What is the esophagus?

The esophagus is in the chest. It's about 10 inches long. This organ is part of the digestive tract. Food moves from the mouth through the esophagus to the stomach. The esophagus is a muscular tube. The wall of the esophagus has several layers:

Inner layer or lining (mucosa): The lining of the esophagus is moist so that food can pass to the stomach. Submucosa: The glands in this layer make mucus. Mucus keeps the esophagus moist. Muscle layer: The muscles push the food down to the stomach. Outer layer: The outer layer covers the esophagus.

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. When normal 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 does not need them, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. Growths in the wall of the esophagus can be benign (not cancer) or malignant (cancer). The smooth inner wall may have an abnormal rough area, an area of tiny bumps, or a tumor. Benign growths are not as harmful as malignant growths:

Benign growths: o are rarely a threat to life

o o o

can be removed and probably won't grow back don't invade the tissues around them don't spread to other parts of the body

Malignant growths: o may be a threat to life sometimes

o o o

can be removed but can grow back can invade and damage nearby tissues and organs can spread to other parts of the body

Esophageal cancer begins in cells in the inner layer of the esophagus. Over time, the cancer may invade more deeply into the esophagus and nearby tissues. Cancer cells can spread by breaking away from the original tumor. They may enter blood vessels or lymph vessels, which branch into all the tissues of the body. The cancer cells may attach to other tissues and grow to form new tumors that may damage those tissues. The spread of cancer cells is called metastasis. See the Staging section for information about esophageal cancer that has spread.

Types of Esophageal Cancer

There are two main types of esophageal cancer. Both types are diagnosed, treated, and managed in similar ways. The two most common types are named for how the cancer cells look under a microscope. Both types begin in cells in the inner lining of the esophagus:

Adenocarcinoma of the esophagus: This type is usually found in the lower part of the esophagus, near the stomach. In the United States, adenocarcinoma is the most common type of esophageal cancer. It's been increasing since the 1970s. Squamous cell carcinoma of the esophagus: This type is usually found in the upper part of the esophagus. This type is becoming less common among Americans. Around the world, however, squamous cell carcinoma is the most common type.

Risk Factors
When you get a diagnosis of cancer, it's natural to wonder what may have caused the disease. Doctors can seldom explain why one person develops esophageal cancer and another doesn't. However, we do know that people with certain risk factors are more likely than others to develop esophageal cancer. A risk factor is something that may increase the chance of getting a disease. Studies have found the following risk factors for esophageal cancer:

Age 65 or older: Age is the main risk factor for esophageal cancer. The chance of getting this disease goes up as you get older. In the United States, most people are 65 years of age or older when they are diagnosed with esophageal cancer. Being male: In the United States, men are more than three times as likely as women to develop esophageal cancer. Smoking: People who smoke are more likely than people who don't smoke to develop esophageal cancer. Heavy drinking: People who have more than 3 alcoholic drinks each day are more likely than people who don't drink to develop squamous cell carcinoma of the esophagus. Heavy drinkers who smoke are at a much higher risk than heavy drinkers who don't smoke. In other words, these two factors act together to increase the risk even more. Diet: Studies suggest that having a diet that's low in fruits and vegetables may increase the risk of esophageal cancer. However, results from diet studies don't always agree, and more

research is needed to better understand how diet affects the risk of developing esophageal cancer. Obesity: Being obese increases the risk of adenocarcinoma of the esophagus. Acid reflux: Acid reflux is the abnormal backward flow of stomach acid into the esophagus. Reflux is very common. A symptom of reflux is heartburn, but some people don't have symptoms. The stomach acid can damage the tissue of the esophagus. After many years of reflux, this tissue damage may lead to adenocarcinoma of the esophagus in some people. Barrett esophagus: Acid reflux may damage the esophagus and over time cause a condition known as Barrett esophagus. The cells in the lower part of the esophagus are abnormal. Most people who have Barrett esophagus don't know it. The presence of Barrett esophagus increases the risk of adenocarcinoma of the esophagus. It's a greater risk factor than acid reflux alone. Many other possible risk factors (such as smokeless tobacco) have been studied. Researchers continue to study these possible risk factors. Having a risk factor doesn't mean that a person will develop cancer of the esophagus. Most people who have risk factors never develop esophageal cancer.

Symptoms
Early esophageal cancer may not cause symptoms. As the cancer grows, the most common symptoms are:

Food gets stuck in the esophagus, and food may come back up Pain when swallowing Pain in the chest or back Weight loss Heartburn A hoarse voice or cough that doesn't go away within 2 weeks

These symptoms may be caused by esophageal cancer or other health problems. If you have any of these symptoms, you should tell your doctor so that problems can be diagnosed and treated as early as possible.

Diagnosis
If you have a symptom that suggests esophageal cancer, your doctor must find out whether it's really due to cancer or to some other cause. The doctor gives you a physical exam and asks about your personal and family health history. You may have blood tests. You also may have:

Barium swallow: After you drink a barium solution, you have x-rays taken of your esophagus and stomach. The barium solution makes your esophagus show up more clearly on the x-rays. This test is also called an upper GI series.

Endoscopy: The doctor uses a thin, lighted tube (endoscope) to look down your esophagus. The doctor first numbs your throat with an anesthetic spray, and you may also receive medicine to help you relax. The tube is passed through your mouth or nose to the esophagus. The doctor may also call this procedure upper endoscopy, EGD, or esophagoscopy. Biopsy: Usually, cancer begins in the inner layer of the esophagus. The doctor uses an endoscope to remove tissue from the esophagus. A pathologist checks the tissue under a microscope for cancer cells. A biopsy is the only sure way to know if cancer cells are present. You may want to ask the doctor these questions before having a biopsy:

Where will the procedure take place? Will I have to go to the hospital? How long will it take? Will I be awake? Will it hurt? Will I get an anesthetic? What are the risks? What are the chances of infection or bleeding afterward? How do I prepare for the procedure? How long will it take me to recover? How soon will I know the results? Will I get a copy of the pathology report? If I do have cancer, who will talk to me about the next steps? When?

Staging
If the biopsy shows that you have cancer, your doctor needs to learn the extent (stage) of the disease to help you choose the best treatment. Staging is a careful attempt to find out the following

how deeply the cancer invades the walls of the esophagus whether the cancer invades nearby tissues whether the cancer has spread, and if so, to what parts of the body

When esophageal cancer spreads, it's often found in nearby lymph nodes. If cancer has reached these nodes, it may also have spread to other lymph nodes, the bones, or other organs. Also, esophageal cancer may spread to the liver and lungs. Your doctor may order one or more of the following staging tests:

Endoscopic ultrasound: The doctor passes a thin, lighted tube (endoscope) down your throat, which has been numbed with anesthetic. A probe at the end of the tube sends out

sound waves that you can't hear. The waves bounce off tissues in your esophagus and nearby organs. A computer creates a picture from the echoes. The picture can show how deeply the cancer has invaded the wall of the esophagus. The doctor may use a needle to take tissue samples of lymph nodes. CT scan: An x-ray machine linked to a computer takes a series of detailed pictures of your chest and abdomen. Doctors use CT scans to look for esophageal cancer that has spread to lymph nodes and other areas. You may receive contrast material by mouth or by injection into a blood vessel. The contrast material makes abnormal areas easier to see. MRI: A strong magnet linked to a computer is used to make detailed pictures of areas inside your body. An MRI can show whether cancer has spread to lymph nodes or other areas. Sometimes contrast material is given by injection into your blood vessel. The contrast material makes abnormal areas show up more clearly on the picture. PET scan: You receive an injection of a small amount of radioactive sugar. The radioactive sugar gives off signals that the PET scanner picks up. The PET scanner makes a picture of the places in your body where the sugar is being taken up. Cancer cells show up brighter in the picture because they take up sugar faster than normal cells do. A PET scan shows whether esophageal cancer may have spread. Bone scan: You get an injection of a small amount of a radioactive substance. 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. Laparoscopy: After you are given general anesthesia, the surgeon makes small incisions (cuts) in your abdomen. The surgeon inserts a thin, lighted tube (laparoscope) into the abdomen. Lymph nodes or other tissue samples may be removed to check for cancer cells. Sometimes staging is not complete until after surgery to remove the cancer and nearby lymph nodes. 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 esophageal cancer spreads to the liver, the cancer cells in the liver are actually esophageal cancer cells. The disease is metastatic esophageal cancer, not liver cancer. For that reason, it's treated as esophageal cancer, not liver cancer. Doctors call the new tumor "distant" or metastatic disease. These are the stages of esophageal cancer:

Stage 0: Abnormal cells are found only in the inner layer of the esophagus. It's called carcinoma in situ. Stage I: The cancer has grown through the inner layer to the submucosa. (The picture shows the submucosa and other layers.) Stage II is one of the following: o The cancer has grown through the inner layer to the submucosa, and cancer cells have spread to lymph nodes.
o

Or, the cancer has invaded the muscle layer. Cancer cells may be found in lymph nodes.

Or, the cancer has grown through the outer layer of the esophagus.

Stage III is one of the following: o The cancer has grown through the outer layer, and cancer cells have spread to lymph nodes.
o

Or, the cancer has invaded nearby structures, such as the airways. Cancer cells may have spread to lymph nodes.

Stage IV: Cancer cells have spread to distant organs, such as the liver.

Treatment
People with esophageal cancer have several treatment options. The options are surgery, radiation therapy, chemotherapy, or a combination of these treatments. For example, radiation therapy and chemotherapy may be given before or after surgery. The treatment that's right for you depends mainly on the following:

where the cancer is located within the esophagus whether the cancer has invaded nearby structures whether the cancer has spread to lymph nodes or other organs your symptoms your general health

Esophageal cancer is hard to control with current treatments. For that reason, many doctors encourage people with this disease to consider taking part in a clinical trial, a research study of new treatment methods. Clinical trials are an important option for people with all stages of esophageal cancer. See the Taking Part in Cancer Research section. You may have a team of specialists to help plan your treatment. Your doctor may refer you to specialists, or you may ask for a referral. You may want to see a gastroenterologist, a doctor who specializes in treating problems of the digestive organs. Other specialists who treat esophageal cancer include thoracic (chest) surgeons, thoracic surgical oncologists, medical oncologists, and radiation oncologists. Your health care team may also include an oncology nurse and a registered dietitian. If your airways are affected by the cancer, you may have a respiratory therapist as part of your team. If you have trouble swallowing, you may see a speech pathologist. Your health care team can describe your treatment choices, the expected results of each, and the possible side effects. Because cancer therapy often damages healthy cells and tissues, side effects are common. Before treatment starts, ask your health care team about possible side effects and how treatment may change your normal activities. You and your health care team can work together to develop a treatment plan that meets your needs.

You may want to ask your doctor these questions before your treatment begins:

What is the stage of the disease? Has the cancer spread? Do any lymph nodes show signs of cancer? What is the goal of treatment? What are my treatment choices? Which do you recommend for me? Why? Will I have more than one kind of treatment? What can I do to prepare for treatment? Will I need to stay in the hospital? If so, for how long? What are the risks and possible side effects of each treatment? For example, am I likely to have eating problems during or after treatment? How can side effects be managed? What will the treatment cost? Will my insurance cover it? Would a research study (clinical trial) be appropriate for me? Can you recommend other doctors who could give me a second opinion about my treatment options? How often should I have checkups?

Surgery
There are several types of surgery for esophageal cancer. The type depends mainly on where the cancer is located. The surgeon may remove the whole esophagus or only the part that has the cancer. Usually, the surgeon removes the section of the esophagus with the cancer, lymph nodes, and nearby soft tissues. Part or all of the stomach may also be removed. You and your surgeon can talk about the types of surgery and which may be right for you. The surgeon makes incisions into your chest and abdomen to remove the cancer. In most cases, the surgeon pulls up the stomach and joins it to the remaining part of the esophagus. Or a piece of intestine may be used to connect the stomach to the remaining part of the esophagus. The surgeon may use either a piece of small intestine or large intestine. If the stomach was removed, a piece of intestine is used to join the remaining part of the esophagus to the small intestine. During surgery, the surgeon may place a feeding tube into your small intestine. This tube helps you get enough nutrition while you heal. Information about eating after surgery is in the Nutrition section. You may have pain for the first few days after surgery. However, medicine will help control the pain. Before surgery, you should discuss the plan for pain relief with your health care team. After surgery, your team can adjust the plan if you need more relief.

Your health care team will watch for signs of food leaking from the newly joined parts of your digestive tract. They will also watch forpneumonia or other infections, breathing problems, bleeding, or other problems that may require treatment. The time it takes to heal after surgery is different for everyone and depends on the type of surgery. You may be in the hospital for at least one week. You may want to ask your doctor these questions about surgery:

Do you suggest surgery for me? If so, which type? Will you remove lymph nodes and other tissue? Will you remove part or all of the stomach? Why? What are the risks of surgery? How will I feel after surgery? How will pain be controlled after surgery? How long will I be in the hospital? Am I likely to have eating problems? Will I need a special diet? Will I need a feeding tube? If so, for how long? How do I take care of it? Who can help me if I have a problem? Will I have any lasting side effects?

Radiation Therapy
Radiation therapy (also called radiotherapy) uses high-energy rays to kill cancer cells. It affects cells only in the treated area. Radiation therapy may be used before or after surgery. Or it may be used instead of surgery. Radiation therapy is usually given with chemotherapy to treat esophageal cancer. Doctors use two types of radiation therapy to treat esophageal cancer. Some people receive both types:

External radiation therapy: The radiation comes from a large machine outside the body. The machine aims radiation at your cancer. You may go to a hospital or clinic for treatment. Treatments are usually 5 days a week for several weeks. Internal radiation therapy (brachytherapy): The doctor numbs your throat with an anesthetic spray and gives you medicine to help you relax. The doctor puts a tube into your esophagus.

The radiation comes from the tube. Once the tube is removed, no radioactivity is left in your body. Usually, only a single treatment is done. Side effects depend mainly on the dose and type of radiation. External radiation therapy to the chest and abdomen may cause asore throat, pain similar to heartburn, or pain in the stomach or the intestine. You may have nausea and diarrhea. Your health care team can give you medicines to prevent or control these problems. Also, your skin in the treated area may become red, dry, and tender. You may lose hair in the treated area. A much less common side effect of radiation therapy aimed at the chest is harm to the lung, heart, or spinal cord. You are likely to be very tired during radiation therapy, especially in the later weeks of external radiation therapy. You may also continue to feel very tired for a few weeks after radiation therapy is completed. Resting is important, but doctors usually advise patients to try to stay as active as they can. Radiation therapy can lead to problems with swallowing. For example, sometimes radiation therapy can harm the esophagus and make it painful for you to swallow. Or, the radiation may cause the esophagus to narrow. Before radiation therapy, a plastic tube may be inserted into the esophagus to keep it open. If radiation therapy leads to a problem with swallowing, it may be hard to eat well. Ask your health care team for help getting good nutrition. See the Nutrition section for more information. You may want to ask your doctor these questions before having radiation therapy:

Which type of radiation therapy can I consider? Are both types an option for me? When will treatment start? When will it end? How often will I have treatments? Will I need to stay in the hospital? What can I do to take care of myself before, during, and after treatment? How will I feel during treatment? Will I be able to drive myself to and from treatment? How will we know the treatment is working? How will I feel after the radiation therapy? Are there any lasting effects?

Chemotherapy
Most people with esophageal cancer get chemotherapy. Chemotherapy uses drugs to destroy cancer cells. The drugs for esophageal cancer are usually given through a vein (intravenous).

You may have your treatment in a clinic, at the doctor's office, or at home. Some people need to stay in the hospital for treatment. Chemotherapy is usually given in cycles. Each cycle has a treatment period followed by a rest period. The side effects depend mainly on which drugs are given and how much. Chemotherapy kills fast-growing cancer cells, but the drug can also harm normal cells that divide rapidly: Blood cells: When chemotherapy lowers the levels of healthy blood cells, you'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. If your levels are low, your health care team may stop the chemotherapy for a while or reduce the dose of drug. There also are medicines that can help your body make new blood cells. Cells in hair roots: Chemotherapy may cause hair loss. If you lose your hair, it will grow back, but it may change in color and texture. Cells that line the digestive tract: Chemotherapy can cause poor appetite, nausea and vomiting,diarrhea, or mouth and lip sores. Your health care team can give you medicines and suggest other ways to help with these problems. Other possible side effects include a skinrash, joint pain, tingling or numbness in your hands and feet, hearing problems, or swollen feet or legs. Your healthcare team can suggest ways to control many of these problems. Most go away when treatment ends. You may want to ask your doctor these questions before having chemotherapy:

Which drugs will I get? When will treatment start? When will it end? How often will I have treatments? Where will I go for treatment? Will I have to stay in the hospital? What can I do to take care of myself during treatment? How will we know the treatment is working? Will I have side effects during treatment? What side effects should I tell you about? Can I prevent or treat any of these side effects? Can these drugs cause side effects later on?

Second Opinion
Before starting treatment, you might want a second opinion about your diagnosis and treatment plan. You may want to find a medical center that has a lot of experience with treating esophageal cancer. You may even want to talk to several different doctors about all of the treatment options, their side effects, and the expected results.

Some people worry that the doctor will be offended if they ask for a second opinion. Usually the opposite is true. Most doctors welcome a second opinion. And many health insurance companies will pay for a second opinion if you or your doctor requests it. If you get a second opinion, the second doctor may agree with your first doctor's diagnosis and treatment plan. Or the second doctor may suggest another approach. Either way, you have more information and perhaps a greater sense of control. You can feel more confident about the decisions you make, knowing that you've looked at your options. It may take some time and effort to gather your medical records and see another doctor. In most cases, it's not a problem to take several weeks to get a second opinion. The delay in starting treatment usually will not make treatment less effective. To make sure, you should discuss this delay with your doctor. There are many ways to find a doctor for a second opinion. You can ask your doctor, a local or state medical society, a nearby hospital, or a medical school for names of specialists.

Supportive Care
Esophageal cancer and its treatment can lead to other health problems. You can have supportive care before, during, or after cancer treatment. Supportive care is treatment to control pain and other symptoms, to relieve the side effects of therapy, and to help you cope with the feelings that a diagnosis of cancer can bring. You may receive supportive care to prevent or control these problems and to improve your comfort and quality of life during treatment. Cancer Blocks the Esophagus You may have trouble swallowing because the cancer blocks the esophagus. Not being able to swallow makes it hard or impossible to eat. It also increases the risk of food getting in your airways. This can lead to a lung infection like pneumonia. Also, not being able to swallow liquids or saliva can be very distressing. Your health care team may suggest one or more of the following options:

Stent: You get an injection of a medicine to help you relax. The doctor places a stent (a tube made of metal mesh or plastic) in your esophagus. Food and liquid can pass through the center of the tube. However, solid foods need to be chewed well before swallowing. A large swallow of food could get stuck in the stent. Laser therapy: A laser is a concentrated beam of intense light that kills tissue with heat. The doctor uses the laser to destroy the cancer cells blocking the esophagus. Laser therapy may make swallowing easier for a while, but you may need to repeat the treatment several weeks later. Photodynamic therapy: You get an injection, and the drug collects in the esophageal cancer cells. Two days after the injection, the doctor uses an endoscope to shine a special

light (such as a laser) on the cancer. The drug becomes active when exposed to light. Two or three days later, the doctor may check to see if the cancer cells have been killed. People getting this drug must avoid sunlight for one month or longer. Also, you may need to repeat the treatment several weeks later. Radiation therapy: Radiation therapy helps shrink the tumor. If the tumor blocks the esophagus, internal radiation therapy or sometimes external radiation therapy can be used to help make swallowing easier. Balloon dilation: The doctor inserts a tube through the blocked part of the esophagus. A balloon helps widen the opening. This method helps improve swallowing for a few days. Other ways to get nutrition: See the Nutrition section for ways to get food when eating becomes difficult.

Pain Cancer and its treatments may cause pain. It may be painful to swallow, or you may have pain in your chest from the cancer or from a stent. Your health care team or a pain control specialist can suggest ways to relieve or reduce pain. Sadness and Other Feelings It's normal to feel sad, anxious, or confused after a diagnosis of a serious illness. Some people find it helpful to talk about their feelings. See the Sources of Support section. Nutrition It's important to meet your nutrition needs before, during, and after cancer treatment. You need the right amount of calories, protein, vitamins, and minerals. Getting the right nutrition can help you feel better and have more energy. However, when you have esophageal cancer, it may be hard to eat for many reasons. You may be uncomfortable or tired, and you may not feel like eating. Also, the cancer may make it hard to swallow food. If you're getting chemotherapy, you may find that foods don't taste as good as they used to. You also may have side effects of treatment such as poor appetite, nausea,vomiting, or diarrhea. If you develop problems with eating, there are a number of ways to meet your nutrition needs. A registered dietitian can help you figure out a way to get enough calories, protein, vitamins, and minerals:

A dietitian may suggest a change in the types of foods you eat. Sometimes changing the texture, fiber, and fat content of your foods can lessen your discomfort. A dietitian may also suggest a change in the portion size and meal times. A dietitian may recommend liquid meals, such as canned nutrition beverages, milk shakes, or smoothies. If swallowing becomes too difficult, your dietitian and your doctor may recommend that you receive nutrition through a feeding tube. Sometimes, nutrition is provided directly into the bloodstream with intravenous nutrition.

Nutrition After Surgery A registered dietitian can help you plan a diet that will meet your nutrition needs. A plan that describes the type and amount of food to eat after surgery can help you prevent weight loss and discomfort with eating. If your stomach is removed during surgery, you may develop a problem afterward known as the dumping syndrome. This problem occurs when food or liquid enters the small intestine too fast. It can cause cramps, nausea,bloating, diarrhea, and dizziness. There are steps you can take to help control dumping syndrome:

Eat smaller meals. Drink liquids before or after eating solid meals. Limit very sweet foods and drinks, such as cookies, candy, soda, and juices.

Also, your health care team may suggest medicine to control the symptoms. After surgery, you may need to take daily supplements of vitamins and minerals, such as calcium, and you may need injections of vitamin B12. You may want to ask a registered dietitian these questions about nutrition:

How do I keep from losing too much weight? How do I know whether I'm getting enough calories and protein? What are some sample meals that would meet my needs? How can I include my favorite foods without causing or worsening digestive problems? Are there foods or drinks that I should avoid? What vitamins and minerals might I need to take?

Follow-Up Care
You'll need checkups after treatment for esophageal cancer. Checkups help ensure that any changes in your health are noted and treated if needed. If you have any health problems between checkups, you should contact your doctor. Checkups may include a physical exam, blood tests, chest x-ray, CT scans, endoscopy, or other tests. You may want to ask your doctor these questions after you have finished treatment:

How often will I need checkups? Which follow-up tests do you suggest for me? Between checkups, what health problems or symptoms should I tell you about?

Sources of Support
Learning you have esophageal cancer can change your life and the lives of those close to you. These changes can be hard to handle. It's normal for you, your family, and your friends to need help coping with the feelings that a diagnosis of cancer can bring. Concerns about treatments and managing side effects, hospital stays, and medical bills are common. You may also worry about caring for your family, keeping your job, or continuing daily activities. Here's where you can go for support:

Doctors, nurses, and other members of your health care team can answer questions about treatment, working, or other activities. Social workers, counselors, or members of the clergy can be helpful if you want to talk about your feelings or concerns. Often, social workers can suggest resources for financial aid, transportation, home care, or emotional support. Support groups also can help. In these groups, patients or their family members meet with other patients or their families to share what they have learned about coping with the disease and the effects of treatment. Groups may offer support in person, over the telephone, or on the Internet. You may want to talk with a member of your health care team about finding a support group. Information specialists at 1-800-4-CANCER and at LiveHelp (http://www.cancer.gov/help) can help you locate programs, services, and publications. They can send you a list of organizations that offer services to people with cancer.

Taking Part in Cancer Research

Doctors all over the country are conducting many types of clinical trials (research studies in which people volunteer to take part). Clinical trials are designed to answer important questions and to find out whether new approaches are safe and effective. Research already has led to advances that have helped people live longer, and research continues. Doctors are trying to find better ways to care for people with esophageal cancer:

Surgery: Surgeons are studying whether small cuts can be used instead of long incisions. The surgeon makes small cuts in the neck, chest, and abdomen. The surgeon sees inside the chest with a laparoscope, and the cancer-containing esophagus is removed.

Chemotherapy and biological therapy: NCI is sponsoring a study of biological therapy (a monoclonal antibody) combined with chemotherapy. Supportive care: Doctors are also testing ways to manage the problems caused by cancer and its treatment. Even if the people in a trial do not benefit directly, they may still make an important contribution by helping doctors learn more about cancer and how to control it. Although clinical trials may pose some risks, doctors do all they can to protect their patients. If you're interested in being part of a clinical trial, talk with your doctor.

National Cancer Institute Information Resources

You may want more information for yourself, your family, and your doctor. The following NCI services are available to help you. Telephone NCI's Cancer Information Service (CIS) provides accurate, up-to-date information about cancer to patients and their families, health professionals, and the general public. Information specialists translate the latest scientific information into plain language, and they will respond in English or Spanish, as well as through TRS providers for the hearing or speech impaired. Calls to the CIS are confidential and free.
Telephone: 1-800-4-CANCER ( 1-800-422-6237 )

Internet NCI's Web site provides information from numerous NCI sources. It offers current information about cancer prevention, screening, diagnosis, treatment, genetics, supportive care, and ongoing clinical trials. It has information about NCI's research programs, funding opportunities, and cancer statistics.
Web site: http://www.cancer.govSpanish Web site: http://www.cancer.gov/espanol

If you're unable to find what you need on the Web site, contact NCI staff. Use the online contact form at http://www.cancer.gov/contact or send an email to cancergovstaff@mail.nih.gov. Also, information specialists provide live, online assistance through LiveHelp at http://www.cancer.gov/help.

Esophagus Cancer At A Glance

While the exact cause(s) of cancer of the esophagus is not known, risk factors have been identified. The risk of cancer of the esophagus is increased by long-term irritation of the esophagus, such as with smoking, heavy alcohol intake, and Barrett's esophagitis.

Diagnosis of cancer of the esophagus can be made by barium X-ray of the esophagus and confirmed by endoscopy with biopsy of the cancer tissue. Cancer of the esophagus can cause difficulty and pain with swallowing solid food. Treatment of cancer of the esophagus depends on the size, location, and the extent of cancer spread, as well as the age and health of the patient.

