All About Liver Cancer
What is the liver?
The liver is the largest solid organ of the body and is located on the right side of the abdomen just beneath the right diaphragm. Surrounding organs include the gall bladder (located just behind the liver), the small intestine, part of the colon (large intestine), the right kidney, and the head of the pancreas. The liver is triangular in shape and is divided into a right and left lobe, the right lobe being the larger of the two. It provides several important functions to the body including:
- Filtering the blood to remove and process toxins
- Synthesizing and excreting bile, which is important in processing fat from our diet
- Helping regulate blood sugar (glucose) levels
- Producing factors that play an important role in blood clotting
The liver is a very vascular structure, containing a large number of blood vessels, and receives blood through two separate systems: the hepatic artery and the portal vein. Blood from the abdomen and lower body flows through the liver where it is processed. It then proceeds to the inferior vena cava and ultimately empties into the heart. In large part, due the vascular nature of the liver, it is a very common site to which cancers from other areas of the body to spread (also known as metastasis).
What is liver cancer?
Normally, cells in the body will grow and divide to replace old or damaged cells. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells will stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow uncontrolled. Tumors of the liver occur when there is an error in the regulation of growth of any of the cells in the liver, including the liver cells themselves (hepatocytes), the bile duct cells, or the blood vessels within the liver.
Tumors can either be benign or malignant. Benign tumors grow uncontrolled. They do not break off and spread beyond where they started, and do not invade into surrounding tissues. Malignant tumors, however, will invade and damage other tissues around them. They can also gain the ability to break off from where they started and spread to other parts of the body (metastasize), usually through the blood stream or through the lymphatic system where the lymph nodes are located. Over time, the cells of a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that, we cannot tell what types of cells they started from.
There are a number of benign liver tumors. Hemangiomas are the most common benign tumor of the liver, and occur when a benign, blood-filled tumor forms within the liver. Other benign tumors include adenomas (benign tumors of the hepatocytes) and focal nodular hyperplasia (a localized growth of several types of liver cells). Although these tumors do not invade surrounding tissues or metastasize, it is often difficult to tell the difference between benign and malignant tumors on radiographic imaging.
In addition to being a common site of metastasis for cancers from other sites in the body, primary liver cancers can arise from within the liver itself. Cancer arising from the hepatocytes is known as hepatocellular carcinoma (HCC). It is the most common type of primary liver cancer and accounts for around 70% of all liver cancers. Cancers that arise from the bile ducts within the liver are known as cholangiocarcinomas and represent 10-20% of all liver cancers. These cancers can arise from the bile ducts within the liver (known as intrahepatic cholangiocarcinomas) or from in the bile ducts as they lead away from the liver (known as extrahepatic cholangiocarcinomas). Other types of rare cancers can occur within the liver. These include hemangiosarcomas (malignant blood-filled tumors), hepatoblastoma (a rare cancer that develops in very young children), and fibrolamellar liver cancer (rare cancer that occurs in teens and young adults with no history of liver disease).
What causes liver cancer and am I at risk?
In 2015 there will be an estimated 35,660 new liver cancers diagnosed (including hepatocellular and cholangiocarcinoma), with an estimated 24,550 deaths related to hepatocellular cancer. Liver cancer is much more common in other areas of the world, particularly in sub-Saharan Africa and Southeast Asia. Worldwide, liver cancer is the fifth most common cancer with a half a million people afflicted each year. The number of people who develop liver cancer is increasing both abroad and in the United States.
