller than 2 cm. and does invade blood vessels, or is larger than 2 cm and does not invade local blood vessels.
"Stage III" means the cancer has spread to local lymph glands around the liver.
"Stage IV" means the cancer has invaded the major veins supplying the liver (IVA) or that the cancer has spread to distant organs (IVB).

How Curable Is Liver Cancer?

This depends upon the type of cancer, its stage, location, and the treatment selected. In general, historic 5 year survivals by stage are:

The overall survival rate at 5 years for all comers is ~10%, since most patients have advanced stage disease when diagnosed. It is important to note that the above averages include demise from all causes, including heart attacks, accidents, etc. Also, it is important to realize that survival rates from liver cancer itself have been increasing with earlier detection and improved treatment.

What is the Conventional Treatment for Liver Cancer?

Surgery is the standard treatment for liver cancer if it is operable. Only about 30% of patients are candidates for surgery, since those with advanced cirrhosis and higher stage are not surgically curable. Surgery is at best a local therapy and does not do anything to cure disease which has spread. If the tumor is small, then only a "subsegment" of the liver should be removed (the smallest amount possible) under real-time ultrasound to localize the tumor. For larger tumors, several segments, or a whole lobe of the liver needs to be removed. The death rate from surgery depends upon its extent, but ranges from 5 to 30% in the world's literature.The overall death risk from major liver surgery is 10% in America today. Other risks include infection (10%), bleeding problems (10%) liver failure (5%), heart attack and stroke (5%). Fortunately, the liver regrows and only 10% of it is necessary to preserve life. If multiple areas of tumor are seen, then each can be removed with a "metastatectomy" procedure, which merely focuses on removing visible tumor. This has been shown to prolongue life when cancer has spread to the liver from the colon, in a major study. Although less than 1/3 of patients are candidates for surgery, it has historically been the only method of curing localized liver cancer. With improved surgical techniques, more patients are being considered for surgery than previously.

Radiation Therapy has been used for over 40 years for liver cancer, but has been limited by the poor tolerance of the normal liver to radiation. Radiation doses of over 35 Gray (units of radiation) to the whole liver carry a high risk of producing fatal radiation hepatitis . The dose required to cure liver cancer is over 50 Gray, so you can see that conventional "external beam" radiotherapy to the whole liver is impractical. Even though smaller areas of the liver can withstand a higher dose, radiating small areas of the liver is not curative unless the cancer is very localized. Conventional Radiation does have its uses, however. It can relieve pain from the tumor streching the nerve-rich capsule of the liver. It can also help relieve obstruction of the bile ducts, reducing worrisome jaundice and the itching it produces. It is a relatively easy treatment to get, and can be used for many who cannot tolerate radical surgery. Like surgery, radiation is a local, or at best regional, treatment-- it cannot cure cancer which has spread to distant body areas. Nonetheless, refinements in Radiation technology and targeting make it more useful than ever before.

Prior to beginning radiation therapy, the patient is seen by a"Radiation Oncologist" that is a physician specializing in the use of radiation. It may be preferable to see a younger, more recently trained radiation oncologist, since the prestige of the field, and the difficulty getting a position and training in this specialty has dramatically increased in the past 2 decades. There are 2 basic types of radiation treatment given today-- "External Beam" therapy and "Brachytherapy" . External Beam means that a ray of high energy photons is shone onto the area, usually from several different angles to homogenize (smooth out) the dose. Brachytherapy means that radioactive sources are actually placed into the tumor area, from a period of time ranging from hours to days, or sometimes even permanent "seeds" are used. Both methods may be used in a given patient.

