What Is Cancer?

Cancer is the general name for a group of more than 100 diseases in which cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because abnormal cells grow out of control. Untreated cancers can cause serious illness and even death. How a normal cell becomes cancer Normal body cells grow, divide, and die in an orderly fashion. During the early years of a person's life, normal cells divide more quickly until the person becomes an adult. After that, cells in most parts of the body divide only to replace worn-out or dying cells and to repair injuries. Cancer cells develop because of damage to DNA. This substance is in every cell and directs all of the cell's activities. Most of the time when DNA becomes damaged, either the cell dies or is able to repair the DNA. In cancer cells, the damaged DNA is not repaired. People can inherit damaged DNA, which accounts for inherited cancers. Many times though, a persons DNA gets damaged by things in the environment, like, chemicals, viruses, tobacco smoke or too much sunlight. How cancers differ Cancers can begin in many different parts of the body. But, different types of cancer can act very differently. For example, lung cancer and breast cancer are very different diseases. They grow at different rates and respond to different treatments. That's why people with cancer need treatment that is aimed at their particular kind of cancer. How cancer spreads (metastasis) Because cancer cells keep growing and dividing, they are different from normal cells. Instead of dying, they outlive normal cells and continue to grow and make new abnormal cells. Cancer usually forms as a tumor (a lump or mass.) Some cancers, like leukemia, do not form tumors. Instead, these cancer cells involve the blood and blood-forming organs, and circulate through other tissues where they grow.

Cancer cells often travel through the bloodstream or through the lymph system to other parts of the body where they begin to grow and replace normal tissue. This spreading process is called metastasis. Even when cancer has spread to a different part of the body it is still named for the place in the body where it started. For example, breast cancer that has spread to the liver is metastatic breast cancer, not liver cancer. Prostate cancer that has spread to the bone is called metastatic prostate cancer, not bone cancer. Remember that not all tumors are cancerous. Benign (non-cancerous) tumors do not spread to other parts of the body (metastasize) and are very rarely life-threatening. How common is cancer? Half of all men and one-third of all women in the US will develop cancer during their lifetimes. Today, millions of people are living with cancer or have had cancer. The risk of developing most types of cancer can be reduced by changes in a person's lifestyle, for example, by quitting smoking, limiting time in the sun, being physically active, and eating a better diet. The sooner a cancer is found and treated, the better the chances are for living for many years. Who Gets Cancer? Anyone can get cancer at any age; however, about 77% of all cancers are diagnosed in people age of 55 and older. The rate of cancer occurrence (called the incidence rate) varies from group to group. Today, millions of people are living with cancer or have been cured of the disease. The sooner a cancer is found and the sooner treatment begins, the better a patient's chances are of a cure. That's why early detection of cancer is such an important weapon in the fight against cancer. What Are the Risk Factors for Cancer? A risk factor is anything that increases a person's chance of getting a disease. Some risk factors can be changed, and others cannot. Risk factors for cancer can include a person's age, sex, and family medical history. Others are linked to cancer-causing factors in the environment. Still others are related to lifestyle choices such as tobacco and alcohol use, diet, and sun exposure. 2

Having a risk factor for cancer means that a person is more likely to develop the disease at some point in their lives, however, having one or more risk factors does not necessarily mean that a person will get cancer. Some people with one or more risk factors never develop the disease, while other people who do develop cancer have no apparent risk factors. Even when a person who has a risk factor is diagnosed with cancer, there is no way to prove that the risk factor actually caused the cancer. Different kinds of cancer have different risk factors. Some of the major risk factors include the following: Cancers of the lung, mouth, larynx, bladder, kidney, cervix esophagus, and pancreas are related to tobacco use, including cigarettes, cigars, chewing tobacco, and snuff. Smoking alone causes one-third of all cancer deaths. Skin cancer is related to unprotected exposure to strong sunlight. Breast cancer risk factors include several factors: age; changes in hormone levels throughout life, such as age at first menstruation, number of pregnancies, and age at menopause; obesity; and physical activity. Some studies have also shown a connection between alcohol consumption and an increased risk of breast cancer. Also, women with a mother or sister who have had breast cancer are more likely to develop the disease themselves. While all men are at risk for prostate cancer, several factors can increase the chances of developing the disease, such as age, race, and diet. The chance of getting prostate cancer goes up with age. Prostate cancer is more common among African-American men than among white men. (We do not yet know why this is so.) A high-fat diet may play a part in causing prostate cancer. Also, men with a father or brother who have had prostate cancer are more likely to get prostate cancer themselves.

Overall, environmental factors, defined broadly to include tobacco use, diet, and infectious diseases, as well as chemicals and radiation cause an estimated 75% of all cancer cases. Among these factors, tobacco use, unhealthy diet, and physical activity are more likely to affect personal cancer risk. Research shows that about one-third of all cancer deaths are related to dietary factors and lack of physical activity in adulthood. Certain cancers are related to viral infections and could be prevented by behavior changes or vaccines. 3

Can Cancer Be Prevented? Smoking and drinking alcohol cause some people to get certain types of cancer. These cancers might be prevented by avoiding tobacco and alcohol. The best idea is to never use tobacco at all. Cigarettes, cigars, pipes and smokeless tobacco cause cancer and should not be used. People who already smoke should try to quit. Former smokers have less risk of cancer than do people who continue to smoke. The chances of getting skin cancer can be lowered by staying in the shade as much as you can, wearing a hat and shirt when you are in the sun, and using sunscreen. We know that our diet, (what we eat) is linked to some types of cancer, although the exact reasons are not yet clear. The best advice is to eat a lot of fresh fruits and vegetables and whole grains like pasta and bread, and to cut down on high fat foods. There are tests, called screening examinations that adults should have in order to find cancer early. If cancer is found early it can often be cured. What Causes Cancer? Some kinds of cancer are caused by things people do. Smoking can cause cancers of the lungs, mouth, throat, bladder, kidneys and several other organs, as well as heart disease and stroke. While not everyone who smokes will get cancer, smoking increases a person's chance of getting the disease. Drinking a lot of alcohol has also been shown to increase a person's chance of getting cancer of the mouth, throat, and some other organs. This is especially true if the person drinks and smokes. Radiation (x-rays) can cause cancer. But the x-rays used by the doctor or dentist are safe. Too much exposure to sunlight without any protection can cause skin cancer. In many cases, the exact cause of cancer remains a mystery. We know that certain changes in our cells can cause cancer to start, but we don't yet know exactly how this happens. Many scientists are studying this problem. Signs and Symptoms of Cancer 4

What are signs and symptoms? A symptom is a signal of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the person who has them, but may not be easily seen by anyone else. For example, chills, weakness, aches, and feeling short of breath may be symptoms of pneumonia. A sign is also a signal that something is not right in the body. But signs are signals that can be seen by a doctor, nurse, or other health care professional. Fever, fast breathing, and abnormal breathing sounds heard through a stethoscope may be signs of pneumonia. Having one symptom or sign may not be enough to figure out what's causing it. For example, a rash in a child could be a sign of a number of things, such as poison ivy, an infectious disease like measles, a skin infection, or a food allergy. But if the child has the rash along with other signs and symptoms like a high fever, chills, achiness, and a sore throat, then a doctor can get a better picture of the illness. In many cases, a patient's signs and symptoms alone do not give the doctor enough clues to figure out the cause of an illness. Then medical tests, such as x-rays, blood tests, or a biopsy may be needed. How does cancer cause signs and symptoms? Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, how big it is, and how much it affects nearby organs or tissues. If a cancer has spread (metastasized), symptoms may appear in different parts of the body. As a cancer grows, it can begin to push on nearby organs, blood vessels, and nerves. This pressure creates some of the signs and symptoms of cancer. If the cancer is in a critical area, such as certain parts of the brain, even the smallest tumor can cause early symptoms. But sometimes cancer starts in places where it will not cause any symptoms until it has grown quite large. Pancreas cancers, for example, do not usually grow large enough to be felt from the outside of the body. Some pancreatic cancers do not cause symptoms until they begin to grow around nearby nerves (this causes a backache). Others grow around the bile duct and block the flow of bile. This causes a yellowing of the eyes and skin called jaundice. By the time a pancreatic cancer 5