There are a number of risk factors that are associated with liver cancer. In the United States, the most common risk factor for liver cancer is liver cirrhosis. Sixty to eighty percent of patients presenting with liver cancer have some signs of cirrhosis. Cirrhosis results from scar formation within the liver, most commonly due to chronic alcohol use. Chronic infection with hepatitis C virus (HCV) is also a common cause of liver cancer in the United States. Worldwide, other risk factors, such as chronic infection with hepatitis B virus (HBV) and aflatoxin B1 food contamination are more common. Aflatoxin is a toxic chemical that is produced by a fungus commonly seen in tropical regions. Presence of the fungus on food in these regions leads to chronic exposure to the toxin, resulting in an increased risk of developing liver cancer. Tobacco use has also been associated with increased risk; however, it is not as strong of a risk factor as alcohol-induced liver cirrhosis. Other environmental factors include exposure to thorium dioxide (Thorotrast, a contrast agent previously used for radiographic imaging that is no longer used), vinyl chloride, arsenic exposure, and use of anabolic steroids. Several inherited diseases can increase the risk of liver cirrhosis, and therefore increase the risk of developing liver cancer. These diseases include hemochromatosis (where the body absorbs and stores too much iron), Wilson's disease (where the body inappropriately retains too much copper), and alpha-1-antitrypsin deficiency (a deficiency in a key enzyme that can lead to emphysema of the lung and cirrhosis of the liver). Patients with a family history of liver cancer may also be at increased risk. Finally, males are about twice as likely to develop liver cancer as females. This may be due to a genetic predisposition of males for liver cancer, but may also be due to the fact that males are more likely to be exposed to the risk factors discussed above.
There is growing evidence for a link between the damage caused by non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (liver inflammation) and metabolic syndrome (a combination of conditions, including high blood pressure, blood sugar and cholesterol and excess fat around the waist) in the development of hepatocellular cancer.
How can I prevent liver cancer?
The best way to prevent liver cancer is to avoid the risk factors that are associated with it. Avoiding the excessive use of alcohol and quitting smoking can reduce the risk of liver cancer. Preventing and treating HBV and HCV infections is also important. A vaccine for HBV is available and people who are at high risk for exposure to the virus (such as health care workers and individuals with high-risk sexual practices) should be vaccinated. HCV is spread through blood transfusions, unprotected intercourse, and the sharing of needles by IV drug users. Although there is no vaccine for HCV, avoiding the means by which it is spread can significantly reduce the risk of being infected. Once infected with HBV or HCV, appropriate treatment of the infection can reduce the risk of developing liver cancer.
In other parts of the world, altering the way that foods are stored and processed can decrease the risk of aflatoxin exposure. Proper treatment of water can reduce the risk of arsenic in drinking water. Appropriate treatment of inherited diseases associated with cirrhosis and liver cancer can reduce the risk of developing either cirrhosis or liver cancer. While the risk of liver cancer can never be reduced to zero, it can be significantly reduced by avoiding known risk factors.
What are the signs of liver cancer and is there a screening test?
Liver cancer usually does not cause a lot of symptoms until the cancer is quite advanced. Because of this, early stage liver cancers are rarely detected. When patients do develop symptoms, they may have abdominal pain, feelings of abdominal fullness or bloating (sometimes due to ascites, or a collection of fluid within the abdominal cavity), fatigue, loss of appetite, and weight loss. Currently there is no approved screening test for liver cancer. One potential screening test has been blood levels of alpha-fetoprotein (AFP). AFP is a protein that is found at high levels in fetal blood, but normally disappears once the baby is born. AFP levels increase in the presence of HCC and can be a marker of the development of liver cancer. While some patients who are at high risk for developing liver cancer are routinely tested for AFP levels, this is generally not a good screening tool. Not all liver cancers produce high levels of AFP in the blood, and by the time most patients are found to have high AFP levels, the tumor is already at an advanced stage.
Other blood proteins may potentially be used as screening tools for liver cancer. Several studies have shown the use of proteins such as des-gamma-carboxy prothrombin (DCP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) may also be used as markers of liver cancer formation; however, in practice, these are infrequently used. Additional studies with these and other proteins are needed before they can be used more extensively for liver cancer screening.
In general, it is reasonable for patients at high risk for liver cancer to be screened. These patients included those infected with HBV or HCV, those with a known history of liver cirrhosis, and patients with inherited diseases known to be associated with cirrhosis. In these patients, annual AFP levels are often followed and if AFP levels are found to rise from one year to the next, appropriate follow-up testing should be ordered. In addition, patients with cirrhosis often undergo routine screening with ultrasound of the liver. It is important to note that when a patient with long-standing liver cirrhosis suddenly gets worse, liver cancer is frequently a cause. The Child-Pugh score is a system of grading the degree of cirrhosis, with a range from A (least impaired) to C (most impaired) and helps guide physicians as to which treatments are appropriate.