The next step is to mark out the treatment area with a "simulation" procedure. This involves placing the patient on a mock machine, and taking X-rays. It takes about an hour. Small tattoo marks are commonly placed on the patient's chest to designate the treatment area. Information from the simulation and any relevant scans is placed intoa"Treatment Planning Computer" and a"plan" is generated. This "plan" shows how much radiation is being given to the tumor, and how much to surrounding normal tissues. It also says what optimal radiation beam energies should be used for external beam treatment. Special lead-like blocks, placed into the head of the treatment machine, can be used to protect normal tissue. The "plan" is reviewed by the radiation oncologist and a specially trained radiation physicist. The patient then returns to the deparment for their treatment start (these departments are nearly always in the hospital basement). For external beam, the patient is placed on a hard table, in a special shielded room, and aligned with laser lights. Treatment is given as tolerated, usually Monday through Friday for 2 to 6 weeks, at a dose of 1 to 2 gray per day. It takes only several minutes per day, and is painless . If a treatment day is missed, it is simply tacked on to the end so that the full prescribed dose is given. The patient does not become radioactive, get burned, or lose scalp hair. The side effects of radiation therapy are specific to the area being radiated. "Acute" effects occur during the treatment period, while "late" effects may occur months to years afterward.

Acute effects are usually minimal, with minor skin redness in the treatment area, fatigue and mild nausea with therapy. The most fearsome acute reaction is radiation hepatis, leading to irreversible liver failure. However, the risk for this is less than 5% if proper dosing and techniques are used. Long term complications of radiating the liver include injury to its blood vessels leading to loss of liver function, or even Budd-Chiari syndrome which is where blood clots obstruct the liver's blood flow. In spite of these possible complications, modern radiation is usually well tolerated.

If "brachytherapy" is used, as is common for Klatskin tumors or others involving the bile drainage system, special catheters are threaded up into the liver through the bile ducts. It may be possible to do this endoscopically, that is with a tube placed down through the mouth, through the stomach and into the intestine. The tube is guided up through the intestinal opening for the common bile duct, and from there up into the liver proper. The actual procedure is similar to where dye is endoscopically injected into the bile ducts and pancreas, called "endoscopic retrograde cholangio pancreatography" or "ERCP" for short. The technology can also be used to place "stents" into the bile ducts to restore their patency if compressed by tumor, and allow for bile drainage and diminishment of jaundice. If an endoscopic procedure is not possible due to blockage by tumor, a small "open procedure" to thread the catheters in surgically may be done instead. Sources of radioactive Iridium-192 are loaded up into the catheters, commonly for 3 to 5 days during which the patient remains in the hospital. The sources are then removed and the patient goes home. The procedure may be repeated 2 to 4 weeks later. While having good ability to shrink tumors, and possibly extend survival, radiation alone is not commonly curative for liver cancer.

Chemotherapy has been generally disappointing for liver cancer, and has not been curative. Conventional drugs include 5-Fluorouracil (5-fU) , Adriamycin, and Cisplatinum . Since liver cancer patients are often older, and have poor liver function (necessary to metabolize these drugs) this makes aggressive chemotherapy hard to tolerate. Side effects of these agents include lowered blood cell counts leading to anemia and infection, diarrhea and mouth sores (5-FU), hair thinning, kidney and nerve damage (cisplatinum), and heart and lung damage (adriamycin). Combinations of chemotherapy agents have not been consistently superior in results to single drugs, but response is usually increased (perhaps up to 70%). Furthermore, combination treatment will have additive "toxicity" (side-effects) of each agent. The most studied agent for liver cancer is 5-Fluorouracil. Each agent is given intravenously, in "cycles" 3 - 4 weeks apart. The cisplatin is commonly given only on the first day of each cycle, and the 5-FU is given as a slow intravenous "infusion" over 5 days. The "response" to this combination therapy is up to 70%, with 20% of patients having "complete response" . If the response is complete (no evidence of disease left) it lasts an average of 6 months. Unfortunately, cancers become resistant to chemotherapy much as bacteria develop resistance to antibiotics. Thus, even an excellent response to chemotherapy does not mean definite cure, or even improved survival. While there is shrinkage of the tumor in most patients, it is temporary and overall survival has not been increased with conventional chemotherapy.

What is the Latest, Effective Therapy for Liver Cancer?