SOURCE: U.S. National Institutes of Health, National Cancer Institute

Last Editorial Review: 11/21/2008

Magnetic Resonance Imaging (MRI Scan)

Medical Reviewer: William C. Shiel Jr., MD, FACP, FACR

What is an MRI scan? When are MRI scans used? What are the risks of an MRI scan? How does a patient prepare for an MRI scan and how is it performed? How does a patient obtain the results of the MRI scan? Pictures of an MRI of the spine MRI Scan At A Glance Patient Discussions: Magnetic Resonance Imaging (MRI Scan) - Helped With Your Diagnosis Find a local Doctor in your town

Tiger Woods: Stress Fracture and Torn ACL

Medical Author: Benjamin Wedro, MD, FAAEM Medical Editor: Melissa Conrad Stppler, MD June 2008 - In the last few months, Tiger Woods has won nine out of the 12 golf tournaments he has entered. So who cares? Whenever he tees it up, it's Tiger against the field, and Tiger always wins. But Tiger has met his match. While his mind was willing, his body has suffered a breakdown. The medical story goes like this. In the midst of his latest winning streak, Tiger ruined his left knee, tearing the anterior cruciate ligament (ACL) and damaging the cartilage. Most people can't easily walk with this injury; Tiger played on. In mid-April he underwent arthroscopyto trim the damaged cartilage and began golf practice almost immediately. Without his surgeon's blessing, he played and won the USGA Open 2008. Only afterwards was it revealed that he had sustained a stress fracture in his tibia. The pain on his face could now be understood. It is time to pay the piper. Tiger is done for the year, with knee reconstruction surgery and months of rehab in his future.

Read more about Tiger Woods injury and recovery prognosis

What is an MRI scan?

An MRI (or magnetic resonance imaging) scan is a radiology technique that uses magnetism, radio waves, and a computer to produce images of body structures. The MRI scanner is a tube surrounded by a giant circular magnet. The patient is placed on a moveable bed that is inserted into the magnet. The magnet creates a strong magnetic field that aligns the protons of hydrogen atoms, which are then exposed to a beam of radio waves. This spins the various protons of the body, and they produce a faint signal that is detected by the receiver portion of the MRI scanner. The receiver information is processed by a computer, and an image is produced. The image and resolution produced by MRI is quite detailed and can detect tiny changes of structures within the body. For some procedures, contrast agents, such as gadolinium, are used to increase the accuracy of the images.

When are MRI scans used?

An MRI scan can be used as an extremely accurate method of disease detection throughout the body. In the head, trauma to the brain can be seen as bleeding or swelling. Other abnormalities often found include brain aneurysms, stroke, tumors of the brain, as well as tumors or inflammation of the spine. Neurosurgeons use an MRI scan not only in defining brain anatomy but in evaluating the integrity of the spinal cord after trauma. It is also used when considering problems associated with the vertebrae or intervertebral discsof the spine. An MRI scan can evaluate the structure of the heart and aorta, where it can detect aneurysms or tears. It provides valuable information on glands and organs within the abdomen, and accurate information about the structure of the joints, soft tissues, and bones of the body. Often, surgery can What

are the risks of an MRI scan?

An MRI scan is a painless radiology technique that has the advantage of avoiding x-ray radiation exposure. There are no known side effects of an MRI scan. The benefits of an MRI scan relate to its precise accuracy in detecting structural abnormalities of the body. Patients who have any metallic materials within the body must notify their physician prior to the examination or inform the MRI staff. Metallic chips, materials, surgical clips, or foreign material (artificial joints, metallic bone plates, or prosthetic devices, etc.) can significantly distort the images obtained by the MRI scanner. Patients who have heart pacemakers, metal implants, or metal chips or clips in or around the eyeballs cannot be scanned with an MRI because of the risk that the magnet may move the metal in these areas. Similarly, patients with artificial heart valves, metallic ear implants, bullet fragments, and chemotherapy or insulin pumps should not have MRI scanning.

During the MRI scan, patient lies in a closed area inside the magnetic tube. Some patients can experience a claustrophobic sensation during the procedure. Therefore, patients with any history of claustrophobia should relate this to the practitioner who is requesting the test, as well as the radiology staff. A mild sedative can be given prior to the MRI scan to help alleviate this feeling. It is customary that the MRI staff will be nearby during MRI scan. Furthermore, there is usually a means of communication with the staff (such as a buzzer held by the patient) which can be used for contact if the patient cannot tolerate the scan. be deferred or more accurately directed after knowing the results of an MRI scan.
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MRI Scan (cont.)

Medical Reviewer: William C. Shiel Jr., MD, FACP, FACR

IN THIS ARTICLE What is an MRI scan? When are MRI scans used? What are the risks of an MRI scan? How does a patient prepare for an MRI scan and how is it performed? How does a patient obtain the results of the MRI scan? Pictures of an MRI of the spine MRI Scan At A Glance Patient Discussions: Magnetic Resonance Imaging (MRI Scan) - Helped With Your Diagnosis MRI Scan Index Find a local Doctor in your town

How does a patient prepare for an MRI scan and how is it performed?
All metallic objects on the body are removed prior to obtaining an MRI scan. Occasionally, patients will be given a sedative medication to decrease anxietyand relax the patient during the MRI scan. MRI scanning requires that the patient lie still for best accuracy. Patients lie within a closed environment inside the magnetic machine. Relaxation is important during the procedure and patients are asked to breathe normally. Interaction with the MRI technologist is maintained throughout the test. There are loud, repetitive clicking noises which occur during the test as the scanning proceeds. Occasionally, patients require injections of liquid intravenously to enhance

the images which are obtained. The MRI scanning time depends on the exact area of the body studied, but ranges from half an hour to an hour and a half.

How does a patient obtain the results of the MRI scan?

After the MRI scanning is completed, the computer generates visual images of the area of the body that was scanned. These images can be transferred to film (hard copy). A radiologist is a physician who is specially trained to interpret images of the body. The interpretation is transmitted in the form of a report to the practitioner who requested the MRI scan. The practitioner can then discuss the results with the patient and/or family. Future Scientists are developing newer MRI scanners that are smaller, portable devices. These new scanners apparently can be most useful in detecting infections and tumors of the soft tissues of the hands, feet, elbows, and knees. The application of these scanners to medical practice is now being tested.

Pictures of an MRI of the spine

This patient had a herniated disc between vertebrae L4 and L5. The resulting surgery was a discectomy

Picture of herniated disc between L4 and L5

Cross-section picture of herniated disc between L4 and L5

MRI Scan At A Glance

MRI scanning uses magnetism, radio waves, and a computer to produce images of body structures. MRI scanning is painless and does not involve x-ray radiation. Patients with heart pacemakers, metal implants, or metal chips or clips in or around the eyes cannot be scanned with MRI because of the effect of the magnet. Claustrophobic sensation can occur with MRI scanning.

Last Editorial Review: 4/5/2007

CT Scan (Computerized Tomography, CAT Scan)

Medical Author: Melissa Conrad Stppler, MD Medical Editor: Charles Patrick Davis, MD, PhD

CT scan facts What is a CT scan? Why are CT scans performed? Are there risks in obtaining a CT scan? How does a patient prepare for CT scanning, and how is it performed? Patient Discussions: CT Scan (Computerized Axial Tomography) - Causes Patient Discussions: Ct Scan - Helped With Your Diagnosis Find a local Doctor in your town

CT scan facts

CT scanning adds X-ray images with the aid of a computer to generate cross-sectional views of anatomy. CT scanning can identify normal and abnormal structures and be used to guide procedures. CT scanning is painless. Iodine-containing contrast material is sometimes used in CT scanning. Patients with a history of allergy to iodine or contrast materials should notify their physicians and radiology staff.

What is a CT scan?
Computerized (or computed) tomography, and often formerly referred to as computerized axial tomography (CAT) scan, is an X-ray procedure that combines many X-ray images with the aid of a computer to generate cross-sectional views and, if needed, three-dimensional images of the internal organs and structures of the body. Computerized tomography is more commonly known by its abbreviated names, CT scan or CAT scan. A CT scan is used to define normal and abnormal structures in the body and/or assist in procedures by helping to accurately guide the placement of instruments or treatments. A large donut-shaped X-ray machine or scanner takes X-ray images at many different angles around the body. These images are processed by a computer to produce cross-sectional pictures of the body. In each of these pictures the body is seen as an X-ray "slice" of the body, which is recorded on a film. This recorded image is called a tomogram. "Computerized axial tomography" refers to the recorded tomogram "sections" at different levels of the body. Imagine the body as a loaf of bread and you are looking at one end of the loaf. As you remove each slice of bread, you can see the entire surface of that slice from the crust to the center. The body is seen on CT scan slices in a similar fashion from the skin to the central part of the body being examined. When these levels are further "added" together, a three-dimensional picture of an organ or abnormal body structure can be obtained.
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CAT Scan (cont.)

Medical Author: Melissa Conrad Stppler, MD Medical Editor: Charles Patrick Davis, MD, PhD

IN THIS ARTICLE CT scan facts What is a CT scan? Why are CT scans performed? Are there risks in obtaining a CT scan? How does a patient prepare for CT scanning, and how is it performed? Patient Discussions: CT Scan (Computerized Axial Tomography) - Causes Patient Discussions: Ct Scan - Helped With Your Diagnosis CAT Scan Index Find a local Doctor in your town

Why are CT scans performed?

CT scans are performed to analyze the internal structures of various parts of the body. This includes the head, where traumatic injuries, (such as blood clots or skull fractures), tumors, and infections can be identified. In the spine, the bony structure of the vertebrae can be accurately defined, as can the anatomy of the intervertebral discs and spinal cord. In fact, CT scan methods can be used to accurately measure the density of bone in evaluatingosteoporosis. Occasionally, contrast material (an X-ray dye) is placed into the spinal fluid to further enhance the scan and the various structural relationships of the spine, the spinal cord, and its nerves. Contrast material is also often administered intravenously or through other routes prior to obtaining a CT scan (see below). CT scans are also used in the chest to identify tumors, cysts, or infections that may be suspected on a chest X-ray. CT scans of the abdomen are extremely helpful in defining body organ anatomy, including visualizing the liver, gallbladder, pancreas, spleen, aorta, kidneys, uterus, and ovaries. CT scans in this area are used to verify the presence or absence of tumors, infection, abnormal anatomy, or changes of the body caused by trauma. The technique is painless and can provide extremely accurate images of body structures in addition to guiding the radiologist in performing certain procedures, such as biopsies of suspected cancers, removal of internal body fluids for various tests, and the draining of abscesses which are

deep in the body. Many of these procedures are minimally invasive and have markedly decreased the need to perform surgery to accomplish the same goal.

Are there risks in obtaining a CT scan?

A CT scan is a very low-risk procedure. The most common problem is an adverse reaction to intravenous contrast material. Intravenous contrast is usually an iodine-based liquid given in the vein, which makes many organs and structures, such as the kidneys and blood vessels, much more visible on the CT scan. There may be resulting itching, a rash, hives, or a feeling of warmth throughout the body. These are usually self-limiting reactions that go away rather quickly. If needed, antihistamines can be given to help relieve the symptoms. A more serious allergic reaction to intravenous contrast is called an anaphylactic reaction. When this occurs, the patient may experience severe hives and/or extreme difficulty in breathing. This reaction is quite rare, but is potentially life-threatening if not treated. Medications which may include corticosteroids, antihistamines, and epinephrine can reverse this adverse reaction. Toxicity to the kidneys which can result in kidney failure is an extremely rare complication of the intravenous contrast material used in CT scans. People with diabetes, dehydrated individuals, or patients who already have impaired kidney function are most prone to this reaction. Newer intravenous contrast agents have been developed, such as Isovue, which have nearly eliminated this complication. The amount of radiation a person receives during a CT scan is minimal. In men and nonpregnant women, it has not been shown to produce any adverse effects. If a woman is pregnant, there may be a potential risk to the fetus, especially in the first trimester of the pregnancy. If a woman is pregnant, she should inform her doctor of her condition and discuss other potential methods of imaging, such as an ultrasound, which are not harmful to the fetus. However, most physicians suggest that all radiation exposure to patients should be kept to a minimum; those patients that doctor shop or repeatedly go to emergency departments for a "CT put themselves at risk for radiation-caused problems.

How does a patient prepare for CT scanning, and how is it performed?

In preparation for a CT scan, patients are often asked to avoid food, especially when contrast material is to be used. Contrast material may be injected intravenously, or administered by mouth or by an enema in order to increase the distinction between various organs or areas of the body. Therefore, fluids and food may be restricted for several hours prior to the examination. If the patient has a history of allergy to contrast material (such as iodine), the requesting physician and radiology staff should be notified. All metallic materials and certain clothing around the body are removed because they can interfere with the clarity of the images. Patients are placed on a movable table, and the table is slipped into the center of a large donutshaped machine which takes the X-ray images around the body. The actual procedure can take from half an hour to an hour and a half. If specific tests, biopsies, or interventions are performed by the radiologist during CT scanning, additional time and monitoring may be required. It is important during the CT scan procedure that the patient minimizes any body movement by

remaining as still and quiet as is possible. This significantly increases the clarity of the X-ray images. The CT scan technologist tells the patient when to breathe or hold his/her breath during scans of the chest and abdomen. If any problems are experienced during the CT scan, the technologist should be informed immediately. The technologist directly watches the patient through an observation window during the procedure, and there is an intercom system in the room for added patient safety. CT scans have vastly improved the ability of doctors to diagnose many diseases earlier in their course and with much less risk than previous methods. Further refinements in CT scan technology continue to evolve which promise even better picture quality and patient safety. CT scans known as "spiral" or "helical" CT scans can provide more rapid and accurate visualization of internal organs. For example, many trauma centers are using these scans to more rapidly diagnose internal injuries after serious body trauma. High resolution CT scans (HRCT) are used to accurately assess the lungs for inflammation and scarring. CT angiography is a newer technique that allows noninvasive imaging of the coronary arteries. Note that some CT scanners may not be able to accommodate patients that weigh over 400 pounds. REFERENCES: Braunwald, Eugene, et al. Harrisons's Principles of Internal Medicine. 15th ed. McGraw-Hill, 2001. Tramma, Simone, et al. "Helical CT Scans and Lung Cancer Screening." CDC NIOSH Science Blog. 10 Jan. 2011. <http://blogs.cdc.gov/niosh-science-blog/2011/01/helical/>. Previous editor: William C. Shiel Jr., MD, FACP, FACR

Last Editorial Review: 4/27/2012

Ultrasound
Medical Author: Benjamin Wedro, MD, FACEP, FAAEM Medical Editor: William C. Shiel Jr., MD, FACP, FACR

Introduction What is an ultrasound? What is ultrasonography? For what purposes are ultrasounds used? Diagnostic uses Screening uses Therapeutic uses What are the risks of ultrasound? How do patients prepare for an ultrasound? How are the results of ultrasound interpreted and communicated to the physician?

Related ultrasound article: Ultrasound - on eMedicineHealth Patient Discussions: Ultrasound - Diagnosis Find a local Doctor in your town

Introduction
While the patient's history and physical examination are the building blocks of making a medical diagnosis, the ability to peer inside the body can be a powerful tool. Ultrasound is an imaging technique that provides that ability to medical practitioners.

What is an ultrasound?
Ultrasound produces sound waves that are beamed into the body causing return echoes that are recorded to "visualize" structures beneath the skin. The ability to measure different echoes reflected from a variety of tissues allows a shadow picture to be constructed. The technology is especially accurate at seeing the interface between solid and fluid filled spaces. These are actually the same principles that allow SONAR on boats to see the bottom of the ocean.

Ultrasound (cont.)
Medical Author: Benjamin Wedro, MD, FACEP, FAAEM Medical Editor: William C. Shiel Jr., MD, FACP, FACR

IN THIS ARTICLE Introduction What is an ultrasound? What is ultrasonography? For what purposes are ultrasounds used? Diagnostic uses Screening uses Therapeutic uses What are the risks of ultrasound? How do patients prepare for an ultrasound? How are the results of ultrasound interpreted and communicated to the physician? Patient Discussions: Ultrasound - Diagnosis Ultrasound Index Find a local Doctor in your town

What is ultrasonography?
Ultrasonography is body imaging using ultrasound in medical diagnosis. A skilled ultrasound technician is able to see inside the body using ultrasonography to answer questions that may be asked by the medical practitioner caring for the patient. Usually, aradiologist will oversee the ultrasound test and report on the results, but other types of physicians may use ultrasound as a diagnostic tool. For example, obstetricians use ultrasound to assess the fetus duringpregnancy. Surgeons and emergency physicians use ultrasound at the bedside to assess abdominal pain or other concerns.

A transducer, or probe, is used to project and receive the sound waves and the return signals. A gel is wiped onto the patient's skin so that the sound waves are not distorted as they cross through the skin. Using their understanding of human anatomy and the machine, the technician can evaluate specific structures and try to answer the question asked by the patient's physician. This may take a fair amount of time and require the probe to be repositioned and pointed in different directions. As well, the technician may need to vary the amount of pressure used to push the probe into the skin. The goal will be to "paint" a shadow picture of the inner organ that the health care practitioner has asked to be visualized. The physics of sound can place limits on the test. The quality of the picture depends on many factors.

Sound waves cannot penetrate deeply, and an obese patient may be imaged poorly. Ultrasound does poorly when gas is present between the probe and the target organ. Should the intestine be distended with bowel gas, organs behind it may not be easily seen. Similarly, ultrasound works poorly in the chest, where the lungs are filled with air. Ultrasound does not penetrate bone easily. The accuracy of the test is very much operator dependent. This means that the key to a good test is the ultrasound technician.

Ultrasound can be enhanced by using Doppler technology which can measure whether an object is moving towards or away from the probe. This can allow the technician to measure blood flow in organs such as the heartor liver, or within specific blood vessels.

For what purposes are ultrasounds used?

Ultrasound is not limited to diagnosis, but can also be used in screening for disease and to aid in treatment of diseases or conditions.

Diagnostic uses
Obstetrics Ultrasound routinely for assessing the progression of pregnancy. Pelvic ultrasounds can be obtained trans-abdominally where the probe is placed on the abdominal wall, or trans-vaginally, where the probe is placed in the vagina. For example ultrasound in obstetrics is used to diagnose growths or tumors of the ovary,uterus, Fallopian tubes. Cardiology Echocardiography Echocardiography (echo=sound + cardio=heart + graphy=study) evaluates the heart, the heart's valve function, and blood flow through them. It also evaluates the heart wall motion and the amount of blood the heart pumps with each stroke.

Echocardiography can be performed in two ways: trans-thoracic: the probe is place on chest wall to obtain images, and trans-esophageal: where the probe is placed through the mouth into the esophagus. Anatomically, the esophagus sits near the heart and allows clearer images. However, this approach is a little more invasive. Different groups of illnesses can be assessed by echocardiography:

Valves in the heart keep blood flowing in one direction when the heart pumps. For example, when the heart beats, blood is pumped from the left ventricle through the aortic valve into the aorta and the rest of the body. The aortic valve prevents blood from back-flowing into the heart as it fills for the next beat. Echocardiography can determine if the valve is narrow or leaking (regurgitating, insufficient). By following how the patient fares clinically, repeated echocardiograms can help determine whether valve replacement or repair is warranted. The same principles apply to the mitral valve which keeps blood flowing from the left atriumto the left ventricle. The heart muscle pumps blood to the body. If the heart weakens, the amount of blood it pumps with each beat can decrease, leading tocongestive heart failure. The echocardiogram can measure the efficiency of the heart beat and how much blood it pumps; which assists in determining whether medications are needed. It also is used to monitor how well medications are working. Echocardiography can visualize the heart chambers to detect blood clots in conditions such as atrial fibrillation (an irregular heart rhythm). In other situations, the test can help diagnose endocarditis (an infection of the heart valves) by visualizing "vegetations" (an infected mass) on the valves themselves. Echocardiography also can detect abnormal fluid collections (pericardial effusions) in the pericardium. Echocardiograms are used to diagnose and monitor pulmonary artery hypertension.

Blood vessels Ultrasound can detect blood clots in veins (superficial or deep venous thrombosis) or artery blockage (stenosis) and dilatation (aneurysms). Some examples of ultrasound testing include:

Carotid ultrasound is performed in patients with transient ischemic attacks (TIAs) or strokes to determine whether the major arteries in the neck are blocked causing the decreased blood supply to the brain. The aorta is the large blood vessel leaving the heart that supplies blood to the rest of the body. The walls of the aorta are under significant pressure from the force of the heartbeat and over time, may weaken and widen. This is called an aneurysm, and it can be detected in the abdomen by ultrasound (abdominal aortic aneurysm). For those patients with small

aneurysm, observation may be recommended and the aneurysm size followed over time by repeated tests.

Veins can also be evaluated by ultrasound and it is a common test to assess whether swelling in a leg is due to a blood clot, deep vein thrombosis (DVT) or another cause.

Abdominal structures Aside from its use in obstetrics, ultrasound can evaluate most of the solid structures in the abdominal cavity. This includes the liver, gallbladder,pancreas, kidneys, bladder, prostate, testicles, uterus, and ovaries.

Ultrasound is the preferred to test to screen for gallstones or an infected gallbladder. The ultrasound can reveal the stones as well as signs of infection, including thickening of the gallbladder wall and fluid surrounding the gallbladder. The ultrasound may find blockage in the bile ducts. For those patients where the radiation of a CT scan (computerized tomography) is a potential risk (pregnant patients or children), ultrasound may be used to look for diseases like appendicitis or kidney stones. Ultrasound is the test of choice to diagnose testicular torsion. Pelvic ultrasound is used in gynecology to help assess non-pregnancy related issues like lower abdominal pain, ovarian cysts, uterine fibroids, uterine growths, and endometriosis.

The neck The thyroid gland can be imaged using ultrasound looking for nodules, growths, or tumors. Knee joint Ultrasound can be used to detect bulging of fluid from a swollen knee joint into the back of the knee, called a Baker's cyst.

Screening uses
Ultrasound may be used to screen for blood vessel diseases. By measuring blood flow and blockage in the carotid arteries, the test can predict potential risk for future stroke. Similarly, by measuring the diameter of the aorta in the abdomen, ultrasound can screen for aneurysm (abnormal dilatation) and the risk of rupture. These tests may be indicated for an individual patient or they may be offered as a community wide health screening assessment.

Therapeutic uses
Ultrasound may be used to help physicians guide needles into the body. In situations where an intravenous line is required but it is difficult to find a vein, ultrasound guidance may be used to identify larger veins in the neck, chest wall, or groin.

Ultrasound may be used to guide a needle into a cavity that needs to be drained (for example, an abscess) or a mass that needs to be biopsied, where a small bit of tissue is removed for analysis.

What are the risks of ultrasound?

There are no known risks to ultrasound, and as technology has improved, the machines have become smaller, portable and available for use at the patient's bedside.

How do patients prepare for an ultrasound?

Preparation for ultrasound is minimal. Generally, if internal organs such as the gallbladder are to be examined, patients are requested to avoid eating and drinking with the exception of water for six to eight hours prior to the examination. This is because food causes gallbladder contraction, minimizing the size, which would be visible during the ultrasound. In preparation for examination of the baby and womb during pregnancy, it is recommended that mothers drink at least four to six glasses of water approximately one to two hours prior to the examination for the purpose of filling the bladder. The extra fluid in the bladder moves air-filled bowel loops away from the womb so that the baby and womb are more visible during the ultrasound test.

How are the results of ultrasound interpreted and communicated to the physician?
The ultrasound is generally performed by a technician. The technician will notice preliminary structures and may point out several of these structures during the examination. The official reading of the ultrasound is given by a radiologist, a physician who is an expert at interpreting ultrasound images. The radiologist records the interpretation and transmits it to the practitioner requesting the test. Occasionally, during the ultrasound test the radiologist will ask questions of the patient and/or perform an examination in order to further define the purpose for which the test is ordered, or to clarify preliminary findings. Plain x-rays might be ordered to further evaluate early findings. A summary of results of all of the above is reported to the health care practitioner who requested the ultrasound. They then are discussed with the patient in the context of overall health status.

Last Editorial Review: 10/22/2008http://www.medicinenet.com/ultrasound/page5.htm

Esophagoscopy is a procedure in which a flexible endoscope is inserted through the mouth, or more rarely, through the nares, and into the esophagus. The endoscope uses a charge-coupled device to display magnified images on a video screen. The procedure allows visualization of the esophageal mucosa from the upper esophageal sphincter all the way to the esophageal gastric junction, or EG junction.

This procedure is one of several procedures that fall under the category of upper endoscopy, including gastroscopy, esophagogastroduodenoscopy (EGD), and enteroscopy. Esophagoscopy alone is uncommon, as it is generally performed as part of a more complete upper endoscopic procedure in which the esophagus,stomach, and portions of the small intestine are explored endoscopically. In the United States, esophagoscopy is usually performed under moderate sedation, which is achieved by administering a narcotic and benzodiazepine in combination. In Europe and Asia, however, the procedure is commonly performed without the use of sedation. Topical anesthesia is sometimes implemented to improve patient tolerance and comfort. Very seldom general anesthesia is used in patients who are difficult to sedate or are at higher risk of airway compromise. The following topic focuses on transoral esophagoscopy. For information regarding transnasal esophagoscopy, see the article Transnasal Esophagoscopy. Esophagoscopy is routinely performed in an outpatient setting, although inpatient and emergency room management of gastrointestinal diseases often require urgent inpatient upper endoscopy including but not limited to esophagoscopy. Moreover, certain conditions require routine esophageal endoscopic surveillance and therapeutics. In such cases, a procedure may be limited to esophageal exploration alone. The indications for esophagoscopy are as follows: Food bolus or foreign object impaction Evaluation and management of gastroesophageal reflux disease (GERD) including noncardiac chest pain. Screening and surveillance of Barrett esophagus (see video below)
This video, captured via esophagoscopy, shows a long circumferential segment of Barrett esophagus. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Treatment and surveillance of esophageal varices Evaluation and management of dysphagia, including dilation of esophageal strictures Evaluation and management of odynophagia Evaluation and management of esophageal cancer including placement of esophageal stents Evaluation of the esophagus after abnormal imaging studies

Contraindications
Esophagoscopy is considered a safe procedure with a complication risk of approximately 1 per 1000 procedures.[1, 2] Absolute contraindications include the following: Hemodynamic instability Failure to obtain consent Possibility of perforation Relative contraindications to esophagoscopy include the following: Anticoagulation in the appropriate setting (ie, esophageal dilation) Head and neck surgery Pharyngeal diverticulum History of procedure intolerance

Technique
Prior to the procedure, a full history should be obtained from the patient, and all previous and current medical records should be reviewed. A full physical examination should be performed with special attention given to the oral cavity and pharynx. The thyroid and parathyroid glands should be palpated, and palpation for cervical and supraclavicular lymph nodes should be performed when esophageal cancer is suspected. The existence of poor dentition should be documented. Informed consent must be obtained prior to the procedure. The risks, benefits, complications, and alternative treatments must be reviewed with the patient. The patient is placed in the left lateral decubitus position. Moderate sedation is then accomplished using a combination of narcotic and benzodiazepine, which are infused intravenously in incremental doses. The scope is then inserted into the oropharynx with visualization of the epiglottis and vocal cords. The scope is then advanced through the piriformis sinuses and into the esophageal lumen. Air insufflation is used to distend the esophageal lumen. Careful inspection of the esophagus is then accomplished and the findings are photodocumented.