causes these signs or symptoms, it is usually in an advanced stage. This means it has grown and spread beyond the place it started the pancreas. A cancer may also cause symptoms like fever, extreme tiredness (fatigue), or weight loss. This may be because cancer cells use up much of the bodys energy supply, or they may release substances that change the way the body makes energy from food. Or the cancer may cause the immune system to react in ways that produce these symptoms. Sometimes, cancer cells release substances into the bloodstream that cause symptoms which are not usually linked to cancer. For example, some cancers of the pancreas can release substances which cause blood clots in veins of the legs. Some lung cancers make hormone-like substances that raise blood calcium levels. This affects nerves and muscles, making the person feel weak and dizzy. How are signs and symptoms helpful? Treatment is most successful when cancer is found as early as possible. Finding cancer early usually means it can be treated while it is still small and is less likely to have spread to other parts of the body. This often means a better chance for a cure, especially if the cancer can be removed with surgery. A good example of the importance of finding cancer early is melanoma skin cancer. Skin cancer can be easy to remove if it has not grown deep into the skin. The 5-year survival rate (percentage of people living at least 5 years after diagnosis) at this stage is nearly 100%, Once melanoma has spread to other parts of the body, the 5-year survival rate drops below 20%. Sometimes people ignore symptoms. They may not know that symptoms could mean something is wrong. Or they may be frightened by what the symptoms might mean and don't want to get medical help. Some symptoms, such as tiredness, are more likely to have a cause other than cancer and can seem unimportant, especially if there is an obvious cause or the problem only lasts a short time. In the same way, a person may reason that a symptom like a breast lump is probably a cyst that will go away by itself. But no symptom should be ignored or overlooked, especially if it has been there for a long time or is getting worse.

Most likely, any symptoms you may have will not be caused by cancer, but its important to have them checked out by a doctor, just in case. If cancer is not the cause, a doctor can help figure out what is and treat it, if needed. Sometimes, it is possible to find cancer before you have symptoms. The American Cancer Society and other health groups recommend cancerrelated check-ups and certain tests for people even though they have no symptoms. This helps find certain cancers early, before symptoms occur. For more information on early detection tests, see our document, American Cancer Society Guidelines for the Early Detection of Cancer. But keep in mind, even if you have had these recommended tests, it is still important to see a doctor if you have any symptoms. General cancer signs and symptoms You should know some of the general (non-specific) signs and symptoms of cancer. But remember, having any of these does not mean that you have cancer many other things cause these signs and symptoms, too. Unexplained weight loss Most people with cancer will lose weight at some point. An unexplained weight loss of 10 pounds or more (when you're not trying to lose weight) may be the first sign of cancer. This happens most often with cancers of the pancreas, stomach, esophagus, or lung. Fever Fever is very common with cancer, but it more often happens after cancer has spread from where it started. Almost all patients with cancer will have fever at some time, especially if the cancer or its treatment affects the immune system. This can make it harder for the body to fight infection. Less often, fever may be an early sign of cancer, such as blood cancers like leukemia or lymphoma.

Fatigue Fatigue is extreme tiredness that does not get better with rest. It may be an important symptom as cancer grows. It may happen early, 7

though, in cancers like leukemia, or if the cancer is causing blood loss, which can happen with some colon or stomach cancers. Pain Pain may be an early symptom with some cancers such as bone cancers or testicular cancer. A headache that does not go away or respond to treatment may be a symptom of a brain tumor. Back pain can be a symptom of cancer of the colon, rectum, or ovary. Most often, pain that is linked to cancer is a symptom of cancer that has already metastasized (spread from where it started). Skin changes Along with cancers of the skin (see the next section), some other cancers can cause skin symptoms or signs that can be seen. These signs and symptoms include: darker looking skin (hyper pigmentation) yellowish skin and eyes (jaundice) reddened skin (erythema) itching excessive hair growth

Signs and symptoms of certain cancers Along with the general symptoms, you should watch for certain other common symptoms and signs which could suggest cancer. Again, there may be other causes for each of these, but it is important to see a doctor about them as soon as possible. Change in bowel habits or bladder function Long-term constipation, diarrhea, or a change in the size of the stool may be a sign of colon cancer. Pain when passing urine, blood in the urine, or a change in bladder function (such as needing to pass urine more or less often than usual) could be related to bladder or prostate cancer. Any changes in bladder or bowel function should be reported to a doctor. Sores that do not heal Skin cancers may bleed and look like sores that do not heal. A longlasting sore in the mouth could be an oral cancer and should be dealt 8

with right away, especially in people who smoke, chew tobacco, or often drink alcohol. Sores on the penis or vagina may either be signs of infection or an early cancer, and should not be ignored. White patches inside the mouth or white spots on the tongue White patches inside the mouth and white spots on the tongue may be leukoplakia. Leukoplakia is a pre-cancerous area that is caused by ongoing irritation. It is often caused by smoking or other tobacco use. People who smoke pipes or use oral or spit tobacco are at high risk for developing leukoplakia. If it is not treated, leukoplakia can become oral cancer. Any long-lasting mouth changes should be checked by a doctor or dentist right away. Unusual bleeding or discharge Unusual bleeding can happen in early or advanced cancer. Blood in the sputum (phlegm) may be a sign of lung cancer. Blood in the stool (or a dark or black stool) could be a sign of colon or rectal cancer. Cancer of the cervix or the endometrium (lining of the uterus) can cause unusual vaginal bleeding. Blood in the urine may be a sign of bladder or kidney cancer. A bloody discharge from the nipple may be a sign of breast cancer. Thickening or lump in the breast or other parts of the body Many cancers can be felt through the skin. These cancers occur mostly in the breast, testicle, lymph nodes (glands), and the soft tissues of the body. A lump or thickening may be an early or late sign of cancer and should be reported to a doctor, especially if youve just found it or notice it has grown in size. Indigestion or trouble swallowing While they most often are caused by other things, indigestion or swallowing problems may be signs of cancer of the esophagus (the swallowing tube that goes to the stomach), stomach, or pharynx (throat). Recent change in a wart or mole or any new skin change Any wart, mole, or freckle that changes color, size, or shape, or loses its definite borders should be reported to a doctor right away. Any new skin 9

changes should be reported as well. A skin change may be a melanoma which, if found early, can be treated successfully. Nagging cough or hoarseness A cough that does not go away may be a sign of lung cancer. Hoarseness can be a sign of cancer of the larynx (voice box) or thyroid. Although the signs and symptoms listed are the ones more commonly seen with cancer, there are many others that are less common and are not listed here. If you notice any major changes in the way your body works or the way you feel, especially if it lasts for a long time or gets worse, let a doctor know. If it has nothing to do with cancer, the doctor can find out more about what's going on and treat it, if needed. If it is cancer, you'll give yourself the best chance to have it treated early, when treatment is most likely to be effective. What Is Remission? Remission is a period of time when the cancer is responding to treatment or is under control. In a complete remission, all the signs and symptoms of the disease disappear. It is also possible for a patient to have a partial remission in which the cancer shrinks but does not completely disappear. Remissions can last anywhere from several weeks to many years. Complete remissions may continue for years and be considered cures. If the disease returns, another remission often can occur with further treatment. A cancer that has recurred may respond to a different type of therapy, including a different drug combination. What Is Staging? Staging is the process of finding out how far the cancer has spread. Staging the cancer is a vital step in determining your treatment choices, and it will also give your health care team a clearer idea of the outlook for recovery. Staging can take time, and people are usually anxious to begin treatment soon. Do not worry that the staging process is taking up treatment time. Keep in mind that by staging the cancer, you and your oncologist will know which treatments are likely to be the most effective before beginning the treatment. There is more than one system for staging. The TNM system is the one used most often. It gives three key pieces of information: 10

T describes the size of the tumor, and whether the cancer has spread to nearby tissues and organs. N describes how far the cancer has spread to nearby lymph nodes. M shows whether the cancer has spread (metastasized) to other organs of the body.