For the most common type of liver cancer, hepatocellular carcinoma, the most effective therapy continues to be surgical removal of the cancer if it is small and the patient is medically suited for surgery (i.e. no recent heart attack, acceptible lung function, reasonable anesthesia risk). It has shown that patients who have cancer spread to the liver from colon or rectal cancer can have prolonged survival, and sometimes be cured, if these metastatic tumors are removed with metastatectomy (GITSG study 6584). Certainly for patients with cancer limited to the liver, removal of the tumor remains the only proven curative therapy. The ideal candidate for surgery includes those free of cirrhosis of the liver, without jaundice, and with the tumor localized to a single lobe of the the liver. There should be no spread to lymph nodes or other distant areas. Instead of removing the tumor with a scalpel,"cryosurgery" whereby it is killed by freezing is becoming a useful treatment; it results in less bleeding during surgery and kills tumor cells on the periphery of the cancer. It has been used successfully when there is spread of cancer to the liver from a colon cancer (Steele, Cancer Research 1991 p.6323). The best general surgical results have been seen in Japan, where the cancer is more common and 40% survival is seen at 2 years if the patient has no cirrhosis, and the tumor is totally removed at surgery. If the tumor could not be removed, or if the patient had cirrhosis, the survival at 2 years was only 8% in this Japanese National Study. Most transplant programs (i.e. Dr. Starzl at the University of Pittsburg) will not transplant a cancer patient, especially if they have cirrhosis, since the survival was so poor (less than 10%) when they did this in the 1980's. Many patients succumbed to complications of the transplant, rather than return of their cancer. However, the surgical techniques for liver transplant, and effectiveness of the necessary anti-rejection drugs have improved-- so transplant may again be used. If so, it will still be critical to determine that the cancer has not spread (since this precludes cure by transplant).

Radiation Therapy advances focus on delivering high dose treatment directly to the tumor. Recall that with the normal liver has a poor general tolerance for radiation. Also, the the nearby critical structures (lung and spinal cord) again don't tolerate high dose treatment, and this had limited the usefullnes of the conventional "Exernal Beam" treatments given in standard Radiation Therapy departments. However, better methods have been found for delivering potentially curative doses of radiation to the cancer while sparing the nearby normal tissues. There is an odd paradox of the effectiveness of low dose of radiation (just 11 - 12 Gray) for hepatocellular cancer when it is delivered in an optimal fashion. Historically, Radiation oncologists used catheters (tubes) loaded with radioactive seeds (usually Ceasium-137) fed up through the gallbladder ducts to try to locally radiate the cancer, while sparing nearby normal tissues.This"brachytherapy" hassuffered from an uneven distribution of radiation to the tumor, and the impossibility of using it without surgically implanting a catheter deep into the liver if the tumor was centrally located (not near where the bile ducts connect into the liver, where the aforementioned endoscope can often be utilized). While brachytherapy is still useful for low-lying cancers in the liver (Klatskin Tumors) or for those of the bile ducts themselves, it is not useful for a larger tumor which has spread through the liver (and is therefore inoperable without total transplant). A further advancement in Radiation Therapy is "Intra-Operative Radiation Therapy ("IORT") which involves aiming a beam of electrons at the area around the cancer, at the time of surgery. A special operating suite is used for this, and a single high dose of radiation is given while the chest is open at surgery. Again, the problem with this is the limited tolerance of the liver to radiation, but at least the area around the liver (lymph nodes, pancreas, esophagus, small intestine) may be well treated with IORT to help sterilize any cancer cells that have escaped there. The use of IORT for digestive organ cancers is done at major Academic Universities including Harvard, Memorial Sloan Kettering, and the Mayo Clinic.

The newest technique for delivering radiation is "Radioisotope Therapy" with "131-antiferritin" whereby 30 to 150 "millicuries" of this radioactive material are given into an arm vein ("intravenously"). This radioisotope material has an affinity for liver cancer and binds with it, locally radiating it and killing it. Radiation kill cells when they attempt to divide, so it is possible that a tumor will continue to shrink even after therapy is completed. Moreover, simply seing a residual "tumor" after therapy does not mean that any cancer cells remain; the swollen area may be merely due to scarring and inflammation. Only if the cancer actually grows after treatment can it be considered not to have cured the patient (but it may still have relieved symptoms). The 131-antiferritin treatment is most useful when combined with other therapies. Specifically, it may render a previously inoperable tumor now operable, so the patient can go ahead with potentially curative surgery. In the Radiation Therapy Oncology Group (RTOG) studies, those patients "converted to resectable status" (by having their liver tumors shrunk by the pre-operative Radioisotope Therapy) had a survival exceeding 80% at 3 years when their tumors could then be removed! This compares to the less than 5% projected survival at 3 years (based on historical exerience) if the patients had not received this new form of treatment. It can also be used in conjunction with chemotherapy for medically inoperable patients. Dr. Stanley Order at Johns Hopkins University in Baltimore has been a pioneering investigator of this "radioisotope" approach.