How is liver cancer diagnosed?
When liver cancer is suspected, the physician should perform a thorough history and physical examination. If a liver tumor is suspected or a patient is at high risk for developing a liver cancer, a number of diagnostic tests may be performed:
An ultrasound is a test that uses sound waves to produce an image of the internal body. The physician or technician places a wand over the target area and glides it over the skin. Lubricant or gel is placed on the skin in order to improve the ability of the sound waves to enter to body. The wand emits sound waves that enter the body and bounce off the internal structures. An echo is produced which is detected by a sensor within the wand. The different densities and shapes of the internal structures cause the sound waves to echo differently, and these differences are detected by the wand. Liver tumors can often be imaged by ultrasound; however, in patients with cirrhosis, it is often difficult to identify liver tumors on ultrasound. Nevertheless, ultrasounds are often used to screen for and diagnose liver cancers because they are very easy to perform and have little to no risk to the patient.
Computed tomography (CT) is often used to diagnose liver cancers. A CT scan is performed by taking multiple small x-ray pictures (similar to conventional chest x-rays or dental x-rays) using a machine that rotates around the patient. A sophisticated computer program adds up these multiple x-rays to produce cross-sectional images of the body. In order to produce the highest quality images, CT scans are often performed using contrast (or dye) which helps to outline structures within the body. Contrast can be given intravenously and/or by mouth in the form of a liquid or pudding. A small percentage of patients are allergic to contrast. If you are, it is important to let your doctors know before ordering the CT scan. Patients who are allergic can often receive non-contrasted CT scans, or take medication prior to receiving the scan to avoid an allergic reaction. CT scans are very useful in diagnosing liver tumors; however, many benign tumors are often difficult to distinguish from malignant tumors on CT scan. CT scans often give more detailed images than ultrasounds and are often used to help diagnose liver cancers.
Often, when there is difficulty seeing a tumor on CT or ultrasound, or if there is question about whether a tumor is benign or malignant, magnetic resonance imaging (MRI)is performed. MRI uses electromagnetic waves and very strong magnets to create an internal image of the body. Different structures absorb these magnetic waves differently, and these differences are detected and used to construct a very detailed image of the body by a computer. No radiation is used during this procedure. Like CT scans, MRIs are often performed using special contrast that is administered intravenously; however, unlikely the dye used in CT scans, allergy to MRI dye is uncommon. The area in which patients lie is fairly small, so some patients can feel claustrophobic while undergoing the procedure. In addition, while ultrasound and CT scans often take only a few minutes, MRI scans can be much longer, sometimes up to one or two hours. For patients that cannot tolerate the feeling of being in a small space for such a long time, open MRI scanners are available that have a larger space for patients to lie in while being imaged. However, open MRIs still take a long time to obtain, and often the images are of poorer quality than with closed MRI scanners. Regardless, MRI can be an invaluable tool in helping to diagnose liver cancer.
Angiography is a procedure in which a small tube (called a catheter) is threaded into a blood vessel, often placed through the groin. Contrast is injected directly into the blood vessels leading the liver and x-rays are taken that can show highly vascular liver tumors. This procedure is infrequently performed because it is much more invasive in nature than ultrasound, CT, or MRI.
Fluorodexoyglucose-positron emission tomography (FDG-PET) takes advantage of the fact that rapidly growing tissue needs energy. Glucose is a sugar that is often used by cells as an energy source, and FDG-PET uses radioactive glucose to find areas in the body that are rapidly growing. While FDG-PET has been used in a number of cancers to help with diagnosis, its role in liver cancer has never been proven. Nevertheless, it is sometimes used to help in the diagnosis of liver cancer.
A number of blood tests can be used to help determine a patient's risk of liver cancer (as discussed under "What are the signs of liver cancer and is there a screening test?"). An elevated AFP can increase the suspicion that a tumor is malignant if it is unclear by imaging whether a tumor is benign or malignant. Other blood tests can help determine the extent of liver involvement or if there is pre-existing liver conditions that would predispose a patient to developing liver cancer, including liver functions tests such as AST, ALT, total bilirubin and albumin.