Letters or numbers after the T, N, and M give more details about each of these factors. For example, a tumor classified as T1, N0, M0 is a tumor that is very small, has not spread to the lymph nodes, and has not spread to distant organs of the body. Once the TNM descriptions have been established, they can be grouped together into a simpler set of stages, stages 0 through stage IV (0-4). In general, the lower the number, the less the cancer has spread. A higher number, such as stage IV (4), means a more serious, widespread cancer. After looking at your test results, your doctor will tell you the stage of your cancer. Be sure to ask your doctor any questions you might have about what the stage of your cancer means and how it will impact your treatment options. How Is Cancer Treated? The number of treatment choices you have will depend on the type of cancer, the stage of the cancer, and other individual factors such as your age, health status, and personal preferences. You are a vital part of your cancer care team - you should discuss with them which treatment choices are best for you. Don't be afraid to ask as many questions as you have. Make sure you understand your options. A cancer diagnosis usually gives people a sense of urgency in making choices about treatment and services. However, take the time to consider all the options available to you so you will be as well informed as possible. The four major types of treatment for cancer are surgery, radiation, chemotherapy, and biologic therapies. You might also have heard about hormone therapies such as tamoxifen and transplant options such as those done with bone marrow. What Treatment Will Be Best for Me?

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Your cancer treatment will be entirely based on your unique situation. Certain types of cancer respond very differently to different types of treatment, so determining the type of cancer is a vital step toward knowing which treatments will be most effective. The cancer's stage (how widespread it is) will also determine the best course of treatment, since early-stage cancers respond to different therapies than later-stage ones. Your overall health, your lifestyle, and your personal preferences will also play a part in deciding which treatment options will be best for you. Not all types of treatment will be effective in your situation, so be sure that you understand your options. Don't be afraid to ask questions; it is your right to know what treatments are most likely to help you and what their side effects may be. Palliative versus Curative Goals: Before starting treatment, ask about the goal of treatment. Is the purpose of the treatment to cure the cancer, control it, or treat symptoms? Sometimes the goal of treatment can change. Biologic Therapies There is a lot of evidence that suggests that the immune system, the body's natural defense mechanism, plays a major role in the body's response to cancer. At least some forms of cancer occur when the immune system fails to destroy cancer cells or to prevent their growth. Biologic therapy is an effective treatment for certain cancers. It is sometimes called immunotherapy, biotherapy, or biological response modifier therapy. Biologic therapies use the body's immune system to fight cancer or to lessen the side effects of some cancer treatments. Biologic therapies can act in several ways in cancer treatment. These include interfering with cancer cell growth, acting indirectly to help healthy immune cells control cancer, and helping to repair normal cells damaged by other forms of cancer treatment. There are several kinds of biologic therapy now in use. More than one kind of biologic therapy may be used, or biologic therapy may be combined with chemotherapy or radiation therapy to treat cancer. For more information, please see Immunotherapy. Chemotherapy While surgery and radiation therapy are used to treat localized cancers, chemotherapy is used to treat cancer cells that have metastasized (spread) to other parts of the body. Depending on the type of cancer 12

and its stage of development, chemotherapy can be used to cure cancer, to keep the cancer from spreading, to slow the cancer's growth, to kill cancer cells that may have spread to other parts of the body, or to relieve symptoms caused by cancer. Chemotherapy is treatment with powerful medicines that are most often given by mouth or by injection. Unlike radiation therapy or surgery, chemotherapy drugs can treat cancers that have spread throughout the body, because they travel throughout the body in the bloodstream. Often, a combination of chemotherapy is used instead of a single drug. Chemotherapy is given in cycles, each followed by a recovery period. The total course of chemotherapy is often about six months, usually ranging from three to nine months. After a cancer is removed by surgery, chemotherapy can significantly reduce the risk of cancer returning. The chances of cancer returning and the potential benefit of chemotherapy depend on the type of cancer and other individual factors. For more information, please see our section on Making Treatment Decisions: Chemotherapy Principles. Side effects of chemotherapy Side effects of chemotherapy depend on the type of drugs, the amounts taken, and the length of treatment. The most common are nausea and vomiting, temporary hair loss, increased chance of infections, and fatigue. Many of these side effects can be uncomfortable or emotionally upsetting. However, most side effects can be controlled with medicines, supportive care measures, or by changing the treatment schedule. If you experience side effects, ask your doctor about ways to help ease or eliminate them. Also, keep your doctor informed of all side effects that you experience, as some may require immediate medical attention. Fatigue is one of the most common side effects of radiation and chemotherapy. Like most other side effects, it will disappear once the treatment is complete. You can help yourself by getting enough rest, eating a well-balanced diet, drinking plenty of liquids, and by planning your activities to include frequent rest periods. Though it is not medically harmful, hair loss can be an upsetting side effect. Most people feel that their hairstyle is a part of their identity, so it is only normal that hair loss is distressing. Some people experience hair loss during chemotherapy treatments (and sometimes with radiation treatment to the head) while others do not, even with the same drugs. Not all drugs cause hair loss. When it does occur, the hair 13

almost always grows back after the treatments are completed. If hair loss does occur, it usually begins within two weeks of the start of therapy and gets worse 1-2 months after the start of therapy. Hair regrowth often begins even before therapy is completed. Most people are able to find suitable ways of managing the hair loss until it grows back, with specially designed hats, scarves, and wigs. People having chemotherapy sometimes become discouraged about the length of time their treatment is taking or the side effects they are having. If that happens to you, talk to your doctor. There are ways to reduce the side effects or make them easier to manage. Keep in mind that the expected benefits of the treatment should outweigh any problems you might have because of it. Clinical Trials The purpose of clinical trials: Studies of promising new or experimental treatments in patients are known as clinical trials. A clinical trial is only done when there is some reason to believe that the treatment being studied may be valuable to the patient. Treatments used in clinical trials are often found to have real benefits. Researchers conduct studies of new treatments to answer the following questions: Is the treatment helpful? How does this new type of treatment work? Does it work better than other treatments already available? What side effects does the treatment cause? Are the side effects greater or less than the standard treatment? Do the benefits outweigh the side effects?* In which patients is the treatment most likely to be helpful? Types of clinical trials: There are 3 phases of clinical trials in which a treatment is studied before it is eligible for approval by the FDA (Food and Drug Administration). Phase I clinical trials: The purpose of a phase I study is to find the best way to give a new treatment and how much of it can be given safely. The cancer care team watches patients carefully for any harmful side effects. The treatment has been well tested in lab and animal studies, but the side effects in patients are not completely known. Doctors conducting the clinical trial start by giving very low doses of the drug to the first patients and increasing the dose for later groups of patients until side effects appear. Although doctors are hoping to help patients, the main purpose of a phase I study is to test the safety of the drug. 14

Phase II clinical trials: These studies are designed to see if the drug works. Patients are given the highest dose that doesnt cause severe side effects (determined from the phase I study) and closely observed for an effect on the cancer. The cancer care team also looks for side effects. Phase III clinical trials: Phase III studies involve large numbers of patient often several hundred. One group (the control group) receives the standard (most accepted) treatment. The other group receives the new treatment. All patients in phase III studies are closely watched. The study will be stopped if the side effects of the new treatment are too severe or if one group has had much better results than the others. If you are in a clinical trial, you will have a team of experts taking care of you and monitoring your progress very carefully. The study is especially designed to pay close attention to you. However, there are some risks. No one involved in the study knows in advance whether the treatment will work or exactly what side effects will occur. That is what the study is designed to find out. While most side effects disappear in time, some can be permanent or even life threatening. Keep in mind, though, that even standard treatments have side effects. Depending on many factors, you may decide to enroll in a clinical trial. Deciding to enter a clinical trial: Enrollment in any clinical trial is completely up to you, your doctors will explain the study to you in detail and will give you a form to read and sign indicating your desire to take part. This process is known as giving your informed consent. Even after signing the form and after the clinical trial begins, you are free to leave the study at any time, for any reason. Taking part in the study does not prevent you from getting other medical care you may need. To find out more about clinical trials, ask your oncologist. Among the questions you should ask are: Is there a clinical trial for which I would be eligible? What is the purpose of the study? What kinds of tests and treatments does the study involve? What does this treatment do? Has it been used before? Will I know which treatment I receive? What is likely to happen in my case with, or without, this new treatment? 15

What are my other choices and their advantages and disadvantages? How could the study affect my daily life? What side effects can I expect from the study? Can the side effects be controlled? Will I have to be hospitalized? If so, how often and for how long? Will the study cost me anything? Will any of the treatment be free? If I am harmed as a result of the research, what treatment would I be entitled to? What type of long-term follow-up care is part of the study? Has the treatment been used to treat other types of cancers?