The video below shows an example of pediatric esophagoscopy.

Esophagoscopy on a 3-year-old child. The esophagoscope is introduced via the mouth. As the scope enters the esophageal inlet, you can see the larynx with an endotracheal tube passing through the vocal folds. The esophagocscope meets some resistance as it passes through the upper esophageal sphincter. The esophagus is then entered, and the mucosal lining of the esophagus is evaluated. The esophagus is then passed through the lower esophageal sphincter, entering the stomach. The rugae of the stomach are very distinct. The pylorus is visualized first, and then the scope is turned 180, and the lower esophageal sphincter is visualized. You can see the scope coming through the lower esophageal sphincter. Video courtesy of Ravindhra G Elluru, MD, PhD.

Diagnostic and therapeutic procedures include the following: Obtaining biopsies (see video below)
This video, captured via esophagoscopy, shows biopsies being obtained from the esophagus. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Banding esophageal varices (see videos below)

This video, captured via esophagoscopy, shows band ligation of esophageal varices. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video, captured via esophagoscopy, shows band ligation of esophageal varices. One of the varices has a red wale sign, which is a sign of recent bleeding. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video, captured via esophagoscopy, shows band ligation of esophageal varices. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Food bolus or foreign object retrieval using nets, baskets, forceps, and snares Cauterization and Endoclip deployment Dilations using balloon or savory dilators (see video below)
This video, captured via esophagoscopy, shows balloon dilation of the distal esophagus. This is performed in patients with dysphagia who are found to have an esophageal stricture or ring. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Resecting and/or ablating mucosal tissue (see videos below)

This video shows circumferential Barrett esophagus via esophagoscopy. The HALO 360 device is in the esophageal lumen ready to perform radiofrequency ablation. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video, captured via esophagoscopy, shows the use of a HALO 360 device to perform radiofrequency ablation for Barrett esophagus. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video, captured via esophagoscopy, shows the Barrett esophagus after having just undergone a treatment with radiofrequency ablation using the HALO 360. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Performing injections Deploying stents (see video below)

This video shows a stent that has successfully been deployed into the esophageal lumen. This patient had a small esophageal perforation, and the stent was placed to allow him to heal and eat. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Deploying and/or inserting instruments such as capsules and tubes The videos below depict normal findings on esophagoscopy.
This video shows a normal esophageal gastric (EG) junction. This is where the esophageal squamous mucosa meets the gastric columnar mucosa. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video shows esophagoscopy with normal findings. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video shows esophagoscopy with normal findings. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare. This video shows esophagoscopy with normal findings. Video courtesy of Dawn Sears, MD, and Dan C. Cohen, MD, Division of Gastroenterology, Scott & White Healthcare.

Once the procedure is completed, the endoscope is removed from the patient, and the patient is monitored postprocedurally for any possible complications and allowed to recover from sedation. If the procedure was performed in the outpatient setting, the patient is discharged from the endoscopy unit with an escort after approximately 1 hour. Previous Next Section: Complications Esophagoscopy is considered a safe procedure with a complication risk of approximately 1 per 1000 procedures. The mortality rate is between 0.53 deaths per 10,000 procedures.[1, 2, 3] The common complications include the following: Bleeding

Infection Perforation Cardiopulmonary problems Adverse reaction to medications Aspiration, oversedation, hypoventilation, and airway obstruction account for greater than 50% of major complications related to upper endoscopy.[4, 5] Previous Next Section: Training and Certification The American Society for Gastrointestinal Endoscopy (ASGE) recommends understanding of indications, limitations, contraindications, alternatives, principles of conscious sedation, and correct interpretation of endoscopic findings to achieve competency in performing upper endoscopic procedures. Furthermore, ASGE has determined that a minimum of 100 upper endoscopic procedures are required for trainees to attain competency in diagnostic upper endoscopy. Therapeutic upper endoscopy poses further challenges and complexities and therefore requires additional training. ASGE recommendations for the requirements to attain competency in therapeutic upper endoscopy are available through the society Web site (see American Society for Gastrointestinal Endoscopy). Previous Next Section: Recent Advancements Transnasal esophagoscopy is a procedure in which an ultrathin 4-mm flexible endoscope is introduced into the esophagus through the nares. It is a safe and well tolerated procedure that can be performed without sedation in an office-based setting. Transnasal esophagoscopy has been shown to have good results in visualizing the esophageal mucosa; however, its limitation stem from the small channel caliber through which it is not possible to pass many of the instruments necessary to perform therapeutic interventions.[6, 7] For more regarding transnasal esophagoscopy, see the Medscape article called Transnasal Esophagoscopy. Esophageal capsule endoscopy is a procedure in which a capsule the size and shape of a pill with a tiny camera is swallowed by the patient. Multiple images of the esophagus are then obtained for viewing. The procedure does not require sedation and is therefore safer for the patient than traditional esophagoscopy. Additionally, it has been shown to have improved patient tolerance and therefore may have implications with regards to patient willingness to proceed with endoscopic screening and surveillance. This has especially been studied in the setting of esophageal varices. Multiple studies have shown that esophageal capsule endoscopy is good at detecting esophageal varices. [7, 8, 9, 10, 11, 12] A recent multicenter trial evaluated 288 patients undergoing screening and/or surveillance for esophageal varices with both traditional upper endoscopy and esophageal capsule endoscopy. Overall agreement for detecting varices was 85.8% between the 2 procedures.[13] Transnasal esophagoscopy

Transnasal flexible esophagoscopy is a helpful tool that reduces diagnostic delays and the need for endoscopy under general anesthesia. It is a safe and well tolerated procedure that can be performed under local anesthesia and in the outpatient setting.[1] The procedure can be performed for diagnostic and therapeutic purposes. Transnasal esophagoscopy requires no sedation.[1] It is a highly cost-effective tool that is easily learned.[2] The indications for transnasal flexible esophagoscopy include the following: Dysphagia (reported as the most common indication)[3] Screening tool for patient with reflux or globus sensation[4, 5] - A recent prospective multicenter crosssectional study has even recommended it for use in the primary care population, with 38% of the participants reported with esophageal findings that altered their management. [6]

Screening tool in patients with head and neck cancer[4] - In addition, it can be used for the detection of metachronous esophageal squamous cell carcinoma (SCC) in the esophagus. [7] Evaluation of a possible foreign body[4] Procedures such as dilation of a stricture or injection of botulinum toxin in the lower esophageal sphincter[8] Cough[3] Tracheoesophageal puncture replacement under direct vision,[4] with excellent speech outcomes[9] Extrinsic esophageal compression[3] Candidiasis[3] Foreign body removal - This was once considered as a contraindication, but transnasal esophagoscopy is now being increasingly used as diagnostic and therapeutic tool for the extraction of foreign bodies with quick discharge of patients in less than an hour. [10] Previous Next Section: Contraindications Patients with bleeding diathesis or abnormal coagulation profile[11] Previous Next Section: Anesthesia After positioning the patient and obtaining informed consent, start examining the nasal cavities. Spray the more patent nostril with a 1:1 ratio of oxymetazoline (Afrin) 0.05% and lidocaine (Xylocaine) 4%. Then spray the oropharynx with lidocaine (Xylocaine) 10% and ask the patient to swallow immediately. Lubricate the endoscope with viscous lidocaine 2%.[4] Previous Next Section: Equipment Local anesthetic and oxymetazoline sprays Viscous lidocaine A distal video chip transnasal endoscope with a camera built into its tip (eg, Pentax 80K series digital video endoscope [5.1-mm diameter])[1] Suction, irrigation, and insufflation all attached to the endoscope (in the distal video chip endoscope) or linked to the EndoSheath (in an add-on camera transnasal endoscope)[1] Television monitor Video cassette recorder Light source Pentax biopsy forceps Previous Next Section: Positioning Seat the patient upright on a treatment couch across from the endoscopist.[1] The endoscope stack is kept behind the patient, in view of the endoscopist. [1] If patient safety is in question, the patient should lie down on the couch for resuscitation, if needed.[1] Previous Next Section: Technique Explain the procedure to the patient and obtain informed consent. Check all equipment before beginning the procedure (see image below).

Checking all instruments is crucial before starting the endoscopy.

Pass the endoscope parallel to the floor of the nose or between the middle and inferior turbinates (see

image below).
floor.

Advancement of the scope intranasally parallel to the nasal

When the nasopharynx is reached, turn the flexible scope downward (see images below). Closely observe the nasopharynx, hypopharynx, and glottis for any abnormalities. [12]

Advancement of the scope at the level of the nasopharynx.

Advancement of the scope past the base of the tongue.

As soon as the hypopharynx is reached, ask the patient to flex his head forward to reach his chest. At that time, ask the patient to swallow. This relaxes the cricopharyngeus. [11] See images below.

Flexible endoscope passing into the hypopharynx. Scope passing through the cricopharyngeus as the patient is asked to swallow.

Under direct visualization, advance the scope through the cervical esophagus toward the cardia. Asking the patient to phonate a vowel facilitates entry of the scope through the esophagogastric junction. This maneuver relaxes the lower esophageal sphincter and also allows movement of the diaphragm.[12]

Rotate the scope 360 while angulating upward to look for the gastroesophageal junction and the

gastric cardia. This is called the J maneuver.[12] See images below.

360-degree rotation of the scope to view the gastroesophageal junction (J maneuver).

Air insufflation to view the stomach. Scope at the level of the gastroesophageal junction and stomach.

Remove the endoscope gently, using intermittent insufflation and suction, while taking close look at

the esophageal lumen (see images below).[12]

scope with careful attention to the monitor. Air insufflation in the stomach. Slow withdrawal of the scope allows careful visualization of the esophageal mucosa.

Slow withdrawal of the

Previous Next Section: Pearls Compared to the transoral esophagogastroduodenoscopy (EGD), the transnasal route has the advantage of not stimulating the uvula and the posterior part of the tongue, thus not stimulating the gag reflex.[13] Most complications encountered in regular sedated oral endoscopy are usually due to sedation. Cardiopulmonary complications account for over 50 % of complications. [2] Previous Next Section: Complications Transient anterior epistaxis[1] Vomiting or gagging[11] Vasovagal syncope[4] Bleeding and infection (if a biopsy is performed) Esophageal perforation (This is a very rare complication, reported once in the literature so far.[14] ) Laryngospasm[15]

Esophageal Cysts

In 1711, Blasius initially described esophageal cysts as duplications. In 1881, Roth also described these cysts, which can be divided into 2 categories. The term esophageal cysts applies to both categories. 1. Simple epithelial-lined cysts

2. Esophageal duplication, which is an embryologic duplication of a portion of the muscle and submucosa of the esophagus without epithelial duplication Next Section: History of the Procedure The diagnosis and treatment of esophageal cysts is still evolving. Diagnosis is aided by the relatively recent developments of CT scans and endoscopic ultrasonography. Treatment is currently moving from thoracotomy to less-invasive procedures, including video-assisted thoracoscopic surgery (VATS) and endoscopic treatment.[1, 2] Previous Next Section: Problem Symptoms are caused by compression of surrounding structures. Sixty percent of esophageal cysts occur in the lower third of the esophagus, where difficulty swallowing from compression is the most common symptom; 20% occur in the upper third of the esophagus, where respiratory difficulty from compression of the tracheobronchial tree is the most common symptom; and 20% occur in the middle third of the esophagus, where retrosternal chest pain and difficulty swallowing are the most common symptoms. Posterior cysts in the lower third of the esophagus can cause cardiac arrhythmias. The larger the cyst, the greater the chance of it causing symptoms. Previous Next Section: Epidemiology

Frequency
The true incidence of esophageal cysts is unknown. Esophageal cysts are rare.[3, 2] Many patients with esophageal cysts are asymptomatic and never diagnosed. No large study has defined the true incidence of esophageal cysts in the United States or internationally. Cysts are usually grouped with other benign lesions of the esophagus. Cysts comprise up to 20% of benign esophageal lesions. Up to 80% of cysts are diagnosed in childhood. Previous Next Section: Etiology Esophageal cysts develop from aberrant elements of the esophageal wall. Simple cysts are duplication of the epithelium, whereas true esophageal duplications are duplications of the submucosa and the muscle wall without duplication of the epithelium. Maldevelopment of the posterior division of the primitive foregut is the embryologic defect responsible for esophageal cysts. The lining of the cyst can vary and can include squamous columnar, cuboidal, pseudostratified, ciliated, and gastric mucosae. Hemorrhage can be the presenting symptom if gastric mucosa is present in the cyst. The other types of mucosa are not specifically associated with particular symptoms. Previous Next Section: Pathophysiology Embryologic duplication of specific elements of the esophageal wall causes cysts. Cysts are duplication of the epithelium. True duplications are duplication of the muscle and submucosa. Previous Next Section: Presentation Many children with esophageal cysts are asymptomatic. Most cysts are diagnosed during childhood.[2] Most adults (67%) with cysts are symptomatic. Chest pain (tightness or fullness) is the most common presentation.[1] Dysphagia may also occur.[1] Hematemesis can occur if gastric epithelium is present in the cyst. Most esophageal cysts develop in the right posteroinferior mediastinum. Although rare, malignant degeneration can occur.[4] Previous

Next Section: Indications All esophageal cysts should be evaluated and, eventually, resected. Radiographs guided by history and physical examination findings usually confirm the diagnosis. Plain chest radiographs can reveal a cyst within the mediastinum. Barium swallow studies reveal compression of the esophagus without ulceration. CT scan reveals a fluid-filled cystic structure originating from the esophagus. Endoscopy demonstrates extrinsic compression with intact mucosa. Endoscopic ultrasonography reveals a cystic, filled structure in connection with the esophagus. MRI scans can also help diagnose esophageal cysts. Nearly 75% of patients with esophageal cysts eventually become symptomatic; therefore, cysts should be resected when they are diagnosed. Previous Next Section: Relevant Anatomy Embryologically, the upper gastrointestinal tract develops from the posterior division of the primitive foregut. During the fourth week of gestation, the primitive foregut develops an anterior diverticulum, which becomes the respiratory bud. Meanwhile, the posterior division develops into the esophagus and upper gastrointestinal tract. The tracheoesophageal septum separates the primitive esophagus from the primitive trachea. As the esophagus continues to develop, the epithelium eventually obliterates the lumen and later recannulizes. As expected based on the common embryologic origin, bronchogenic and esophageal cysts can occur together. Esophageal cysts develop from aberrant elements of the esophageal wall. Simple cysts are duplication of the epithelium, whereas true esophageal duplications are duplications of the submucosa and the muscle wall without duplication of the epithelium. Esophageal cysts and duplications do not usually communicate with the lumen of the esophagus. Esophageal cysts usually occur in the neck, chest, and abdomen. Previous Next Section: Contraindications All cysts should be resected unless the patient's other medical ailments prohibit operation. Previous Laboratory studies do not specifically aid in the diagnosis of esophageal cysts. Laboratory evaluation should be guided by the patient's other medical problems. Next Section: Imaging Studies CT scan is the radiologic modality of choice to aid in diagnosis and operative preparation (see image

below). CT scan of esophageal cyst demonstrated by the white line. Chest radiographic findings that suggest a mass in the mediastinum should be followed by a CT scan. See Indications. Previous Next Section: Diagnostic Procedures Esophagoscopy should be performed to rule out an intrinsic component, which should be biopsied to exclude malignancy. If endoscopic ultrasonography is available, then esophagoscopy should be performed to further delineate the extent of the cyst. See Indications. Previous Proceed to Treatment & Management Medical therapy has no role in the management of esophageal cysts.

Next Section: Surgical Therapy Simple cysts are enucleated, whereas duplications are excised. [5] Previously, a posterolateral thoracotomy was required to remove the cyst or the duplication; however, video-assisted thoracoscopic surgery (VATS) is currently used to enucleate cysts and resect duplications, and it is the procedure of choice.[1, 6] Also described in the literature is endoscopic treatment of esophageal duplications, which, essentially, create a lumen from the cyst into the esophageal lumen.[2] Previous Next Section: Preoperative Details Preoperative workup should focus on 2 facets.

A thorough history and physical examination is important to elucidate comorbid conditions that can be addressed prior to the operation, thus decreasing morbidity. A thorough radiological workup demonstrates the anatomy of the cyst and assists in the planning of the operation. Previous Next Section: Intraoperative Details Prior to induction of anesthesia, an epidural catheter is placed for pain control. Alternatively, an ON-Q pain pump (VQ OrthoCare, Irvine, Calif) can be placed at the time of operative intervention. Anesthesia is administered, and a double-lumen endotracheal tube is placed. The patient is then placed in the full lateral position. A nonrib-spreading thoracotomy is performed (3-6 cm), with an additional Thoracoport (Tyco Healthcare, Mansfield, Mass) used for visualization. Esophageal muscle fibers are carefully separated to expose the cyst. Blunt dissection is then used to enucleate the cyst. If a duplication is present, it is excised in a similar manner. During dissection, preserve both vagus nerves and the phrenic nerves. After the lesion is removed, the muscle layers are reapproximated, thus preventing pseudodiverticula formation. Simultaneous esophagoscopy to illuminate the esophagus assists in visualization of the mucosa. Chest tube(s) is placed, and the incisions are closed in standard fashion. An alternative to VATS includes a posterolateral thoracotomy with the addition of the above steps. Previous Next Section: Postoperative Details Most patients do well, with minimal morbidity. Aggressive pulmonary toilet and early mobilization prevents pulmonary complications. Adequate analgesia is essential to patient cooperation with pulmonary toilet. If the mucosa was not violated, the patient can be started on liquids within 1-2 days of the operation. If the mucosa was violated, then placement of a drain assists in determining the presence of a leak. An esophagram can be used to assess esophageal integrity. Previous Next Section: Follow-up Patients require close follow-up care. Pseudodiverticulum can develop if the muscle is not reapproximated. Complications of vagal injury develop if these nerves are not preserved. Recurrence is rare, especially if the entire cyst was excised. Previous Next Section: Complications The overall complication rate is very low. Most complications are inherent to the thoracotomy or VATS. Complications include pneumonia, persistent air leak, deep venous thrombosis,esophageal leak or pseudodiverticulum, vagus nerve paralysis, and wound infection.[7] Previous Next Section: Outcome and Prognosis If the entire cyst is excised, recurrence is rare. The morbidity rate is low. Overall, most patients do well in both the short and long term. Previous Next Section: Future and Controversies

The future of the treatment of esophageal cysts lies in the advancement of minimally invasive operative techniques, which will lessen morbidity and mortality rates. Endoscopic treatment has been reported as a feasible and reasonable alternative. Recently, robotic-assisted thoracic surgery has also been used for resection of an esophageal cyst.

Endoscopic Therapies for the Prevention and Treatment of Early Esophageal Neoplasia
Susi Green; Pradeep Bhandari; John DeCaestecker; Hugh Barr; Krish Ragunath; Janusz Jankowski; Rajvinder Singh; Gaius Longcroft-Wheaton; Cathy Bennett Authors and Disclosures Posted: 11/22/2011; Expert Rev Gastroenterol Hepatol. 2011;5(6):731-743. 2011 Expert Reviews Ltd.

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Abstract and Introduction When to Consider Endotherapy Surgical Treatment Endoscopic Treatments Expert Commentary Five-year View
References Sidebar

Abstract and Introduction

Abstract

Esophageal cancers have traditionally been diagnosed late and prognosis has been dire. For many years the only real treatment option was esophagectomy with substantial morbidity and mortality. This situation has now changed dramatically. Improvements have been achieved in surgical outcomes and there is an array of new effective treatment options now available, particularly for the increasing proportion diagnosed with early-stage disease. Minimally invasive endoscopic therapies can now prevent, cure or palliate esophageal cancers. This article aims to investigate the role and evidence base for these new therapeutic options.
Introduction

The vast majority of esophageal cancers (>85%) are either adenocarcinomas or squamous cell carcinomas (SCCs). Both arise from either metaplastic or dysplastic epithelium. In the West, most are adenocarcinomas arising on a background of Barrett's esophagus (BE), a condition where the distal squamous esophageal mucosa is replaced with metaplastic columnar epithelium as a result of chronic gastroesophageal reflux. Patients with this condition have a 20-fold increased risk of developing esophageal adenocarcinoma, the fastest growing cause of cancer mortality in developed countries. Surveillance endoscopy is frequently recommended every 2 years among patients known to have BE so that early signs of progression to neoplasia can be detected and treated at a curable stage. The presence of high-grade dysplasia (HGD) in BE is a strong predictor for imminent development of esophageal adenocarcinoma. Until recently, the available options for management of HGD included frequent surveillance with intensive biopsy to detect the development of cancer and surgical resection for those fit for an operation. However, esophagectomy is associated with appreciable mortality and

morbidity.[1,2] New endoscopic techniques have enabled recognition and mapping of subtle visible dysplasia within the BE and new endoscopic resectional and ablative techniques have been reported from expert centers that appear to offer a successful alternative to surgery in early esophageal neoplasia.

When to Consider Endotherapy

The esophageal wall consists of an innermost mucosal layer, a loose submucosal layer and a surrounding muscular layer. The exact depth of invasion into the mucosal and submucosal layers can be described as follows (Figure 1):

Figure 1. Depth of invasion terminology. EP: Epithelium; HGIN: High-grade intraepithelial neoplasia; LP: Lamina propria; MM: Muscularis mucosa; SM: Submucosa. Reprinted with permission from [3].

(Enlarge Image)

Mucosa (M): o M1: limited to the epithelium o M2: invades into the lamina propria o M3: invades in the muscularis mucosa Submucosa (SM): o SM1: invades into the upper third of the submucosa o SM2: invades into the middle third of the submucosa o SM3: invades into the lower third of the submucosa

It is clear from Table 1 [411] that estimates for the risk of lymph node metastases vary considerably. This is partly due to the influence of other variables that contribute to the risk, such as poor differentiation and lymphovascular invasion, and partly because surgical series tend to show higher risks than endoscopic resectional studies. There is a suggestion that this is due to histological blocks being cut for at less-frequent intervals for surgical specimens, leading to underestimation of the depth of malignant invasion.[3] It may be reasonable to consider curative endotherapy as an alternative to esophagectomy if the chance of dying from missed and untreated lymph node metastases after endotherapy is comparable with the chance of dying from the more thorough surgical procedure. Endoscopic resectional studies suggest a very low chance of metastases when the depth of invasion does not exceed SM1 for those with BE cancer,[3,12] or M2 for those with squamous malignancies.[811] Surgical mortality will be influenced by the age and fitness of the patient. Choice of treatment must therefore be individualized based on disease stage, comorbidities and informed patient preference.

Assessing the Primary Lesion

It is relatively straightforward to assess penetration depth after excision when the lesion is in the laboratory, but ideally information would be available prior to removal to guide the decision-making process. The crucial information dictating whether a lesion is endoscopically curable is whether it penetrates beyond SM1. Careful endoscopic assessment can suggest, although not prove, this categorization.

Endoscopic Assessment
Description of the BE segment should be by the validated Prague system, defining the distal end by the upper margin of the gastric fold, the upper limit of circular BE and the maximal extent of BE (circular or noncircular). Endoscopic assessment of the lesion will include size, position, morphology, surface and blood vessel pattern and ability to lift away from the underlying muscular layers following a submucosal injection. The assessment should be carried out by experts with good-quality, highresolution endoscopes. Many expert endoscopists have used the Paris system (Figure 2) to describe the macroscopic appearance of esophageal early neoplasia, although this system was developed in Japan for use in early stomach neoplasia. Lesions harboring deep invasion are likely to be larger;[7] with polypoid (Paris type 1s, IIa), depressed (Paris IIc) and excavated areas (Paris type III);[13,14] have disruption of the normal blood vessels and mucosal surface patterns, [15] and not lift normally after submucosal injection ('non-lifting sign').[16]

Figure 2. Diagram demonstrating Paris classification of macroscopic appearance of early esophageal neoplasia.

(Enlarge Image)

There are a variety of techniques that may aid this assessment. Chromoendoscopy (normally using acetic acid for BE[17] and Lugol's iodine for squamous neoplasia[18]) will accentuate the mucosal surface patterns. Electronic chromoendoscopy techniques such as narrow-band imaging highlight the pattern of superficial blood vessels using narrow wavelength of light towards the blue and green end of the spectrum, which are preferentially absorbed by hemoglobin.[19] Confocal laser endomicroscopy enables visualization of mucosal characteristics at the cellular level a 'virtual biopsy' which has shown promise in detailed characterization of early neoplasia once it has been detected. [20] Saliva, mucous and bubbles on the esophageal mucosa prevent adequate mucosal visualization and interfere with all advanced imaging techniques. Mucolytics and bubble-breakers may be used as a preendoscopic drink to allow improved dye contact and mucosal visualization. [21]

High-frequency Endoscopic Ultrasound

Endoscopic ultrasound (EUS) is used extensively in staging a variety of cancers. Use of higher frequencies (2030 MHz) allows visualization of more superficial structures such as the layers of the esophageal wall. Initial results were promising in assessing early esophageal lesions. In 2004, a prospective study showed correct assessment of invasion beyond SM1 by endoscopic assessment in 89%, by EUS in 86% and by a combination in 91.5% of lesions.[14] More recent data have suggested that use of EUS has little, if anything, to add to expert endoscopic assessment and tends to understage T1 cancers.[2224] A recent meta-analysis of studies comparing EUS to the final T stage in esophageal early neoplasia (from endoscopic resection or surgical specimens) has shown an

accuracy of only 65% for EUS.[24] Endoscopic resection (techniques described later) is therefore now accepted as the T-staging procedure of choice in early esophageal neoplasia.[22,24]

Esophageal Mucosal Abnormalities Underlying Neoplasia

Removal of the primary lesion without treatment of the residual surrounding premalignant metaplastic or dysplastic epithelium leaves a significant risk of metachronous cancers developing.[25] Adenocarcinomas arise from BE metaplasia, transformed from squamous to columnar epithelium due to repeated exposure to noxious substances such as acid reflux and bile acids.[26,27] These transformed cells are then prone to acquiring genetic abnormalities, resulting in activation of oncogenes or inactivation of tumor-suppressor genes, enabling neoplastic progression.[28] BE has the advantage that the premalignant section is easily visualized (with a salmon pink color at endoscopy) and usually limited,[29] offering an obvious target for eradication therapy. Conversely, up to a third of SCCs present with synchronous tumors at multiple, often distant, macroscopically normal sites within the esophagus or even in the airways. [30] This can be explained partly by a similarity in the risk factors associated with all aerodigestive SCCs (smoking, alcohol consumption, genetic and dietary factors),[31] but there is also a field change that can extend over large areas.[32] Seemingly separate primary cancers can have a common clonal origin, even when located in remote locations (e.g., the tonsils and distal esophagus [33]). These background changes must be considered when using therapies that leave the residual esophagus in place.