Chemotherapy advancements include giving high doses of the most effective drugs through a major artery in the liver, called the hepatic artery. This treatment is called "Hepatic Artery Infusion" and has mostly been done the 5-Fluoruracil (5-FU).

The advantage of this treatment is that the tumor gets much higher doses of the drug,
compared to other normal tissues in the body. The liver has no chance to detoxify the drug (inactivate it) since it is coming into the arterial rather than the venous side of the liver. Chemotherapy can be used along with conventional radiation ("chemoradiation" ) and has resulted in an average survival of 20 months for locally advanced disease, with some patients living much longer. The radiation when given in combination with chemotherapy must be precisely targeted to reduce the risk of "radiation hepatitis", so is given by sophisticated radiation therapy departments that have "3-dimensional conformal treatment planning". This means that computer simulations are made to show how to precisely target the radiation beams to the tumor, while sparing the nearby normal liver. The usual drugs used for chemoradiation are adriamycin and 5-Fluorouracil, this treatment usually results in at least a 50% reduction in the size of the tumors in the liver. If the tumor starts growing during any cycle of chemotherapy, the agents used should be switched, since a good result may be gotten by using a different ("non-cross-resistant") drug. It is helpful to have some tumor to "follow" with scans during chemoradiation, to see that it is getting smaller (that is the treatment is working). However, even if no visible tumor remains after surgery, it may be reasonable to give chemotherapy to destroy any hidden cancer cells which have spread from the main tumor ("micrometastasis") . Curing liver cancer requires both "local control" of disease in and around the liver, and control of any cancer cells which have escaped distantly. Only chemotherapy travels through the body ("systemically") to obliterate micrometastasis, so it should always be considered for the patient who wishes to have the best chance for cure.

Transcather Arterial Embolization (TAE) means using a gel foam to injected into an artery in the liver to "starve off" the blood supply of an inoperable tumor, and perhaps convert it (shrink it) to being operable. It can be done prior to surgery to reduce bleeding during the operation, which is always a concern to the surgeon (given the livers extensive blood supply). It can also be used in conjunction with local chemotherapy to the liver to further concentrate the drug upon the tumor area. The first thing to establish is which particular blood vessels feed the area of interest. Sometimes a simple (contrast) CT scan may tell the appropriate artery for injection, while for other patients direct right and left arteriography (injecting contrast under fluoroscopy) is necessary. For the actual embolization agents, things besides gelfoam (gelatin soaked sponges) that have been used include degradable starch microspheres (Spherex), iodized oil, or Yttrium glass beads. Another substance that can be injected in the liver is Ethanol (the same alcohol in alcoholic beverages, purified of course). Although unconfirmed in America, Japanese investigators have injected ethanol directly into the liver under ultrasound guidance (with a needle placed through the skin of the chest) and found a 5-year survival rate of 80% in patients with local disease. This was even more effective than surgery for patients with operable cancers. This has been done by whole groups of investigators in Japan, and is an intruiging therapy, and is now recommended as a standard therapy for minute HCC.

The fact that embolization has been done extensively in the Far East for liver cancer has allowed much information to be collected on its side-effects. In fact, most of the literature on embolization is published in respectable journals (i.e. Cancer and Journal of Hepatology ) by Oriental authors. There is over a 90% risk of acute high fever, 70% risk of abdominal pain and absolutely no appetite ("anorexia") with weight loss. These side effects can last days to months. About 25% of patients get an increase in their blood liver enzymes (SGOT, SGPT, GGT) showing liver damage. Decreased liver protien production leads to abdominal swelling from collected fluid ("ascites") in 20% of patients. Also possible is precipitating an acute attack of gallstones (cholecystitis) or painful artery spasm from the procedure.