Complementary and Alternative Therapies Complementary and alternative therapies are a diverse group of health care practices, systems, and products that are not part of usual medical treatment. They may include products such as vitamins, herbs, or dietary supplements, or procedures such as acupuncture, massage, and a host of other types of treatment. There is a great deal of interest today in complementary and alternative treatments for cancer. Many are now being studied to find out if they are truly helpful to people with cancer. You may hear about different treatments from family, friends, and others, which may be offered as a way to treat your cancer or to help you feel better. Some of these treatments are harmless in certain situations, while others have been shown to cause harm. Most of them are of unproven benefit, Complementary medicine or methods as those that are used along with your regular medical care. If these treatments are carefully managed, they may add to your comfort and well-being. Alternative medicines are defined as those that are used instead of your regular medical care. Some of them have been proven not to be useful or even to be harmful, but are still promoted as cures. If you choose to use these alternatives, they may reduce your chance of fighting your cancer by delaying, replacing, or interfering with regular cancer treatment. Before changing your treatment or adding any of these methods, discuss this openly with your doctor. Some methods can be safely used along with standard medical treatment. Others, however, can interfere with standard treatment or cause serious side effects. That is why it's important to talk with your doctor Cancer Pain 16

Pain is one of the reasons people fear cancer so much. If someone you know has cancer, it is normal to be afraid of witnessing pain. In fact, there are some cancers, which cause no physical pain at all. When it does occur, cancer pain can happen for a variety of reasons. Some people have pain as a result of the growth of a tumor or as a result of advanced cancer, while others may experience pain as a result of treatment side effects. You should also know that doctors can treat and manage cancer pain with modern techniques and medicines. A great deal of progress has been made in pain control, so pain can be reduced or alleviated in almost all cases. Even patients with advanced disease can be kept comfortable. You may also be concerned that someone taking pain medication for cancer will become addicted to the medication. However, all evidence shows that people who take prescribed drugs for cancer pain do not become addicted. In addition, some methods of pain reduction, such as acupuncture and guided imagery, do not involve drugs. What Should I Ask My Doctor About Cancer? Your relationship with your doctor is a critical part of your care. Ideally, you will have one doctor who coordinates all of your care. This doctor should be someone with whom you feel comfortable, someone you feel listens to your concerns and answers all of your questions thoughtfully and thoroughly. Your doctor will explain your diagnosis, health status, treatment options, and progress throughout treatment Like all successful relationships, your relationship with your doctor is a two-way street. It is your responsibility to ask questions and become educated about your treatment and health - to become an active part of your cancer care team. Doctors differ in how much information they give to people with cancer and their families. Likewise, people who are newly diagnosed also differ in the amount of information they need or want. If your doctor is giving you too much or too little information, let them know. Ask them whatever questions you have, and keep them informed of your needs. As in any relationship, clear and honest communication is the key to success. Your doctor will discuss your treatment plan with you. The following are examples of questions to ask during the discussion:

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What type of cancer do I have? What is the stage or extent of my cancer? What is my prognosis, as you view it? What treatment do you recommend and why? What is the goal of treatment; cure or control of my symptoms? What are the possible risks or side effects of treatment? What are the pros and cons of my treatment? Are there other treatments for me to consider? How often will I need to come in for treatment or tests? How long will my treatments last? What if I miss a treatment? Will my life change? Will I need to make changes in my work, family life, and leisure time? What are the names of the drugs I will take? What are they for? What other drugs or treatments may I have to take? How will you know that my treatment is working? Why do I need a blood test and how often? If other specialists take part in my care, who will coordinate my entire treatment program? What symptoms or problems should I report right away? If I do not feel sick, does that mean the treatment is not working? What are the chances that my cancer may recur (come back), with the treatment programs we have discussed? What can I do to be ready for treatment? Will I still be able to have children after treatment? Are there any special foods I should or should not eat? Can I drink alcoholic beverages? What costs will I have? What is the best time to call you if I have a question?

Make sure that all your concerns and questions, no matter how small, have been answered. It may take more than one visit to discuss all of your concerns, as new questions may come to mind. It may be hard to remember all your doctor says to you. Some people find it helpful to take notes, bring a family member or friend, tape record the conversations, and/or bring a prepared list of questions and write down the doctor's answers. Remember that you have the right to a second opinion about your diagnosis and the recommended treatment. Asking for a second opinion does not mean that you don't like or trust your doctor. Doctors understand you need to feel that every possibility for the best treatment

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is being explored. You can also ask your doctor if they have consulted with other specialists at their treatment center. For additional information, please see Talking with Your Doctor and choosing a Doctor and a Hospital. The History of Cancer What Is Cancer? Cancer develops when cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells. Normal body cells grow, divide, and die in an orderly fashion. During the early years of a person's life, normal cells divide more rapidly until the person becomes an adult. After that, cells in most parts of the body divide only to replace worn-out or dying cells and to repair injuries. Because cancer cells continue to grow and divide, they are different from normal cells. Instead of dying, they outlive normal cells and continue to form new abnormal cells. Cancer cells often travel to other parts of the body where they begin to grow and replace normal tissue. This process, called metastasis, occurs as the cancer cells get into the bloodstream or lymph vessels of our body. When cells from a cancer like breast cancer spread to another organ like the liver, the cancer is still called breast cancer, not liver cancer. Cancer cells develop because of damage to DNA. This substance is in every cell and directs all its activities. Most of the time when DNA becomes damaged the body is able to repair it. In cancer cells, the damaged DNA is not repaired. People can inherit damaged DNA, which accounts for inherited cancers. Many times though, a person's DNA becomes damaged by exposure to something in the environment, like smoking. Cancer usually forms as a solid tumor. Some cancers, like leukemia, do not form tumors. Instead, these cancer cells involve the blood and blood-forming organs and circulate through other tissues where they grow.