Ultimately, the most important diagnostic test for liver cancer is a biopsy. To perform a biopsy, the physician uses a needle or a small pair of scissors or clamps to remove a piece of the tumor. This can be done surgically during an exploratory laporatomy, where the surgeon makes a long incision to expose the abdominal contents (including the liver) for inspection. A surgeon can also perform a biopsy by laparoscopy, inserting a fiberoptic camera through a small hole in the abdomen and using this camera to help find where the biopsy needs to be taken. Biopsies can also be performed under the guidance of ultrasound, CT, or MRI where a long needle is used to suck out a small piece of the tumor. Transvenous biopsies can be performed by inserting a catheter into a vein (usually in the neck) and guiding the catheter through veins to the liver. A needle within the catheter is used to obtain a piece of the tumor. Whatever the procedure used to obtain the biopsy, the tissue is then sent to a pathologist who looks at the tissue underneath a microscope to determine whether the tumor is cancerous or not. This information is reported in a pathology report.
How is liver cancer staged?
Once a diagnosis of liver cancer is made, additional tests should be ordered to determine the extent of the disease. A CT scan or MRI of the abdomen and pelvis should be performed if it hasn't already been done, to look for abnormally enlarged lymph nodes, which can result from spread of the cancer, and to examine for metastatic disease.
Liver cancer is most commonly staged using the TNM staging system, which is determined by the American Joint Committee on Cancer (AJCC). The "T stage" represents the extent of the primary tumor itself. The "N stage" represents the degree of involvement of the lymph nodes. The "M stage" represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows:
- TX Primary tumor cannot be assessed
- T0 No evidence of primary tumor
- T1 Solitary tumor without invasion of blood vessels in the liver (not including major branches of the portal of hepatic vein)
- T2 Solitary tumor with invasion of blood vessels in the liver (not including major branches of the portal or hepatic vein) OR multiple tumors, none of which are >5 cm in size
- T3a Multiple tumors at least one of which is >5 cm in size
- T3b Single tumor or multiple tumors of any size that involves a major branch of the portal vein or hepatic vein
- T4 Tumors that directly invade into adjacent organs (not including the gall bladder) OR a tumor that invades the lining of the abdomen
- NX The regional lymph nodes cannot be assessed
- N0 No evidence of spread to the lymph node
- N1 Regional lymph nodes are involved with tumor
- M0 No evidence of distant spread of the cancer
- M1 Evidence of distant spread of the cancer including spread to non-regional lymph node chains
The stage of the cancer is reported grouping the various combinations of the T, the N, and the M stage into one stage group. Stage groups are reported as Stage I to Stage IV as follows:
- Stage I T1 N0 M0
- Stage II T2 N0 M0
- Stage IIIA T3a N0 M0
- Stage IIIB T3b N0 M0
- Stage IIIC T4 N0 M0
- Stage IVA Any T N1 M0
- Stage IVB AnyT AnyN M1
There are other staging systems for liver cancer, such as the Barcelona Clinic Liver Cancer (CLIP) staging system, which takes into account patients' liver function (using the Child-Pugh score) and other prognostic indicators, unlike the AJCC system.
The Child Pugh score helps to determine the functional status of the liver. It evaluates the severity of liver disease. Points (from 1-3) are assigned for each of the following: evidence of ascites (fluid in the abdomen), encephalopathy (confusion), bilirubin and albumin levels, and bleeding time. These points are combined to give a total score ranging from 5-15. Based on the number score, a letter grade of A, B or C is assigned. A Childs Pugh score of A indicates good liver function, whereas C means that the liver is not working well.
Although the systems of cancer staging are quite complicated, they are designed to help physicians describe the extent of the cancer, and therefore, help to direct what type of treatment is given.
How is liver cancer treated?