Surgical Treatment
Up till the last 10 years surgery has been the treatment of choice for HGD and early cancer in the esophagus; it remains the mainstay of treatment for more advanced cancer. There are advantages of surgery, including confidence that the lesion, including the entire segment of the esophagus from which it arose and the associated lymph nodes, have been removed, with robust data showing longterm disease-free survival. Balanced against this are the effects of major surgery on patients' health and quality of life.[2,34,35] Surgical mortality will depend upon the age, comorbidities of the patient and the center performing the surgery: high-volume centers have lower mortality.[36,37] There is no doubt that surgical mortality and morbidity have improved, but there are still significant considerations, even among those units offering minimal-access techniques such as vagal-sparing esophagectomy and transhiatal esophagectomy. Several studies have indicated that nondysplastic BE may recur after surgery, so surgically treated patients may still require subsequent endoscopic surveillance. [38,39] The results of some recent surgical series are summarized in Table 2.

Endoscopic Treatments
Endoscopic treatments aim to remove or destroy the abnormal tissue, allowing replacement with new squamous epithelium. These techniques will be described individually in the following sections, followed by a consideration of their applicability to different clinical early esophageal neoplasia scenarios. The role of combinations of techniques (endoscopic resection to remove and stage visible lesions combined with ablative techniques to destroy remaining 'at risk' epithelium) will be introduced.

Endoscopic Resectional Techniques

Endoscopic resectional techniques encompass a range of methods that excise the mucosal and submucosal layers of the esophagus from the underlying muscular layer (muscularis propria), itself only a few millimeters thick. This offers a cure for superficial lesions. It also has an important diagnostic role, allowing more reproducible assessment of histology and of T staging compared with standard biopsy or EUS.[23,24,44,45]

Endoscopic Resection
Endoscopic resection (ER; previously termed endoscopic mucosal resection) is an accepted method for the treatment of early cancers in the upper GI tract[46,47] and was first devised in the 1980s. A variety of methods have since been developed, mainly in Japan. Since the early 1990s, two types of 'suck and cut' technique have gained popular international support owing to relative ease of use and efficacy: ER with cap[48] and ER with ligation.[49] There is little advantage of either technique over the other in terms of maximum diameter of resected specimen, resection area, complication or recurrence rates.[50] The first step in either technique is to accurately identify the margins of the lesion. The lesion will then be marked (usually with a series of small diathermy spots) as the periphery of the lesion can become more difficult to identify later in the procedure. Endoscopic resection with cap uses a transparent cap with a circumferential groove at the bottom into which a snare can be sited. First the lesion is 'lifted' from the muscle layer using a submucosal injection to create a cushion and prevent perforation of the muscle layer. Various solutions are used but usually contain a basic fluid (e.g., saline, gelofusin or hyaluronic acid), adrenaline (e.g., 1:100,000) to reduce ooze from small blood vessels and a dye (e.g., indigo carmine) to highlight the submucosal plane. Suction is then used to pull the lesion into the cap, the snare is deployed to encompass the lesion and diathermy is used to remove the area. Endoscopic resection with ligation uses a transparent cylinder preloaded with elastic bands such as those used for the ligation of varices. Suction is used to pull the lesion into the cap and the rubber band deployed to create a pseudopolyp, which can then be snared with a standard diathermy loop. This method will pull only the mucosal layer into the cap, and 'lifting' is therefore unnecessary. Some practitioners will choose to lift areas of concern as a final confirmation of lack of invasion. [16] Others feel that lifting makes the area tighter and more difficult to suck into the cap, particularly in larger lesions. Lesions of up to approximately 2 cm in diameter can be removed en bloc and larger lesions must be removed piecemeal (taking small adjacent areas).[50,51] Piecemeal resections can make histopathological confirmation of complete removal impossible, but this can be established endoscopically by carefully assessing the edges of the base post-resection.

Endoscopic Submucosal Dissection

Endoscopic submucosal dissection (ESD) can be used to remove even very large lesions en bloc. ESD is now popular in Japan but has limited availability in the West, mainly because it is demanding in terms of time and the skill level of the operator. The technique involves lifting the lesion with a submucosal cushion as previously described, cutting around the area circumferentially and then dissecting through the submucosal layer to remove the lesion using various knives inserted down the endoscope.[52] ESD can also be useful for lesions that have become tethered to the deeper layers owing to scar tissue through previous biopsies or incomplete attempts at endoscopic removal. [53]

Efficacy & Safety Considerations

The endoscopic choice for larger lesions is therefore between piecemeal ER or en bloc ESD. ER is associated with a risk of bleeding of approximately 3% and has a perforation rate of 0.15%, although both of these problems can usually be dealt with safely during the procedure. [5456] Residual islands of abnormal tissue between 'bites' or positive resection margins can lead to local recurrence, 21.5% of patients over 63 months in one study of early neoplasia in BE.[57] Recurrence can occur from months to years after resection but can usually be removed by further resection. Intense endoscopic follow-up is therefore required and should continue in the long term.

Endoscopic submucosal dissection is associated with higher complication rates and is more difficult to perform. However, the specimens it provides are excellent enabling pathologists to stage the tumor and assess resection margins. Local recurrence after ESD is rare. [58] Most, but not all, of the data related to esophageal ESD involve squamous cell cancer from Japan. A recently published prospective study was able to demonstrate successful ESD for esophageal squamous neoplasia by European experts[59] and a small American series has shown promising results in using ESD for BErelated HGD and early adenocarcinoma.[60] The fact remains that ESD is a highly specialized technique originally developed for gastric lesions. ESD in the esophagus poses new challenges due to limited space and lack of retroflexion (unless a junctional lesion), and serious consequences if ESD leads to perforation.

Ablation Therapies
Ablation therapies can be used either as an alternative or as an adjunct to ER. There are a variety of ablation therapies available. Radiofrequency Ablation Radiofrequency ablation (RFA) is a recent development that delivers thermal energy by radiofrequency electrodes. The RFA system uses two delivery systems, a focal device 'HALO90' (BRRX Medical, Inc.), with the electrode array mounted on a small articulated platform attached to the tip of the endoscope, and a circumferential device 'HALO 360' (BRRX Medical, Inc.), with electrodes coiled around an inflatable balloon. The energy level used is optimized to ablate the full thickness of the epithelium (7001000 m) without affecting the submucosa.[61] The circumferential balloon is generally used for the initial treatment. The correct balloon is chosen using a preinserted sizing balloon. The treatment balloon is then positioned, inflated, activated, deflated and moved in a stepwise manner to deliver energy twice to the entire circumferential area. Patients are often advised to take a liquid-only diet, ranitidine and sucralfate for a week in addition to a daily proton-pump inhibitor (PPI) as maintenance therapy. The patient then returns for repeat endoscopy after 3 months with careful inspection for residual abnormalities. If the area looks normal, multiple biopsies are taken from the neosquamous epithelium. Any abnormalities detected macroscopically or microscopically are treated with either the circumferential or focal device and the process repeated every 23 months until clear. Efficacy & Safety Considerations Overall RFA seems to have good efficacy and an improved safety profile when compared with other ablation therapies,[62] particularly if both the circumferential and the focal devices are used.[13] It is simple to administer and good results have been reported in multicenter community registries outside major centers.[63] A well-performed multicenter randomized controlled trial has shown significantly lower progression of HGD to cancer compared with sham treatment after 1 year of follow-up, coupled with 90% HGD eradication, also significantly better than sham.[62] The vast majority of the available research has taken place in BE neoplasia but there are some promising early results in squamous neoplasia.[64,65] Postprocedural mild chest pain and odynophagia are common but self-limiting (maximum 5 days).[13,66]Esophageal function does not seem to be affected as measured by esophageal diameter, lower esophageal sphincter pressure and length, contraction amplitude or compliance of the gastroesophageal junction.[67] The treatment has been shown to be cost-effective compared with esophagectomy.[68] Most endoscopic ablation techniques cause scarring through to the submucosa, rendering subsequent ER difficult. This does not seem to be the case with RFA, after which ER can be carried out in the usual way.[69]Biopsies taken after RFA treatment contain subepithelial structures with equal prevalence to those taken after sham treatment, suggesting that biopsy is an adequate method to evaluate

treatment response and the presence of buried intestinal metaplasia.[70] However, it should be noted that this is a relatively new treatment modality and the long-term consequences are unknown. There seems to be a higher incidence of complications (superficial mucosal lacerations and stenoses) in patients who have undergone ER prior to RFA. It is therefore advised that the balloon is inflated to a slightly smaller diameter in that group, and that the longitudinal length (<2 cm) and circumferential extent (<50%) of ER is restricted.[71] Photodynamic Therapy Photodynamic therapy (PDT) is used in a wide variety of malignancies. It utilizes a phototoxic reaction to induce cell death. A light-sensitive photosensitizing agent is administered that is absorbed by most cells. Normal cells clear the agent much faster than those undergoing neoplastic growth.[72] At a specific time after administration of the medication (usually a couple of days), it is activated by exposure to light of an optimum wavelength using fiber-optic diffusers inserted down the working channel of the endoscope. This causes resident oxygen molecules to enter a toxic state in cells retaining the photosensitizer, thereby causing a partially selective tumor cell necrosis.[73] Efficacy & Safety Considerations Patients undergoing PDT will be rendered photosensitive after treatment. The length of time is dependent upon the photosensitizer used and can be up to 6 weeks, but is much shorter with aminolevulinic acid.[7476] During this period they must use protective clothing and eyewear whenever exposed to sunlight, as sunscreen does not provide adequate protection. For these reasons and because of the evidence supporting equivalent or better efficacy for RFA (see later), PDT is currently less-frequently used. Argon Plasma Coagulation A cheaper alternative to PDT is argon plasma coagulation (APC).[77] Most endoscopy units will have all the necessary equipment and be familiar with its use in the treatment of telangiectasia, gastric antral vascular ectasia and bleeding. Argon gas is sprayed from the probe tip towards the lesion. A high-voltage spark is then delivered that ionizes the argon and grounds in the nearest tissue, causing necrosis through electrocoagulation. Different depths of necrosis can be achieved by varying the power of the generator, the distance of the probe from the tissue, the rate of gas flow and the duration of application. Efficacy & Safety Considerations Typical penetration depths are only 23 mm, making esophageal wall perforation unlikely. This does mean that treatment is relatively superficial and many need to be repeated on multiple occasions for deeper lesions.[78] Odynophagia, chest pain and fever may occur after treatment.[77]Compared with RFA, there has been little-reported study of its efficacy, limited to small case series.[7779] The largest, of approximately 30 patients, showed similar efficacy and durability of response to RFA, but clearly more published work would be of value. The Weisbaden group have used APC as an adjunct to ER, successfully reducing recurrence and metachronous lesions. [57,80] Cryotherapy Cryotherapy or cryoablation is a promising novel technique involving application of cold nitrogen or carbon dioxide gas to the abnormal area to destroy the target cells. [81] A spray catheter is inserted through the working channel of the endoscope and the liquid nitrogen is sprayed in bursts at the worst areas for a total of up to 40 s, allowing time between cycles for thawing to ensure tissue reperfusion. Efficacy & Safety Considerations Limited available evidence suggests cryotherapy to be a safe treatment, with only minor complications such as postprocedural chest pain being reported. [82] It is not yet available in the UK.

Complications of Endotherapies

Buried BE The neosquamous epithelium formed after ablation therapies can grow over and cover areas of dysplasia or cancer, concealing them to the endoscopist's view and allowing them to progress without detection, even with intense endoscopic follow-up.[83] Buried areas will also be difficult to treat with further ablative therapy. This phenomenon can occur after any ablation therapy, PPI or simple cold biopsy of the area.[8486] In providing protection from further noxious injury the neosquamous epithelium may provide these areas with a low malignant potential,[87] allowing them to atrophy over time.[88] It is also possible that these buried areas occur as a normal part of BE rather than only as a result of treatment. [66] In a study involving 208 patients and 33,658 biopsies, there were no patients in whom the buried BE contained their most advanced dysplasia.[85] However, there have been published case reports of adenocarcinomas being detected beneath the neosquamous epithelium,[45,77,89,90] although it is not clear whether they have developed from buried glands or whether they were pre-existing cancers that were buried after their development. Radiofrequency ablation probably has a lower propensity for causing buried dysplasia than either PDT or APC.[71,91] One large study of RFA in BE even reported a lower rate of buried glands after RFA (5%) than after sham treatment (40%; p < 0.001).[66] A systematic review reported a sole positive post-RFA biopsy out of a total of 8500 studied,[13] although it may be that the glands have simply been missed by inadequate biopsies, which often do not include lamina propria.[69] Strictures Esophageal strictures form after ablative therapies due to scarring of the deeper esophageal tissues. They are more common if the therapy is applied circumferentially but are generally amenable to treatment with endoscopic dilatation.[63,92] Strictures occur in up to 34% after PDT and less commonly after APC,[77,93] most of which develop within a month of treatment.[94] Risk factors for stricture formation include extent of therapy and performance of ER prior to treatment.[94] RFA targets the more superficial layers, hence stricture formation is unusual, occurring in 12% of patients after sole therapy,[13] or up to 8% after prior ER, with a narrow esophagus at baseline (a common consequence of reflux), or with a longer length of BE.[13,63,95] Postcryotherapy strictures do not seem to be a common problem, developing in 3% of patients in one study.[82] When stepwise ER has been used to removed the entire BE mucosa in the esophagus over a series of treatments, stenosis has occurred in up to 88% of patients.[96]

Selecting the Appropriate Option

Nondysplastic BE Dysplasia is a histological diagnosis characterized by architectural abnormalities such as nuclear enlargement, pleomorphism, hyperchromatism and stratification, as well as by other changes such as atypical mitoses and loss of cytoplasmic maturation.[97] BE metaplasia without these changes carries a risk of cancer development of less than 1% per year. [70,98100] This group are generally offered an endoscopic surveillance program to detect any progression rather than treatment at this stage. There is no strong evidence to suggest that either PPI therapy or fundoplication has benefit in preventing progression to adenocarcinoma and both can lead to buried BE.[101] There have been promising results with the use of RFA and cryotherapy to completely ablate the entire BE area, but these are largely preliminary at present and surveillance would continue to be required postablation.[102,103] Unless risk stratification can be shown to predict progression, it is unlikely that ablation of nondysplastic BE will be cost effective, and can certainly not be currently endorsed. BE With Low-grade Dysplasia Low-grade dysplasia (LGD) within BE is notoriously difficult to diagnose histologically, particularly when there is inflammation present. As part of a Dutch study designed to evaluate the natural history of LGD in BE, the original histology specimens of 147 patients

from non-university hospitals with this diagnosis were reviewed by two experts. After review, only 22 of the 147 patients retained their original diagnosis. One was upgraded to HGD, 14 had indeterminate results, and 110 were downgraded to nondysplastic BE.[104] These inaccuracies may, in part, account for marked variability in estimates of the natural history.[105107] In a recent large multicenter long-term US follow-up series where the diagnosis of LGD was confirmed by two blinded pathologists, the progression to HGD or cancer was 1.83% per year. Studies have suggested that PDT, APC and RFA are at least partially effective in eradication of LGD,[66,77] but diagnostic difficulties make research in this area difficult to interpret and massively controversial. As for nondysplastic BE, such low rates of progression would not make eradication of LGD a cost-effective option unless individuals at high risk can be identified (which was not the case in this study).[108] Current guidelines continue to recommend intensified surveillance with acid suppression to detect any progression rather than therapy at this stage (esophagogastroduodenoscopy within 6 months, then every 6 months[201] or yearly[109] with comprehensive biopsies[110] until no dysplasia is found on two consecutive endoscopies). BE With HGD or Early Cancer High-grade dysplasia and early, intramucosal cancers with welldifferentiated histology and no lymphovascular invasion (EC) developing within BE have a very low risk of nodal spread.[111]There are no randomized controlled trials comparing esophagectomy to endotherapies in HGD/EC.[112] With a lack of good evidence, therapy may be unduly influenced by the personal bias of the treating clinician. Among 87 HGD/EC patients, 12% first seen by a gastroenterologist compared with 86% first seen by a surgeon underwent esophagectomy.[113] Advocates of esophagectomy for HGD/EC argue that 40% of postresection specimens contain missed adenocarcinoma but the vast majority of these missed tumors are at an early stage, also amenable to endoscopic cure.[114] Only 11% of those with a visible lesion and 3% of those without have cancers invading the submucosa, potentially benefiting from surgical excision.[114] Whether this represents a reasonable risk in order to avoid esophagectomy must be assessed on an individual basis. Historically, intensive endoscopic surveillance was often advised, particularly to those with comorbidities. Results were not always unreasonable,[115] but with such minimally morbid therapies now available it would now be unusual not to treat. It is unusual for significant dysplasia not to be visible with careful examination, even if not immediately apparent.[17,116] Specific visualized lesions can be removed by ER,[109] and treatment of the residual BE should be considered to reduce the risk of further neoplasia, which remains high in this group of patients. Argon plasma coagulation and PDT have successfully eradicated the BE area in this context,[117,118] but do not eliminate recurrent dysplasias completely. A recent prospective randomized trial suggests that similarly high rates of eradication of the residual BE can be achieved with RFA but with lower rates of stenosis (14% of 21 patients).[96] Stepwise radical endoscopic resection has been used to remove the entire BE area over a series of treatment sessions.[119] A large (169 patients) retrospective study of stepwise ER in patients with BE less than 5 cm in length showed sustained (32-month) complete eradication of neoplasia in 95.3%, but half of all patients developed a symptomatic stricture. [120] All attempts should be made to visualize and remove the lesion, including referral to an expert center with high-definition endoscopy with image enhancement. If the HGD or EC remains elusive and esophagectomy is not appropriate, then ablation therapy of the 'flat' metaplasia/dysplasia without ER may be adequate treatment but should be considered palliative. In ten patients with HGD or early adenocarcinoma treated with APC, eight regressed completely, one with HGD pretreatment remained with HGD and one with HGD pretreatment progressed to adenocarcinoma.[78] Both PDT and RFA have been shown to reduce the risk of HGD progressing to cancer. In a 208patient, multicenter trial comparing PDT and PPI with PPI alone, there was an increase in HGD

elimination (77 vs 33%; p < 0.0001), and a decrease in progression to cancer (15 vs 29%; p = 0.004) at 5 years in the PDT group.[121] PDT has also been shown to be effective in eradicating small locally invasive adenocarcinomas.[122] In a sham-controlled RFA trial, complete eradication of HGD was achieved in 81.0% of those in the active treatment group, compared with 19.0% of those in the control group (p = 0.001). Overall, patients in the RFA group (LGD and HGD) had less disease progression (3.6 vs 16.3%; p = 0.03) and fewer cancers (1.2 vs 9.3%; p = 0.045).[66] The same group were able to demonstrate improved disease-specific quality of life after RFA treatment.[123] RFA is not ideal in nodular areas due to its shallow depth of penetration.[96] A recent study showed promising results using cryotherapy in 98 HGD patients, many of whom had already failed one or more other therapies. After a mean of four treatments per patient, HGD was eradicated in 97% and all dysplasia (LGD or HGD) was eradicated in 87%.[82] NICE guidance currently recommends the use of ER, RFA or PDT in the treatment of flat HGD and it does not prioritize one therapy over another. APC is recommended only as an adjunct to ER.[202] The position with regards to optimum treatment for HGD within BE is therefore unclear. The controversy largely centers on which course of endoscopic therapy yields the best long-term outcome, and there is a lack of randomized controlled trials to investigate this adequately. It is our contention that the most likely position that will emerge will involve endoscopic resection of visible neoplasia followed by ablation of the remaining BE. There are now studies emerging that suggest that this is associated with a lower rate of local recurrence than EMR alone.[124] Ablation as a single modality of therapy will only ever be an option for completely flat neoplasia (a minority of cases), and concern over the lack of a significant tissue sample to exclude more invasive disease is likely to limit its use for this purpose. Squamous Dysplasias & Early Cancers Squamous cell dysplasias have a propensity for both synchronous and metachronous lesions. A careful search of the entire esophagus should be made with chromoendoscopy (12% iodine) and examination of the airways should be considered. The Japanese reported good results for ER in SCC in the late 1990s, with 5-year survival rates of 95%.[125] More recent Western experience has also been positive. In one study of 65 patients with HGD/EC, a total of 179 resections were performed with a 7-year survival rate of 77% (80% of mortality attributable to comorbidities).[126]Japanese guidelines recommend that endoscopic resection be restricted to SCCs, which do not invade deeper than the muscularis mucosa [127] (more cautious than in adenocarcinoma) as they have a higher propensity for lymph node micrometastases. Some groups have successfully pushed the limits of invasion to SM1,[128,129] in some cases by combining ER with chemo- and radio-therapy,[130,131] but this is not standard practice. Early results in ESD for SCC have been promising. Two separate Japanese groups have recently published results from 102 patients and 43 patients, respectively. [52,132] They report a 95 and 100% en bloc resection rate, 0 and 2.5% local recurrence rate (mean follow-up: 21 and 17 months), 0 and 7% perforations (all managed successfully with endoscopic clipping) and 7 and 16% stricture formation requiring dilation, respectively. The advantages of ESD over ER are more pronounced in the treatment of squamous (over BE) neoplasias owing to their more aggressive nature and the consequent need for very accurate assessment of the depth of invasion, even in the intramucosal cancers. However, the technique remains very challenging and is confined to very few centers outside Japan. A recent retrospective study presented the results of PDT in early SCC (invading the mucosa or submucosa). All patients were assessed as unfit for esophagectomy and had lesions deemed too large to resect endoscopically. Complete remission was achieved in 87% and 5-year survival (despite the comorbidities of the group) was 76%.[133] Preliminary reports are promising for RFA. In one small study, four out of six patients with high-grade squamous dysplasia had complete resolution of

dysplasia after treatment,[134] and a case report describes a patient in whom a superficial 3.5 cm SCC was successfully eradicated.[64] A recent prospective case series of 13 patients treated with RFA from the Amsterdam group have shown a complete response with no recurrences at a median follow-up of 17 months.[65] This group also found that the energy delivery at an individual session is best reduced in the treatment of squamous as compared with BE dysplasias in order to reduce complications. This is likely to be because the thickness and the lymphatic supply of the esophageal wall layers differs between columnar- and squamous-lined esophagus. BE results in a thicker mucosal layer with a reduplicated and thickened muscularis mucosae.[65] Preliminary endoscopic resection is strongly recommended before ablation in order to correctly stage early squamous neoplasia, since the likelihood of lymph node metastases becomes significant if invasion is deeper than T1 m2.[135]

Expert Commentary
Endoscopic therapies have transformed the treatment of esophageal cancers. The ultimate goal of ablation therapy is to eradicate all malignancy and all areas retaining an exaggerated malignant potential. Endoscopic surveillance could then be stopped, reducing costs and inconvenience. No ablation therapy is yet able to offer this as recurrence or metachronous lesions can occur after even the most effective of treatments. Repeat local therapy is usually possible and successful, but does rely on patients attending for surveillance endoscopies; some will inevitably fail to attend the follow-up appointments upon which success may depend.[65,136] The excellent outcomes of ER and ablation therapies discussed throughout this article have so far been reported from very few Western centers with a high degree of expertise and large numbers of procedures being performed. We believe that all early neoplasia should be assessed and managed by a multidisciplinary team approach at high-volume centers to achieve optimum patient outcomes

Five-year View
Several abnormalities have been identified in BE cells undergoing malignant change: alterations in the tumor-suppressor genes p53[137] and p16 and the cyclin D1 proto-oncogene[138] and aneuploid or tetraploid cells. A recent prospective study suggests that inactivation of p53 is associated with development of tetraploid cells,[139] which have, in turn, been associated with the development of adenocarcinoma.[140] These studies have been shown in only two centers and have not been replicated more widely. There is hope that these could be important, but the techniques and methodology still need to be validated further. Other factors such as male gender, a young age, a family history of esophageal adenocarcinomas, long-segment BE or the presence of intestinal metaplasia[141] are also important, and a long-term goal will be to stratify malignant risk in those with BE. Large-scale genetic studies are being planned to investigate both risk factors for BE and to predict progression for those with BE to cancer, potentially enabling surveillance and treatment recommendations to be individualized. Ablation therapies and their indications continue to evolve. RFA is a particularly new and promising technique. Currently there is not adequate evidence available as to whom it should be offered. It may be that those with LGD or even nondysplastic BE may benefit, particularly if judged high risk by the aforementioned factors. Long-term results post-RFA are eagerly awaited. A current European multicenter randomized trial is seeking to address potential benefits of RFA in BE LGD. [203] It is our view that the role for ESD in BE neoplasia is likely to shrink as dual modality therapy of ER and RFA gain popularity and acceptance. Its use will be restricted to some select lesions that are difficult to resect by conventional ER techniques but for those lesions it could prove invaluable. ESD combined with laparoscopic regional lymph node dissection[142] and endoscopic full-thickness

resection[143] may, in the future, take us a step closer to avoiding some of the negative outcomes of traditional surgery. Management of HGD and early mucosal cancer in BE has great national and international variance (both surgical and endoscopic therapies). Recently, an international consensus group was convened to provide consensus recommendations based on available medical literature regarding the management of HGD with BE esophagus and early mucosal esophageal cancer (Barrett's Dysplasia and Cancer Taskforce [BAD CAT] consensus group). BAD CAT is due to report in 2011. [144]

Chromoendoscopy

Author: Anil Minocha, MD, FACP, FACG; Chief Editor: Kurt E Roberts, MD more...

Background
Chromoendoscopy is an endoscopic technique that uses stains during endoscopy to highlight differences in mucosa, as well as dysplastic and malignant changes that are not apparent in white light. Chromoendoscopy is used to increase the detection rates for various pathologic processes during endoscopy. Chromoendoscopy is often used in surveillance of the esophagus for Barrett's esophagus, evaluation of polyps in the colon, and surveillance of dysplasia in inflammatory bowel disease.[1]

Indications
Chromoendoscopy has been used in the evaluation of Barrett esophagus,[2]esophageal adenocarcinoma,[3] gastric metaplasia and adenocarcinoma,[4] colon polyps,[5] colon cancer,[6] and surveillance in inflammatory bowel disease.[7]

Contraindications
The contraindications to chromoendoscopy would be any of the usual contraindications to endoscopy or a history of an allergic reaction to the dye or stain used in the specific clinical situation. Chromoendoscopy is not routinely performed during general endoscopy. It is performed in centers that specialize in this field or on a case-by-case basis as indicated by the clinical situation and dictated by the endoscopist's and center's experience.

Periprocedural Care
Patient Preparation
The usual preparation prior to upper endoscopy or colonoscopy and sedation administration is undertaken in the standard manner. Thereafter, specialized preparation of mucosa is done depending on the endoscopic procedure, dye or stain used, suspected lesion, and planned therapy of that lesion.