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Not all tumors are cancerous. Benign (noncancerous) tumors do not spread to other parts of the body (metastasize) and, with very rare exceptions, are not life threatening. Different types of cancer can behave very differently. For example, lung cancer and breast cancer are very different diseases. They grow at different rates and respond to different treatments. That is why people with cancer need treatment that is aimed at their particular kind of cancer. Cancer is the second leading cause of death in the United States. Half of all men and one-third of all women in the US will develop cancer during their lifetimes. Today, millions of people are living with cancer or have had cancer. The risk of developing most types of cancer can be reduced by changes in a person's lifestyle, for example, by quitting smoking and eating a better diet. The sooner a cancer is found and treatment begins, the better are the chances for living for many years. Oldest Descriptions of Cancer Cancer has afflicted humans throughout recorded history. It is no surprise that from the dawn of history doctors have written about cancer. Some of the earliest evidence of cancer is found among fossilized bone tumors, human mummies in ancient Egypt, and ancient manuscripts. Bone remains of mummies have revealed growths suggestive of the bone cancer, osteosarcoma. In other cases, bony skull destruction as seen in cancer of the head and neck has been found. Our oldest description of cancer (although the term cancer was not used) was discovered in Egypt and dates back to approximately 1600 B.C. The Edwin Smith Papyrus, or writing, describes 8 cases of tumors or ulcers of the breast that were treated by cauterization, with a tool called "the fire drill." The writing says about the disease, "There is no treatment." Origin of the Word Cancer The origin of the word cancer is credited to the Greek physician Hippocrates (460-370 B.C.), considered the "Father of Medicine." Hippocrates used the terms carcinos and carcinoma to describe nonulcer forming and ulcer-forming tumors. In Greek these words refer to a crab, most likely applied to the disease because the finger-like

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spreading projections from a cancer called to mind the shape of a crab. Carcinoma is the most common type of cancer. Renaissance Period During the Renaissance, beginning in the 15th century, scientists in Italy developed a greater understanding of the human body. Scientists such as Galileo and Newton began to use the scientific method, which later began to be used to study disease. Autopsies, performed by Harvey (1628), allowed an understanding of the circulation of blood through the heart and body that had remained a mystery. In 1761, Giovanni Morgagni of Padua was the first to do something considered routine today. He performed autopsies to relate the patient's illness to the pathologic findings after death. This laid the foundation for scientific oncology, the study of cancer. The famous Scottish surgeon John Hunter (1728-1793) suggested that some cancers might be cured by surgery and described how the surgeon might decide which cancers to operate on. If the tumor had not invaded nearby tissue and was "moveable," he said, "There is no impropriety in removing it." A century later the development of anesthesia allowed surgery to flourish and the classic cancer operations such as radical mastectomy were developed.

Nineteenth Century The 19th century saw the birth of scientific oncology with the discovery and use of the modern microscope. Rudolf Virchow, often called the founder of cellular pathology, provided the scientific basis for the modern pathologic study of cancer. As Morgagni had correlated the autopsy findings observed with the unaided eye with the clinical course of illness, so Virchow correlated the microscopic pathology. This method not only allowed a better understanding of the damage cancer had done to a patient but also laid the foundation for the development of cancer surgery. Body tissues removed by the surgeon could now be examined and a precise diagnosis made. In addition, the

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pathologist could tell the surgeon whether the operation had completely removed the tumor. Cancer Causes From the earliest times, physicians have wondered about the cause of cancer. The Egyptians blamed cancers on the Gods. Humoral Theory: Hippocrates believed that the body contained 4 humors (body fluids) - blood, phlegm, yellow bile, and black bile. A balance of these fluids resulted in a state of health. Any excesses or deficiencies caused disease. An excess of black bile collecting in various body sites was thought to cause cancer. This theory of cancer was passed on by the Romans and was embraced by the influential doctor Galen's medical teaching, which remained the unchallenged standard through the Middle Ages for over 1300 years. During this period, the study of the body, including autopsies, was prohibited for religious reasons, thus limiting knowledge. Lymph Theory: Among theories that replaced the humoral theory of cancer was cancer's formation by another fluid, lymph. Life was believed to consist of continuous and appropriate movement of the fluid parts through solids. Of all the fluids, the most important were blood and lymph. Stahl and Hofman theorized that cancer was composed of fermenting and degenerating lymph varying in density, acidity, and alkalinity. The lymph theory gained rapid support. John Hunter (17231792) agreed that tumors grow from lymph constantly thrown out by the blood. Blastema Theory: In 1838, German pathologist Johannes Muller demonstrated that cancer is made up of cells and not lymph, but he was of the opinion that cancer cells did not arise from normal cells. Muller proposed that cancer cells arose from budding elements (blastema) between normal tissues. His student, Rudolph Virchow (1821-1902), the famous German pathologist, determined that all cells, including cancer cells, are derived from other cells. Chronic Irritation: Virchow proposed that chronic irritation was the cause of cancer, but he falsely believed that cancers "spread like a liquid." A German surgeon, Karl Thiersch, showed that cancers metastasize through the spread of malignant cells and not through some unidentified fluid.

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Trauma: Despite advances in the understanding of cancer, from the late 1800s until the 1920s, cancer was thought by some to be caused by trauma. This belief was maintained despite the failure to cause cancer in experimental animals by injury. Parasite Theory: In the 17th and 18th centuries, some believed that cancer was contagious. In fact, the first cancer hospital in France was forced to move from the city in 1779 because of the fear of the spread of cancer throughout the city. A Nobel Prize was wrongly awarded in 1926 for scientific research documenting stomach cancer being caused by a certain worm. With the inability to confirm this research, scientists lost interest in the parasite theory. Modern Day Carcinogens More recently, other causes of cancer were discovered and documented. In 1911 Peyton Rous, at the Rockefeller Institute in New York, described a sarcoma in chickens caused by what later became known as the Rous sarcoma virus. He was awarded the Nobel Prize for that work in 1968 .In 1915 cancer was induced in laboratory animals for the first time by a chemical, coal tar, applied to rabbit skin at Tokyo University. One hundred and fifty years had passed since the most destructive source of chemical carcinogens known to man, tobacco, was first identified in London by the astute clinician John Hill. It was to be many years until tobacco was "rediscovered" as a carcinogen. Today we recognize and avoid many specific substances that cause cancer: coal tars and their derivatives such as benzene, some hydrocarbons, aniline (a substance used to make dyes), asbestos, and others. Radiation from a variety of sources, including the sun, is known to lead to cancer. To ensure the public's safety, the government has set occupational standards for many substances, such as benzene, asbestos, hydrocarbons in the air, arsenic in drinking water, radiation, and so on. Several viruses are now linked to cancer: Long-standing liver infection with the hepatitis virus can lead to cancer of the liver. A variety of the herpes virus, the Epstein-Barr virus, causes infectious mononucleosis and has been implicated in nonHodgkin's lymphomas and nasopharyngeal cancer. 23

The human immunodeficiency virus (HIV) is associated with an increased risk of developing several cancers, especially Kaposi's Sarcoma and non-Hodgkin's lymphoma. Human papilloma viruses (HPVs) have been linked to cancers of the cervix, vulva, and penis.

Many of these associations were recognized long before scientists understood the mechanism by which the cancer was produced Cancer Epidemiology During the 18th century, 3 important observations were made that launched the field of cancer epidemiology. Bernardino Ramazzini, an Italian doctor, reported in 1713 the virtual absence of cervical cancer and relatively high incidence of breast cancer in nuns and wondered whether this was in some way related to their celibate lifestyle. This observation was an important step toward identifying and understanding the importance of hormonal factors such as pregnancy and infections related to sexual contact in modifying cancer risk. Percival Pott of Saint Bartholomew's Hospital in London described in 1775 an occupational cancer in chimney sweeps, cancer of the scrotum, caused by soot collecting under their scrotum. This research led to many additional studies that identified a number of occupational carcinogenic exposures and led to public health measures to reduce cancer risk. John Hill of London was the first to recognize the dangers of tobacco. In 1761, only a few decades after tobacco became popular in London, he wrote a book entitled Cautions Against the Immoderate Use of Snuff. Cancer Treatments: Surgery Ancient physicians and surgeons knew that cancer would usually come back after it was removed by surgery. The Roman physician Celsus wrote, "After excision, even when a scar has formed, none the less the disease has returned." Galen was a 2nd-century Roman doctor whose books were preserved for centuries and who was thought to be the highest medical authority for over a thousand years. Galen viewed cancer much as Hippocrates had, 24