Surgery provides the best chances for cure for patients with liver cancer; however, only patients with cancer that has not spread beyond the liver are candidates for surgical resection for cure. Liver cancer surgery can consist of either resection of a portion of the liver (known as a partial hepatectomy) or removal of the whole liver followed by liver transplantation . The type of surgery that is performed depends on the location of the tumor, the size of the tumor, and the overall health of the patients. Unfortunately, it is common for liver cancer to have grown or spread to a point where surgery is not possible. In addition, because it is common for patients with liver cancer to have additional medical problems such as cirrhosis, many patients whose cancers are considered resectable, are excluded from surgery due to their overall health.
In general, only patients with good liver function can tolerate a partial hepatectomy. For patients with poor liver function or who have extensive cirrhosis, liver transplantation is an option unless the cancer is too extensive or in a location that makes transplantation too difficult. Transplantation can treat both the cancer and the underlying liver disease. However, the number of liver donors is far smaller than the number of patients who may benefit from liver transplant and too often, patients who would otherwise be good candidates for liver transplantation are unable to receive them due to the lack of available organs.
For patients with tumors that have not spread beyond the liver, but cannot undergo resection of the tumor due to its location, a number of local treatments have been investigated as treatment. These include: cryosurgery/ablation, radiofrequency ablation, ethanol injections, transarterial chemoembolization and radioembolization.
In cryosurgery, liquid nitrogen or argon is used to cool probes that are inserted directly into the tumor during an operative procedure. The probes freeze the cancer cells, killing them. This technique has the advantage of treating very little normal tissue, thereby reducing the risk of side effects from the treatment. However, it can only be used to treat tumors that can be seen by the naked eye (no more than 5 tumors that measure less than 5 cm) or by ultrasound and requires an operation to perform.
Radiofrequency Ablation (RFA)
Another local treatment for liver cancer is radiofrequency ablation (RFA). Radiofrequency ablation consists of inserting a probe directly into the tumor and killing cancer cells with the use of electrodes that are inside the probe. These electrodes emit high-energy heat. This technique can be performed through the skin, and does not always require an open operation (although it can be performed during surgery as well). However, technically, it is more difficult to perform than cryosurgery. It is used on lesions less than 3 cm.
Ethanol injections are performed by injecting ethanol (alcohol) directly into tumors using small needles. The high concentration of ethanol used in these injections can result in killing of the tumor. Only small tumors (less than 2 cm, no larger than 5 cm) can be treated in this manner; however, for patients with a small number of small tumors, ethanol injections can be result in reasonable rates of tumor control. In general, in the US, RFA has replaced ethanol injection.
Chemotherapy is a medication that is usually given intravenously or as a pill. It goes to the bloodstream and throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance of finding those cells and killing them. In general, use of chemotherapy in liver cancer has been difficult because liver cancers have been found to be relatively resistant to cytotoxic chemotherapy, and because most patients with liver cancer have defects in their overall liver function. Chemotherapy is often processed within the liver, and a decrease in liver function can make the delivery of chemotherapy more difficult.
Chemotherapy can be used in liver cancer when the cancer has spread outside of the liver; however, the overall effectiveness of this treatment has been limited. It can also be used in the adjuvant setting, immediately after surgical resection of a tumor that has not spread beyond the liver. Despite the theoretical advantages of chemotherapy after surgery, a number of studies have failed to show an improvement in tumor control with the use of adjuvant chemotherapy (chemo given after surgery). Several different chemotherapy drugs have been studied for patients who have unresectable disease (not eligible for surgery), including 5-FU, oxaliplatin, doxorubicin, cisplatin, capecitabine and thalomide. These agents have been used in combination, and as single agents, but they have not been found to be very effective in treating hepatocellular cancer. Bevacizumab, a monoclonal antibody that targets the tumor's blood supply, has also been studied and did not show significant effect on stopping the disease progression.
Newer treatments include the use of targeted therapies. Targeted therapies are drugs that are designed to block specific steps in the development of cancer at the molecular level. A medication called Sorafenib is the first targeted therapy to demonstrate an improvement in survival in patients with advanced HCC. Sorafenib is a form of biologic therapy that is also being studied in combination with chemotherapy and local therapies. In addition there are ongoing studies evaluating the use of sorafenib after liver transplantation. Other agents that target proteins on the tumor cell are being investigated.
