Liver Cancer

(Hepatocellular Carcinoma)

Primary liver cancer, also known as hepatocellular carcinoma, is a cancer that begins in the liver. Each year in the United States, approximately 15,000 men and 6,000 women are diagnosed with primary liver cancer. 

The liver is also the most common site to which cancer has spread (metastasized) from other parts for the body, most commonly the colon, lungs, or breast. When this happens, it is NOT liver cancer. Instead, the cancer is named for the organ it originated from (the primary site). For example, colon cancer that spreads to the liver is called metastatic colon cancer. It is not liver cancer. In the U.S., metastatic cancer in the liver is far more common than primary liver cancer.

Liver Anatomy and Function

The liver is a vital organ, meaning that one cannot live without it. The liver serves many critical functions including metabolism of drugs and toxins, removing degradation products of normal body metabolism (for example clearance of ammonia and bilirubin from the blood), and synthesis of many important proteins and enzymes (such as factors necessary for blood to clot).

•  The liver is the largest organ inside your abdomen. It is found behind your ribs on the right side of your body.

• The liver does important work to keep the patient healthy:

• It removes harmful substances from the blood.

• It makes enzymes and bile that help digest food.

• It also converts food into substances needed for life and growth.

• The liver gets its supply of blood from two vessels. Most of its blood comes from the hepatic portal vein. The rest comes from the hepatic artery. 

About Cancer Cells. Cancer begins in cells, the building blocks that make up tissues. Tissues make up the organs of the body. Normal cells grow and divide to form new cells as the body needs them. Wheormal cells grow old or get damaged, they die, and new cells take their place. Sometimes, this process goes wrong. New cells form when the body doesn’t need them, and old or damaged cells don’t die as they should. The buildup of extra cells often forms a mass of tissue called a growth, nodule, or tumor.

Tumors in the liver can be benign (not cancer) or malignant (cancer). 

Benign Tumors

• are rarely a threat to life

• can be removed and usually don’t grow back

• don’t invade the tissues around them

• don’t spread to other parts of the body

Malignant Tumors

• may be a threat to life

• sometimes can be removed but can grow back

• can invade and damage nearby tissues and organs (such as the stomach or intestine)

• can spread to other parts of the body

Hepatocellular Carcinoma

Most primary liver cancers begin in hepatocytes (liver cells). This type of cancer is called hepatocellular carcinoma or malignant hepatoma. Liver cancer cells can spread by breaking away from the original tumor. They mainly spread by entering blood vessels, but liver cancer cells can also be found in lymph nodes. The cancer cells may attach to other tissues and grow to form new tumors that may damage those tissues. See the Staging section for information about liver cancer that has spread.

Risk Factors

The more risk factors a patient has, the greater the chance that liver cancer will develop. Studies have found the following risk factors for liver cancer:

• Infection with hepatitis B virus (HBV) or hepatitis C virus (HCV): Liver cancer can develop after many years of infection with either of these viruses. Around the world, infection with HBV or HCV is the main cause of liver cancer.

• HBV and HCV can be passed from patient to patient through blood (such as by sharing needles) or sexual contact. An infant may catch these viruses from an infected mother. Although HBV and HCV infections are contagious diseases, liver cancer is not. The patient can’t catch liver cancer from another patient.

• HBV and HCV infections may not cause symptoms, but blood tests can show whether either virus is present. If so, the doctor may suggest treatment. Also, the doctor may discuss ways to avoid infecting other patients.

• In patients who are not already infected with HBV, hepatitis B vaccine can prevent HBV infection. Researchers are working to develop a vaccine to prevent HCV infection.

• Heavy alcohol use: Having more than two drinks of alcohol each day for many years increases the risk of liver cancer and certain other cancers. The risk increases with the amount of alcohol that a patient drinks.

• Aflatoxin: Liver cancer can be caused by aflatoxin, a harmful substance made by certain types of mold. Aflatoxin can form on peanuts, corn, and other nuts and grains. In parts of Asia and Africa, levels of aflatoxin are high. However, the United States has safety measures limiting aflatoxin in the food supply.

• Iron storage disease: Liver cancer may develop among patients with a disease that causes the body to store too much iron in the liver and other organs.

• Cirrhosis: Cirrhosis is a serious disease that develops when liver cells are damaged and replaced with scar tissue. Many exposures cause cirrhosis, including HBV or HCV infection, heavy alcohol use, too much iron stored in the liver, certain drugs, and certain parasites. Almost all cases of liver cancer in the United States occur in patients who first had cirrhosis, usually resulting from hepatitis B or C infection, or from heavy alcohol use.

• Obesity and diabetes: Studies have shown that obesity and diabetes may be important risk factors for liver cancer.

Symptoms

Early liver cancer often doesn’t cause symptoms. When the cancer grows larger, one or more of these common symptoms may occur:

• Pain in the upper abdomen on the right side

• A lump or a feeling of heaviness in the upper abdomen

• Swollen abdomen (bloating)

• Loss of appetite and feelings of fullness

• Weight loss

• Weakness or feeling very tired

• Nausea and vomiting

• Yellow skin and eyes, pale stools, and dark urine from jaundice

• Fever

These symptoms may be caused by liver cancer or by other health problems. With any of these symptoms, a doctor should be consulted so that problems can be diagnosed and treated as early as possible.

Majority of the liver cancer patients in the final stage of the disease develop jaundice. Jaundice indicates presence of blockages in the liver and in case of final stage liver cancer it signifies shutdown of the liver. The gallbladder and liver of a healthy individual produce bile salts; the primary function of bile salts is aiding the process of digestion and breaking down the nutrients present in foods. Patients in the final stage of liver cancer develops blockage in their bile ducts due to growth of cancer cells; as a result of this bile salts leak and enters the patients’ bloodstream. The blood with bile chemicals then starts circulating into different tissues of the patient’s body causing discoloration or yellowing.

 

Diagnosis

The following tests are used to diagnose liver cancer:

• Physical exam: Your doctor feels your abdomen to check the liver, spleen, and other nearby organs for any lumps or changes in their shape or size. Your doctor also checks for ascites, an abnormal buildup of fluid in the abdomen. Also, your skin and eyes may be checked for signs of jaundice.

• Blood tests: Many blood tests may be used to check for liver problems. One blood test detects alpha-fetoprotein (AFP). High AFP levels could be a sign of liver cancer. Other blood tests can show how well the liver is working.

• CT scan: An x-ray machine linked to a computer takes a series of detailed pictures of your liver and other organs and blood vessels in your abdomen. The patient may receive an injection of contrast material so that your liver shows up clearly in the pictures. On the CT scan, your doctor may see tumors in the liver or elsewhere in the abdomen.

• MRI: A large machine with a strong magnet linked to a computer is used to make detailed pictures of areas inside your body. Sometimes contrast material makes abnormal areas show up more clearly on the picture.

• Ultrasound test: The ultrasound device uses sound waves that can’t be heard by humans. The sound waves produce a pattern of echoes as they bounce off internal organs. The echoes create a picture (sonogram) of your liver and other organs in the abdomen. Tumors may produce echoes that are different from the echoes made by healthy tissues.

• Biopsy: A biopsy is usually not needed to diagnose liver cancer, but in some cases, the doctor may remove a sample of tissue. A pathologist uses a microscope to look for cancer cells in the tissue. Tissue can be obtained through several methods:

• A needle through the skin: The doctor inserts a thieedle into the liver to remove a small amount of tissue. CT or ultrasound may be used to guide the needle. The most common risk of a needle biopsy is bleeding, especially because liver cancer is a tumor that has many blood vessels (vascular). Rarely, new small areas of tumor can be seeded from the tumor into the liver along the needle track.

• Laparoscopic Surgical Procedure: The surgeon makes a few small incisions in your abdomen. A thin, lighted tube (laparoscope) is inserted through the incision. The laparoscope has a tool to remove tissue from the liver.

• Open Surgical Procedure: The surgeon can remove tissue from the liver through a large incision

Staging

If liver cancer is diagnosed, the doctor needs to learn the extent (stage) of the disease to help determine the optimal treatment. Staging is an attempt to find out whether the cancer has spread, and if so, to what parts of the body.

When liver cancer spreads, the cancer cells may be found in the lungs. Cancer cells also may be found in the bones and in lymph nodes near the liver.

When cancer spreads from its original place to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary tumor. For example, if liver cancer spreads to the bones, the cancer cells in the bones are actually liver cancer cells. The disease is metastatic liver cancer, not bone cancer. It’s treated as liver cancer, not bone cancer. Doctors sometimes call the new tumor “distant” or metastatic disease.

To learn whether the liver cancer has spread, one or more of the following tests may be used:

• CT scan (CAT scan) of the Chest: A CT scan often can show whether liver cancer has spread to the lungs. A CT scan procedure that makes a series of detailed pictures of areas inside the body, such as the chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

• PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose thaormal cells do.

 

• Bone scan: The doctor injects a small amount of a radioactive substance into your blood vessel. It travels through the bloodstream and collects in the bones. A machine called a scanner detects and measures the radiation. The scanner makes pictures of the bones. The pictures may show cancer that has spread to the bones.

Treatment

Treatment options for  liver cancer are surgery (including a liver transplant), ablation, embolization, targeted therapy, radiation therapy, and chemotherapy. A combination of these treatments may be used.

The appropriate treatment depends on the following:

• the number, size, and location of tumors in your liver

• how well your liver is working and whether the patient have cirrhosis

• whether the cancer has spread outside your liver

• the patient’s age and general health including the ability to handle potential side effects

At this time, liver cancer can be cured only when found at an early stage (before it has spread) and removed surgically. For patients who are not surgical candidates, other treatments are available. Patients with liver cancer may also consider enrolling in a clinical trial. These are research studies testing new treatments and are an important option for patients with all stages of liver cancer.