and his views set the pattern for cancer management for centuries. He considered the patient incurable after a diagnosis of cancer had been made. Even though medicine progressed and flourished in some ancient civilizations, there was little progress in cancer treatment. The approach to cancer was Hippocratic (or Galenic) for the most part. To some extent this view that cancer cannot be cured has persisted even into the 20th century. This has served to fuel the fear patients have of the disease. Some people, even today, consider all cancer incurable and delay consulting a doctor until it is too late. Treatments for cancer went through a slow process of development. The ancients recognized that there was no curative treatment once a cancer had spread and that intervention might be more harmful than no treatment at all. Galen did write about surgical cures for breast cancer if the tumor could be completely removed at an early stage. Surgery then was very primitive with many complications, including blood loss. It wasn't until the 19th and early 20th centuries that major advances were made in general surgery and specifically in cancer surgery. There were great surgeons before the discovery of anesthesia. John Hunter, Astley Cooper, and John Warren achieved lasting acclaim for their swift and precise surgery. But when anesthesia became available in 1846, there emerged the great surgeons whose work so rapidly advanced the art that the next hundred years became known as "the century of the surgeon." Three surgeons stand out because of their contributions to the art and science of cancer surgery: Bilroth in Germany, Handley in London, and Halsted at Johns Hopkins. Their work led to "cancer operations" designed to remove the entire tumor together with the lymph nodes in the region where the tumor was located. William Stewart Halsted, professor of surgery at Johns Hopkins University, developed the radical mastectomy during the last decade of the 19th century. His work was based in part on that of W. Sampson Handley, the London surgeon who believed that cancer spread outward by invasion from the original growth. Halsted did not believe that cancers usually spread through the bloodstream: "Although it undoubtedly occurs, I am not sure that I have observed from breast cancer, metastasis which seemed definitely to have been conveyed by way of the blood vessels." He believed that 25

adequate local removal of the cancer would be curative -- if the cancer later appeared elsewhere, it was a new process. That belief led him to develop the radical mastectomy for breast cancer. This became the basis of cancer surgery for almost a century until it was replaced by the work of modern surgeons through clinical trials. Today, the radical mastectomy is almost never performed and the "modified radical mastectomy" is performed less frequently than before. In many cases, local removal of the primary tumor (lumpectomy) coupled with radiation therapy and chemotherapy is equally effective and much less disabling than the radical procedures. At the same time Halsted and Handley were developing their radical operations, another surgeon was asking, "What is it that decides which organs shall suffer in a case of disseminated cancer?" Stephen Paget, an English surgeon, concluded that cancer cells spread by way of the bloodstream to all organs of the body but were able to grow only in a few organs. In a brilliant leap of logic he drew an analogy between cancer metastasis and seeds that "are carried in all directions, but they can only live and grow if they fall on congenial soil." Paget's conclusion that cells from a primary tumor spread through the bloodstream but could grow only in certain, and not all, organs was an accurate and highly sophisticated hypothesis that was confirmed by the techniques of modern cellular and molecular biology almost a hundred years later. This understanding of metastasis became a key element in recognizing the limitations of cancer surgery. It eventually allowed doctors to develop systemic treatments used after surgery to destroy cells that had spread throughout the body and to use less mutilating operations, for example, in treating many types of cancer. Today these systemic treatments may also be used before surgery. Less invasive surgical techniques are being studied and/or used. Cryosurgery (also called cryotherapy or cryoablation) is a surgical technique being studied to treat localized prostate cancer by freezing the cells with a metal probe. It is less invasive than radical prostatectomy, so there is less blood loss, a shorter hospital stay, a shorter recovery period, and less pain than radical surgery. Cancer Treatments: Hormone Therapy Another 19th-century discovery laid the groundwork for an important modern method to treat and prevent breast cancer. Thomas Beatson graduated from the University of Edinburgh in 1874 and developed an interest in the relation of the ovaries to milk formation in the breasts, 26

probably because he grew up near a large sheep farm in rural Scotland. In 1878 he discovered that the breasts of rabbits stopped producing milk after he removed the ovaries. He described his results to the Edinburgh Medico-Chirurgical Society in 1896: "This fact seemed to me of great interest, for it pointed to one organ holding control over the secretion of another and separate organ." Because the breast was "held in control" by the ovaries, Beatson decided to test removal of the ovaries (oophorectomy) in advanced breast cancer. He found that oophorectomy often resulted in the improvement of breast cancer patients. He also suspected that "the ovaries may be the exciting cause of carcinoma" of the breast. He had discovered the stimulating effect of the female ovarian hormone (estrogen) on breast cancer, even before the hormone itself was discovered. His work provided a foundation for the modern use of hormone therapy, such as tamoxifen, for the treatment and prevention of breast cancer. A half century after Beatson's discovery, a urologist at the University of Chicago, Charles Huggins, reported dramatic regression of metastatic prostate cancer following removal of the testes. Later, drugs that blocked male hormone were found to be effective treatment for prostate cancer, and these drugs are now being studied to determine if they have a role in prevention of prostate cancer. New drugs to block the effects of male hormones and prevent prostate cancer growth are being developed. Studies are also underway to find the most effective combination of current hormonal treatments and to determine the value of using hormone therapy before or after radiation therapy. Studies of intermittent hormone therapy are also in progress. Cancer Treatments: Radiation As the 19th century was drawing to a close, in 1896 a German physics professor, Wilhelm Conrad Roentgen, presented a remarkable lecture entitled "Concerning a New Kind of Ray." Roentgen called it the "X-ray", with "X" being the algebraic symbol for an unknown quantity. There was immediate worldwide excitement. Within months, systems were being devised to use X-rays for diagnosis, and within 3 years radiation was used in the treatment of cancer. In 1901 Roentgen received the first Nobel Prize awarded in physics. Radiation therapy began with radium and with relatively low-voltage diagnostic machines. In France a major breakthrough took place when it 27

was discovered that daily doses of radiation over several weeks would greatly improve therapeutic response. The methods and the machines for delivery of radiation therapy have steadily improved. Today, radiation is delivered with great precision in order to destroy malignant tumors while minimizing damage to adjacent normal tissue. At the beginning of the 20th century, shortly after radiation began to be used for diagnosis and therapy, it was discovered that radiation could cause cancer as well as cure it. Many early radiologists used the skin of their arms to test the strength of radiation from their radiotherapy machines, looking for a dose that would produce a pink reaction (erythema) that looked like sunburn. They called this the "erythema dose," and this was considered an estimate of the proper daily fraction of radiation. In retrospect, it is no surprise that many developed leukemia. Advances in technology are making it possible to aim radiation more precisely than in the past. This method, called conformal radiation therapy, helps to treat only the area involved by the cancer. Radiation is focused to avoid the normal tissues as much as possible. This is expected to increase the effectiveness and reduce the side effects of radiation therapy. Studies are in progress to find out which radiation techniques are best suited for specific categories of patients. A related technique, conformal proton beam radiation therapy, uses a similar approach to focusing radiation on the cancer. But instead of using X-rays, this technique uses proton beams. Protons are parts of atoms that cause little damage to tissues they pass through but are very effective in killing cells at the end of their path. This means that proton beam radiation can deliver more radiation to the cancer while reducing side effects of nearby normal tissues. Stereotactic surgery and stereotactic radiation therapy are terms that describe several techniques used to deliver a large, precise radiation dose to a small tumor. The term surgery may be confusing because no incision is actually made. The most common site being treated with this technique is the brain. The linear accelerator, or a special machine known as a Gamma Knife, can be used to deliver this treatment. Research is ongoing to produce delivery systems to treat sites other than the brain. Intraoperative radiation therapy (IORT) is a form of treatment that delivers radiation at the time of surgery directly to the cancer or the adjacent tissues after the cancer has been removed. It is more 28