Clinical Utility
Barrett Esophagus and Esophageal Adenocarcinoma The increasing prevalence of Barrett esophagus and its recognition as a premalignant lesion has engendered a great deal of interest in recognizing metaplastic and dysplastic changes. [8] The increasing use of endoscopic therapy for dysplasia and adenocarcinoma has given further impetus to this concept. Chromoendoscopy is considered by some as a tool in recognizing high risk lesions within Barrett esophagus and in facilitating definitive therapy.[2] The most commonly used dye is methylene blue. Magnification chromoendoscopy is an important adjunctive technique that enhances the sensitivity and specificity.[9] Evaluating lesions in the absence of biopsies based on staining has also been shown to be useful.[10] Unfortunately, the sensitivity and specificity are wide ranging. Randomized controlled trials have shown conflicting results and also equivalency to routine endoscopy. [11] Esophageal Squamous Cancer

Lugol iodine is most commonly used to survey patients at risk for squamous cell carcinoma, including patients with tobacco abuse, alcohol abuse, or past head and neck cancer. [12] The sensitivity is between more than 90% but the specificity is variable.[1] The dye may also be used to guide resection of early lesions. Gastric Metaplasia and Cancer Chromoendoscopy has been used to detect and demarcate dysplasia, intestinal metaplasia, or malignancy.[4, 13, 14] Methylene blue and congo red are used in a combination to differentiate abnormal gastric mucosa (which does not stain) from normal mucosa (which stains red or blue).[15] This may be of utility in high-risk groups targeted for intensive surveillance.[16] There is some evidence that Helicobacter pylori detection in the stomach is better with phenol red chromoendoscopy, although this concept has not been evaluated in clinical trials. [17, 18] Phenol red staining is being studied in assessing the functional recovery of gastric mucosa after H. pylori eradication therapy.[19] Colorectal Adenoma There have been many randomized trials for enhanced adenoma detection with chromoendoscopy using indigo carmine staining.[5, 20, 21] Pohl et al conducted a large randomized controlled trial comparing standard endoscopy to pancolonic chromoendoscopy and showed that chromoendoscopy significantly increased the detection rate for adenomas, flat lesions, and serrated lesions. There was an increase in the mean withdrawal time.[5] Other trials have shown mixed results.[22] There may be a advantage to chromoendoscopy in detecting flat lesions. [23] An increased cancer detection rate or survival rate has not been demonstrated. Chromoendoscopy is currently not of significant utility in screening or surveillance colonoscopy. Colorectal Cancer Chromoendoscopy also has a limited and experimental role in endoscopically assessing the depth of known colorectal cancer.[6] Inflammatory Bowel Disease The difficulty in identifying dysplasia and carcinoma in chronic ulcerative colitis has led to the evaluation of chromoendoscopy in this particular high-risk situation. Many trials have shown that dysplasia detection is improved significantly and reproducibly. [7, 24, 25] The accumulation of evidence may have an impact on chronic ulcerative colitis surveillance guidelines.[26] Evidence with regard to carcinoma detection in this setting is equivocal.[27]

New Technologies
Preliminary evaluations of computerized virtual chromoendoscopy for screening colonoscopy have shown similar efficacy to chromoendoscopy without the logistical difficulties or preparing and applying vital dyes.[28, 29] Magnification endoscopy, spectroscopy, confocal laser endomicroscopy and endocytoscopy have a important role in the evaluation of inflammatory bowel disease and surveillance of chronic ulcerative colitis.[30] Use of these techniques in Barrett esophagus has also led better detection of dysplasia, particularly in the absence of discrete lesions. [14]

Safety
Lugol iodine can rarely cause esophagitis or gastritis. Hyperthyroidism or hypersensitivity to iodine should preclude the use of this agent. Methylene blue can cause discoloration of urine and feces. No serious adverse effects of other vital dyes have been described. General precautions should include aspiration and contact precautions.[1]

Technique
Approach Considerations
The agents used in chromoendoscopy are commercially available and inexpensive. They are not specifically made for endoscopy. They are prepared and diluted based on the practices of the chromoendoscopists. Common staining agents used are Lugol solution, methylene blue, toluidine

blue, crystal violet, indigo carmine, congo red, and phenol red. Special spray catheters are used to spray a fine mist on to the mucosa.[1] The agents are classified as absorptive, contrast, or reactive agents. Absorptive stain are absorbed by or diffuse into specific cells. Contrast agents seep between cells and enhance the surface. Reactive agents undergo chemical reactions with specific cell components and undergo color change.[1]

General Approach
Application of some staining agents requires the application of mucolytic agents such as N-acetyl cysteine to remove mucus from epithelium to allow optimal results with staining. The agent may be applied to a specific area or to the whole mucosal surface of interest. The abnormal mucosa may stain positively (ie, taking up the dye) or negatively (ie, remaining unstained or understained). In general, the minimum amount of dye required is used. Excess dye is suctioned or washed. The time required for optimal staining is variable and depends on the targeted tissue and the stain used. The table below details the properties and uses of each agent.[1] Table. Common Stains, Mode of Action, and Indications[1] (Open Table in a new window)
Stain Absorptive Lugol solution (iodine and potassium Glycogen-containing normal squamous Esophageal squamous cell cancer and Property Clinical Indication

iodide)

epithelium is stained dark brown;

dysplasia

inflammation, columnar mucosa, dysplasia,

Barrett esophagus

and cancer remain unstained

Methylene blue (methylthioninium

Absorptive epithelial cells of the small

Barrett esophagus

chloride)

bowel, colon, and intestinal metaplasia at

Gastric intestinal metaplasia and cancer

any site are stained blue; dysplasia and

Chronic ulcerative colitis

cancer is variably stained or unstained

Toluidine blue (tolonium chloride) Crystal violet (methylrosaniline chloride

Nuclei of malignant cells are stained blue Absorbed into intestinal and neoplastic

Oral and esophageal squamous cell cancer Barrett esophagus

cells; nuclear stain

Colonic neoplasms

Contrast

Indigo carmine (indigotindisulfonate

Nonabsorbed dark bluish dye highlighting

Colonic neoplasms

sodium)

mucosal topography

Chronic ulcerative colitis

Reactive Congo red (biphenylenenaphthadene Color change from red to dark blue/black Ectopic gastric mucosa

sulfonic acid)

in presence of acid at pH 3

Gastric cancer

Adequacy of vagotomy

Phenol red (phenolsulfonephthalein)

Color change from yellow to red in

H. pylori infection

presence of alkali (eg, from hydrolysis of

urea to ammonia and carbon dioxide by

urease-producing H. pylori)

Chromoendoscopy is not an advanced endoscopic technique and is not technically difficult to learn. However, interpretation of the staining patterns requires training and may not always be easy. There is evidence that there is significant intraobserver and interobserver variation. [31, 32]

Guidelines for the Management of Oesophageal and Gastric Cancer

William H Allum; Jane M Blazeby; S Michael Griffin; David Cunningham; Janusz A Jankowski; Rachel Wong Authors and Disclosures Posted: 10/25/2011; Gut. 2011;60(11):1449-1472. 2011 BMJ Publishing Group Ltd and British Society of Gastroenterology

Abstract and Introduction

Introduction
Over the past decade the Improving Outcomes Guidance (IOG) document has led to service reconfiguration in the NHS and there are now 41 specialist centres providing oesophageal and gastric cancer care in England and Wales. The National Oesophago-Gastric Cancer Audit, which was supported by the British Society of Gastroenterology, the Association of Upper Gastrointestinal Surgeons (AUGIS) and the Royal College of Surgeons of England Clinical Effectiveness Unit, and sponsored by the Department of Health, has been completed and has established benchmarks for the service as well as identifying areas for future improvements.[13]The past decade has also seen changes in the epidemiology of oesophageal and gastric cancer. The incidence of lower third and oesophago-gastric junctional adenocarcinomas has increased further, and these tumours form the

most common oesophago-gastric tumour, probably reflecting the effect of chronic gastro-oesophageal reflux disease (GORD) and the epidemic of obesity. The increase in the elderly population with significant co-morbidities is presenting significant clinical management challenges. Advances in understanding of the natural history of the disease have increased interest in primary and secondary prevention strategies. Technology has improved the options for diagnostic and therapeutic endoscopy and staging with cross-sectional imaging. Results from medical and clinical oncology trials have established new standards of practice for both curative and palliative interventions. The quality of patient experience has become a significant component of patient care, and the role of the specialist nurse is fully intergrated. These many changes in practice and patient management are now routinely controlled by established multidisciplinary teams (MDTs) which are based in all hospitals managing these patients.

Structure of the Guidelines

The original guidelines described the management of oesophageal and gastric cancer within existing practice. This paper updates the guidance to include new evidence and to embed it within the framework of the current UK National Health Service (NHS) Cancer Plan.[4] The revised guidelines are informed by reviews of the literature and collation of evidence by expert contributors. [5] The key recommendations are listed. The sections of the guidelines are broadly the same layout as the earlier version, with some evidence provided in detail to describe areas of development and to support the changes to the recommendations. The editorial group (WHA, JMB, DC, JAJ, SMG and RW) have edited the individual sections, and the final draft was submitted to independent expert review and modified. The strength of the evidence was classified guided by standard guidelines. [6]

Categories of Evidence
Ia: Evidence obtained from meta-analysis of randomised controlled trials (RCTs). Ib: Evidence obtained from at least one randomised trial. IIa: Evidence obtained from at least one well-designed controlled study without randomisation. IIb: Evidence obtained from at least one other type of well-designed quasi-experimental study. III: Evidence obtained from well-designed descriptive studies such as comparative studies, correlative studies and case studies. IV: Evidence obtained from expert committee reports, or opinions or clinical experiences of respected authorities.

Grading of Recommendations
Recommendations are based on the level of evidence presented in support and are graded accordingly. Grade A requires at least one RCT of good quality addressing the topic of recommendation. Grade B requires the availability of clinical studies without randomisation on the topic of recommendation. Grade C requires evidence from category IV in the absence of directly applicable clinical studies.

Summary of Recommendations

Prevention
There is no established chemoprevention role for upper gastrointestinal (UGI) cancer, and trials are currently assessing this (grade C). The role of surveillance endoscopy for Barrett's oesophagus or endoscopy for symptoms remains unclear, and trials are currently assessing this (grade B).

Diagnosis
All patients with recent-onset 'dyspepsia' over the age of 55 years and all patients with alarm symptoms (whatever their age) should be referred for rapid access endoscopy with biopsy (grade C). A minimum of six biopsies should be taken to achieve a diagnosis of malignancy in areas of oesophageal or gastric mucosal abnormality (grade B). Endoscopic findings of benign stricturing or oesophagitis should be confirmed with biopsy (grade C). Gastric ulcers should be followed up by repeat gastroscopy and biopsy to assess healing and exclude malignancy (grade B). Patients diagnosed with high grade dysplasia should be referred to an UGI MDT for further investigation (grade B). High resolution endoscopy, chromoendoscopy, spectroscopy, narrow band imaging and autofluorescence imaging are under evaluation and their roles are not yet defined (grade C).

Staging
Staging investigations for UGI cancer should be co-ordinated within an agreed pathway led by a UGI MDT (grade C). Initial staging should be performed with a CT including multiplanar reconstructions of the thorax, abdomen and pelvis to determine the presence of metastatic disease (grade B). Further staging with endoscopic ultrasound in oesophageal, oesophago-gastric junctional tumours and selected gastric cancers is recommended, but it is not helpful for the detailed staging of mucosal disease (grade B). For T1 oesophageal tumours or nodularity in high grade dysplasia, staging by endoscopic resection should be used to define depth of invasion (grade B). Positron emission tomography (PET)-CT scanning should be used in combination with endoscopic ultrasound (EUS) and CT for assessment of oesophageal and oesophago-gastric junctional cancer (grade B). Laparoscopy should be undertaken in all gastric cancers and in selected patients with lower oesophageal and oesophago-gastric junctional tumours (grade C).

Pathology
Diagnosis of high grade dysplasia in the oesophagus and stomach should be made and confirmed by two histopathologists, one with a special interest in gastrointestinal disease (grade C). Reports on oesophageal and gastric resection specimens should concur with the Royal College of Pathologists (RCPath) (grade B). Oesophago-gastric junctional tumours should be classified as type I (distal oesophageal), type II (cardia) and type III (proximal stomach) (grade C).

Treatment: Decision-making

Treatment recommendations should be undertaken in the context of a UGI MDT taking into account patient co-morbidities, nutritional status, patient preferences and staging information. Recommendations made by the MDT should be discussed with patients within the context of a shared decision-making consultation (grade C).

Treatment: Endoscopy
Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) can eradicate early gastro-oesophageal mucosal cancer. EMR should be considered in patients with oesophageal mucosal cancer and both EMR and ESD should be considered for gastric mucosal cancer (grade B). The role of EMR in patients with macroscopic abnormalities within Barrett's oesophagus and ablation of residual areas of dysplasia requires further research (grade C).

Treatment: Surgery
All patients should have antithrombotic (grade A, 1b) and antibiotic prophylaxis (grade C) instituted at an appropriate time in relation to surgery and postoperative recovery. Oesophageal and gastric cancer surgery should be performed by surgeons who work in a specialist MDT in a designated cancer centre with outcomes audited regularly (grade B). Surgeons should perform at least 20 oesophageal and gastric resections annually either individually or operating with another consultant both of whom are core members of the MDT. The individual surgeon and team outcomes should be audited against national benchmarked standards (grade B).

Treatment: Oesophageal Resection

There is no evidence favouring one method of oesophageal resection over another (grade A), and evidence for minimal access techniques is limited (grade C). The operative strategy should ensure that adequate longitudinal and radial resection margins are achieved with lymphadenectomy appropriate to the histological tumour type and its location (grade B).

Treatment: Gastric Resection

Distal (antral) tumours should be treated by subtotal gastrectomy and proximal tumours by total gastrectomy (grade B). Cardia, subcardia and type II oesophago-gastric junctional tumours should be treated by transhiatal extended total gastrectomy or oesophago-gastrectomy (grade B). Limited gastric resections should only be used for palliation or in the very elderly (grade B). The extent of lymphadenectomy should be tailored to the age and fitness of the patient together with the location and stage of the cancer (grade C). Patients with clinical stage II and III cancers of the stomach should undergo a D2 lymphadenectomy if fit enough (grade A; Ib). The distal pancreas and spleen should not be removed as part of a resection for a cancer in the distal two-thirds of the stomach (grade A; Ib). The distal pancreas should be removed only when there is direct invasion and still a chance of a curative procedure in patients with carcinoma of the proximal stomach (grade A; Ib). Resection of the spleen and splenic hilar nodes should only be considered in patients with tumours of the proximal stomach located on the greater curvature/posterior wall of the

stomach close to the splenic hilum where the incidence of splenic hilar nodal involvement is likely to be high (grade C).

Treatment: Chemotherapy and Radiotherapy

Oesophageal Squamous Cell Carcinoma There is no evidence to support the use of preoperative radiotherapy in oesophageal squamous cell carcinoma (grade A; Ia). Chemoradiation is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus (grade A; Ia). Localised squamous cell carcinoma of the middle or lower third of the oesophagus may be treated with chemoradiotherapy alone or chemoradiotherapy plus surgery (grade A; Ib). There is no evidence to support routine use of adjuvant chemotherapy in oesophageal squamous cell carcinoma (grade A; Ia).

Oesophageal Adenocarcinoma (Including Type I, II and III Oesophago-gastric Junctional Adenocarcinoma) Preoperative chemoradiation improves long-term survival over surgery alone (grade A; Ia). There is no evidence to support the use of preoperative radiotherapy in oesophageal adenocarcinoma (grade A; Ia). Preoperative chemotherapy with cisplatin and 5-fluorouracil (5-FU) improves long-term survival over surgery alone (grade A; Ia). Perioperative chemotherapy (combined preoperative and postoperative) conveys a survival benefit and is the preferred option for type II and III oesophago-gastric junctional adenocarcinoma (grade A; Ib).

Gastric Adenocarcinoma
Perioperative combination chemotherapy conveys a significant survival benefit and is a standard of care (grade A; Ib). Adjuvant chemotherapy alone is currently not standard practice for resected adenocarcinoma but has survival benefits in non-Western populations and should be considered in patients at high risk of recurrence who have not received neoadjuvant therapy (grade A; Ia). Adjuvant chemoradiotherapy improves survival and is a standard of care in the USA, and should be considered in patients at high risk of recurrence who have not received neoadjuvant therapy (grade A; Ib). Intraperitoneal chemotherapy remains investigational (grade B).

Palliative Treatment
Palliative treatment should be planned by the MDT taking into account performance status and patient preference, with early direct involvement of the palliative care team and the clinical nurse specialist (CNS) (grade C).

Oesophageal Cancer
Palliative external beam radiotherapy can relieve dysphagia with few side effects, but the benefit is slow to achieve (grade B).

Palliative brachytherapy improves symptom control and health-related quality of life (HRQL) where survival is expected to be longer than 3 months (grade A; Ib). Palliative chemotherapy provides symptom relief and improves HRQL in inoperable or metastatic oesophageal cancer (grade A; Ib). Palliative combination chemotherapy improves survival compared with best supportive care in oesophageal squamous cell carcinoma, adenocarcinoma and undifferentiated carcinoma (grade A; Ib). Trastuzumab in combination with cisplatin/fluoropyrimidine should be considered for patients with HER2-positive oesophago-gastric junctional adenocarcinoma as there is an improvement in disease-free survival (DFS) and overall survival (OS) (grade A; Ib). Oesophageal intubation with a self-expanding stent is the treatment of choice for firm stenosing tumours (capable of retaining an endoprosthesis), >2 cm from the cricopharyngeus, where rapid relief of dysphagia in a one-stage procedure is desirable, particularly for patients with a poor prognosis (grade B). Antireflux stents confer no added benefit above standard metal stents (grade A; Ib). Covered expandable metal stents are the treatment of choice for malignant tracheooesophageal fistulation or following oesophageal perforation sustained during dilatation of a malignant stricture (grade B). Laser treatment is effective for relief of dysphagia in exophytic tumours of the oesophagus and gastric cardia, and in treating tumour overgrowth following intubation (grade A; Ib). For patients whose dysphagia is palliated using laser therapy, the effect can be prolonged substantially by using adjunctive external beam radiotherapy or brachytherapy (grade A; Ib). Photodynamic therapy (PDT) is experimental and its use is not currently recommended (grade B). Argon plasma coagulation (APC) may be useful in treating overgrowth above and below stents and in reducing haemorrhage from inoperable tumours (grade C). There is no indication for local ethanol injection for symptom palliation (grade B).

Gastric Adenocarcinoma
Palliative combination chemotherapy for locally advanced and/or metastatic disease provides HRQL and survival benefit (grade A; Ia). Trastuzumab in combination with cisplatin/fluoropyrimidine should be considered for patients with HER2-positive gastric tumours as there is an improvement in DFS and OS (grade A; Ib). The use of other targeted agents should be confined to the context of clinical trials (grade B). Second-line irinotecan confers a small survival benefit over best supportive care (BSC), but is not currently approved by the National Institute for Health and Clinical Excellence (NICE) (grade A; Ib). Patients of good performance status should be considered for second-line chemotherapy in the context of clinical trials if available.

Follow-up
There is a lack of UK-centred randomised evidence evaluating follow-up strategies (grade C). Audit should be structured with particular reference to outcome measures and should be regarded as a routine part of the work of the MDT (grade C). The development of a role for CNSs in follow-up should be actively pursued (grade C).

Epidemiology
Incidence

Over the past 20 years there has been an annual increase in incidence of adenocarcinoma of the oesophago-gastric junction in the UK. Demographically the peak age group affected is between 50 and 60 years of age, and the male to female ratio varies between 2:1 and 12:1. There have been parallel increases in adenocarcinoma of the gastric cardia, which now accounts for ~50% of all gastric cancers. The age group affected and the sex incidence are similar to those of adenocarcinoma of the lower oesophagus, suggesting a similar aetiology. Despite the rise in gastric cardia tumours, the incidence of gastric cancer is declining, with rates 11% lower in 2000 compared with 1990, because of a decreased incidence in distal gastric tumours.

Aetiology
The relationship between the development of oesophagogastric junctional cancer and chronic GORD is now well established. The risk associated with GORD is related to Barrett's metaplasia. There is also a three- to sixfold excess risk among overweight individuals.[7] Obesity predisposes to hiatus hernia and reflux, and hence contributes mechanically to increase risk. However, data from a number of studies demonstrate an effect independent of reflux. Lindblad and colleagues have reported a 67% increase in the risk of oesophageal adenocarcinoma in patients with a body mass index (BMI) >25, and this increases with increasing BMI. This effect was noted irrespective of the presence of reflux symptoms.[8] The increased risk was only found in obese women (BMI >30), whereas in men it was observed in both overweight (BMI 2529.9) and obese (BMI >30) individuals. The Million Women study confirmed this effect, with 50% of cases of oesophageal adenocarcinoma in postmenopausal women being attributed to obesity.[9] Further evidence is accumulating to support different types of obesity, with the 'male pattern' of abdominal obesity (central and retroperitoneal) more likely to be associated with malignant transformation. This acts as a potent source of growth factors, hormones and regulators of the cell cycle, resulting in a predisposition to developing the metabolic syndrome. In the general population the metabolic syndrome occurs in 1020%, and recent evidence demonstrated that 46% of those with Barrett's oesophagus and 36% of those with GORD have features of the metabolic syndrome. The factors released by centrally deposited fat may have an effect on the process of metaplasia transforming to dysplasia.[10] The role of Helicobacter pylori infection in the aetiology of oesophago-gastric junctional cancer is evolving. The hypochlorhydria associated with H pylori in association with ammonia production from urea by the bacteria may protect the lower oesophagus by changing the content of the refluxing gastric juice. In countries with an increase in oesophago-gastric junctional cancer, there has been a corresponding decrease in incidence of H pyloriinfection. Furthermore, community-based approaches to eradicate H pylori infection in the treatment of ulcer and non-ulcer dyspepsia may be inadvertently contributing to the increase in these cancers. Increases in incidence in true cardia (type II) and type III junctional cancers have parallelled the increase in type I cancers, and the natural history appears to be similar. Some consider the inflammation and metaplasia associated with cardia cancer to be caused by H pylori infection despite many cases presenting with reflux. Recently Hansen and colleagues have proposed that cardia cancer has two distinct aetiologies.[11] In a nested casecontrol study, serum from a defined population cohort followed for the development of gastric cancer was tested for H pylori antibodies and for evidence of atrophic gastritis using as surrogate markers gastrin levels and the pepsinogen I to pepsinogen II ratio. H pylori seropositivity and gastric atrophy were associated with the risk of non-cardia gastric cancer. In cardia cancer there were two distinct groups. In one, serology for H pylori was negative and there was no evidence of gastric atrophy, and in the other H pylori was positive and there was evidence of atrophy. The authors concluded that the former group behaved like non-cardia cancer and were more likely to be diffuse type, and the latter like oesophageal adenocarcinoma and likely to be intestinal type. Such different characteristics would imply a different carcinogenic process at the two sites.

Preventive Strategies
Primary prevention is largely dependent on population education to alter social habits. A reduction in tobacco and alcohol consumption and an increase in a diet of fresh fruit and vegetables may reduce cancer incidence. Intervention trials to prove efficacy of these dietary strategies are lacking. In addition there is an enormous public health need to prevent obesity, which may lead to a reduction in incidence of UGI cancers. The role of H pylorieradication is important, although the potential paradoxical effect on oesophageal junctional adenocarcinoma needs further evaluation. Secondary prevention strategies exploit the natural history and detection of premalignant conditions. Identification of p53 expression and aneuploidy in biopsies of Barrett's oesophagus has been shown to predict the risk of progression.[12] These biomarkers, however, are not validated for routine clinical use. Increasing levels of cyclo-oxygenase-2 (COX-2) in the mucosa are present in the progression of atrophic gastritis to intestinal metaplasia and gastric cancer. However, smoking, acid and H pylori are all associated with COX-2 expression. Recently it has been shown in colorectal cancer, with a similar trend in oesophageal adenocarcinoma, that the level of cytoplasmic -catenin is directly proportional to survival (ie, low levels with poor survival and high levels with good survival). [13] Aspirin and other non-steroidal agents inhibit COX-2 and could be chemopreventative for gastric cancer. Aspirin may have an effect in Barrett's metaplasia and, in combination with acid suppression, may minimise progression to dysplasia. The Aspirin Esomeprazole Chemoprevention Trial (AspECT trial) has successfully completed recruitment of 2513 patients into four arms (20 mg of esomeprazole alone, 80 mg of esomeprazole alone, 20 mg of esomeprazole with low dose aspirin and 80 mg of esomeprazole with low dose aspirin) and may demonstrate whether such a strategy can have a secondary cardiac and cancer preventive effect.[14] Currently advice about chemoprevention using aspirin cannot be given until this trial is complete in 2019. The role of surveillance is yet to be proven, and in this regard the Barrett's Oesophagus Surveillance Study is recruiting another 2500 patients to examine the role of 2-yearly endoscopy versus symptomatic need for endoscopy to reduce oesophageal adenocarcinoma. The role of host genetic susceptibility is shortly to be reported in a genome-wide assessment study called Inherited Predisposition to Oesophageal Diseases which is part of the UK-wide ChOPIN/EAGLE translational science infrastructure.[15]

Diagnosis
Symptomatic Presentation
The UK Department of Health has specified the 'at risk' symptoms for oesophago-gastric cancer which guide referral of patients for investigation and recommends urgent investigation to be performed within 2 weeks of referral.[16] In the Department of Health guide patients with new-onset dyspepsia are recommended urgent referral for gastroscopy only if they are over 55 years. However, early referral for more patients even with minimal symptoms should be considered because clinical diagnosis is often inaccurate and early tumours will not be associated with typical symptoms. Approximately 70% of patients with early gastric cancer (EGC) have symptoms of uncomplicated dyspepsia with no associated anaemia, dysphagia or weight loss.[17] It has recently been demonstrated that use of alarm symptoms to select patients for endoscopy causes patients with localised disease to be overlooked.[18] Clinical diagnosis is very inaccurate in distinguishing between organic and non-organic disease and therefore all patients deemed to be 'at risk' patients with dyspepsia should be considered for endoscopy even though the overall detection rate is only 13%.[19] In summary, patients with dyspepsia who are older than 55 years of age with persistent new-onset symptoms or those with alarm features at any age should undergo an endoscopy. An endoscopy with biopsies should be considered for patients in whom there is a clinical suspicion of malignancy even in the absence of alarm features.