Specialists who treat liver cancer include transplant and hepatobiliary surgeons, surgical oncologists, gastroenterologists, medical oncologists, and radiation oncologists. The healthcare team also includes an oncology nurse and a registered dietitian.

Surgery

Liver Resection

Surgery is an option for patients with an early stage of liver cancer. The surgeon may remove the whole liver or only the part that has cancer. If the whole liver is removed, it’s replaced with healthy liver tissue from a donor.

A liver resection is the removal of part of the liver. Surgery to remove part of the liver is also called a partial hepatectomy. A patient with liver cancer may have part of the liver removed if lab tests show that the liver is working well and if there is no evidence that the cancer has spread to nearby lymph nodes or to other parts of the body.

The surgeon removes the tumor along with a margin of normal liver tissue around the tumor. 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.

As much as 80 percent of the liver may be removed. The surgeon leaves behind normal liver tissue. The remaining healthy tissue takes over the work of the liver. Also, the liver can regrow the missing part. The new cells grow over several weeks.

It takes time to heal after surgery, and the time needed to recover is different for each patient. The patient may have pain or discomfort for the first few days. Medicine can help control your pain. Before surgery, the patient should discuss the plan for pain relief with your doctor or nurse. After surgery, your doctor can adjust the plan if the patient need more pain control.

It’s common of a patient to feel tired or weak for a while. Also, the patient may have diarrhea and a feeling of fullness in the abdomen.

The health care team will watch the patient for signs of bleeding, infection, liver failure, or other problems.

Liver Transplant

A liver transplant is an option if the tumors are small, the disease has not spread outside the liver, and suitable donated liver tissue can be found.

Donated liver tissue comes from a deceased patient or a live donor. If the donor is living, the tissue is part of a liver, rather than a whole liver.

While the patient wait for donated liver tissue to become available, the health care team monitors your health and provides other treatments.

When healthy liver tissue from a donor is available, the transplant surgeon removes your entire liver (total hepatectomy) and replaces it with the donated tissue. After surgery, your health care team will give the patient medicine to help control your pain. The patient may need to stay in the hospital for several weeks. During that time, your health care team monitors how well your body is accepting the new liver tissue. The patient’ll take medicine to prevent your body’s immune system from rejecting the new liver. These drugs may cause puffiness in your face, high blood pressure, or an increase in body hair.

Other Procedures and Treatments

Ablation

Methods of ablation destroy the cancer in the liver. They are treatments to control liver cancer and extend life. They may be used for patients waiting for a liver transplant. Or they may be used for patients who can’t have surgery or a liver transplant. Surgery to remove the tumor may not be possible because of cirrhosis or other conditions that cause poor liver function, the location of the tumor within the liver, or other health problems.

Methods of ablation include the following:

• Radiofrequency ablation ( RFA) is the destruction of tumors with heat from radiofrequency waves. The doctor uses a special probe that contains tiny electrodes to kill the cancer cells with heat. Ultrasound, CT, or MRI may be used to guide the probe to the tumor. Usually, the doctor can insert the probe directly through your skin, and only local anesthesia is needed. Sometimes, surgery under general anesthesia is needed. The doctor inserts the probe through a small incision in your abdomen (using a laparoscope) or through a wider incision that opens your abdomen. Some patients have pain or a slight fever after this procedure. Staying overnight in the hospital is not usually needed.

• Laser Albation

• Microwave ablation, used less frequently than RFA, destroys liver tumors using heat generated by microwave energy. The surgeon inserts a small laparoscopic port or open incision to access the tumor. A CT scan or ultrasonic guidance is used to pinpoint the exact location of the tumor. A thin antenna, which emits microwaves, is then inserted into the tumor. This produces intense heat which destroys cancer cells, often within 10 minutes. Microwave ablation is faster than RFA and thus reduces the time patients must remain under general anesthesia.  Surgeons can also ablate multiple liver tumors simultaneously and ablate larger tumors than with RFA.

• Cryosurgery: A treatment that uses an instrument to freeze and destroy abnormal tissue, such as carcinoma in situ. This type of treatment is also called cryotherapy. The doctor may use ultrasound to guide the instrument.

• Percutaneous Ethanol Injection: Ultrasound is used to guide a thieedle into the liver tumor. Alcohol (ethanol) is injected directly into the tumor and kills cancer cells. The procedure may be performed once or twice a week. Usually local anesthesia is used, but if the patient have many tumors in the liver, general anesthesia may be needed.  The patient may have fever and pain after the injection.

Embolization

For those who can’t have surgery or a liver transplant, embolization or chemoembolization may be an option. The doctor inserts a tiny catheter into an artery in your leg and moves the catheter into the hepatic artery. For embolization, the doctor injects tiny sponges or other particles into the catheter. The particles block the flow of blood through the artery. Depending on the type of particles used, the blockage may be temporary or permanent.

Without blood flow from the hepatic artery, the tumor dies. Although the hepatic artery is blocked, healthy liver tissue continues to receive blood from the hepatic portal vein.

For chemoembolization, the doctor injects an anticancer drug (chemotherapy) into the artery before injecting the tiny particles that block blood flow. Without blood flow, the drug stays in the liver longer.

The patient must be sedated for this procedure, but general anesthesia is not usually needed. The patient will probably stay in the hospital for 2 to 3 days after the treatment.

Embolization often causes abdominal pain, nausea, vomiting, and fever. Your doctor can give the patient medicine to help lessen these problems. Some patients may feel very tired for several weeks after the treatment.

Targeted Therapy

Patients with liver cancer who cannot have surgery or a liver transplant may receive a drug called targeted therapy. Sorafenib (Nexavar) tablets were the first targeted therapy approved for liver cancer.

Targeted therapy slows the growth of liver tumors. It also reduces their blood supply. The drug is taken by mouth.

Side effects include nausea, vomiting, mouth sores, and loss of appetite. Sometimes, a patient may have chest pain, bleeding problems, or blisters on the hands or feet. The drug can also cause high blood pressure. The health care team will check your blood pressure often during the first 6 weeks of treatment.

Radiation Therapy

Radiation therapy uses high-energy rays to kill cancer cells. It may be an option for a few patients who can’t have surgery. Sometimes it’s used with other approaches. Radiation therapy also may be used to help relieve pain from liver cancer that has spread to the bones.

Doctors use two types of radiation therapy to treat liver cancer:

External radiation therapy: The radiation comes from a large machine. The machine aims beams of radiation at the chest and abdomen.

Internal radiation therapy: The radiation comes from tiny radioactive spheres. A doctor uses a catheter to inject the tiny spheres into your hepatic artery. The spheres destroy the blood supply to the liver tumor. The side effects from radiation therapy include nausea, vomiting, or diarrhea. Your health care team can suggest ways to treat or control the side effects.

Chemotherapy

Chemotherapy, the use of drugs to kill cancer cells, is sometimes used to treat liver cancer. Drugs are usually given by vein (intravenous). The drugs enter the bloodstream and travel throughout your body.

Chemotherapy may be given in an outpatient part of the hospital, at the doctor’s office, or at home. Rarely, the patient may need to stay in the hospital.

The side effects of chemotherapy depend mainly on which drugs are given and how much. Common side effects include nausea and vomiting, loss of appetite, headache, fever and chills, and weakness.

Some drugs lower the levels of healthy blood cells, and the patient’re more likely to get infections, bruise or bleed easily, and feel very weak and tired. Your health care team will check for low levels of blood cells. Some side effects may be relieved with medicine.

Supportive Care

Liver cancer and its treatment can lead to other health problems. The patient can have supportive care before, during, and after cancer treatment.

Supportive care is treatment to control pain and other symptoms, to relieve the side effects of therapy, and to help the patient cope with the feelings that a diagnosis of cancer can bring. The patient may receive supportive care to prevent or control these problems and to improve your comfort and quality of life during treatment.

Pain Control

Liver cancer and its treatment may lead to pain. Your doctor or a specialist in pain control can suggest several ways to relieve or reduce pain:

• Pain medicine: Medicines often can relieve pain. (These medicines may make patients drowsy and constipated, but resting and taking laxatives can help.)

• Radiation therapy: Radiation therapy can help relieve pain by shrinking the cancer.

• Nerve block: The doctor may inject alcohol into the area around certaierves in the abdomen to block the pain.

The health care team may suggest other ways to relieve or reduce pain. For example, massage, acupuncture, or acupressure may be used along with other approaches. Also, the patient may learn to relieve pain through relaxation techniques such as listening to slow music or breathing slowly and comfortably.

Nutrition

Nutrition is important before, during, and after cancer treatment. Patients need sufficient amount of calories, protein, vitamins, and minerals. This may be a challenge because the patient may feel uncomfortable or tired, and may not feel like eating. The patient also may have side effects of treatment such as poor appetite, nausea, vomiting, or diarrhea. A doctor, a registered dietitian, or another health care provider can advise the patient about ways to have a healthy diet. 

Careful planning and checkups are important. Liver cancer and its treatment may make it hard for the patient to digest food and maintain your weight. The treatment team will monitor the patient for weight loss, weakness, and lack of energy.

Follow-up Care

The patient will need regular checkups (such as every 3 months) after treatment for liver cancer because the cancer may come back (a recurrence). Checkups help ensure that any changes in health are noted and treated if required. Checkups may include a physical exam, blood tests, ultrasound, CT scans, or other tests.

For patients 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 isn’t being rejected. Patients 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.