commonly used in abdominal or pelvic cancers and in cancers that have a tendency to return. IORT minimizes the amount of tissue that is exposed to radiation because normal tissues can be moved out of the way during surgery and shielded, thus allowing a higher dose of radiation to the cancer. Research into this type of treatment is ongoing. The disadvantage of IORT is that, unless a dedicated machine is available in the operating room, the patient must be transported to the radiation therapy department during the procedure to receive the treatment and then returned to the operating room to complete the surgery. Hyperthermia refers to the use of heat. Heat has been found to kill cancer cells, but when used alone, it does not destroy enough cells to cure the cancer. Heat, delivered by microwaves or ultrasound, has been studied in combination with radiation and may, in some instances, enhance the effect of the radiation. Chemical modifiers or radiosensitizers are substances that make cancer more sensitive to radiation. The goal of research into these types of substances is to develop agents that will make the tumor more sensitive without affecting normal tissues. Research is also ongoing to find substances that may protect normal cells from radiation. Boron neutron capture therapy is an experimental type of radiation therapy that is sometimes used in brain tumors. A compound containing the element, boron, is injected into the patient's blood and concentrates in the brain tumor. The brain is then irradiated with neutrons from a nuclear reactor. When a neutron hits a boron atom, a type of radiation is released that has high energy but does not extend far into the surrounding normal brain tissue. The value of this approach remains to be determined. Cancer Treatments: Chemotherapy The century of the surgeon had begun with the discovery of anesthesia in 1846. Fifty years later, in 1896, Roentgen presented his famous paper on the X-ray. During World War II, naval personnel who were exposed to mustard gas as a result of a military action were found to have severe bone marrow depression. During that same period, the U.S Army was studying a number of agents related to mustard gas in order to develop more effective agents and to develop protective measures. In the course of that work, compound called nitrogen mustard was studied and found to have substantial activity against a cancer of the 29

lymph nodes called lymphoma. This agent served as the model for a long series of similar but more effective agents (called "alkylating" agents) that killed rapidly proliferating cancer cells by damaging their DNA. Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a compound related to the vitamin, folic acid, produced remission in acute leukemia in children. Aminopterin blocked a critical chemical reaction needed for DNA replication. That drug was the predecessor of methotrexate, a commonly used cancer treatment drug today. Since then, other researchers discovered drugs that blocked different functions involved in cell growth and replication. The era of chemotherapy had begun. The first cure of metastatic cancer was obtained in 1956 when methotrexate was used to treat a rare tumor called choriocarcinoma. Over the years, the development and use of chemotherapy drugs have resulted in the successful treatment of many people with cancer. Other cancers that can now be cured regularly with chemotherapy, even when widespread, include acute childhood leukemia, testicular cancer, and Hodgkin's disease. Many other cancers can be controlled for long periods of time, even if not cured now several approaches are being studied to improve the activity and reduce the undesirable side effects of chemotherapy. These include: New drugs, new combinations of drugs, and new delivery techniques Novel approaches to targeting drugs more specifically at the cancer cells (such as liposomal therapy and monoclonal antibody therapy) to produce fewer side effects Drugs to reduce side effects, like colony-stimulating factors and chemoprotective agents (such as dexrazoxane and amifostine) Hematopoietic stem cell transplantation Agents that overcome multidrug resistance

Liposomal therapy is a new technique that uses chemotherapy drugs that have been packaged inside liposomes (synthetic fat globules). This liposome, or fatty coating, helps them penetrate the cancer cells more selectively and decreases possible side effects (such as hair loss, nausea, and vomiting). Examples of liposomal medications are Doxil (the encapsulated form of doxorubicin) and Daunoxome (the encapsulated form of daunorubicin).

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Monoclonal antibodies, a special type of antibody produced in laboratories, can be designed to guide chemotherapy medications directly to the tumor. Monoclonal antibodies (or proteins) bind to tumorassociated cell surface antigens and destroy tumor cells through a variety of methods. Early in the 20th century, the only curable cancers were small and localized enough to be completely removed by surgery. Later, radiation was used after surgery to control small tumor growths that were not surgically removed. Finally, chemotherapy was added to destroy small tumor growths that had spread beyond the reach of the surgeon and radiotherapist. The use of chemotherapy after surgery to destroy the few remaining cancer cells in the body is called adjuvant therapy. Adjuvant therapy was tested first in breast cancer and found to be effective. It was later used in colon cancer, cancer of the testis, and others. A major discovery was the advantage of multiple chemotherapeutic agents (known as combination chemotherapy) over single agents. Some types of very fast-growing leukemias and lymphomas (tumors involving the cells of the bone marrow and lymph nodes, respectively) responded extremely well to combination chemotherapy, and clinical trials led to gradual improvement of the drug combinations used. Many of these tumors can be cured today by appropriate combination chemotherapy. The approach to patient treatment has become more scientific with the introduction of clinical trials on a wide basis throughout the world. These clinical trials compare new treatments to standard treatments and contribute to a better understanding of treatment benefits and risks. Clinical trials test theories about cancer learned in the basic science laboratory and also test ideas derived from the clinical observations on cancer patients. They are essential to continued progress. Cancer Treatments: Biologic Therapy Scientists' understanding of the biology of cancer cells has led to the development of biologic agents that mimic some of the natural signals that the body uses to regulate growth. This cancer treatment, called biological response modifier (BRM) therapy, biologic therapy, biotherapy, or immunotherapy, has proven effective for several cancers through the clinical trial process. Some of these biologic agents, occurring naturally in the body, can now be produced in the laboratory. Examples are interferons, interleukins, 31

and other cytokines. These agents are given to patients to imitate or influence the natural immune response either by directly altering the cancer cell growth or acting indirectly to help healthy cells control the cancer. One of the most exciting applications of biologic therapy has come from identifying certain tumor targets, called antigens, and aiming an antibody at these targets. This method was first used to localize tumors in the body for diagnosis and more recently has been used to attack cancer cells. Scientists are also studying vaccines that would boost the body's immune response to cancer cells and thereby prevent cancer from developing. Twentieth-Century Understanding of Cancer By the middle of the 20th century, scientists had in their hands the instruments needed to begin solving the complex problems of chemistry and biology presented by cancer. James Watson and Francis Crick, who received the Nobel Prize for their work, had discovered the exact chemical structure of DNA, the basic material in genes. DNA was found to be the basis of the genetic code that gives orders to all cells. After learning how to translate this code, scientists were able to understand how genes worked and how they could be damaged by mutations (changes or mistakes in genes). These modern techniques of chemistry and biology answered many complex questions about cancer. Scientists already knew that cancer could be caused by chemicals, radiation, and viruses, and that sometimes cancer seemed to run in families. But, as our understanding of DNA and genes increased, we learned that it was the damage to DNA by chemicals and radiation or introduction of new DNA sequences by viruses that often led to the development of cancer. It became possible to pinpoint the exact site of the damage to a specific gene. Further, scientists discovered that sometimes defective genes are inherited and that sometimes these inherited genes are defective at the same points that chemicals exerted their effect. In other words, most carcinogens caused genetic damage (mutations), mutations led to abnormal groups of cells (called clones), mutant clones evolved to even more malignant clones over time, and the cancer progressed by more and more genetic damage and mutations. Normal cells with damaged 32

DNA die; cancer cells with damaged DNA do not. The recent discovery of this critical difference answers many questions that have troubled scientists for many years. Slowly, medical scientists are identifying the genes that are damaged by chemicals or radiation and the genes that, when inherited, can lead to cancer. The recent discovery of two genes that cause some breast cancers, BRCA1 and BRCA2, represents considerable promise because many people who have a higher probability of developing breast cancer can now be identified Other genes have been discovered that are associated with some cancers that run in families, such as cancers of the colon, rectum, kidney, ovary, esophagus, lymph nodes, and pancreas and skin melanoma. Familial cancer is not nearly as common as spontaneous cancer, causing less than 15% of all cancers, but it is important to understand these cancers because with continued research in genetics we may be able to identify persons at very high risk. The Impact of Modern Biology on Cancer Treatment The knowledge of molecular biology and genetics that is coming from basic science laboratories throughout the world is already having an influence on cancer treatment as it is on cancer detection and diagnosis. Angiogenesis is a normal process, the growth of new blood vessels, necessary for growth and for wound healing. It has recently been determined that in order for a tumor to grow, it must develop its own blood supply. Drugs have now been developed that, in laboratory animals, can prevent new blood vessels from developing. Some of these drugs are already in trial in human beings with cancer and are showing considerable promise. Signal transduction is the complicated process by which growth signals are transmitted to the nucleus of the cell. Many efforts have been made to interfere with that signaling. One agent has been highly successful in a chronic form of leukemia (for which it is now being used regularly) and is showing promise in other cancers. Genetic Therapy As we learn more about the molecular genetics of cancer, we are able to take advantage of specific genetic characteristics. For example, some patients with breast cancer have too many copies of a gene called Her2/neu. Scientists have been able to develop an