Endoscopy
Video endoscopy and endoscopic biopsy remain the investigations of choice for diagnosis of oesophageal and gastric cancer performed by an experienced endoscopist, trained according to the Guidelines of the Joint Advisory Group on Gastrointestinal Endoscopy. [20] It is recommended that endoscopy reporting should be in a standard manner detailing descriptions, dimensions and locations of lesions in relation to anatomical landmarks. Failure to diagnose UGI malignancy at the patient's first endoscopy is consistently in the range of 10%, while a further 1020% require a second gastroscopy.[21 22] The principal factors associated with the need to re-endoscope are failure to suspect malignancy and (as a consequence) failure to take adequate numbers of biopsies. In oesophageal endoscopic examination the diagnostic yield to detect high risk premalignant lesions in Barrett's reaches 100% when six or more samples are obtained using standard biopsy forceps. [23] Multiple four quadrant biopsies of the oesophagus at 2 cm intervals along its entire length have been shown to increase diagnostic accuracy and allow differentiation of high grade dysplasia from adenocarcinoma, particularly when endoscopic mucosal abnormalities are present.[24 25] Whether or not the index endoscopy should be done on or off proton pump inhibitor (PPI) therapy is controversial. Inflammation can confound the diagnosis of dysplasia, whereas one retrospective study suggested that PPIs may mask endoscopic findings.[21] However, treatment with a PPI may also delay diagnosis or result in a misdiagnosis on first endoscopy. [21] In particular the ability of PPIs to 'heal' malignant ulcers or alter their appearance has not been fully appreciated. [26] Overall, PPIs should be stopped for the first endoscopy. For subsequent endoscopies in patients known to have Barrett's oesophagus, continuing treatment can decrease inflammation, making targeted biopsies and histological assessment easier. If the lumen is obstructed by tumour then an ultrathin endoscope (OD, 5.36 mm) should be used. Oesophageal dilatation for the purposes of diagnosis should be avoided due to the high risk of perforation which may deny these patients a chance of cure. [27]

Endoscopic Adjuncts
Chromoendoscopy and high resolution endoscopy have been introduced in selected centres although their role has yet to be defined. Contrast enhancing and vital dyes sprayed onto the oesophago-gastric mucosa can aid in the detection of early lesions. The most well established are Lugol's iodine for dysplastic and malignant squamous mucosa and indigo carmine for early cancer in gastric mucosa. [28 29] Acetic acid chromoendoscopy enhances detection of occult neoplasia in Barrett's. [30] Currently, these techniques are only recommended in selected patients deemed at high risk. Furthermore, with the advent of new endoscopic modalities such as narrow band imaging and autofluorescence and with the development of magnifying (zoom) and confocal endoscopes, these techniques may be superseded.[31] However it should be emphasised that there are no randomised data to indicate that these modern techniques are as good as conventional histopathology let alone suitable to replace it.[32] There is increasing interest in ultrathin nasal endoscopy and non-endoscopic approaches which have the potential to be used in the outpatient setting with increased patient acceptability. [33 34]

Higher Risk Groups

Individuals at increased risk of oesophago-gastric cancer on the basis of family history (tylosis) or a premalignant condition (Barrett's oesophagus, pernicious anaemia, intestinal metaplasia of the stomach or previous gastric surgery) may be considered for endoscopic monitoring. These decisions are complex and should be determined by balancing the magnitude of the benefits against the perceived clinical risks of the procedure and patient preferences. Patients with a family history of gastric cancer should be assessed to determine the risk of hereditary diffuse gastric cancer and referred for management at appropriate centres.[35] The principal condition for which endoscopic

surveillance may be recommended in the UK is for diagnosed Barrett's oesophagus. Currently there are not any recommendations to screen individuals with reflux for the presence of Barrett's oesophagus in the primary care population. However, in the annual report of the Chief Medical Officer published in 2008, minimally invasive screening tests were put high on the research agenda due to the worrying increase in the incidence of oesophageal adenocarcinoma. [36] The recent report of spoge cytology to select for endoscopy is a novel and encouraging approach. [33]

Staging
Advances in therapeutic techniques including the use of multimodality treatment regimens require accurate initial staging and assessment of treatment response. Imaging techniques should provide staging assessment according to the TNM classification. Since up to 50% of patients present with metastatic disease, initial assessment must establish the presence or absence of distant disease. Precise local staging is required to determine the depth of tumour spread in early tumours which may be amenable to endoscopic resection. In more advanced tumours accurate local staging should include depth of invasion with reference to surgical margins with clear delineation of craniocaudal and radial margins and presence and extent of lymph node metastasis to determine the likelihood of regional control. The principal imaging modalities for staging are multidetector CT (MDCT), EUS and PET integrated with CT (PET-CT). Although MDCT has been the initial modality to exclude gross metastatic disease, all three techniques should be used in combination to provide comprehensive staging detail.

Technique
Endoscopy
Endoscopy and EMR is an essential method to stage early neoplasia. It is indicated for the assessment of areas of Barrett's with dysplasia and nodularity where invasive disease is suspected. The depth of resection is usually into the submuosa. In a comparative study Wani and colleagues found submucosa in 88% of EMR samples compared with 1% of biopsy samples, and the overall interobserver agreement for the diagnosis of neoplasia was significantly greater for EMR specimens than biopsy specimens.[37]It allows assessment not only of depth of penetration but also of degree of differentiation and vascular and lymphatic involvement. It is superior to EUS in staging early T1 cancers.[3840]

CT Scanning
MDCT images of the chest, abdomen and pelvis are acquired at fine collimation enabling multiplanar reformats to be performed with the same resolution as axial images (slice thickness should be 2.55 mm). The studies should be performed after intravenous contrast unless contraindicated. One litre of water can be used as an oral contrast agent. It is optimal to give ~200 ml just prior to the scan for oesophageal cancer and 400 ml for gastric cancer. Antiperistaltic agents together with gas-forming granules can be administered prior to scanning to achieve maximum distension, although generally sufficient distension is achieved from using water alone. Tumours in dependent areas such as at the oesophago-gastric junction can be imaged prone or in the decubitus position. The use of multiplanar reformat images in addition to axial images improves the accuracy particularly for T3 versus T4 disease, due to the ability to evaluate possible invasion of tumour into its surrounding structures in multiple planes.[41 42] MDCT also allows for volumetric analysis, so-called 'virtual endoscopy'. Some recent experimental studies in small patient cohorts have shown an additional benefit of using the virtual endoscopy images together with conventional axial images. The three-dimensional (3D) endoscopic view improves radiological detection of early tumours which manifest as shallow ulcers, not detected on the axial images.[43 44]

Endoscopic Ultrasound
EUS should be performed by experienced endosonographers utilising the full range of modern radial and linear equipment.[45 46] Outcome is experience related. Centres should perform at least 100 staging examinations annually, and each centre should have at least one fully trained endosonographer. EUS examination may be limited by stricture formation. Dilatation has a high risk of perforation. [47] Options to assess strictured cancers include the blind tapered probe which improves the percentage of traversable tumours or the miniprobe in combination with guidewire placement under radiological screening.[48] Nodal metastases are suggested by four echo pattern characteristics: (1) size >10 mm; (2) welldefined boundary; (3) homogeneously low echogenicity; and (4) rounded shape. All four may only be present in 25% of cases thus significantly reducing sensitivity. [49 50] EUS fine needle aspiration (FNA) cytology of potential nodal disease has been shown to improve accuracy. At least three passes with the EUS-guided FNA needle are recommended to maximise sensitivity.[51] Although EUS alone is not suitable for M staging, combination with FNA is an accurate and safe method for assessment of solid lesions such as adrenal or liver metastases or for aspiration of ascites.[52 53]

PET and PET-CT Scanning

The combination of metabolic assessment with 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) PET and integrated CT provides both functional and anatomical data. The key advantage of the technique is that patient position is unchanged between each procedure and this allows for reliable co-registration of the PET and the CT data. Several technical issues remain to be evaluated such as the use of iodinated contrast media, CT technique, and optimal FDG dose and uptake period.

T Staging
EMR is the preferred approach for assessing mucosal and submucosal penetration in small early (T1) cancers. EUS is more accurate for T staging in more advanced lesions because of the precise visualisation of the separate layers of the oesophageal and gastric wall. MDCT is limited for early stage disease. Similarly, studies with PET-CT have reported failure to detect early stages (T1 and T2) and poorly cellular mucinous tumours. In addition, smooth muscle activity and GORD may artefactually produce false-positive results. In gastric cancer, tumour site, size and histological type affect FDG-PET detection. Distal tumours, T1 and T2 tumours, and diffuse-type cancers show consistently low rates of detection.[54]

N Staging
The assessment of nodal disease by each technique is variable according to the anatomical relationship of lymph nodes to the primary tumour. EUS (alone or in combination with CT) has a sensitivity of 91% for detecting local nodal disease.[55] Although PET-CT can identify local nodes, avid uptake by the adjacent tumour can obscure uptake by small volume metastatic nodes. For regional and distant nodal disease, PET-CT has been shown to have a similar or better accuracy than conventional EUS-CT (sensitivity and specificity 46% and 98% vs 43% and 90%, respectively; sensitivity and specificity 77% and 90% vs 46% and 69%, respectively). Thus a combined approach with CT, EUS and PET-CT has the highest possible yield for accurately assessing nodal status. [55]

M Staging
Conventional imaging with EUS and CT has a wide range of accuracy for detecting metastatic disease (sensitivity 3746%, specificity 6380%). The addition of PET has significantly improved detection rates (sensitivity 6978%, specificity 8288%), and this is particularly advantageous for identifying

unsuspected metastatic disease which is present in up to 30% of patients at presentation. The American College of Surgical Oncology Group trial of PET to identify unsuspected metastatic disease has demonstrated some limitations, with 3.7% false-positive and 5% false-negative rates.[56] PET has similar limitations to CT in detecting peritoneal disease possibly due to lesion sizes of <5 mm and a low viable cancer cell to fibrosis ratio.[54] The most recent studies with PET-CT have shown superior accuracy over PET and CT performed separately, particularly in the neck, locoregional nodes and in postoperative fields. Further evaluation (including surgical excision or biopsy) of PET/CT-positive unusual nodes or single 'hot spots' is recommended because of the potential risk of false positives.

Laparoscopy
Laparoscopy is established for direct visualisation of low volume peritoneal and hepatic metastases as well as assessing local spread for operability, particularly in gastric cancer. de Graaf and colleagues have reported additional treatment information from laparoscopy in 17.1% of distal oesophageal and 17.2% of oesophago-gastric junctional tumours, as well as 28% of gastric cancers. [57] The addition of peritoneal cytology has been debated, with regard to whether positive cytology in the presence of operable gastric cancer with subserosal or serosal invasion would change surgical planning. Nath and colleagues have recently shown that patients with oesophageal and junctional cancers with positive peritoneal cytology have a poor prognosis, with a median survival of 13 (range 3.122.9) months.[58] The authors concluded that such patients should not proceed to radical surgery and be considered for palliative intervention.

MRI
There is no clear evidence that MRI offers any advantage over CT and EUS in the local staging of oesophageal or gastric cancer.[59 60] The majority of studies to date have used either low field strength magnets or ex vivo analysis.[61] There has been some recent development using a high resolution technique with an external surface coil for local staging of oesophageal cancer which shows promise, although the work requires substantiating in a larger clinical series. [62] MRI is also useful in the characterisation of indeterminate liver lesions detected on CT.[63 64]

Bronchoscopy
Tumours at or above the level of the carina may invade the tracheobronchial tree, and this can be assessed with bronchoscopy and biopsy if indicated. In experienced hands, EUS alone may be sufficiently accurate to exclude airway invasion, but if there is uncertainly a bronchoscopy should be performed.[65] This may be supplemented with endobronchial ultrasound in combination, if appropriate, with guided aspiration for cytology of mediastinal nodes.

Pathology
The RCPath and the Pathology Section of the British Society of Gastroenterology strongly advocate that there should be standardisation of reporting guidelines of all cancers.[66] Such an approach is intended to provide both the patient and clinican with prognostic information, allowing the clinician to determine the most appropriate clinical management and facilitate audit of diagnostic and therapeutic interventions.

Process
The RCPath Guidelines recommend approaches to the practical handling of biopsies and endoscopic and surgically resected specimens. Histopathologists are advised to ensure all pathological material from patients referred to the MDT is reviewed and correlated with clinical and radiological information. In addition specimens of squamous and glandular dysplasia and high grade dysaplasia and early cancer in Barett's metaplasia should be reported by two independent, named expert pathologists. [67]

Referral for Review or Specialist Opinion

Referral for Treatment All patients referred for specialist treatment must be reviewed and discussed by the MDT. The complete diagnostic pathology report must be available and the histological and/or cytological material should be reviewed prior to, and at, the meeting. This is particularly important if there is a significant discrepancy with the clinical/radiological findings. A formal report should be issued by the reviewing pathologist to the clinician or pathologist initiating the referral. Where patients have been referred for non-surgical oncology treatment, requests for specialist biomarker studies will be coordinated between the treating oncology service, their local pathology service and the referring hospital's pathology service, as appropriate. Referral for Specialist Opinion In cases of diagnostic difficulty, referral will be made to the Lead Pathologist of the specialist MDT, although referral to other specialists within or outside the network may be appropriate in individual cases. Cases referred for individual specialist or second opinion will be dealt with by the individual pathologist and a report issued by them. Where relevant, tissue blocks should be made available to allow any further investigations that are deemed appropriate. It is strongly recommended that slides and blocks are not posted together: if they are, then there is a danger that the entire specimen is lost for ever. All diagnostic material should be reviewed and presented at the MDT meeting so that the individual case can be discussed with full knowledge of all relevant pathological findings. External diagnoses of dysplasia, especially when further treatment is being considered (such as radical surgery, EMR, ESD or ablation therapy), should also be reviewed at an MDT meeting and the diagnosis confirmed by at least two gastrointestinal pathologists. More unusual tumours (such as lymphoma, melanoma, endocrine tumours, small cell carcinoma or gastrointestinal stromal tumour (GIST)) should be reviewed in the course of the MDT meeting.

Data Sets for Reporting

The data sets have been subdivided into core and non-core data. Core data are the suggested minimum requirement for appropriate patient management, such data having been shown to be of prognostic significance. Non-core data are additional data that do not have a sufficient basis in published evidence to be a requirement, but may be of potential interest and use in patient management. The data items required for diagnostic biopsies, endoscopic resection specimens and therapeutic resections are shown in Table 1. Specimen photography is invaluable in recording the macroscopic appearances of pathological specimens and aids with radiological audit. Photography should include the undissected specimen to demonstrate margins and potential defects in margins, and also the entire sliced specimen to demonstrate the quality of surgery and the extent of depth of spread of the tumour. In both oesophageal and gastric cancer, the end resection margins are also very important and should be sampled in all cases. Submucosal lymphovascular spread, in particular, can result in involvement of margins, particularly of the proximal oesophageal margin at a very considerable distance from the primary tumour. For circumferential margin assessment, there is little value in attempting to measure the distance from the tumour to the circumferential margin if there has been previous surgical dissection of the specimen for perioesophageal lymph nodes; therefore, it is recommended that all oesophagectomy specimens are left entirely in situ after surgical removal to allow the pathologist to assess circumferential resection margins accurately. The data set items may be reported in a proforma either within or instead of the free text part of the pathology report, or recorded as a separate proforma. In general the recording of both free text report and of all items in the RCPath data sets is recommended, the latter in a structured way, either directly onto such a proforma or alternatively using the same structure on the pathology report. Trusts and MDTs should work towards recording and storing the data set items as individually categorised items

in a relational database, so as to allow electronic retrieval and to facilitate the use of pathology data in clinical audit, service planning and monitoring, research and quality assurance. It is anticipated that such data recording will become a requirement as part of recommendations of the UK National Cancer Intelligence Network.[69] Laboratories should use an agreed diagnostic coding system (eg, SNOMED). All malignancies should be reported to the local Cancer Registry. Grading Conventions Riddell-type classifications are recommended for the grading of all dysplasia in the UGI tract.[70] The Revised Vienna classification of gastrointestinal epithelial neoplasia can be used but this system has not found particular favour in the UK.[71] The WHO invasive carcinoma grade system is recommended for tumour grading.[72] Staging Conventions The RCPath Guidelines have been based on the TNM 5th/6th editions. There were, however, discrepancies between the two editions and, as a result, the guidelines recommended TNM 6 for oesophageal cancer and TNM 5 for gastric cancer. However, pathological staging of oesophago-gastric junctional cancer was not defined. The Siewert classification was recommended, although this largely describes clinical features.[73 74] For practical purposes, the guidelines recommended that if >50% of the tumour involved the oesophagus the tumour should be classified as oesophageal, if <50% as gastric. Tumours exactly at the junction should be classified according to their histology, so squamous cell, small cell and undifferentiated carcinomas should be oesophageal and adenocarcinomas should be gastric. In 2009 the Union for International Cancer Control in collaboration with the American Joint Committee on Cancer published TNM 7th edition which has significantly changed the staging descriptions. [75 76] The issue of oesophago-gastric junctional cancer has disappeared. Tumours including the oesophagus and within 5 cm of the oesophago-gastric junction are classified as oesophageal cancers and all others are gastric cancer. The T stage has now become consistent with T2 and T3 tumours defined for both sites; the previous T2a and T2b subgroups in gastric cancer have been removed. Nodal staging for both oesophageal and gastric cancers has been unfied with N0, N1, N2 and N3 subgroups. This revision has created significant concerns particularly as historical comparisons will now be more difficult. The RCPath has recently recommended that TNM 7 should be adopted in the UK. This will take some time to implement and the effect on practice is likely to evolve. The current consensus is that TNM 7 will become the standard for staging, but the clinical classification will continue with the Siewert system as this will influence the selection of surgical procedure. The effect on clinical trials, however, is more difficult to predict as the current large trials are based on TNM 5 and 6 criteria.

Pretreatment Assessment
The aim of preoperative co-morbidity assessment is to provide the opportunity of optimising the patient's physiological status to undergo potentially curative treatment (including surgery or definitive chemoradiotherapy). There are a number of established risk predictors, but there is a lack of consensus on the selection criteria for patients undergoing gastric and oesophageal resection or radical chemoradiotherapy or radiotherapy alone.

Exercise Testing
Poor exercise tolerance correlates with an increased risk of perioperative complications which are independent of age and other patient characteristics. Although exercise capacity is a subjective estimation it can be a useful measure of functional cardiorespiratory reserve. Any patient who remains asymptomatic after climbing several flights of stairs, walking up a steep hill, running a short distance, cycling, swimming or performing heavy physical activity should tolerate UGI surgery. However, it is important to appreciate that an apparent ability to perform these activities does not exclude

cardiorespiratory disease and, indeed, this is a major criticism of exercise testing performed in the absence of cardiopulmonary monitoring.[77] Malnourished patients will also exhibit a reduced exercise tolerance. The true value of preoperative exercise testing currently remains debatable. In the absence of accepted evidence-based data, and the lack of an agreed protocol, exercise testing for UGI cancer surgery patients remains an area worthy of consideration and evaluation but should not be used as a sole criterion for denying someone an operation. Stair Climbing Patients with poor exercise tolerance, defined as an inability to climb two flights of stairs without stopping, have more co-morbidity, higher ASA (American Society of Anesthesiologists) scores and postoperative complications. Although this test is a subjective assessment, there is some evidence that where this is not possible there is an almost 90% chance of developing postoperative cardiorespiratory complications.[78 79]Desaturation during exercises equivalent to climbing three flights of stairs, suggesting an inability to meet the increased metabolic demands of exercise, appears to have some predictive power as regards postoperative complications in patients undergoing lung reduction surgery. Exercise-induced hypotension, possibly indicating ventricular impairment secondary to coronary artery disease, is an ominous sign and must be further investigated.[77] Cardiopulmonary Exercise (CPX) Testing CPX testing is a dynamic non-invasive objective test that evaluates the ability of the cardiorespiratory system to adapt to a sudden increase in oxygen demand.[79] The ramped exercise test is performed on a cycle ergometer with ECG monitoring and analysis of expired carbon dioxide and oxygen consumption, the latter being directly related to oxygen delivery and a linear function of cardiac output when exercising. A 24% incidence of previously undetected and 'silent' ischaemic heart disease has been reported during CPX testing. [79] With increasing exercise, oxygen consumption will eventually exceed oxygen delivery. Aerobic metabolism becomes inadequate to meet the metabolic demands, and blood lactate rises, reflecting supplementary anaerobic metabolism. The value for oxygen consumption at this point is known as the anaerobic threshold (AT), expressed as ml/kg/min. A greater mortality has been reported in patients with an AT <11 ml/kg/min undergoing major abdominal surgery, the risk being compounded by the presence of ischaemic heart disease.[79] Advocates of CPX testing claim the results can be used to stratify operative risk, identify those who will most benefit from presurgery optimisation and facilitate anaesthetic and postoperative care. It may be particularly useful in those patients in the intermediate risk group of the ACC/AHA (American College of Cardiology/American Heart Association) preoperative cardiac evaluation guidelines. A valued reliable preoperative assessment of risk is crucial in this group, but can be fraught with difficulties.[79] In a study of 91 patients who had undergone transthoracic oesophagectomy, maximum oxygen uptake during exercise correlated well with postoperative cardiopulmonary complications.[80] The authors concluded that transthoracic oesophagectomy can safely be performed on patients with a maximum oxygen uptake of at least 800 ml/min/m2. This conclusion has been disputed in a recent study of 78 consecutive patients who had CPX testing prior to oesophagectomy, where CPX testing was found to be only of limited value in predicting postoperative cardiopulmonary morbidity. [81] Limitations of CPX testing can occur in patients with reduced lower limb function related to osteoarthritis or limb dysfunction. Shuttle Walk Test A simpler and more viable alternative to CPX testing is incremental and progressive shuttle walk testing (SWT).[82] SWT endurance appears to correlate well with oxygen utilisation seen in CPX. In a study of 51 patients undergoing oesophageal resection, preoperative SWT was a sensitive indicator of 30 day operative mortality. Although the causes of death or complications were not recorded, no patient who walked >350 m on SWT died. [83] The authors suggest

that the inability to maintain adequate oxygen delivery, as reflected by an exercise tolerance of <350 m at SWT, may impair wound healing and increase anastomotic failure. Patients with musculoskeletal disease and morbid obesity may be unable to complete any form of dynamic exercise testing. In such circumstances, upper limb ergometry, pharmacologically induced myocardial stress testing monitored by thallium imaging or ECHO cardiography may be an alternative. Meticulous history taking, clinical examination, baseline investigations and exercise testing will help identify those patients who need further non-invasive or invasive investigation such as echocardiography, myocardial stress testing, imaging and angiography. [84] Only after thorough assessment can the appropriateness of the planned anaesthesia and surgery be determined.

Nutritional Status
Preoperative malnutrition is associated with higher rates of morbidity, including infection, delayed wound healing and pulmonary complications (including adult respiratory distress syndrome with associated increased mortality).[85] Malnutrition is common and may be related to dysphagia, disease cachexia or neoadjuvant chemotherapy. Assessment of nutritional status at presentation and before surgery is therefore recommended. Malnutrition is defined as: A BMI of <18.5 kg/m 2 Unintentional weight loss >10% within the last 36 months A BMI <20 kg/m2 and unintentional weight loss >5% within the last 36 months.

Additional biochemical measures can contribute to the assessment of nutritional status, although serum albumin which reflects an acute phase response is not a reliable marker of malnutrition.[86]

Perioperative Optimisation
Appropriately directed perioperative care is associated with an improved surgical outcome in those with recognised risk predictors. Establishing that current treatment for co-existing cardiorespiratory disease is optimal is essential prior to any additional interventions directed towards optimising preoperative status.

-Blockade
There has been much interest in adrenergic -blockade prior to major surgery as a means of improving ischaemic ventricular dysfunction.[87] Current ACC/AHA guidelines suggest that -blockers should be considered in all patients with an identifiable cardiac risk as defined by the presence of more than one clinical risk factor.[86 88] For the treatment to be efficacious, patients should be optimally -blocked in the weeks preceding elective surgery and continued throughout the immediate postoperative period. Although no particular -blocker has been identified as preferable, long-acting blockers initiated before surgery were thought to be superior to shorter acting drugs.[88] The protective mechanism of -blockers is unclear, the control of heart rate being only part of the explanation. In contrast, recent critical expert re-evaluation of perioperative -blockade has questioned the validity of some of the evidence that -blockers are indeed cardioprotective.[89] Adverse effects can be associated with -bockade, especially the non-selective -blockers. Vagal responses to surgery and anaesthesia can be exacerbated by concomitant -blockade, and responses to sympathomimetic inotropes may be altered.

Statins

There is growing interest in statins as a pre-emptive intervention treatment in the preoperative period in patients with ischaemic heart disease or hypercholesterolaemia. A meta-analysis of postoperative outcome following cardiac, vascular and non-cardiac surgery demonstrated a significant reduction in early postoperative mortality in patients taking long-term statins.[90] An alternative review, however, felt that the evidence for the routine perioperative use of statins to reduce cardiovascular risk was currently lacking.[91] To date no specific studies evaluating perioperative statin treatment and postoperative outcome following gastric or oesophageal surgery have been reported. Current ACC/AHA guidelines on perioperative cardiovascular care recommend that patients should continue statin treatment throughout the operative period.[84] Until further prospective studies can clarify the true value of statins in the perioperative period, their continuation is at the discretion of the attending clinician.

Goal-directed Haemodynamic Preoptimisation

The normal physiological response to surgery is to increase oxygen delivery by an increase in cardiac output. Shoemaker and colleagues showed that patients who incurred an oxygen debt as a consequence of limited cardiorespiratory reserve incurred more postoperative morbidity and mortality.[92] Non-survivors tended to have the greatest and most persistent oxygen debt. Goal-directed optimisation aims to attain predetermined target physiological parameters that are known to correlate with a favourable outcome. With the aid of invasive monitoring, using crystalloid, colloid, blood, inotropes and oxygen, heart rate, stroke volume, haemoglobin and oxygen saturation can be manipulated. Following a period of preoptimisation, a reduction in mortality and length of hospital stay was reported, with preoperative fluid loading considered the most important factor. [93] A positive effect on surgical outcome after oesophagectomy has been demonstrated with judicious fluid administration. [94] When fluid loading alone fails to attain the predetermined physiological targets, inotropes such as dopexamine, dobutamine and epinephrine have been used. However, they can alter regional blood flow, cause tissue hypoxia and increase myocardial oxygen demand, provoking ischaemia. An adequate cardiac output is not necessarily synonymous with good regional or anastomotic blood flow. Goal-directed preoptimisation may be beneficial in appropriately selected high risk patients. It has been advocated that only those patients undergoing surgery for which mortality exceeds 20% and those identified as high risk during risk stratification should be considered.

Nutritional Support
Patients who are identified as malnourished prior to surgery should be considered for preoperative nutritional support for 1014 days.[95] Liquid nutritional products containing immunonutrients, namely arginine, omega-3 fatty acids and nucleotides, have been used in preoperative and postoperative patients undergoing surgery for UGI malignancies. Some, but not all, RCTs have demonstrated a reduction in postoperative infective complications in both malnourished and normally nourished patients when used for 57 days preoperatively.[9698] Studies in malnourished patients included use of both preoperative and postoperative immunonutrition and it may be that this group of patients require immunonutrition both preoperatively and postoperatively to gain benefit. Its use may also reduce length of hospital stay.[98100] Postoperative feeding via the jejunal route is routine in some centres, and this may improve nutritional status, although evidence to show improved clinical outcomes compared with standard care is currently lacking. It is recommended that nutritional support should be provided for all patients who are malnourished or at risk of malnutrition and have an inadequate oral intake defined as having eaten little or nothing for >5 days and/or likely to eat little or nothing for the next 5 days or longer. Preferably

this should be given via the gastrointestinal tract if it is functioning and adequate access can be obtained.