Text on this page, and images bearing the NCI logo, were reproduced, in whole or in part, from the websites of the National Cancer Institute (NCI) at http://www.cancer.gov/cancertopics/wyntk/liver/allpages, the originator of the content. Any modifications, including explanatory or supplemental material, were added to enhance the reader’s understanding.

Liver cancer occurrence has been steadily increasing since the early 1980s in the U.S. Before 2010, the American Cancer Society estimated that 24,120 new cases and 18,910 deaths would occur in the U.S. during this year (2010). ⁽¹⁾ Liver cancer is the fifth major cause of cancer related deaths in the U.S, it has the fastest growing death rate of all cancers in the country. ⁽²⁾ Liver cancer currently carries a poor prognosis since most of the cases are not detected at early stages. This cancer is the seventh most common cancer in women and the fifth in men and it has a higher incidence in Europe, Australia and the United States. ⁽³⁾

Below is a list of the information found within this section:

Anatomy of the Liver. The liver forms part of the gastrointestinal system, which is responsible for breaking down food into smaller parts that can be used by cells.  The liver is located in the abdomen, below the ribcage. It is a large organ with many different functions, including: ⁽¹⁾

• Production and secretion of bile and bile salts to help digestion and absorption.

• Production of insulin-like growth factor (IGF-I).

• Production of clotting factors.

• Release of glucose into the blood to provide energy for cells.

• Production of urea, a waste product.

• Cholesterol production.

Behind the liver there’s a small organ called the gallbladder, which function’s to store bile produced by the liver and empty it into the small intestine to aid digestion and absorption. ⁽²⁾

The large number of different cell types in the liver makes it vulnerable to the formation of more than one type of cancer. As with tumors that form in any other locations, these can be either invasive (malignant) or contained (benign).⁽³⁾

Types of Liver Cancer

Hepatocellular carcinoma (HCC)
The most common type of liver cancer is hepatocellular carcinoma and it is the result of a tumor formed by the abnormal growth of the liver-specific cells called hepatocytes (‘hepat’ and ‘hepato’ are derived from the Greek word for liver).  Most patients with this type of cancer are over 50 and it is more common in males than in females. Hepatocellular carcinoma can metastasize, and when it does, it frequently goes to nearby lymph nodes and to the lungs. ⁽¹⁾

Cholangiocarcinoma

This kind of carcinoma, also known as bile duct cancer, arises from the connective tissues of the tubes that connect the liver to the gallbladder and the gallbladder to the small intestine (hepatic bile ducts) as well as the ducts, located inside the liver (intrahepatic ducts). Most cholangiocarcinomas are adenocarcinomas (they form in glandular tissue)but they frequently grow slowly and don’t metastasize for long periods of time. Because the cancer has few specific symptoms and can be confused with other liver conditions (hepatitis or cirrhosis), it is difficult to detect early and is usually in advanced form when discovered. The average age of patients at diagnosis with cholangio carcinoma is 65. ⁽²⁾

Hepatoblastoma

Hepatoblastoma characteristically develops in children; it is most frequently diagnosed in infants between 14 and 24 months and almost all patients are diagnosed by the age of 5. ⁽³⁾ Older children  and adults can develop this carcinoma, but it is very rare. This malignancy is the result of an uncontrolled proliferation of undeveloped liver cells (hepatocytes). Hepatoblastoma is usually found in only one place (unifocal), it’s uncommon for it to metastasize. ⁽⁴⁾

Risk Factors

Hepatitis C Virus (HCV): For Western countries, including the U.S. infection with hepatitis C is the leading cause of both HCC and chronic liver disease. It is of special importance because unlike hepatitis B virus, there is no vaccine available for hepatitis C virus. ⁽¹⁾

Excessive alcohol intake:

Alcohol liver disease is the second most common risk factor for HCC in the U.S., after infection with hepatitis C virus.⁽²⁾

Geography:More than 80% of HCC cases appear in Eastern Asia or sub-Saharan Africa. North and South America, Northern Europe and Oceania have much lower incidence rates. ⁽³⁾

Ethnicity:In the United States, HCC incidence rate of Asians is twice as high as that of African Americans and four times that of whites.⁽³⁾

Sex:

Males have a higher liver cancer rate than females. The difference in the male:female ratio is greatest among Europeans. The difference between the rates is likely caused by different exposure to risk factors including alcohol consumption, cigarettes, and infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). More on HBV and HCV.⁽³⁾

Age:

In developed countries (including Canada and the United States) and most Asian populations, the peak of HCC incidence rate is in people 75 years old and older. On the other hand, the peak in African men occurs between 60 and 65 years old and then decreases. The peak age for African women occurs between 65 and 70 years old and then decreases.⁽³⁾

Hepatitis B Virus (HBV):

Those who carry HBV have a 5 to 15 fold increased risk of developing HCC over the general population. Between 70 and 90% of HCCs related to the presence of HBV are diagnosed in patients that suffer from cirrhosis.

In places with high HCC incidence rates, HBV is usually transmitted from mother to child (vertical transmission), whereas in areas with low HCC incidence rates patients usually get infected with HBV through sexual and parenteral ways (horizontal transmission). ⁽³⁾

Obesity:

A 16-year period study in the United States showed a 5 fold increase in cancer mortality in people with great body mass index in contrast to those who had a normal body mass index. Liver cancer is frequently found in patients with metabolic disarrangements. ⁽³⁾

Diabetes Mellitus:

Many studies around the world have found a significant relationship between diabetes and the development of HCC. Between 10 and 20% of cirrhosis patients have overt diabetes and a higher percentage present impaired glucose tolerance. ⁽³⁾

Tobacco:

The association between smoking and HCC still is not yet clear. Studies have produced conflicting results, showing both negative and positive relationships. However, two studies focused on women both reported a positive association, so smoking may be a higher risk factor for women than men. ⁽³⁾

Exposure to aflotoxins: flatoxins are a type of mycotoxin, toxic chemicals made by some types of fungi. Aflatoxin is produced by Aspergillus fungi when the fungus grows on improperly stored food products. Aflatoxins are capable of causing DNA mutations, including the tumor suppressor, TP53  (p53). Aflatoxins may be found in peanuts, tree nuts, corn, wheat and other grains, and oil seeds.

Symptoms & Detection

Liver cancer generally does not have symptoms. Nonspecific symptoms that can be associated with HCC may include:· Yellowish color of the skin (Jaundice)· Inability to eat (Anorexia)· Weight Loss· Abdominal pain and/or swelling. A surveillance ultrasound is recommended every six months for individuals with a high risk of developing HHC.In patients with liver cirrhosis, if the ultrasound reveals a suspicious liver lesion, a CT or MRI can be used to determine if the abnormality (lesion) is HCC. If the patient has no underlying cirrhosis or if imaging results prove inconclusive a biopsy can be used.

 Staging & Pathology Report

If there is suspicion that a patient may have liver cancer, a sample of tissue (biopsy) may be taken for examination. After a biopsy is taken, the physician who performed the biopsy sends the specimen to a pathologist. The pathologist examines the specimen at both the macroscopic (visible with the naked eye) and microscopic (requiring magnification) levels and then sends a pathology report to the physician. The report contains information about the tissue’s appearance, cellular make up, and state of disease or normalcy. For more information about pathology reports, refer to theDiagnosis & Detection section.

A variety of staging systems have been used for liver cancer. T/N/M and the Barcelona Clinic Liver Cancer staging system (BCLC) are the most common.⁽¹⁾

The BCLC uses a four-stage system:

A. Includes patients with asymptomatic early tumors

B. Patients with asymptomatic multinodular HCC

C. Patients with symptomatic tumors and/or invasive tumor pattern

D. End stage disease. Should only receive symptomatic treatment.

Tumor Biology

TP53:
p53 is a tumor suppressor gene in charge of regulating cell division and apoptosis. About half of all human tumors have a mutation in the TP53tumor suppressor gene. Several studies have reported that mutations in p53 have a critical role in the development of HCC.⁽¹⁾

pRb: pRb is a tumor suppressor gene. Together with TP53 it regulates cell division. the disruptionof the pRb pathway in HCC is similar to that of other cancers. ⁽²⁾

Ras: The human ras protein family is a family of proteins that drive cell division. A recent study reported that some of the Ras family inhibitor are inactivated in human HCC, demonstrating the role of Ras pathway signals in liver cancer. ⁽¹⁾

NOTCH 2:

The NOTCH family is involved in several cell functions, such as proliferation, differentiation and cell death (apoptosis).⁽³⁾Hepatoblastoma can be the result of more than one type of translocation in the long arm (q) of chromosome 1.  The NOTCH 2 protein has been found to delay the maturation of hepatoblasts during liver development; its expression is associated to the differentiation of the hepatoblasts into hepatocytes and biliary cells. It is thought that NOTCH 2 contributes to hepatoblastoma by keeping a population of hepatoblasts from differentiating.⁽

Treatment

Treatment options for HCC depend on how well the  liver is functioning, the tumor stage, and the physical status of the patient. As our focus is on the biology of the cancers and their treatments, we do not give detailed treatment guidelines. Instead, we link to organizations in the U.S. that generate the treatment guidelines.

Learn about treatment guidelines for HCC from the National Comprehensive Cancer Network (NCCN).

A study from 2011 suggests that liver cancer may arise from a type of cancer stem cell that is resistant to chemotherapy, and has the ability tometastasize to the rest of the body.  These capabilities make it possible for liver cancer to recur after it is surgically removed.