Transarterial Chemoembolization (TACE)
Chemoembolization of the hepatic arterytakes advantage of the fact that many liver cancers receive a large portion of their blood supply through the hepatic artery. By injecting chemotherapy through a catheter into the hepatic artery, the blood flow through the artery is blocked and the blood supply to the tumor is disrupted. The use of hepatic artery embolization is still being studied for use in patients with both resectable and unresectable liver cancer. It is first line therapy for multifocal tumors in patients with Child-Pugh class A liver disease.
Radioembolization (Yttrium 90 microspheres) provides internal delivery of high dose radiation to the tumor area while sparing normal tissue. A catheter is threaded into the groin, passed into the liver, and the micropsheres are delivered to the tumor.
Another potential method of treating liver cancer is radiation therapy. The radiation comes in the form of high energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. These x-rays are similar to those used for diagnostic x-rays, with a much high energy. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Because cancer cells are not as good as normal, healthy cells at repairing DNA damage, radiation results in more damage to the cancer cells than to normal cells. Radiation therapy exploits this difference to treat cancers while relatively sparing normal tissue.
Although modern techniques allow radiation to be delivered in a very specific manner, a significant amount of normal liver is still treated when radiation therapy is used. Because of this, radiation is not routinely part of the treatment of liver cancers. Its use is most often reserved for cases in which other treatment options have failed, or when the liver cancer has spread outside of the body and is causing specific problems due to the location to which it has spread (for example, bone). A significant amount of research is currently underway that explores additional methods of improving the delivery of radiation to liver cancers. Avenues of research have included the use of breath holding techniques, stereotactic body radiation, radiosensitizers (chemicals that are given together with radiation to improve the sensitivity of liver cancers to radiation), and radiolabeled antibodies (radioactive molecules attached to antibodies that specifically find and attach to liver cancer cells). Radiation therapy may be given along with Sorafenib or chemoembolization. When chemoembolization is combined with radiation, outcomes are improved compared to chemoembolization alone. Proton beam therapy is also being investigated in hepatocellular cancer as part of the multi-disciplinary approach to treatment.
How successful is treatment for liver cancer?
Surgical resection is the only known cure for liver cancer. However, even in patients who can undergo surgery, more than half experience a recurrence later on. For patients who have a liver transplant, there is about a 20% risk of recurrence. In general, the outcomes after treatment for liver cancer are less than optimal, particularly for patients who cannot undergo surgical resection of their cancers. Clearly, additional research is necessary to improve the overall outcome of these cancers.
After I am treated for liver cancer, how will I be followed?
Close follow-up after treatment for liver cancer is critical because of the high rate of recurrence in patients who have been treated and because of the high risk of developing a second liver cancer in patients with severe liver cirrhosis. The National Comprehensive Cancer Network (NCCN) recommends that follow up care should be performed every 3-6 months for the first two years following treatment, then every 6-12 months for years 3-5. Follow-up care should include treatment of underlying medical problems such as hepatitis or alcoholism, routine blood tests including blood markers such as AFP, and radiographic imaging such as CT scans and MRIs. Prompt evaluation and treatment of suspicious findings is critical.
After treatment, talk with your oncology team about receiving a survivorship care plan, which can help you manage the transition to survivorship and learn about long-term concerns and life after cancer. You can create your own survivorship care plan on OncoLink.
Ultimately, treatment of liver cancer should be a cooperative effort between a patient and their physicians. It is a multidisciplinary approach including surgery, medical oncology, interventional radiology, hepatology and radiation oncology. It is important that patients know about their disease so that they can make informed decisions about their treatment. This article is intended to help answer some of the common questions patients face when they have liver cancer. If you have any additional questions, please contact your care provider.
American Liver Foundation Education resources and support services for liver disease.
National Cancer Institute - Liver Cancer homepage
National Institute of Health Medline Plus - Liver Cancer Provides information on treatment and research, including educational information in Spanish.
Abou-Alfa GK, Schwartz L, Ricci S, et al Phase II study of sorafenib in patients with advanced hepatocellular carcinoma J Clin Oncol 2006; 24:4293-4300.
Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum. Lancet Oncol 5(7):408-418, 2004-09-27.