Despite the risk, there is growing evidence that Trans Arterial Embolization, in combination with local chemotherapy, gives better results than chemotherapy alone. In fact, in the studies reported, embolization in conjunction with chemotherapy has been consistently superior than any chemotherapy alone. Almost all studies have used large, discreet injections ("bolus") of chemotherapy into the liver, but in fact giving the chemotherapy by slow, continuous infusion after embolization may be superior. Although the embolization techniques give better responses, they are more dangerous in the face of high bilirubin (over 2.0 mg/dl) or if their are pre-existing blood clots in the liver veins ("portal thrombi"), or severe cirrhosis. In these cases, embolization can precipitate total liver failure and should be avoided. In all patients it is advisable to start with a lower dose of chemotherapy (DeVita "Cancer" c. 1994), say 50% of the full dose, and then work up as we see the liver tolerates the treatment.

For advanced (metastatic) disease, or locally advanced disease causing symptoms of pain, fatigue and anorexia, several options are now available:

Tamoxifen is a female anti-estrogen pill used extensively for breast cancer treatments. Almost 50% of patients with hepatocellular cancer have "estrogen receptors" and the growth of the cancer may be slowed by giving this oral hormone (which is taken as a 10 milligram pill three times per day). There was a significant improvement in 1 year survival for patients with advanced liver cancer in patients who took tamoxifen, and the side effects (mostly hot flashes in women) are generally easy to tolerate.

Interferon-alpha-2a is an "immune" agent normally found within the body. When given in a large Chinese study, which compared it to useless placebo, it resulted in a significant shrinkage of tumor and increase in survival compared to placebo. The dose was 50,000,000 units given as a muscle injection 3 times per week. Common side effects are fever and weekness from interferons.

Mitoxantrone is a chemotherapy agent which is less toxic than adriamycin, and gives a response rate of just 20% and no increase in survival. It may help reduce the symptoms from advanced disease, but the side-effects may be worse than the relief it affords! It is widely used by American oncologists for lack of anything better.
Morphine and similar narcotic drugs are "God's own medicine" for cancer pain (a famous quote by the American medical pioneer Sir Wm. Osler) and should never be withheld for fear of causing addiction in a cancer patient. Addiction only results when these narcotics not taken for actual pain, but self-administered just to feel good.

There are many newer preparations on the market (i.e. fentanyl patches) that give aconstant level of pain relief without the roller-coaster up and down effects of the older morphine pills. As Osler said, cure sometimes, palliate often, comfort always!

Any patient with liver cancer should not rely on merely a drug or ray to help them, but should embark upon a program of enhanced nutrition, exercise, spirituality, mind-over-cancer, and positive mental attitude. Experience shows that those with a positive attitude tend to do best, whatever the stage of their disease. It is also appropriate to choose a reasonable alternative therapy (see Cancer Answer transcript on this), while doing conventional treatment. Using this multi-faceted approach will give you the confidence of knowing that you have done everything possible do help ensure a successful outcome for a liver cancer problem.

It is critical to get proper treatment for a diagnosis of liver cancer, this can literally make the difference between life and death. Understanding your options for liver cancer will give you the peace of mind knowing that you have done everything possible.

Some cancers, like liver cancer and pleural mesothelioma, are preventable. If you've been exposed to asbestos, find a mesothelioma law firm with plenty of asbestos attorneys that can help your case.

CancerAnswers's material explains, in plain English, the definition, types, frequency, symptoms, evaluation, historical and latest treatment for liver cancer. We describe surgery, radiation, chemotherapy, and tell you their results. We tell you everything you need to know to make the right choices today to deal with a liver cancer problem.

This is the full transcript, offered freely in the spirit of internet sharing, of CancerAnswers' report on Liver Cancer. Much more, including latest additional treatments for Liver Cancer can be found on our order page. Thank you for using CancerAnswers as your information resource.