Liver cancer types are segregated into trio groups, namely:

Localized resectable (several T1/T2, N0, M0 tumor types). In case cancer is in a preliminary staging & the remnant

liver is in good health, then surgical procedure – partial hepatectomy might help in curing the person. Regrettably, solely miniscule numbers of individuals having liver cancer would be part of this group. A crucial aspect which affects result is the tumor size & if it has developed in blood vessels. A large-sized tumor (over two inch athwart) or a tumor invading blood vessels has a greater likelihood of recurring in the liver or metastasizing to other areas post-surgery. The utility of the remnant of the organ & the individual’s overall health are also vital.

 

 

Scientific studies are presently probing if patients undergoing surgical procedure would be benefited when offered other therapies alongside surgical procedure. A trial found that chemo-embolization pre-surgery protracted life among several patient types post-surgery. In one trial those patient types offered interferon post-surgery had a greater likelihood of surviving twelve months post-surgery. Yet, there are several trials that disagree & further trials are necessary for uncovering the worth (in case any) for including other therapies to surgical procedure.

Localized unresectable (several T1-T4, N0, M0 tumor types). These comprise of those tumor types which have not yet metastasized however are quite large-sized to be excised with safety. They include cancer which is present in particular regions which makes it trickier in removal, cancer forms with duo or more tumor types or cancer forms among patients having liver in poor condition. In such cases treatment by partial hepatectomy mostly isn’t an ideal choice and might rather require liver transplant in case doable.

Liver transplant is a major surgery that involves removal & replacement of the organ with another healthy one by donors. Though it is a complicated procedure it has been helpful to several individuals and could treat cancer & any fundamental liver condition. The five-year survival rate in patient types that underwent liver transplantation for treating cancer in their livers is around sixty percent.

In case one is an inapt entrant for liver transplant then the physician might advice tumor ablation employing procedures. Some choices might comprise of embolization (alongside or not including chemotherapy or radiotherapy), targeted therapies using sorafenib, chemo (systemic/through hepatic artery infusion), &/or conformal radiotherapy.

Though it is quite improbable that therapy other than transplant would be cancer-curative, it could allay symptoms & lengthen life. However, such therapies are not identified to cure the disease; a scientific study is yet a favourable option.

Advanced (inclusive of every N1/M1 tumor types). In this situation, the liver cancer has metastasized all through the organ or past the organ reaching the lymph nodes or some organ. Since such cancer types are common, they are not curable through surgical procedure.

In case the person’s liver functions satisfactorily – Child Pugh class A/B then targeted therapies with sorafenib might assist in controlling cancerous development for some period of time & might assist in prolonging existence.

Similar to localized resectable cancer, scientific studies on targeted therapy, novel strategies for chemo (novel medicines & regional chemo), novel types of radiotherapy (using radiosensitizer or target through antibodies) among other novel therapies (gene therapy, immunotherapies) might also be of assistance. Such scientific studies are additionally crucial for bringing about improvement in the prognosis of patient populaces in the near future.

Therapies like radiotherapy or chemo might be beneficial for allaying pains & other signs. Patients should preferably be discussing what symptoms they are experiencing with their cancer teams, so that their effective treatment could be carried out.

Recurring Liver Cancer Treatment. Cancer recurring or arising post-treatment could be at the analogous location or close to that location it originated or remote – metastasized to organ types like bones or lung. In such cases, therapy following preliminary treatment is based on several aspects like location of relapse, kind of preliminary therapy & extent to which the liver is functional. Those people having localized resectable condition which relapses in the analogous site might be offered additional surgery or local therapies such as embolizations or ablations. In case the cancer is extensive then targeted therapies using sorafenib or chemo might be the choices. Even such a patient could participate in on-going clinical trials apt for him/her. Therapy might even be given for allaying pains & other signs.

Liver Cancer: Diagnosis and Staging

Diagnosis of Liver Cancer. A patient with liver cancer symptoms at Winship Cancer Institute of Emory Universityin Atlanta, Georgia may have one or more of the following procedures to diagnose liver cancer and/or other gastrointestinal cancers:

• Angiogram: A doctor injects a dye into an artery so that the blood vessels in the liver are visible. This can help to identify a tumor. 

• Biopsy: Requires the removal of tissue to be inspected for cancer cells by a pathologist. 

• Blood Tests: Can help detect how well the liver is functioning. 

• CT Scan: Takes a series of detailed pictures of the liver and surrounding organs and tissue in the abdomen. These pictures allow doctors to see tumors in the liver and in the abdomen. 

• MRI: Uses a powerful magnet linked to a computer to create images of a targeted area such as the liver or abdomen in order to see tumors and irregular tissues. 

• Physical Exam: Allows a doctor to feel the abdomen for any lumps or abnormalities (changes in shape or size) in the spleen and surrounding organs.

• Ultrasound: Uses sound waves to create images of the liver and other structures in the abdomen so that a doctor can see any tumors or abnormal tissue.
   

Signs and Symptoms of Liver Cancer

Because most people do not exhibit symptoms of liver cancer early on, it usually remains undetected until it has reached the advanced stages.

For those who do experience symptoms of liver cancer, they may include:

• A yellow discoloration of the skin and whites of the eyes (jaundice)

• Abdominal pain, especially in the upper right part of the abdomen

• Abdominal swelling

• An enlarged liver

• General weakness and fatigue

• Loss of appetite

• Nausea and vomiting

• Weight loss

 

 

 

 

 

 

 

 

 

Management of hepatocellular carcinoma

 

 

 

 

 

Prepared Prof. Igor Y. Galaychuk, MD (2011) by text of

 

Colorectal Cancer

 

 

I. Epidemiology and etiology

A. Incidence. In Ukraine (2012) there were 10,222 (22.5 per 100,000) new cases of colon, and 8971 (19.7 per 100,000) new cases of rectal cancers. The death rates caused by rectal cancer were in men 14.0 and in women 10.8 per 100,000. The death rates caused by colon cancers were 13.8 in men, and in women 13.3 per 100,000. Colorectal cancer is the second most common cause of cancer mortality after lung cancer in the United States and ranks third in frequency among primary sites of cancer in both men and women. Nearly 600,000 cases are diagnosed annually worldwide, accounting for 9% of human cancers. Peak incidence rates are observed in the United States, Australia, and New Zealand. The lowest incidence rates are noted in India and South America and among Arab Israelis. A 10-fold variability is noted from highest to lowest incidence rates. Both the incidence and the mortality rates have declined since they peaked in 1985. Studies of migrant populations have discerned that the incidence of colorectal cancer reflects current geographic location and not the country of origin. This suggests that environmental influences outweigh genetic trends for populations in which the experiences of those people with inherited special risk are pooled with those of lesser risk. Rural dwellers have a lower incidence of colorectal cancer than do urbanites. In the United States, cancer of the colorectum is more common in the East than the West and in the North than the South. The risk for colorectal cancer increases with age, but 3% of colorectal cancers occur in patients younger than 40 years of age. The incidence is 19 per 100.000 population for those younger than 65 years of age and 337 per 100,000 among those older than 65 years of age. In 1999, it is estimated that in the United States, 131,000 new cases of colorectal cancer will develop and an estimated 47,000 persons will die from the disease. In the United States, a person of average risk has a 5% lifetime risk for developing colorectal cancer.

B. Etiology. Multiple forces drive the transformation of colorectal mucosa to cancer. Inheritance and environmental factors, including diet, are both crucial, but the extent of their interdependence as causative variables remains unknown.

1. Polyps. The main importance of polyps is the well-recognized potential of a subset to evolve into colorectal cancer. The evolution to cancer is a multistage process that proceeds through mucosal cell hyperplasia, adenoma formation, and growth and dysplasia, to malignant transformation and invasive cancer. Environmental carcinogens may result in the development of cancer regardless of a patient’s genetic background, but patients with genetically susceptible mucosa inherit a predisposition to abnormal cellular proliferation. Oncogene activation and chromosomal deletion lead to adenoma formation, growth with increasing dysplasia, and invasive carcinoma.

a. Types of polyps. Histologically, polyps are classified as neoplastic or nonneoplastic. Nonneoplastic polyps have no malignant potential and include hyperplastic polyps, mucous retention polyps, hamartomas (juvenile polyps), lymphoid aggregates, and inflammatory polyps. Neoplastic polyps (or adenomatous polyps) have malignant potential and are classified according to the World Health Organization system as tubular (microscopically characterized by networks of complex branching glands), tubulovillous (mixed histology), or villous (microscopically characterized by relatively short, straight glandular structures) adenomas depending on the presence and volume of villous tissue. Polyps larger than 1 cm in diameter, those with high-grade dysplasia, and those with predominantly villous histology are associated with higher risk for colorectal cancer. Colonoscopic polypectoiny and subsequent surveillance can reduce the incidence of colon cancer by 90%, compared with that observed in unscreened controls.

b. Frequency of polyp types. About 70% of polyps removed at colonoscopy are adenomatous, 75% to 85% of which are tubular (no or minimal villous tissue), 10% to 25% are tubulovillous (less than 75% villous tissue), and fewer than 5% are villous (more than 75% villous tissue).

c. Dysplasia may be classified as mild, moderate, or severe. However, it is preferable to classify dysplasia into only two grades: low and high. About 6% of adenomatous polyps’ exhibit severe dysplasia and 4% contain invasive carcinoma at the time of diagnosis.

d. The malignant potential of adenomas correlates with increasing size, the presence and the degree of dysplasia in a villous component, and the patient’s age. Small colorectal polyps (smaller than 1 cm) are not associated with increased occurrence of colorectal cancer; the incidence of cancer, however, is increased 2.5- to 4-fold if the polyp is large (larger than 1 cm) and 5- to 7-fold in patients who initially have multiple polyps. The study of the natural history of untreated polyps larger than 1 cm showed that the risk for progression to cancer is 2.5% at 5 years, 8% at 10 years, and 24% at 20 years. The time to malignant progression depends on the severity of dysplasia: 3.5 years for severe dysplasia and 11.5 years for mild atypia.

e. Management of polyps. Because of the adenoma-cancer relationship and the evidence that resecting adenomas prevents cancer, newly detected polyps should be excised and additional polyps should be sought through colonoscopy. The sensitivity of colonoscopic examinations, particularly for detection of polyps less than 1 cm in diameter, exceeds that of barium enema. Additionally, with colonoscopy, therapeutic polypectomy can be accomplished during the diagnostic examination. The incidence of synchronous adenomas in patients with one known adenoma is 40% to 50%.

f. Intestinal polyposis syndromes.