Thromboembolic Disease
Venous thromboembolism (VTE) is a not infrequent co-morbidity in patients with oesophageal or gastric cancer. This is not only because of the higher risk of VTE for patients with malignancy but also because VTE is associated with some chemotherapy regimens. All patients considered for surgery should be offered VTE prophylaxis according to NICE guidance.[101] Patients who have recently sustained a VTE should be considered for placement of temporary caval filters prior to radical surgery.

Treatment
Endoscopic Therapy
Endoscopic therapy has become an integral part of the multidisciplinary management of oesophageal and gastric cancer. The UK NICE guidance recommends that such procedures need to be carefully audited in high volume tertiary referral centres with access to an oesophageal and gastric cancer surgeon, should be performed by appropriately trained staff, and patient care must be managed through an MDT.[102 103] EMR and ESD, PDT, mucosal ablation using lasers (photothermal), electrocoagulation, APC and radiofrequency ablation (RFA) (thermal) have all been employed to remove dysplasia and early cancer. Most techniques are now being used in combination to eradicate local disease and address any field change abnormality.[104106] It is important to emphasise that patients must have reversal of the underlying abnormality with reflux control and H pylori eradication and have repeat endoscopic surveillance to detect metachronous or recurrent tumours.

Oesophageal Cancer and High Grade Dysplasia

Pathology The pathology of early cancer of the oesophagus varies with histological subtype. In one review, Stein and colleagues reported that submucosal infiltration was more frequent in T1 squamous cancers (80.5%) than in T1 adenocarcinomas (55.4%).[107] The risk of lymph node involvement is also greater in squamous cell carcinoma. An analysis of 1690 lesions has reported the risk of lymph node metastases with early oesophageal squamous carcinomas as being 19% for lesions invading the muscularis mucosa and 44% for lesions invading deeper than the superficial one-third of the submucosa.[108] In contrast, the risk of nodal disease in adenocarcinoma limited to the muscularis mucosa is negligible. In submucosal infiltration of adenocarcinoma the risk of lymph node spread reflects the depth of invasion. Once penetration into the superficial third (sm1) has occurred, the risk is 08% and once through into sm2 and sm3 it rises to at least 26%.[38]

Treatment
Endoscopic Resection Data from the from the Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute (USA) examined patients with stage 0 (Tis N0 M0) and stage 1 (T1 N0 M0) early adenocarcinoma of the oesophagus. This demonstrated no significant difference in survival of patients treated with endoscopic therapy compared with those having a radical surgical resection.[109 110] Endoscopic resection is indicated for early cancer (T1mN0), moderately and well differentiated cancers and mucosal dysplasia.[111] There are now consistent reports indicating a 5 year disease free survival (DFS) of 95% and a low morbidity rate.[112114] Similarly, early mucosal Barrett's cancer and dysplasia can be safely eradicated.[105] The use of a single and purely localised therapy can result in the development of metachronous cancer in up to 30% of patients. The risk of recurrence can be

reduced to 16% by ablation of the remaining Barrett's epithelium with PDT, with a complete long-term control of 96% at a median of 5 years follow-up.[105]Similarly eradication of the Barrett's segment with RFA improves local control particularly for flat areas of dysplasia and reduces the risk of malignant degeneration.[115 116] Comparative studies (non-randomised and retrospective) of surgery and endoscopic ablation therapy for dysplasia and early cancer are misleading because of selection bias.[110 117 118] Patients selected for endotherapy are older with earlier tumours and small segments of Barrett's oesophagus. Overall survival (OS) and cancer-related mortality seem to be very similar (>90%), with significantly fewer complications associated with endotherapy.[110 117 118] Circumferential EMR is associated with stricture formation but can be used to destroy the field change in Barrett's oesophagus and eradication of mucosal cancer.[119 120] Well-designed and conducted RCTs comparing the effectiveness and costeffectiveness of endoscopic therapy with surgical resection are urgently required. Photodynamic Therapy Treatment of early cancer and high grade dysplasia in Barrett's oesophagus, squamous cell dysplasia/cancer and adenocarcinoma of the oesophagus with PDT has resulted in prolonged survival which is comparable with surgery.[118 121123] There are large case series of PDT for the treatment of Tis, T1 early and some T2 squamous cell and adenocarcinoma, with a complete response reported of 4093% with follow-up of 447 months.[118 122125] The main complications have been skin photosensitivity and stricture formation, with perforation occurring in 434% of patients. In a randomised trial using PDT to eradicate high grade dysplasia, patients (208) were randomised 2:1 to endoscopic PDT with omeprazole or received omeprazole (control) only. [126] There was a significant difference (p<0.0001) for PDT (106/138=77%) compared with control (27/70=39%) in complete ablation of high grade dysplasia. The occurrence of adenocarcinoma in the photodynamic group was significantly lower (p<0.006). The response remains robust at 5 year follow-up.[126] PDT is the most cost-effective solution for the management of high grade dysplasia in Barrett's oesophagus when compared with surveillance and radical surgery.[127 128] Thermal Ablation Laser, APC, Electrocoagulation, Cryotherapy, RFA These methods are used to eradicate field change in Barrett's oesophagus, destroy any occult synchronous cancers and prevent the development of metachronous lesions after EMR of all macroscopic lesions. The optimal method of ablation has been much debated.[129] Since APC is in widespread use, many single device and comparative studies have compared this with other methods. Current evidence shows that complete eradication rates vary from 38% to 99%.[130133] It is important to have profound acid suppression.[134] Complications of haemorrhage, perforation and stricture do occur (10%). An RCT comparing APC against endoscopic surveillance following antireflux surgery demonstrated significant reversal of Barrett's (follow-up 12 months) following APC.[135] Randomised studies have compared APC with PDT. The results vary, with no significant difference between ALA (5-aminolaevulinic acid)-PDT and APC, and others finding APC simpler and more effective.[136 137] Photofrin PDT was more effective than APC in eradicating, dysplasia although not significantly so (12 months follow-up). The complication rate was similar but PDT was more costly.[138] Multipolar electrocoagulation requires fewer treatment sessions than APC, with an ablation rate of 88% compared with 81% (APC).[139] None of these trials was able to assess progression to cancer. RFA has proved an effective method for eradication of preneoplastic Barrett's epithelium.[140 141] Recent randomised data compared RFA with sham treatment, and have demonstrated the short-term

effectiveness of RFA. Eradication of dysplasia and prevention of progression to cancer in patients with dysplastic Barrett's oesophagus was achieved using RFA. At 12 months high grade dysplasia was eradicated in 81%, with only 2.4% progressing to cancer (RFA) compared with 19.0% eradication and a 19.0% progression to cancer (sham treatment). Strictures developed in 6%, bleeding in 1%, and 2% of patients needed admission to hospital for pain.[116] Long-term follow-up and further research to establish the role of this intervention are still needed. The optimal management of high grade dysplasia in Barrett's is currently being assessed by an international consensus task force (BArrett's Dysplasia and CAncer Task force; BAD CAT) and is due to report at the end of 2011.

Gastric Cancer
In gastric adenocarcinoma mucosal disease is associated with a 03% incidence of lymph node metastases, rising to 20% for deep submucosal disease.[142 143] Studies show that after 3039 months, two-thirds of patients with EGC (Japanese criteria) and high grade dysplasia (non-invasive neoplasia; Western criteria) will progress to an invasive cancer. [144 145] Long-term survival is now consistently being reported following endoscopic resection of EGC.[146] Thus, the criteria for endoscopic therapy (EMR and ESD) have been extended by the Japanese Gastric Cancer Association from mucosal cancer, well differentiated non-ulcerated small lesion (<2 cm), to any size (elevated), ulcerated (<3 cm) and includes undifferentiated subtype. [106]

Surgery
There is a strong relationship between lower hospital mortality and increasing surgeon and institutional patient volumes.[147 148] Large volume units consistently report hospital mortalities well below 10%. In the National Oesophago-Gastric Cancer Audit during October 2007September 2008, 1109 and 747 patients underwent curative resection for oesophageal and gastric cancer, respectively. The hospital mortality was 5.0% (95% CI 3.8% to 6.4%) for oesophagectomy and 6.7% (95% CI 5.0% to 8.7%) for gastrectomy.[3] The proportion of patients undergoing radical curative resection has fallen. In 1998 overall resection rates were 28% (oesophageal 14%, oesophago-gastric junctional 33% and gastric 31%) decreasing to 20% in 2005 (oesophageal 10%, oesophago-gastric junctional 24% and gastric 23%). These changes are likely to reflect service reconfiguration following implementation of IOG and better staging and MDT working.[1 149] The benefit of surgeon and surgical team volume is less well defined. However, surgeon competence does seem to plateau with increasing experience.[150] A prospective audit of the learning curve for D2 gastrectomy reported that such a plateau was reached after 1525 procedures.[151] A number of factors have influenced surgeon experience including reduction in resection rates, centralisation with a trend towards team working, and reduced working hours in the context of providing a comprehensive UGI surgical service. It would seem therefore that an individual surgeon should be undertaking a minimum of 20 oesophageal and gastric resections annually, either individually or in conjunction with a consultant colleague. The National Oesophago-Gastric Cancer Audit has clearly shown the standards that have been reached, and an individual's practice should be audited against these benchmarked standards. AUGIS has recommended that an ideal oesophago-gastric unit should consist of 46 surgeons each carrying out a minimum of 1520 resections per year serving a population of 12 million.[152]

Oesophageal Surgery
The histological tumour type, its location, the extent of the proposed lymphadenectomy, patient factors and the experience of the surgeon should determine the operative approach. In Western patients there is little evidence that any particular approach is superior to another in terms of OS. A large and well-designed randomised trial in patients with lower oesophageal and type I and II oesophago-gastric

junctional tumours compared transhiatal with transthoracic resection and extended lymphadenectomy.[153 154] Operative morbidity rates were significantly lower in the transhiatal group, but in-hospital mortality rates were similar. Transhiatal surgery was associated with a survival benefit, although this did not reach standard levels of statistical significance (p=0.06). Subgroup analysis showed a slight advantage for transthoracic resection for type I tumours and those which were node positive.[154] In the early postoperative months patients undergoing transhiatal surgery reported fewer problems with activity levels and pain than those undergoing more extensive resection. By 12 months, however, scores were similar in both groups. This information may be important to patients when selecting surgical procedures.[155] Studies claiming benefits for a particular approach usually hide multiple confounders, of which the potential for stage migration as a result of inadequate lymphadectomy is usually important. [154 156] In an era of increasing use of neoadjuvant therapies where specific treatments are increasingly stage dependent, the surgeon should avoid carrying out an operation that is likely to underestimate the extent of disease or leave disease behind. Indeed, prospective longitudinal and population-based studies with a comprehensive evaluation of HRQL have shown that oesophagectomy has an immediate negative impact on all aspects of HRQL, and there is limited slow recovery. [157159] Patients surviving at least 3 years report persistent problems with reflux, dyspnoea and reduced physical activity, and those not living beyond 12 months and likely to have undergone non-curative surgery do not regain preoperative HRQL levels.[160 161] For squamous carcinoma, adequate lymphadenectomy in the mediastinum and abdomen seems logical as most Western patients have middle or upper third tumours. For this reason two- and threephase operations are generally advocated. Transhiatal surgery seems illogical on the grounds that mediastinal lymphadectomy is likely to be compromised. This latter operation seems most suited to patients with early stage tumours thought to be node negative. For adenocarcinomas, most surgeons accept the need for an adequate abdominal lymphadenectomy as the predominant route of lymphatic spread in lower third tumours is in a caudal direction. The extent of mediastinal lymphadenectomy, particularly in the upper half of the mediastinum, remains unclear. Experience from Munich has shown in type II oesophago-gastric junctional tumours that the pattern of lymph node involvement is mediastinal (2.1%), paraoesophageal (15.6%) and intra-abdominal (56 72%).[73] The most widely practised operation is the two-phase Ivor Lewis operation with a laparotomy followed by a right thoracic approach with the anastomosis high in the chest. Some surgeons favour a third stage with a cervical incision to create the anastomosis at this level. This may be an important consideration to gain adequate clearance in proximal tumours. Transhiatal surgery again seems best suited to early stage disease including multifocal high grade dysplasia in patients with very long Barrett's segments. A small group of patients who would not withstand thoracotomy may tolerate a transhiatal approach. There is a growing interest in the use of minimal access techniques to replace conventional open surgery. Prospective cohort studies have shown that clinical outcomes with complete minimally invasive oesophagectomy can be achieved with good short-term outcomes.[162 163] Early experience has shown that lymph node yield from laparoscopic lymphadenectomy is similar to that obtained at open surgery.[164 165] However, there are specific complications with associated significant morbidity and mortality such as gastric tube necrosis (incidence up to 13%) which need better understanding and resolution. In all these studies the impact on gastric tube necrosis on postoperative quality of life is severe because of the necessity to form a cervical oesophagostomy. A prospective cohort study using validated measures of HRQL shows that following minimal access oesophagectomy the impact on HRQL may be less severe than standard open surgery. [166] However, there is insufficient robust evidence to reach meaningful conclusions of the impact of minimal access surgery for oesophageal cancer on HRQL, postoperative clinical outcomes and long-term survival. Consensus guidelines have

been produced by AUGIS which recommends a pragmatic approach for the development of minimal access surgery for oesophageal and gastric cancer resection and should be used for learning curve, audit and research purposes.[167] It is also recommended that these new techniques are carried out by specialist teams with appropriate mentorship and training. However, only data from well-designed and conducted RCTs will be able to demonstrate the effectiveness and cost-effectiveness of minimal access as an alternative to open surgery.

Gastric Surgery
The aim of surgery for gastric cancer is to excise the primary lesion with clear longitudinal and circumferential margins. The type of resection is determined by the position and preoperative stage of the cancer and the planned lymphadenectomy. In EGC which is not suitable for endoscopic resection (see above) proximal or distal partial resection is appropriate with limited lymphadenectomy. Japanese data have demonstrated that resection of the N1 tier of nodes together with the left gastric (station 7) and anterior hepatic nodes (station 8a) (D1 ) for mucosal disease and of the N1 tier with left gastric, anterior hepatic and coeliac axis nodes (station 9) (D1 ) for submucosal disease can achieve the same outcome as D2 lymphadenectomy. The approach to cardia, subcardia and some type II oesophago-gastric junctional cancers can be extended total gastrectomy or oesophago-gastrectomy. The aim is to ensure adequate local clearance, appropriate lymphadenectomy and an uncomplicated anastomosis with low morbidity. Barbour and colleagues have reported that an ex vivo proximal margin of >3.8 cm of normal oesophagus (which equates to 5 cm in vivo) is associated with a minimal risk of anastomotic recurrence and is an independent predictor of survival.[168] The role of intraoperative histological examination of the proximal resection margin is mandatory in this situation. The distal margin is also a potential risk in oesophago-gastrectomy as some tumours infiltrate into the gastric fundus. Lymphadenectomy should include a formal dissection of D2 and posterior mediastinal, perioesophageal nodes. A randomised comparison of transhiatal and left thoracoabdominal extended total gastrectomy has shown superior outcome for the transhiatal group.[169] The authors postulated that this reflected the greater physiological insult associated with thoracotomy. Thus, for these tumours, a transhiatal, extended total gastrectomy should be considered with an oesophagogastrectomy the alternative if an adequate proximal margin cannot be achieved. Non-randomised comparative HRQL data add further support for this approach.[170] Japanese experience has clearly shown that excision of the primary lesion together with the omenta and first two tiers of lymph nodes (N1 and N2) that drain the affected area of the stomach can cure patients even in the presence of lymph node metastasesD2 or systematic lymphadenectomy. In the West, two RCTs have shown little initial difference between D1 and D2 lymphadenectomy. [134 171 172] Long-term follow-up in a Dutch trial has recently been reported, showing better cancer-related survival after D2.[173] Smaller series from specialised European centres have shown equivalent results to the Far East, with operative mortality rates well under 5% with corresponding improvements in survival.[174176] There is emphasis on the greater expertise of the surgeon with avoidance of pancreatic and splenic resection unless specifically indicated. In addition, such expertise is reflected in the management of complications, which is important in maintaining a low operative mortality rate. [177] Much of the stage-specific improvement in survival after D2 resection is likely to be a result of better pathological staging (stage migration factor), particularly stages II and IIIa. Staging is dependent on TNM criteria, and a minimum of 15 lymph nodes should be resected and examined histologically for reliable staging.[74] It should be noted that in the Dutch trial 20% of the D2 group with N2 nodes were still alive at 11 years.[177] Series from both Japan and the West show that a significant proportion of patients with N2 disease survive for >5 years after a D2 resectionit is unlikely that they would survive as long after a lesser lymphadenectomy.

The role of extended lymphadenectomy in which nodes beyond the second tier are resected (eg, nodes in the hepatoduodenal ligament) has been extensively studied. In a retrospective comparison, Robertson and colleagues reported no advantage of D3 over D2.[178] In a recent prospective randomised trial, Wu and colleagues have reported an improved OS with D3 compared with D1.[179] Two multicentre randomised trials in Japan comparing D2 and D4 lymphadenectomy for advanced cancer have recently reported their results.[180 181] Both trials concluded that a D4 resection did not improve survival but did increase operation-related risks. The future trend will be towards node resections that are tailored to the preoperative and operative staging of each case and to the age and fitness of the patient.[182 183] Translating Japanese experience and recommendations to Western practice has not been without problem. As a result, in the recently revised Japanese Rules, the description of D2 dissection has been related to the extent of gastrectomy. In a D1 total gastrectomy, stations 1, 2, 3, 4, 5, 6 and 7 should be resected and in a D2 stations 8a, 9, 10, 11 and 12 are added. In a D1 subtotal gastrectomy, stations 1, 3, 4, 5, 6 and 7 are removed and in a D2 stations 8a, 9, 11p and 12a are added (T Sano, personal communication). It is hoped that this will facilitate a more standard approach to gastric cancer surgery and allow greater ease of comparing outcome across centres. The International Gastric Cancer Association has taken a consensus view to implement a standard data set worldwide for data collection and audit. There has been increasing interest in the potential for laparoscopic resection of gastric cancer, with the procedures being either totally laparoscopic or more usually laparoscopic assisted. Studies have shown the safety of the laparoscopic procedures and confirm that a D2 lymphadenectomy can be performed to the same standard.[184 185] Most published studies are from Asia and largely comprise patients with T1 or T2 cancers. A meta-analysis of open versus laparoscopic-assisted distal gastrectomy (LADG) yielded only a small number of suitable RCTs with small sample sizes and limited follow-up. There were no differences between the groups except for a longer operating time and a reduced nodal yield in LADG.[186] There was a trend to faster postoperative recovery and discharge after LADG. It is likely that the laparoscopic procedures will continue to be developed but, as with oesophageal surgery, it is important that the lessons learnt during the development of safe open gastric cancer surgery should not be forgotten. There is a lack of multicentre randomised trials in gastric cancer with comprehensive patientcompleted assessments of HRQL. In a randomised comparison of D1 or D3 lymphadenectomy, questionnaires administered by a nurse were used to assess HRQL and it was reported that both groups had similar HRQL.[187] Another randomised trial of laparoscopy-assisted or open distal gastrectomy in EGC, also using administered questionnaires, showed HRQL advantages to minimal access surgery.[188] The risk of observer bias in these trials, however, is high because non-blinded observers and not the patients themselves performed the assessments. This is a critical design feature of conducting trials with HRQL outcomes. Prospective patient-reported outcomes evaluating the impact of gastrectomy on HRQL show that there is a marked HRQL deterioration after surgery, and total gastrectomy appears to have greater long-term HRQL deficit than subtotal surgery.[189 190]

Neoadjuvant, Perioperative (Neoadjuvant and Adjuvant) and Adjuvant Therapy

Oesophageal Cancer
Historically, the majority of trials and meta-analyses evaluating combined modality treatment regimens in the treatment of oesophageal cancer have included squamous cell, adeno- and undifferentiated carcinomas, and tumours located in the proximal, mid and lower oesophagus as well as oesophago-

gastric junctional tumours. These recommendations describe the current rationale for treatment strategies based on the main histological subtypes and tumour location. Preoperative Radiotherapy A meta-analysis of preoperative radiotherapy for patients with resectable oesophageal carcinoma (any histological subtype) demonstrated that there was a 34% absolute improvement in OS (HR 0.89; 95% CI 0.78 to 1.01; p=0.062).[191] Preoperative radiotherapy is therefore not recommended for potentially resectable oesophageal squamous cell or adenocarcinoma. Preoperative Chemoradiation Preoperative chemoradiation followed by surgery is superior to surgery alone, as demonstrated in a meta-analysis of 10 RCTs comparing the two strategies.[192] The HR for all-cause mortality was 0.81 (95% CI 0.70 to 0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years. A significant benefit favouring preoperative chemoradiation over surgery alone was observed in oesophageal cancer of both squamous cell carcinoma and adenocarcinoma histological subtypes. There have been two further phase III trials comparing chemoradiation with surgery alone in patients with resectable oesophageal or oesophago-gastric junctional cancer. In the Dutch trial, paclitaxel and carboplatin were given with radiotherapy. [193] The median survival for the combined therapy group was 49 months compared with 26 months for the surgery-alone arm. The majority of patients (74%) had distal oesophageal tumours and ~12% had oesophago-gastric junctional tumours. In the subgroup analysis, the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared with adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16). In the FFCD 9901 trial, patients were randomised to combination 5-FU/cisplatin and radiotherapy.[194] The trial included 195 patients with localised stage I and II oesophageal squamous cell carcinoma (70%) and adenocarcinoma (29%). It was stopped early as there was no advantage to the combination regimen. In addition the operative mortality was significantly greater at 7.3% in those treated with chemoradiotherapy. The authors concluded that triple modality therapy was not indicated for such early stage oesophageal cancers. Preoperative chemoradiation alone and preoperative chemotherapy have not been directly compared in the context of a phase III RCT. A phase III RCT has been conducted comparing preoperative chemotherapy with preoperative chemotherapy and chemoradiation in locally advanced lower oesophageal and gastric cardia adenocarcinoma. This study closed early due to poor accrual. A trend towards improved survival in the chemotherapy plus chemoradiation arm was reported; however, this was associated with higher perioperative morbidity.[195] There is a lack of assessment of HRQL in the RCTs comparing preoperative chemoradiation followed by surgery with surgery alone. Prospective series evaluating HRQL during chemoradiation and surgery show a deterioration of HRQL during preoperative treatment that recovers before surgery. After oesophagectomy there is a dramatic reduction in all aspects of HRQL, but no evidence that undergoing preoperative chemoradiation delays postoperative recovery of HRQL.[196 197] Definitive Chemoradiation Chemoradiation results in superior disease control and survival outcomes compared with radiation alone, but is associated with greater toxicity as seen in a review of 19 RCTs.[198] There are few trials directly comparing definitive chemoradiation with surgery alone. A Chinese study of 80 patients with squamous cell carcinoma randomised to surgery or chemoradiation failed to show superiority of either strategy in terms of early DFS or OS. [199] This trial was powered to show superiority of one treatment over another, but failed to report what magnitude of difference was considered superior. There is also a small Swedish study of 91 patients with either squamous cell carcinoma or adenocarcinoma of the oesophagus (50/50) that did not find any differences in treatment outcomes and equivalent survival.[200] Adding surgery to chemoradiation for squamous cell carcinoma can improve local control rates compared with chemoradiation alone, but combined-modality therapy has not been shown to improve

survival. A European study of 172 patients with squamous cell carcinoma randomised to induction chemotherapy followed by chemoradiotherapy (40 Gy) and surgery, or induction chemotherapy followed by chemoradiotherapy (at least 65 Gy) reported equivalent OS, but better local progressionfree survival in the surgery arm.[201] The addition of surgery also significantly increased treatmentrelated morbidity (12.8% vs 3.5%; p=0.03). A second European study, the French FFCD 9102 trial, recruited 444 patients with potentially resectable oesophageal cancer of predominantly squamous cell carcinoma subtype (90%).[202] After induction chemoradiation, responding patients were randomised to further chemoradiation or surgery. Median OS was 19.3 months for patients randomised to further chemoradiation and 17.7 months for those randomised to surgery. Again toxicity was higher with combined-modality therapy. The study met its primary end point of non-inferiority for 2 year survival (p=0.03). Both the European studies were equivalence studies powered to determine whether the two treatments could be considered equivalent in terms of survival at 2 years. Equivalence was defined as a difference of <10% and 15%. It is questionable for a cancer with such a low survival rate that such differences would be deemed clinically important. The French trial included an observer-assessed measure of HRQL.[202 203] Participants randomised to surgery reported worse HRQL 3 months after treatment, but similar scores in both arms were reported at 2 years. In this trial the HRQL assessment was performed by a non-blinded observer, introducing the possibility of bias. One non-randomised prospective series comparing HRQL between patients selected for definitive chemoradiation versus chemoradiation and surgery showed a similar pattern.[204] In the first few months after treatment, HRQL was more severely comprised following a surgical than a non-surgical approach, but at 1 year scores were similar in both groups. In localised squamous cell carcinoma of the oesophagus, although definitive chemoradiation is a current recommended standard of care, there is a lack of evidence to support either a surgical or a non-surgical approach. The recent UK National Audit shows that the disease is treated by both approaches.[3] Surgery should be considered in those treated with chemoradiation who at the end of treatment have histologically confirmed residual disease. A feasibility RCT is being set up to examine whether it is possible to effectively recruit into a trial comparing these treatment options. Ongoing clinical trials, such as SCOPE-1, are evaluating the additional effect of biological agents to treatment regimens, but trials with both clinical and HQRL outcomes comparing chemoradiation with combination treatments including surgery are still needed. For patients with localised oesophageal adenocarcinoma deemed unsuitable for surgery, definitive chemoradiation is a valid treatment option,[205] with consideration given to participation in relevant clinical trials. Salvage Surgery After Definitive Chemoradiation Local recurrence after primary treatment with definitive chemoradiotherapy may occur in 1030% of patients within the first year. In this situation, attempted salvage curative treatment with oesophagectomy may be an option, but careful consideration by a specialist MDT is required in making this high risk judgement. Repeat staging investigations including PET-CT and EUS are recommended. Surgery should be undertaken by a specialist team, and a recent review summarising earlier studies showed an increased in-hospital mortality rate after salvage surgery (up to 17%) and increased morbidity. [206] Survival benefit is limited. Informing patients of the potential high risks and poor outcomes is a critical part of the decision-making process. The role of this aggressive treatment needs further evaluation. Adjuvant Chemotherapy Morbidity associated with oesophagectomy often precludes patients from receiving adjuvant therapy within an appropriate time frame. Current data do not support the routine use of adjuvant chemotherapy. A meta-analysis of 1001 patients treated with adjuvant chemotherapy in six RCTs did not demonstrate improved outcomes in patients with oesophageal cancer, the majority of whom had squamous cell carcinoma.[207]

Preoperative Chemotherapy The largest study evaluating the role of preoperative chemotherapy is the UK Medical Research Council (MRC) OE02 trial. Eight-hundred and two patients were randomised to surgery alone or two 3-weekly cycles of cisplatin + 5-FU chemotherapy. The group receiving chemotherapy had significantly better OS (HR 0.79; 95% CI 0.67 to 0.93; p=0.004) and 2 year survival (43% vs 34%).[208] Updated results confirm an ongoing benefit with longer term follow-up. The benefit of preoperative chemotherapy was maintained for both DFS and OS, with corresponding HRs of 0.82 (95% CI 0.71 to 0.95; p=0.003) and 0.84 (0.72 to 0.98; p=0.03), respectively. Five-year survival with surgery alone was 17%, compared withy 23% with preoperative therapy.[209] In contrast the US Intergroup-0113 study, which randomised 467 patients to surgery alone or three cycles of cisplatin5-FU chemotherapy, followed by surgery and postoperative cisplatin5-FU chemotherapy in responders, did not report a significant difference in median OS.[210] It has, however been suggested that the failure of the Intergroup-0113 study to demonstrate a survival benefit may have been due to excessive toxicity associated with the chemotherapy regimen as well as a delay to definitive surgery in patients not responding to treatment. In a recent meta-analysis of preoperative chemotherapy, the HR for all-cause mortality for neoadjuvant chemotherapy was 0.90 (95% CI 0.81 to 1.00; p=0.05), corresponding to a 2-year absolute survival benefit of 7%. When analysed by subtype, chemotherapy did not have a significant effect on all-cause mortality for patients with squamous cell carcinoma (HR 0.88; p=0.12); however, there was a significant survival benefit in favour of preoperative chemotherapy for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014).[192] Preoperative chemotherapy is a standard of care for patients with operable mid and distal oesophageal and oesophago-gastric junctional adenocarcinoma. Ongoing studies including the MRC OEO5 trial are evaluating the optimal preoperative regimens. There is a lack of randomised trials of preoperative chemotherapy including HRQL outcomes. One prospective study shows that preoperative chemotherapy leads to a deterioration in generic aspects of health (physical, role and social function), but a simultaneous relief in local tumour symptoms (dysphagia, eating problems and reflux).[211] Preoperative chemotherapy does not appear to delay postoperative recovery of HRQL, but persistent problems with reflux, diarrhoea and shortness of breath continue for at least 3 years after surgery.[161] A comprehensive assessment of HRQL is included in the current MRC OEO5 trial.