2. Diet. Populations with high intake of fat, higher caloric intakes, and low intake of fiber (fruits, vegetables, and grains) tend to have increased risk for colorectal cancer in most but not all studies. Higher calcium intake, calcium supplementation, and regular aspirin use are associated with a lower risk for colorectal cancer in some studies. Increased intake of vitamins C and E and beta-carotene do not appear to decrease the risk for polyp formation. The higher incidence of rectal and sigmoid cancer in men may be related to their greater consumption of alcohol. Postmenopausal women who have taken estrogen replacement therapy appear to have a lower risk for colorectal cancer than those who have not.

3. Inflammatory bowel disease.

a. Ulcerative colitis is a clear risk factor for colon cancer. About 1% of colorectal cancer patients have a history of chronic ulcerative colitis. The risk for the development of cancer in these patients varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and duration of active disease. The cumulative risk is 3% at 15 years, 5% at 20 years, and 9% at 25 years. The recommended approach to the increased risk for colorectal cancer in ulcerative colitis has been annual colonoscopy to determine the need for total proctocolectomy in patients with extensive colitis of more than 8 years’ duration. This strategy is based on the assumption that dysplastic lesions can be detected before invasive cancer has developed. An analysis of prospective studies concluded that immediate colectomy is essential for all patients diagnosed with dysplasia (high grade or low grade). Most important, the analysis demonstrated that the diagnosis of dysplasia does not preclude the presence of invasive cancer. The diagnosis of dysplasia has inherent problems with sampling of specimens and with variation in agreement among observers (as low as 60%, even with experts in the field).

b. Crohn’s disease. Patients with colorectal Crohn’s disease are at increased risk for colorectal cancer, but the risk is less than that of those with ulcerative colitis. The risk is increased about 1.5 to 2 times.

4. Genetic factors.

a. Family history may signify either a genetic abnormality or shared environmental factors or a combination of these factors. About 15% of all colorectal cancers occur in patients with a history of colorectal cancer in first-degree relatives.

b. Gene changes. Specific inherited (adenomatous polyposis coli [APC] gene) and acquired genetic abnormalities (ras gene point mutation; c-myc gene amplification; allele deletion at specific sites of chromosomes 5, 17, and 18) appear to be capable of mediating steps in the progression from normal to malignant colonic mucosa. About half of all carcinomas and large adenomas have associated point mutations, most often in the K-ras gene. Such mutations are rarely present in adenomas smaller than 1 cm. Allelic deletions of 17p- are demonstrated in three-quarters of all colorectal carcinomas, and deletions of 5q- are demonstrated in more than one-third of colonic carcinoma and large adenomas. Two major syndromes and several variants of these syndromes of inherited predisposition to colorectal cancer have been characterized. The two syndromes, which predispose to colorectal cancer by different mechanisms, are FAP and hereditary nonpolyposis colorectal cancer syndrome (HNPCC).

 

(1) FAP. The genes responsible for FAP, APC genes, are located in the 5q21 chromosome region. Inheritance of defective APC tumor-suppressor gene leads to a virtually 100% likelihood of developing colon cancer by 55 years of age. Screening for polyps should begin during early teenage years. The FAP syndrome is associated with the development of gastric and ampullary polyps, desmoid tumors, osteomas, abnormal dentition, and abnormal retinal pigmentation. Variants of FAP include Gardner’s and Turcot’s syndromes.

(2) HNPCC. The autosomal-dominant pattern of HNPCC includes Lynches syndromes I and II, both of which are associated with an increased incidence of predominantly right-sided colon cancer. This genetic abnormality in the mismatch repair mechanism leads to defective excision of abnormal repeating sequences of DNA known as microsatellites (“microsatellite instability”). Retention of these sequences leads to expression of a imitator phenotype characterized by frequent DNA replication errors (RER+ phenotype), which predispose affected people to a multitude of primary malignancies, including endometrial, gastric, ovarian, bladder, and ureteral cancers and biliary tract cancers. Specific mutated genes on chromosomes 2 and 3, known as hMSH2, hMLHl, hPMSl, and hPMS2, have been linked to HNPCC. Patients with HNPCC have a tendency to develop colon cancer at an early age, and screening should begin by 20 years of age for relatives of HNPCC patients. The median age of HNPCC patients with colon cancer at diagnosis was 44 years, versus 68 years for control patients in one study. The prognosis for HNPCC patients appears to be better than for those patients with sporadic colon cancer; the death rate from colon cancer for HNPCC patients is two thirds that for sporadic cases over 10 years.

c. Tumor location. Proximal tumors appear to represent a more genetically stable form of the disease and may arise through the same mechanisms that underlie inherited nonpolyposis colon cancer. Distal tumors show evidence of greater genetic instability and may develop through the same mechanisms that underlie polyposis-associated colorectal cancer.

5. Smoking. Men and women smoking during the previous 20 years have three times the relative risk for small adenomas (less than 1 cm) but not for larger ones. Smoking for more than 20 years was associated with a 2.5 relative risk for larger adenomas.

6. Other factors. Personal or family history of cancer in other anatomic sites (such as breast, endometrium, and ovary) is associated with increased risk for colorectal cancer. Exposure to asbestos (e.g., in brake mechanics) increases the incidence of colorectal cancer to 1.5 to 2 times that of the average population. Other than this association, there appears to be little relationship between occupational exposures and the incidence of colon cancer. Data indicate that HPV infection of the columnar mucosa of the colon may cause benign and malignant neoplasia.

II. Pathology and natural history.

A. Histology. Ninety-eight percent of colorectal cancers above the anal verge are adenocarcinomas. Cancers of the anal verge are most often squamous cell or basaloid carcinomas. Carcinoid tumors cluster around the rectum and cecum and spare the rest of the colon.

B. Location. Two thirds of colorectal cancers occur in the left colon and one third in the right colon. About 20% of colorectal cancers develop in the rectum. Rectal tumors are detected by digital rectal examination in 75% of cases. Nearly 3% of colorectal adenocarcinomas are multicentric, and 2% of patients develop a second primary tumor in the colon.

 

C. Clinical presentation. The common clinical complaints of patients with colorectal cancer relate to the size and location of the tumor. Right-sided colonic lesions most often result in dull and ill-defined abdominal pain, bleeding, and symptomatic anemia causing weakness, fatigue, and weight loss, rather than in colonic obstruction. Left-sided lesions lead commonly to changes in bowel habits, bleeding, gas pain, decrease in stool caliber, constipation, increased use of laxatives, and colonic obstruction.

 

 

D. Clinical course. Metastases to the regional lymph nodes are found in 40% to 70% of cases at the time of resection. Venous invasion is found in up to 60% of cases. Metastases occur most frequently in the liver, peritoneal cavity, and lung, followed by the adrenals, ovaries, and bone. Metastases to the brain are rare. Rectal cancers are three times more likely to reoccur locally than are proximal colonic tumors, in part because the anatomic confines of the rectum preclude wide resection margins and in part because the rectum lacks an outer serosal layer through most of its course. Because of the venous and lymphatic drainage of the rectum into the inferior vena cava (as opposed to the venous drainage of the colon into the portal vein and variable lymphatic drainage), rectal cancer often reoccurs first in the lungs. Colon cancer more frequently reoccurs first in the liver.

 

III. Diagnosis.

A. Diagnostic studies. About 85% of patients diagnosed with colorectal cancer can undergo surgical resection. Patients with incurable cancer may benefit from palliative resection to prevent obstruction, perforation, bleeding, and invasion to adjacent structures. After the clinical diagnosis of colorectal cancer is made, several diagnostic and evaluation steps should be taken.

1. Biopsy confirmation of malignancy is important. If an obstructing lesion cannot undergo biopsy, brush cytology may be feasible.

 

 

2. General evaluation includes a complete physical examination with digital rectal examination. CBC, LFTs, and chest radiograph.

3. Carcinoembryonic antigen (CEA) screening is favored by some physicians as a means of identifying early recurrence despite the limited specificity and sensitivity of this test. A preoperative CEA can be useful as a prognostic factor and to determine if the primary tumor is associated with CEA elevation. Preoperative CEA elevation implies that CEA may aid in early identification of metastases because metastatic tumor cells are more likely to result in CEA elevation in this circumstance.

4. CT or magnetic resonance imaging (MRI) with contrast of the abdomen and pelvis may identify liver or intraperitoneal metastases.

5. Endoscopy or barium enema is indicated to assess the entire colonic mucosa because about 3% of patients have synchronous colorectal cancers and a larger percentile have additional premalignant polyps.

6. EUS significantly improves the preoperative assessment of the depth of invasion of large bowel tumors, especially rectal tumors. The accuracy rate is 95% for EUS, 70% for CT, and 60% for digital rectal examination. In rectal cancer, the combination of EUS to assess tumor extent and digital rectal examination to determine mobility should enable both precise planning of surgical treatment and definition of those patients who may benefit from preoperative chemoradiation. Transrectal biopsy of perirectal lymph nodes can often be accomplished under EUS direction.

 

B. Biologic markers.

1. CEA is the best known marker for monitoring colorectal cancer disease status and for detection of early recurrence and liver metastases. CEA is too insensitive and nonspecific to be valuable for screening of colorectal cancer. Elevation of serum CEA levels, however, does correlate with a number of parameters. Higher CEA levels are associated with histologic grade 1 or 2 tumors, more advanced stages of the disease, and the presence of visceral metastases. Although serum CEA concentration is an independent prognostic factor, its putative value lies in serial monitoring after surgical resection.

2. New markers, such as CA 19-9, may be of value in monitoring recurrences and complement CEA. Monoclonal antibodies (anti-CEA, anti-TAG-72) may also be useful in immunohistologic chemical staining of tissues. The presence of an abnormal number of chromosomes in the tumor cells (aneuploidy) confers a worse prognosis than is observed in patients with diploid tumors. Light microscopic features and stage, however, remain the most reliable prognostic measures.

IV. Staging and prognostic factors.

Staging system. According the TNM system the 6^th edition, 2002, we have:

T       Primary tumor

Tis     Carcinoma in situ: intraepithelial or invasion of the lamina propria

Tl      Invasion of the submucosa

T2     Invasion of the muscularis propria

T3     Invasion through the muscularis propria into subserosa or into nonperitonealized pericolic or perirectal tissues

T4     Perforation of visceral peritoneum or direct invasion into adjacent organs or tissues

N0     No regional lymph node metastases

Nl      Metastases in one to three pericolic or perirectal lymph nodes

N2     Metastases in 4 or more lymph nodes

M0    No distant metastasis

Ml     Distant metastases present

 

Stage          TNM grouping    5-year Survival (%>)    Dukes’ grouping

0        Tis N0 M0                     100

1        T1N0M0                        95                                  A

T2 N0 M0                      90                                  A

II       T3N0M0                        80                                  B

T4 N0 M0                      75                                  B

III      Any T Nl M0                  72                                  C

Any T N2 M0                 60                                  C

Any T N3 M0                          40                         C

IV      Any T Any N Ml                      5                          D

 

B. Prognostic factors.

1. Stage is the most important prognostic factor.

2. Histologic grade significantly influences survival regardless of stage. Patients with well-differentiated carcinomas (grades 1 and 2) have a better 5-year survival than those with poorly differentiated carcinomas (grades 3 and 4).

3. The anatomic location of the tumor appears to be an independent prognostic factor. For equal stages, patients with rectal lesions have a worse prognosis than those with colon lesions, and transverse and descending colon lesions result in poorer outcomes than ascending or rectosigmoid lesions.

4. Clinical presentation. Patients who present with bowel obstruction or perforation have a worse prognosis than patients who present with neither of these problems.

5. Chromosome 18. The prognosis of patients with an allele loss of chromosome 18q is significantly worse than that of patients with no allelic loss. The survival of patients with stage B disease is the same as that for stage A when there is no allelic loss and the same as for stage C when there is allelic loss. Other abnormalities that have been identified and that are of potential value for determining prognosis are located on chromosomes 1, 5, 8, 17, and 22. Identification of these genes or their products is possible using gel electrophoresis or immunohistochemical probes. These observations may ultimately prove to be helpful in selecting patients with stage II disease for adjuvant therapy or stage III patients with better than average prognoses who can avoid the potential toxicity and expense of adjuvant therapy.

V. Screening and prevention.

A. Screening. It is recommended that asymptomatic patients who are 50 years of age and older have a sigmoidoscopic examination (preferably flexible) every 3 to 5 years. An annual digital rectal and fecal occult blood (FOB) test examination is recommended for people 50 years of age and older, but the arguments for this practice are not strongly substantiated. Screening colonoscopy of patients with family history of colorectal cancer in first-degree relatives but no clear evidence of FAP or HNPCC should begin at 40 years of age. The value of testing FOB for screening remains controversial. Better markers for colorectal cancer are being sought because of the high false-positive and false-negative rates associated with FOB.

B. Prevention.

1. Periodic sigmoidoscopy identifies and removes precancerous lesions (polyps) and reduces the incidence of colorectal cancer in patients who undergo colonoscopic polypectomy. The presence of even small recto-sigmoid polyps is associated with polyps beyond the reach of the sigmoidoscope, and their presence should lead to full colonoscopy.

2. Diets that are high in fiber and low in fat or contain calcium supplements or both may deter polyp progression to cancer.

3. Nonsteroidal anti-inflammatory drugs (NSAIDs). In a randomized, double-blind, placebo-controlled study of patients with familial polyposis, the NSAID sulindac at a dose of 150 mg b.i.d. significantly decreased the meaumber and mean diameter of polyps as compared with those in patients given placebo. The size and number of the polyps, however, increased 3 months after the treatment was stopped but remained significantly lower than at baseline. Data further suggest that the use of NSAIDs (aspirin or sulindac) reduces the formation, number, and size of colorectal polyps and reduces the incidence of colorectal cancer, whether familial or nonfamilial. These protective effects require continuous exposure to at least 650 mg of aspirin per day for years.

VI. Management.

A. Surgery is the only universally accepted potentially curative treatment for colorectal cancer. Curative surgery should excise the tumor with wide margins and maximize regional lymphadenectomy while preserving function when possible. For lesions above the rectum, resection of the tumor with a minimum 5-cm margin of grossly negative colon is considered adequate, although the ligation of vascular trunks required to perform an adequate lymphadenectomy may necessitate larger bowel resections. Laparoscopic colectomy approaches have been developed and are being compared with open surgical techniques in a randomized trial. Subtotal colectomy and ileo-proctostomy may be advisable for patients with potentially curable colon cancer and with adenomas scattered in the colon or for patients with a personal history of prior colorectal cancer or a family history of colorectal cancer in first-degree relatives.

1. Arterial supply. Excision of a tumor in the right colon should include the right branch of the middle colic artery as well as the entire ileocolic and right colic artery. Excision of a tumor at the hepatic or splenic flexure should include the entire distribution of the middle colic artery.

2. Avoidance of permanent colostomy in middle and low rectal cancers has been encouraged by the emergence of new surgical stapling techniques.

3. Rectal tumors may be treatable by primary resection and more distal anastomosis, usually without even a temporary (anastomosis protective) colostomy, if the lower edge is above 5 cm from the anal verge. Treatment options for rectal tumors include the following:

a. Middle and upper rectum (6 to 15 cm): anterior resection of rectum

b. Lower rectum (0 to 5 cm): coloanal anastomosis, with or without a pouch, transanal excision, transsphincteric and parasacral approaches, diathermy, primary radiation therapy, or abdomino-perineal (AP) resection

4. Obstructing tumors in the right colon are usually managed by primary resection and primary anastomosis. Obstructing tumors in the left-colon may be managed with initial decompression (proximal colostomy) followed by resection of the tumor and deferred closure of the colostomy. Recent trends, however, favor extending resection and primary anastomosis to include obstructing tumors in the transverse, descending, and even sigmoid colon.

5. Perforated colon cancer requires initial excision of the primary tumor and a proximal colostomy, followed later by reanastomosis and closure of the colostomy.

B. Adjuvant therapy

1. Adjuvant chemotherapy for stage III colon cancer (lymph node involvement) with 5-FU plus levamisole or 5-FU plus leucovorin has reduced the incidence of recurrence by 41% (p < 0.001) in a number of large prospective, randomized trials. One year of therapy with 5-FU plus levamisole improves the 5-year survival rate from 50% to 62% and reduces cancer-related deaths by 33%. More recent trials, however, have shown that 6 months of therapy with 5-FU plus leucovorin is at least as effective and requires half the time to administer. As a consequence, the standard treatment for stage III colon cancer is now 5-FU plus leucovorin.

a. 5-FU and leucovorin are begun simultaneously 3 to 5 weeks after surgery. Two regimens commonly employed in the United States are as follows:

(1) Dosage, Mayo Clinic regimen: leucovorin, 20 mg/m² by 30-minute IV infusion, followed by 5-FU, 425 mg/m² by rapid IV injection, daily for 5 consecutive days for two 4-week cycles and then every 5 weeks thereafter

(2) Dosage, Roswell Park Memorial Institute (RPMI) regimen: leucovorin, 500 mg/m² by 30-minute IV infusion, followed by 5-FU 500 mg/m² by rapid IV injection weekly for (5 of every 8 weeks

(3) The side effects of the Mayo and RPMI regimens are similar. Toxicity of grade III or more is based on the NCI common toxicity criteria. The principal difference in toxicity between the two regimens relates to rates of severe stomatitis and diarrhea. The Mayo regimen is associated with more grade III stomatitis and the RPMI regimen, with a higher rate of grade III diarrhea. Hematologic toxicity seen with both regimens is mainly neutropenia. Grade III or greater neutropenia afflicts about one third of patients at some time during the course of therapy. Nausea and vomiting are generally not severe. Dermatologic side effects are generally limited to erythema and desquamation of sun-damaged skin. Less than 1% of the U.S. population has a deficiency of dihydropyrimidine dehydrogenase (DPD), which is the rate-limiting enzyme in the breakdown of 5-FU. Such patients have severe toxicity and often die after exposure to standard doses because of profound and prolonged neutropenia and mucositis. Cerebellar toxicity occurs relatively commonly in DPD-deficient patients.

b. Other regimens that have been investigated as adjuvant therapy include MOF (methyl-CCNU + vincristine (Oncovin) + 5-FU), 5-FU plus leucovorin + interferon, 5-FU plus levamisole, 5-FU plus leucovorin plus levamisole, portal vein infusion of 5-FU, and infusional 5-FU with levamisole. None of these regimens has been judged superior to the Mayo or RPMI regimens described previously. A regimen using five monthly infusions of a monoclonal antibody to a protein present on the surface of many colorectal cancers led to a survival advantage of similar magnitude to that seen with 5-FU plus leucovorin chemotherapy in the hands of an international group of European investigators.