Gastric Cancer
Perioperative Chemotherapy The MAGIC trial randomised 503 patients with adenocarcinoma of the stomach, oesophago-gastric junction or lower oesophagus to perioperative ECF (epirubicin, cisplatin and infused 5-FU), administered as three cycles before and after surgery, or to surgery alone.[212] Neoadjuvant chemotherapy resulted in tumour downstaging and did not increase the rate of postoperative complications. Perioperative chemotherapy resulted in a statistically significant improvement in OS from 23% to 36%, corresponding to an HR for death of 0.75 (95% CI 0.60 to 0.93; p=0.009). Results from the smaller French study (FNLCC ACCORD-07-FFCD 9703) utilising perioperative cisplatin and 5-FU, currently reported in abstract form only, provide additional data supporting this approach.[213] Perioperative combination chemotherapy has therefore become the standard of care for localised gastric cancer (and type II and III oesophago-gastric junction adenocarcinoma) throughout the UK and most of Europe. Accepted perioperative regimens are ECF or ECX (epirubicin, cisplatin and capecitabine).

There is a lack of well-designed RCTs with HQRL outcomes comparing perioperative treatment strategies for tumours of the stomach or oesophago-gastric junction. The current MRC STO3 trial is addressing these issues with comprehensive assessment of HRQL. Adjuvant Chemotherapy Several meta-analyses have been published suggesting a small survival benefit for adjuvant chemotherapy.[214216] There is, however, considerable variation between the treatment regimens used and outcomes between Western and Asian populations. The Japanese ACTS-GC (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer) trial demonstrated a significant benefit in OS for patients receiving 12 months of S-1 (an oral fluoropyrimidine) monotherapy compared with observation after curative D2 gastrectomy (3 year OS of 80.1% vs 70.1%; p=0.0024). [217] Whether these results are applicable to a Western population remains to be seen. Adjuvant chemotherapy alone is currently not standard practice in the UK; however, it may confer a survival benefit and should be considered in patients at high risk of recurrence who have not received neoadjuvant therapy. Adjuvant Chemoradiotherapy The US Intergroup 0116 trial randomised 556 patients to surgery followed by chemoradiotherapy (radiotherapy 45 Gy in 25 fractions plus bolus 5-FU/leucovorin before, during and after radiotherapy) or surgery alone. Fifty-four per cent of patients had less than D1 resections. A significant benefit in both median OS (36 vs 27 months; p=0.005) and local control rates (30 vs 19 months; p<0.001) was reported.[218]On the basis of this trial, postoperative chemoradiation became a standard of care in the USA. With longer term (>11 years) follow-up, both OS and DFS benefit has been maintained (OS, 35 vs 27 months, p=0.005; DFS, 27 vs 19 months, p<0.001). [219] Elsewhere, however, including in the UK, there has been less enthusiasm regarding this strategy, partly due to the toxicity associated with abdominal chemoradiation but also the uncertainty as to its benefit after 'optimum' surgery. Nevertheless, it should be considered in patients at high risk of recurrence who have not received neoadjuvant therapy, particularly those who have had suboptimal debulking.

Nutrition during Chemotherapy and Radiotherapy

Nutritional status may deteriorate during chemotherapy and radiotherapy as side effects of treatment such as dysphagia, sore mouth and nausea can impinge on appetite and dietary intake. Early individualised nutrition counselling by a dietician with the use of oral supplements, if required, and weekly dietetic follow-up during and after radiotherapy has been demonstrated to contribute to a faster recover in global quality of life and physical function.[220] The aim of such nutrition counselling is to maintain nutritional status and minimise the side effects of the tumour and therapy. Its prolonged benefit after treatment has been demonstrated in patients with colorectal cancer receiving chemoradiation, and it is likely that this would apply to UGI tract patients. [221] If patients experience dysphagia due to tumour or treatment, then enteral nutrition should be given via an enteral feeding tube, a gastrostomy or a jejunostomy. A small study of Polyflex plastic stents suggested that these may be a good alternative to surgical jejunostomy and can be removed at the time of surgery.[222] In patients with gastric outflow obstruction, insertion of a pyloric stent can provide symptomatic relief and allow administration of chemotherapy.

Palliative Treatment for Oesophageal, Oesophago-gastric Junctional and Gastric Cancer

First-line Palliative Chemotherapy for Oesophageal, Oesophago-gastric Junctional and Gastric CancerThe benefits of palliative chemotherapy over Best Supportive Care (BSC) in the treatment of advanced gastric cancer have been demonstrated in four RCTs.[223226] For patients considered suitable

for systemic treatment, palliative chemotherapy improves median survival from 3 to 4 months with BSC alone to 7 to 10 months. Patients with advanced oesophageal cancer appear to derive the same benefits from systemic chemotherapy as those with gastric or oesophago-gastric junctional tumours, and those of good performance status should be offered combination chemotherapy.[227229] Several multicentre studies conducted in the UK that have defined the current standards of care in the treatment of advanced gastric or oesophago-gastric cancer have included patients with oesophageal tumours of squamous cell, adenocarcinoma and undifferentiated carcinoma histological subtypes. Many chemotherapy agents have efficacy in the treatment of advanced gastric cancer, and it is recognised that combination therapy is superior to single-agent therapy. There is, however, no international consensus regarding which combination chemotherapy regimen should be used first line. Until recently, combination therapy with ECF has been the preferred regimen in the UK. In an RCT ECF was shown to have superior response rates (45% vs 21%, p=0.0002), median OS (8.9 vs 5.7 months, p=0.0009) and 2-year survival (13.5% vs 5.4%, p=0.03) over FAMTX (5-FU, adriamycin and methotrexate).[230 231] When compared with MCF (mitomycin C, cisplatin and infused 5-FU) in the treatment of oesophageal, oesophago-gastric junctional and gastric carcinomas, ECF had similar response rates and survival, but was preferable according to HRQL measures.[231] Cisplatin combined with infused 5-FU (CF) is another commonly used regimen. Although ECF and CF have not been directly compared in a phase III randomised trial, a meta-analysis has demonstrated that three-drug regimens containing anthracyclines, cisplatin and 5-FU are superior to two-drug regimens containing either cisplatin/5-FU or anthracyclines/5-FU in terms of OS.[229] The REAL-2 trial is the largest RCT evaluating first-line chemotherapy regimens for advanced oesophago-gastric cancer.[223] In a 22 factorial design, 1002 patients were randomised to ECF, ECX, EOF (epirubicin, oxaliplatin and infused 5-FU) or EOX (epirubicin, oxaliplatin and capecitabine). The study met its primary end points demonstrating non-inferiority in OS for capecitabine compared with infused 5-FU (HR for death, 0.86; 95% CI 0.80 to 0.99) and for oxaliplatin compared with cisplatin (HR for death, 0.92; 95% CI 0.80 to 1.10). There was no significant difference in HRQL between the four arms. EOX resulted in longer OS than ECF (HR for death 0.80; 95% CI 0.66 to 0.97; p=0.02). The combination of EOX is therefore at least as efficacious as ECF, with the additional advantages of a more convenient mode of administration (no requirement for hydration or central venous catheter insertion) and an acceptable toxicity profile. Further trials indicate that it is reasonable to substitute capecitabine for infused 5-FU, and oxaliplatin for cisplatin, in the treatment of advanced oesophagogastric cancer.[214 232] In July 2010, the NICE appraisal of capecitabine determined that use of capecitabine in combination with platinum chemotherapy represented a cost-saving to the NHS over infused 5-FU.[227] The V325 study is a randomised phase III trial comparing docetaxel in combination with cisplatin and infused 5-FU (DCF) with the doublet CF. A statistically significant improvement in OS (9.2 vs 8.6 months; p=0.020) was observed; however, this was at the cost of significantly more toxicity, including febrile neutropenia.[228] In a phase II Swiss trial comparing DCF with ECF, DCF resulted in a much higher rate of complicated neutropenia (41% vs 18%).[233] Docetaxel-containing regimens are not currently approved in the UK for this indication. Patients with adequate performance status with inoperable oesophago-gastric cancer should be considered for combination chemotherapy with EOX or ECX. First-line Palliative Targeted Agents in Combination With Chemotherapy For patients with advanced HER-2-positive oesophago-gastric junctional or gastric cancer, the addition of trastuzumab to a cisplatin and fluoropyrimidine (5-FU or capecitabine) chemotherapy doublet resulted in a statistically significant improvement in response rate (47.3% vs 34.5%; p=0.0017), progression-free

survival (6.7 vs 5.5 months; p=0.0002) and median OS (13.8 vs 11.1 months; p=0.0048).[234] Tumours were considered HER-2 positive if the immunohistochemistry score was 3+ or if fluorescent in situ hybridisation (FISH) was positive for HER-2 overexpression. Trastuzumab is now licensed in the UK for patients with previously untreated metastatic HER-2-positive (defined as IHC 3+) gastric or oesophago-gastric junctional adenocarcinoma. This regimen is a valid first-line treatment option for HER-2-positive advanced gastric and oesophago-gastric junctional cancers. How this regimen compares with chemotherapy-only triplet regimens is unknown. The use of other targeted agents, including cetuximab, panitumumab and bevacizumab, in combination with chemotherapy should remain restricted to the context of clinical trials. Second-line Palliative Chemotherapy for Oesophago-gastric Junctional and Gastric Cancer The standard treatment option for patients with advanced gastric or gastro-oesophageal junction tumours is uncertain, and wherever possible it is recommended that patients are enrolled into a RCT. Data from phase II trials have demonstrated activity in the second-line setting for the following agents/combination regimes: irinotecan in combination with cisplatin or fluoropyrimidines, FOLFOX (folinic acid, 5-FU, oxaliplatin), docetaxel monotherapy, docetaxel in combination with oxaliplatin, and paclitaxel alone or in combination with platinum agents.[235] Chemotherapy to Downstage Initially Inoperable Locally Advanced Disease for Surgery There is anecdotal evidence that in selected cases, palliative chemotherapy may result in sufficient downstaging of initially inoperable locally advanced disease to allow surgical resection. For instance, in the randomised trial comparing ECF with FAMTX in patients with locally advanced disease, 12 out of 43 patients treated with ECF (nine complete resections) and five out of 51 patients treated with FAMTX (four complete resections) proceeded to surgery. Of these 17 patients, nine survived for 2 years from randomisation.[229 231] There have not been any randomised controlled studies to compare the addition of surgery to palliative chemotherapy with palliative chemotherapy alone. Such studies may become possible and worthwhile if minimal access surgery can be achieved with reduced complications and better recovery of HRQL than standard open surgery. Palliative Radiotherapy for Oesophageal Cancer Dysphagia and pain are common symptoms associated with unresectable oesophageal cancer. External beam radiotherapy is a local palliative measure that can improve symptoms and is associated with minimal toxicity, but relief from dysphagia is often slow in onset compared with stent insertion.[236238] Differences in outcome in terms of HRQL, dysphagia-free survival and OS between different 'locoregional' palliative treatments, particularly in the era of more effective chemotherapy, requires further investigation.

Endoscopic Methods
Oesophageal Intubation Oesophageal intubation is an effective means of relieving dysphagia in a single procedure, and stents are now widely used. A Health Technology Assessment (HTA)sponsored pragmatic RCT of the cost-effectiveness of palliative treatments for patients with inoperable oesophageal cancer studied different types of oesophageal tubes and compared these with non-stent alternatives.[239] This study confirmed the observations made previously that although the older rigid plastic tubes (Atkinson and Celestin) were cheap, they were also associated with a worse quality of swallowing and increased late morbidity. Small (18 mm) diameter self-expanding metal stents (SEMS) were as effective as large (24 mm) stents but induced less pain. Two-thirds of patients treated with a metal stent can eat solids initially, and there appears to be little difference between the effectiveness of different types of metal stents,[240]although one small RCT

suggested that covered metal stents are more effective than non-covered stents as they are complicated by less tumour ingrowth.[241] In the HTA trial, dysphagia was actually worse in 10% of patients 6 weeks after stent insertion.[239] In addition, although initial hospital stay was brief, the total number of inpatient days was in the order of 23 weeks, with a median survival of 4 months. There was no difference in cost or effectiveness between SEMS and non-SEMS treatments. It was concluded that an RCT of 18 mm SEMS versus non-stent treatments with survival and HRQL end points would be helpful, as would an audit of palliative patient admissions to determine the reasons and need for inpatient hospital care. Patients can suffer acid reflux after stent insertion. A series of antireflux stents have been developed to overcome this. Several small RCTs have been performed, but results are inconclusive. [207 242] Another new development has been the introduction of plastic (Polyflex) stents. A number of small RCTs have shown that these seem to be more difficult to place and have a higher risk of late complications, particularly migration, than metal stents.[243 244] In addition, some aspects of HRQL were poorer with plastic stents.[245] Early complications after stent insertion are unusual and, in all RCTs, procedural mortality was acceptable at 2%. Late complications are, however, common and occur in up to 25% of patients.[239] These include recurrent dysphagia due to tumour overgrowth for covered or ingrowth for uncovered stents, bolus obstruction and stent migration.[246] In one retrospective study, membrane degradation of covered stents occurred in 8% of cases, leading to tumour ingrowth or reopening of a tracheo-oesophageal fistula which had initially been successfully covered by a stent. [247] The combination of radiotherapy and stents can be complicated. In patients who have had a stent placed before palliative external radiotherapy it is important to realise that stents appear to increase the radiotherapy dose delivered to the oesophageal mucosa.[248] Patients who have been previously treated with radiotherapy who later have stents inserted are at increased risk of complications. These may include increased risk of chest pain or severe complications such as fever, bleeding, perforation and fistula formation, which rose in one study from 3% to 23%.[249251] In another study, these findings were not confirmed.[252] Other small studies suggest that these complications are relevant only in patients with T4 disease.[253 254] Oesophageal Dilatation As increasing numbers of patients are now treated with palliative radiotherapy, postradiotherapy strictures are increasingly common. Dilatation for these can be effective in ~80% of treatment sessions, with fewer complications than stent insertion.[255] Brachytherapy and Stents The SIREC multicentre RCT of 12 Gy brachytherapy versus stent insertion included 209 patients in The Netherlands with inoperable oesophageal cancer. The primary outcome was relief of dysphagia during follow-up, and secondary outcomes were complications, treatment for persistent or recurrent dysphagia, HRQL and cost. Analysis was by intention to treat. Dysphagia improved more rapidly after stent placement (n=108) than after brachytherapy (n=101), but long-term relief of dysphagia was better after brachytherapy. Stent placement had more complications than brachytherapy (33% vs 21%; p=0.02), which was mainly due to an increased incidence of late haemorrhage (13% vs 5%; p=0.05). Groups did not differ for persistent or recurrent dysphagia (p=0.81), or for median survival (p=0.23). Patients undergoing brachytherapy reported significantly better role, emotional, cognitive and social function than those undergoing stent placement. Total medical costs were also much the same for stent placement and brachytherapy. The authors concluded that despite slow improvement, single-dose brachytherapy gave better long-term relief of dysphagia than metal stent placement. Since brachytherapy was also associated with fewer complications than stent placement, they recommended it as the primary treatment for palliation of dysphagia from oesophageal cancer. Unsurprisingly, physical and role function and other generic

aspects of HRQL deteriorated over time before death, but the decline was more pronounced in the stent group.[256] Given the delay to onset of benefit after brachytherapy, patient data from this study and a consecutive series (n=396) were analysed to create a prognostic model to help inform which patients should be offered stents and which should receive single-dose brachytherapy. Significant prognostic factors for survival included tumour length, WHO performance score and the presence of metastases (multivariable p<0.001) together with age and gender. This model could satisfactorily separate patients with a poor, intermediate and relatively good prognosis within the SIREC trial. For the poor prognosis group, the difference in dysphagia-adjusted survival was 23 days in favour of stent placement compared with brachytherapy (77 vs 54 days, p=0.16). For the other prognostic groups, brachytherapy resulted in a better dysphagia-adjusted survival.[257] The costs of both treatments were very similar.[258] In another prospective study, the palliative effect of self-expandable stent placement was compared with that of endoluminal brachytherapy regarding the effect on HRQL and specific symptoms. Sixtyfive patients with advanced cancer of the oesophagus or oesophago-gastric junction were randomised to treatment with either an Ultraflex expandable stent or high dose rate endoluminal brachytherapy with three doses of 7 Gy given in 24 weeks. This study was small and differences in baseline HRQL scores were observed between the two groups, but results were similar to the larger SIREC trial.[259] In a related study by the same group, stenting was considered more cost-effective than brachytherapy.[260] Iatrogenic Perforation and Tracheo-oesophageal Fistulae Small retrospective case series have shown that covered metal stents can be used successfully to cover iatrogenic oesophageal perforation and tracheo-oesophageal fistulae with minimal procedural morbidity and almost zero mortality.[261 262] A small number of patients with high oesophageal tumours involving the trachea or major bronchi may benefit from tracheal stenting. This may be combined with oesophageal stenting, but tracheal stenting should always be done first to minimise the risk of causing stridor. [263] Laser Therapy and Stents Various small retrospective cost-effective analyses have compared oesophageal stenting with laser therapy. The mean survival and the cost were similar. [264 265] In a small prospective randomised trial comparing stents with laser followed by palliative radiotherapy, there was no difference in survival but the costs of laser and radiotherapy were higher than stents. [266] An RCT of 65 patients compared thermal laser ablation with stents. HRQL deteriorated in the stent group but not in the laser-treated group. Patients treated by laser lived longer than patients treated by stent insertion, but the cost of laser therapy was higher.[267] Novel Combinations of Stents With Other Therapies Fifty-three patients were entered into an RCT comparing treatment response with a self-expandable oesophageal stent loaded with [125I]iodine seeds for intraluminal brachytherapy versus treatment response with a conventional self-expandable covered stent in patients with advanced oesophageal cancer. Dysphagia improved in both groups within the first month after stent placement, but was better in the irradiationstent group than in the control group after 2 months (p<0.05). The median and mean survival times were better in the irradiationstent group than in the control group, and the differences were significant (p<0.001). Haemorrhage occurred in a large number of patients in both groups in this study (30%).[268] Photodynamic Therapy PDT using Photofrin is a relatively new technique which remains unproven. PDT was successful in relieving dysphagia for ~9 weeks in 85% of 215 patients treated in one retrospective analysis.[269]Patients living >2 months required re-intervention to maintain palliation of malignant dysphagia, and a multimodality treatment approach was common in this study. In another study, almost half the patients required a second treatment with PDT and 10% were later stented.[270] Given that skin photosensitivity after Photofrin administration lasts for 3 months, and mean

survival is <6 months, this approach has a significant side effect profile. PDT has been suggested as a salvage treatment for local recurrence after chemoradiotherapy. Compared with using it as a primary therapy, the risk of complications for PDT after chemoradiotherapy is eight times higher. [271] Argon Plasma Coagulation APC has been evaluated as palliation in a few studies. A retrospective study of 31 patients described complications and tolerance. These patients underwent a median of five treatments per patient (range 118). Recanalisation enabling passage of the scope was achieved in 89% of treatments. The dysphagia-free interval was 25 days (range 1175 days). Perforation was seen in three patients (10%); procedure-related mortality was 1.2%. The median hospital stay for every treatment was 2 days (range 127 days). APC was well tolerated, safe and effective, and is an easy and cheap technique with no further restrictions than conventional monopolar electrocoagulation.[272] A study to prospectively evaluate a new high-power system (hp-APC) evaluated palliative treatment of oesophageal cancer as one indication. The mean number of treatment sessions required was 2.3 (range 15). Minor complications (pain, dysphagia, neuromuscular irritation or asymptomatic gas accumulation in the intestinal wall) were observed in 13%. Major complications (perforation or stenosis) occurred in two patients (0.9%). Because of the low number of treatment sessions required, it was suggested that hp-APC could be used as an alternative to Nd:YAG laser treatment in tumour debulking.[273] APC also has value in haemorrhage and in recanalisation of blocked stents, particularly with proximal or distal luminal overgrowth.[274]This modality, nevertheless, remains experimental. Injection Therapy In a prospective RCT comparing ethanol injection with laser therapy, both resulted in similar long-term outcomes, but patients treated with ethanol had a much higher use of analgesia, at 78% compared with 5% with laser.[275] In the HTA study, a small number had primary treatment with ethanol. All developed complete dysphagia, leading the authors to recommend that it should not be used as primary treatment.[239]

Follow-up
Regular review of patients following treatment of oesophago-gastric cancer can fulfil a number of roles including aftercare and rehabilitation following therapeutic intervention: symptom management, supportive care and surveillance. The complexity of oesophago-gastric cancer treatment frequently induces symptoms which adversely affect HQRL. Specific post-treatment side effects including dysphagia from anastomotic stricture, diarrhoea related to vagotomy and post-thoracotomy pain need appropriate management. Disorders of physiology are not uncommon and may require careful assessment and treatment by a specialist gastroenterologist. These are often insidious, and change in fat and bile salt absorption as well as bacterial overgrowth may be unrecognised by the inexperienced. Although regular review may identify early recurrence, there is no evidence for specific investigations nor that such an approach can affect OS. Endoscopy, cross-sectional imaging and tumour markers have all been evaluated, but lack specificity or sensitivity. It is accepted that patients may gain psychological support from regular review, although few studies have formally evaluated this, and patients may feel more anxious prior to a planned hospital visit. Regular access to CNS support may obviate this effect. Evidence from The Netherlands shows that nurse follow-up after oesophagectomy is both cost-effective and provides equal if not better patient experience.[276] The concept of survivorship or living beyond cancer is evolving, and experience of patient-led selfreferral rather than clinic review at regular intervals is developing. This requires careful discussion and explanation of potential problems with each patient, taking into account individual risk and prognosis in the context of underlying stage of disease.

Clinical Nurse Specialists

The number of CNSs in the UK has increased to 1800, of which 10% are UGI CNSs.[277] However recent evidence from the NHS peer review programme show that CNS provision for UGI cancer particularly at cancer units is among the lowest for all cancer sites.[278] The role of the nurse includes clinical education, psychological support, research and consultation. [279] The extent of the CNS role is difficult to measure because of the multifaceted nature of the work, complexity of the patient pathway and the more specific requirement to respond to individual patient needs. [280 281] Leary and colleagues have studied the work patterns of 463 CNSs (including gastrointestinal nurses) from the UK.[281] Data demonstrate that 68% of time is spent on clinical matters. of which 48% is physical care and 32% psychological care. Not surprisingly, 33% of the nurses' time is given to telephone advice and 34% spent in an outpatient setting. The remaining time is spent on administration (24%), research (2%) and education (3%). CNSs use 'brokering' skills, provide 'clinical rescue work', advice on symptom control and support, and negotiate care pathways, all of which are intended to prevent adverse events, particularly readmission.[281 282] The impact of psychological care and tailored information given in a supportive environment improves the patients' experience and HQRL.[283] The results from the National Oesophago-Gastric Cancer Audit provide further support from patient experience surveys: 'the CNS role is the pillar in the system'.[1] The MDT is central to patient care, with CNSs having an integral role; consulting with medical, surgical and allied healthcare professionals in order to provide a co-ordinated approach to care, enhancing quality of care and patients' well-being. Nurses also have access to important information particularly acting as the patient's advocate that may influence clinical decisions, and it is therefore essential that MDTs listen to their views.[284]

Outcomes
The assessment and evaluation of outcomes is a fundamental component of the management of oesophago-gastric cancer and was highlighted in the IOG.[149] This process is continuous and should be based around the MDT. The key to outcome measurement is high quality data documentation. Increasingly electronic systems are facilitating databases for MDT work. These do need appropriate administrative support to allow analysis and comparative audit. A recent survey of MDT functioning has stressed the need for adequate time for meetings as well as for preparation prior to meetings. [285
286]

In addition to core clinical information MDT databases should record clinical and pathological stage and details of co-morbidity and performance status and patient-reported outcomes (eg, measures of HQRL and satisfaction with care[287289]). This will allow for case-mix in comparative audit, and information from patient-reported outcome measures can be used to follow-up patients and help with symptom control. Current initiatives within the National Cancer Intelligence Network[69] will allow timely reporting of local and national outcomes. The National Oesophago-Gastric Cancer Audit has set a high standard for evaluation of outcome and has established benchmarks which will form the basis of both qualitative and quantitative performance indicators by which services can be assessed. [13]

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