2. Adjuvant chemotherapy for stage II colon cancer (no lymph node involvement) is controversial. Investigators from the National Surgical Adjuvant Breast Project (NSABP) advocate for adjuvant therapy in this setting because it has produced a small but consistent benefit in patients with stage II disease in serial NSABP trials. Conversely, a meta-analysis of five trials involving about 1000 patients showed a statistically insignificant difference in 5-year survival rates of 82% versus 80% for treated versus untreated patients with stage II disease. Intense efforts have focused on differentiating stage II patients with higher risk for recurrence from those with lower risk through examination of tumor ploidy (number of chromosomes), p53 status, levels of thymidylate synthesis, presence or absence of individual chromosomal mutations, and other parameters. Although none of these is accepted as a standard prognostic determinant, patients with aneuploid tumors had a 5-year survival rate of 54% compared with patients with diploid tumors, who had a 74% 5-year survival in one trial.

3. Adjuvant therapy for rectal cancer. Because of the anatomic confines of the pelvic bones and sacrum, surgeons often cannot achieve wide, tumor-free margins during the resection of rectal cancer. Almost half of recurrences in rectal cancer are in the pelvis.

a. Variations in the use of RT alone or combined with chemotherapy and in surgical technique have been investigated in attempts to improve local control rates. Numerous randomized, controlled studies of both preoperative and postoperative RT alone have demonstrated no improvement in survival; at best, there has been a small decrease in the rate of local recurrence. A number of European surgeons have advocated surgical excision of the rectal mesentery (total mesorectal excision [TME]). The advocates of TME claim a low local recurrence rate but have also noted that rectal stump devascularization results in a higher rate of postoperative anastomotic site leakage.

b. The most effective adjuvant approach, which has become standard practice in the United States, employs combined 5-FU chemotherapy and RT. This approach has significantly reduced the rates of local recurrence, distant metastasis, and cancer-related deaths among patients with stage II and III rectal cancer. The addition to RT of 5-FU (given either by rapid injection or by continuous intra­venous infusion throughout the period of radiation) apparently was crucial to the marked reduction in the local recurrence of rectal cancer. The current standard therapy for stage II and III rectal cancer is 5-FU bolus, 500 mg/m² day for 5 days each month for 2 months both before and after RT. During RT (5040 cGy), 5-FU is given as a radiosensitizer at a dose of 225 mg/m² day by continuous IV infusion. The addition of a nitrosourea, levamisole, or leucovorin to the regimen did not improve the results.

C. Follow-up. About 85% of all recurrences that are destined to occur in colorectal cancer are evident within 3 years after surgical resection. High preoperative CEA levels usually revert to normal within 6 weeks after complete resection.

1. Clinical evaluation. After curative surgical resection, patients with stage II and III colon or rectal cancer are commonly seen more frequently during the first two postoperative years and less frequently thereafter. After 5 years, follow-up is mainly targeted at detection of new primary tumors. The primary goal of follow-up is to detect metastatic disease early. Some patients with colorectal cancer develop a single or a few metastatic sites (known as oligometastases) in the liver, in the lungs, or at the anastomotic site from which the primary bowel cancer was removed that can be resected with curative intent.

2. Chest radiographs appear to be as good as CT scans for detecting recurrence. They are advocated annually or semiannually by those who believe in follow-up testing.

3. Colonoscopy. Patients who presented with obstructing colon lesions that preclude preoperative imaging of the colon should have colonoscopy 3 to 6 weeks after surgery to ensure the absence of a concurrent neoplastic lesion in the remaining colon. The purpose of endoscopy done thereafter is to detect a metachronous tumor, suture line recurrence, or colorectal adenoma. In the absence of obstruction, colonoscopy is performed annually for 1 to 3 years after surgery and, if negative, at 2- to 3-year intervals thereafter.

4. Rising CEA levels call for further studies to identify the site of recurrence and are most often helpful in identifying hepatic recurrences. An elevated CEA calls for further testing using CT of the abdomen, pelvis, and chest as well as other studies as dictated by symptoms. If pelvic recurrence of a rectal cancer is suspected, MRI may be more helpful than CT. The use of hepatic imaging by CT, ultrasound, or MRI at regular intervals is advocated by some oncologists.

D. CEA-based “second-look” laparotomies have not been evaluated in prospective, randomized trials. Retrospective studies of patients undergoing laparotomy for asymptomatic elevations of CEA levels have shown that 60% of cases were judged to be potentially resectable based on preoperative imaging. About 55% of those cases were actually resectable with curative intent, and about 60% of the latter developed recurrence. Only about 10% of patients undergoing laparotomy as a result of preoperative imaging suggesting resectable recurrence remained alive and disease free. This small percentage of success must be viewed against the 10% of patients in whom tumor could not be identified at the CEA-directed second-look operation.

E. Management of isolated recurrence. Early detection and surgical resection of isolated intrahepatic or pulmonary recurrence may be curative or result in improved survival. Those patients most likely to do well have a single lesion in a single site and a disease-free interval of 3 or more years between the primary diagnosis and evidence of metastatic disease. Resection of isolated hepatic metastasis that involves one lobe of the liver may result in a 30% 5-year survival rate. Resection of isolated pulmonary metastasis may result in 5- and 10-year survival rates of 40% and 20%, respectively.

F. Management of advanced colorectal cancer.

1. Chemotherapy. The most commonly used chemotherapeutic agents are 5-FU or floxuridine (FUDR), alone or in combination with leucovorin, and irinotecan (CPT-11).

a. Biochemical modulation of 5-FU with leucovorin. The combination of 5-FU and leucovorin increases the activity as well as the toxicity of 5-FU, results in significant improvement in regression rate, and according to some studies, culminates in improved survival. The partial response rate is about 35%. The dose-limiting toxicities are diarrhea, mucositis, and hematosuppression. Regimens being used with essentially the same response rate involve low-dose or high-dose leucovorin given weekly or for 5 days every 4 to 5 weeks.

b. Continuous intravenous infusion of 5-FU changes the toxicity profile from hematologic to predominantly mucositis and dermatologic (hand-foot syndrome) when compared with bolus administration. Three randomized trials, however, have shown that continuous infusion of 5-FU using an ambulatory infusion pump, as compared with rapid injection, does not result in improved survival. In Europe, it is common practice to administer 5-FU as a 24- to 48-hour short-term infusion. Such regimens have been shown to improve the response rate but have not convincingly extended median survival times as compared with those achieved with bolus therapy.

c. Hepatic arterial infusion takes advantage of the dual nature of hepatic blood supply. Metastases in the liver derive their blood supply predominantly from the hepatic artery, whereas hepatocytes derive blood principally from the hepatic vein. The installation of FUDR into the hepatic artery has been advocated and appears to improve the response rate over 5-FU administered systemically. Problems with this approach include variable anatomy, which makes placement of a single catheter impossible; catheter migration; biliary sclerosis; and gastric ulceration. Progression of extrahepatic disease is a common pattern of failure with this modality. Randomized trials of systemic versus intrahepatic therapy are in progress.

d. Second-line therapy with CPT-11 has been shown to improve survival and quality of life. In patients with recurrent disease refractory to at least one 5-FU regimen, the survival at 1 year of patients treated with supportive care alone or with 5-FU was about 15%, compared with 36% when patients were treated with CPT-11. In the United States, a commonly used regimen for CPT-11 is 125 mg/m² weekly for 4 of every 6 weeks. In Europe, the most common regimen for CPT-11 is 350 mg/m² every 3 weeks.

e. Oxaliplatin is a diaminocyclohexane-containing platinum agent with broad activity in cisplatin-resistant human tumor xenografts. It is in use in Europe and in clinical trials in the United States. It is generally administered in combination with 5-FU and leucovorin.

2. RT may be used as the primary and only treatment modality for small, mobile rectal tumors or in combination with chemotherapy after resection of rectal tumors, RT in palliative doses relieves pain, obstruction, bleeding, and tenesmus in about 80% of cases. In selected cases with locally advanced disease, the use of IORT may provide an advantage. No randomized trials of external-beam versus IORT or IORT plus external-beam therapy have been reported, however.

 

 

Anal Cancer

 

I. Epidemiology and etiology.

A. Incidence. Anal cancers constitute 1% to 2% of large bowel cancers, and 2,500 new cases are diagnosed annually in the United States. Anal canal cancer most commonly develops in patients 50 to 60 years of age and is more frequent in women than in men (women-to-men ratio, 2:1). Cancer of the anal margin is more frequent in men. During the 1990s, however, the incidence of anal canal cancer in men younger than 35 years of age increased, and the gender ratio is reversed in this age group. Anal cancer more frequently afflicts urban than rural populations.

B. Etiology. In most patients with carcinoma of the anus, HPV appears to play a causal role.

1. Infectious agents. HPV, particularly types 16 and 18, is a prime suspect as a causative agent for anal cancer. More than 70% of tumor tissues show HPVDNA by polymerase chain reaction techniques. An HPV-produced protein, E6, inactivates the tumor-suppressor gene p53. The presence of genital warts increases the relative risk by a factor of 30. Although human immunodeficiency virus (HIV) has been suggested as a causative agent, anal tumors are extremely rare in intravenous drug abusers. The relative risk for homosexuals with acquired immunodeficiency syndrome (AIDS) is 84 and for heterosexuals with AIDS is 38. Other associated infections include herpes simplex virus type 2, Chlamydia trachomatis infection in women, and gonorrhea in men.

2. Diseases associated with anal cancer include AIDS, prior irradiation, anal fistulas, fissures, chronic local inflammation, hemorrhoids, Crohn’s disease, lymphogranuloma venereum, condylomata acuminata, carcinoma of cervix, and carcinoma of the vulva. The relative risk for anal cancer development after a diagnosis of AIDS is 63. Sexual activity, particularly with multiple partners, is associated with an increased risk for anal canal cancer.

3. Immune suppression. Kidney transplant recipients have a 100-fold increase in anogenital tumors.

4. Cigarette smoking is associated with an eight-fold increase in the risk for anal cancer.

5. Anal-receptive intercourse in men but not in women is strongly associated with anal cancer at a risk ratio of 33. Studies have shown that the incidence of anal cancer (squamous and transitional cell carcinomas) is six times greater in single men than in married men. Single women are not at an increased risk.

H. Pathology and natural history

A. Anatomy. The anal canal is a tubular structure 3 to 4 cm in length. The junction between the anal canal and perineal skin is known as the anal verge (Hilton’s line). The pectinate (or dentate) line is located at the center of the anal canal. The lining of the anal canal is composed of columnar epithelium in its upper portion and keratinized and nonkeratinized squamous epithelium in its lower portion. Intermediate epithelium (also known as transitional or cloacogenic epithelium, which resembles bladder epithelium) lines a middle zone (0.5 to 1 cm in length) that corresponds to the pectinate line. Anal tumors appear to originate near the mucocutaneous junction and grow either upward into the rectum and surrounding tissue or downward into the perineal tissue.

B. Lymphatics. Some of the upper lymphatics of the anus communicate with those of the rectal ampulla that lead to the sacral, upper mesocolic, and para-aortic lymph nodes. The lower lymphatics communicate with those of the perineum that lead to the superficial inguinal lymph nodes. Of patients undergoing AP resection, 25% to 35% manifest pelvic lymph node metastases.

C. Histology. Squamous cell carcinoma accounts for 63% of cases; transitional cell (cloacogenic) carcinoma, 23%; and mucinous adenocarcinoma, 7% (often with multiple fistulous tracts). Basal cell carcinoma (2%) is curable either by local excision or irradiation. Paget’s disease (2%) is a malignant neoplasm of the intraepidermal portion of the apocrine glands. Malignant melanoma (2%) usually begins at the pectinate line and progresses as single or multiple polypoid masses; the prognosis is poor and depends on tumor size and depth of invasion. Other forms include small cell carcinoma (rare but extremely aggressive), verrucous carcinoma (a polypoid neoplasm closely related to giant condyloma acuminata), Bowen’s disease, embryonal rhabdo-myosarcoma (infants and children), and malignant lymphoma (in patients with AIDS).

III. Diagnosis

A. Symptoms. Bleeding occurs in 50% of patients, pain in 40%, sensation of a mass in 25%, and pruritus in 15%. About 25% of patients do not have symptoms.

B. Physical examination should include digital anorectal examination, anoscopy, proctoscopy, and palpation of inguinal lymph nodes. Anorectal examination may have to be performed under sedation or general anesthesia in patients with severe pain and anal spasm.

C. Biopsy. An incisional biopsy is necessary and preferable to confirm the diagnosis. Excisional biopsy should be avoided. Suspicious inguinal lymph nodes should undergo biopsy to differentiate inflammatory from metastatic disease. Needle aspiration of these nodes may establish the diagnosis; if aspiration is negative, surgical biopsy should be performed.

D. Staging evaluation should include physical examination, chest radiograph, and

LFTs. Pelvic CT

and EUS of the anal canal may be useful. HIV testing is appropriate when warranted by individual patient risk factors.

IV. Staging and prognostic factors.

A. Staging system. The TNM (the 6^th edition, 2002) staging system is determined by size and by invasion into adjacent organs, as follows:

Tis     Carcinoma in situ

Tl      Tumor 2 cm or smaller in greatest dimension

T2     Tumor larger than 2 cm but 5 cm or smaller in greatest dimension

T3     Tumor larger than 5 cm in greatest dimension

T4     Tumor of any size that invades adjacent organ or organs (e.g., vagina, urethra, bladder)

N1     Metastases into perirectal lymph nodes

N2     Ipsilateral metastases into internal iliac and/or inguinal lymph nodes

N3     Metastases into perirectal and inguinal and/or bilateral internal iliac and/or inguinal lymph nodes

M      Distant metastases

B. Prognostic factors.

1. TNM stage. Patients with Tl cancer (lesions smaller than 2 cm in diameter) have a significantly better prognosis than those with larger lesions. Five-year survival rates are more than 80% for patients with Tl and T2 cancers and less than 20% for those with T3 and T4 cancers. The survival is poor even with aggressive therapy for lesions larger than 6 to 10 cm in diameter. In a multivariate analysis, T stage was the only significant independent prognostic factor for anal cancers. Metastases to lymph nodes also results in a poor outcome. Anal canal cancers tend to remain regionally localized, with distant metastases noted in less than 10% of cases.

2. Other factors

a. Histology. The histologic type (i.e., cloacogenic versus epidermoid) has not been found to be prognostically relevant. Keratinizing carcinoma is associated with a better outcome than nonkeratinizing cancers. Patients with mucoepidermoid carcinoma and small cell anaplastic carcinoma have a worse prognosis.

b. Symptoms. Patients without symptoms do better than those with symptoms. Symptoms are usually directly related to the size of the tumor.

c. Tumor grade. Patients with low-grade tumors have a better 5-year survival rate than patients with high-grade tumors (75% versus 25%, respectively). DNA ploidy may or may not have prognostic significance.

V. Prevention and early detection. Early detection depends on the patient’s and physician’s awareness of the disease, the presence of risk factors, and the histologic examination of all surgical specimens, even those removed from minor anorectal surgery. Yearly anoscopy may be indicated in high-risk patients. Anal examination should be performed routinely in patients with cervical and vulvar cancer.

VI. Management. Small tumors of the anal verge or tbe anal canal (less than 2 cm) can be cured in 80% of cases by simple excision with 1-cm margins, and cure by repeat local excision may be possible after local recurrence. Combined chemotherapy and RT are the primary therapeutic modalities for more advanced anal verge or anal canal carcinoma. AP resection is now used as salvage treatment for chemoradiation-resistant disease (i.e., patients who fail to respond or who relapse after a complete response) and for patients who have fecal incontinence at presentation. Considering the rarity of anal canal cancer, randomized trials have led to considerable advances, shifting the standard of therapy from surgery, in which colostomy was routinely necessary as a first approach, to combined-modality chemoradiotherapy, leaving surgery as a last resort.

A. Combined chemoradiation therapy is the primary treatment of choice for anal carcinoma. This combination resulted in higher rates of both local control and survival (82%) and preserved anal function when compared with surgery. The administration of high-dose RT reduced the incidence of persistent carcinoma and eliminated the need for surgical lymphadenectomy. The radiation dose, the number of chemotherapy cycles required to improve the local control rate, and the role (if any) of invasive restaging after completion of therapy remain controversial.

1. Primary therapy. External-beam RT appears to be superior to interstitial implants. RT doses of greater than 5000 cGy do not appear to be necessary. Using mitomycin C plus 5-FU with RT is superior to using 5-FU alone with RT at 4 years of median follow-up with respect to colostomy-free survival (71% versus 59%), locoregional control (82% versus 64%), and disease-free survival (73% versus 51%). The combination of these two drugs when administered concurrently with RT is superior to RT alone. RT regimens vary among institutions; 5-FU is given by continuous intravenous infusion in each case. Two useful regimens are as follows:

a. Radiation Therapy Oncology Group (RTOG):

Mitomycin C: 10 mg/m² IV bolus (day 2)

5-FU: 1000 mg/m²/24 hours by continuous TV infusion (days 2 to 4 and days 28 to 32)

RT: 170 cGy/day between days 1 and 28

Total RT dose: 4500 to 5000 cGy

b. National Tumor Institute (Milan):

Mitomycin C: 15 mg/m² IV bolus (day 1)

5-FU: 750 mg/m²/24 hours by continuous IV infusion (days 1 to 5)

RT: 180 cGy/day for 4 weeks with a 2-week rest

Total RT dose: 5400 cGy (in patients with locally advanced disease, the boost dose is increased but the total dose does not exceed 6000 cGy)

2. Follow-up therapy. Additional 6-week cycles of chemotherapy with mitomycin C and 5-FU are given depending on tumor control or treatment toxicity. Full-thickness biopsy at the original tumor site is performed 6 to 8 weeks after the completion of therapy. Patients are examined at 3-month intervals for the first year and at 6-month intervals thereafter. AP resection is performed for biopsy-proven carcinoma during the follow-up period. Second-line chemotherapy with 5-FU plus cisplatin and AP resection are potentially curative salvage approaches after relapse.

B. Surgery alone. Wide, full-thickness excision is sufficient treatment for discrete, superficial, anal margin tumors and results in an 80% 5-year survival rate unless the tumor is large and deep. AP resection of the anorectum as the exclusive treatment for anal canal tumors and large anal margin tumors results in only a 55% 5-year survival rate.

C. Follow-up of patients with anal cancer every 3 months with digital rectal examination, anoscopy or proctoscopy, and biopsy of suspicious lesions is especially important during the first 3 years after initial treatment because salvage therapy may be curative.

 

 

 

Prepared by Prof.  Igor Y. Galaychuk, MD, DSc

2014