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antibody called trastuzumab (Herceptin) that is active against cancer in those patients. The fact that specific defects can be related to individual kinds of cancer and that, in at least a few cases, can be turned into powerful, very specific tools provides promise that additional tools will be coming from our laboratories Summary The growth in our knowledge of cancer biology and cancer treatment and prevention has been staggering in recent years. Scientists have learned more about cancer in the last decade of the 20th century than has been learned in all the centuries preceding. This does not change the fact, however, that all scientific knowledge is based on the knowledge already acquired by the hard work and discovery of our predecessors. Heredity and Cancer Even as early as the 1800s, it was recognized that some families were more prone to develop specific types of cancer. Though some believed that heredity was a factor, it was uncertain whether other factors, such as shared diet or exposure to toxins, might be responsible for these familial cancers. Cancer is now clearly understood to be a disease of abnormal gene function. Genes are segments of DNA that contain instructions on how to make the proteins the body needs to function. They govern hereditary traits, such as hair color, eye color, and height, as well as susceptibility (likelihood of being affected) to certain diseases, such as cancer. In humans, genes are located on 23 pairs of chromosomes. One of each chromosome pair comes from the mother, the other from the father. Each chromosome can contain hundreds or thousands of genes that are passed from the parents to the child. The genes you were born with are in every cell of your body. We now understand that genes serve 2 major roles in cancer: some contribute to the development of cancer and others stop cancer from developing or growing. Genes that can cause cancer are called oncogenes. Genes that stop or suppress cancer growth are called tumor

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suppressor genes. (For more information, refer to the document, "Oncogenes and Tumor Suppressor Genes.") Even if you were born with healthy genes, some of them can become changed (mutated) over the course of your life. For example, exposure to large doses of radiation can cause changes in the genes of some of the bodys cells and allow cancer to start. This explains why most cancers are not inherited but arise from gene mutations you acquire during your life. The older you get, the more gene mutations you may accumulate. This is why cancer risk increases with age. In contrast, cancers that are inherited tend to occur earlier in life than cancers of the same type that are not inherited. Cancer is such a common disease, especially in older adults, that many families have at least a few members who have had cancer. Only about 5% to 10% of all cancers are the inherited type. The cancer actually is not inherited, but the abnormal gene that can cause the cancer is what is inherited. This document will focus on those cancers that tend to occur in families. Most of the time, different types of cancer occur apparently by chance or are linked with common family habits such as cigarette smoking, which can damage the genes in the lungs, throat, mouth, and several other organs. However, studies have shown that certain cancers can occur to excess in some families. For example, a woman whose mother, sister, or daughter (first-degree relatives) has had breast cancer is about twice as likely to develop breast cancer as a woman whose close female relatives have not had breast cancer. Some of these women have an inherited gene mutation that is linked to higher rates of breast or ovarian cancer. Women with first-degree relatives who have had breast cancer may choose to undergo genetic testing to find out if they have a breast cancer gene mutation. If a mutation is present, the woman has a high chance (or risk) of developing breast cancer before age 40. She may start getting mammograms at a younger age, have special breast cancer screening tests, or take other measures to detect cancer earlier and reduce her chance or risk of getting breast cancer.There are 2 known breast cancer genes. Mutations of the BRCA1 gene are linked to breast and ovarian cancer. Individuals who have these gene mutations also have an increased risk of colon and prostate cancer. BRCA2 gene mutations are related to a higher risk of breast cancer, as well as pancreatic and ovarian cancer, in both men and women.

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A few types of childhood cancers are known to occur more often in some families. Researchers learned about how tumor suppressor genes work through their study of retinoblastoma, a childhood cancer that starts in the eye. About 40% of children with retinoblastoma have inherited an abnormal Rb tumor suppressor gene from one parent. About 85% of children who inherit an abnormal Rb gene from a parent develop a retinoblastoma in one or both eyes. When children inherit Rb mutations from a parent, the mutation is present in every cell of the child's body and, therefore, can be detected by testing DNA of blood cells. Because every person has 2 Rb genes but passes only one of each to their children (the second gene comes from the other parent) the odds that a parent will pass his or her mutated gene on to a child are 1 out of 2. Family studies have shown that retinoblastoma is inherited (or passed by genetic transmission from parent to child) in about 45% of the cases. Even though the child inherited only 1 of the pair of chromosomes or genes for retinoblastoma, he or she is likely to have the disease. This is because there is no backup to stop the mutated gene from making abnormal cells if the healthy Rb gene stops working in even one cell. Patients with the hereditary form of retinoblastoma also have an increased lifetime risk of developing other types of cancer, including osteosarcoma (bone cancer) of the leg and the orbit (bone around the eye). Another example of hereditary cancer risk occurs when a person inherits a mutation in the p53 gene. A normal P53 gene stops the growth of abnormal cells. People with a p53 gene abnormality have a higher risk of breast cancer, sarcoma, leukemia, and tumors of the adrenal gland and central nervous system. This condition is called Li-Fraumeni syndrome. One study showed that 15% of Li-Fraumeni patients who had cancer were diagnosed later with a second cancer, and some developed a third and fourth cancer later on. Many other cancers are associated with having a family history of that cancer. Breast, ovarian, prostate, and colon are some of these cancers. Please refer to the specific Cancer Site documents on our website for more information about a particular type of cancer and its genetic components. Precancerous Diseases In addition to the family cancer patterns, several uncommon types of cancerous and/or precancerous conditions show heredity patterns. Some of the more common syndromes are discussed below. 36

An important precancerous condition among adults is Familial Adenomatous Polyposis (FAP) of the colon, which is characterized by hundreds of polyps in the colon. Without treatment, at least one of these polyps will almost certainly become cancerous. But if the trait of multiple polyposis is diagnosed early in life, surgery to remove the colon can prevent the development of cancer. Another major inherited syndrome that increases a persons risk for colon cancer is called hereditary non-polyposis colorectal cancer or HNPCC. Individuals with this syndrome have up to an 80% lifetime risk of colorectal cancer. Most of these cancers occur before age 50. HNPCC accounts for 1% to 5% of all colorectal cancers, and can also cause endometrial cancer (inside the uterus) in women. The most common type of neurofibromatosis (a syndrome that includes tumors of the nerves) shows up in childhood as dark areas on the skin, which are called caf au lait spots. Children with neurofibromatosis are more likely to have neurofibromas of the skin; cancers of the eye, muscle, or kidney; and sarcomas and leukemias. About half of these cases are hereditary. Several types of endocrine system (hormone or glandular organs) syndromes are known. People with the multiple endocrine neoplasia syndrome type 1 (MEN1) have a high risk of developing tumors of 3 glands the pituitary, parathyroid, and pancreas. The multiple endocrine neoplasia syndrome type 2 (MEN2) increases the risk of parathyroid, adrenal, thyroid, and nerve tumors. Some families have unusual moles on their skin, called dysplastic nevi, which are linked to a higher risk of melanoma. The genetic basis of precancerous moles that run in families was recently identified as a gene called CDKN2A. Families with xeroderma pigmentosum (a very rare skin disorder) tend to develop multiple skin cancers at an early age. They are extremely sensitive to the cancer-promoting effects of sunlight because of a defect in the enzyme that helps skin cells repair DNA damage caused by ultraviolet light. People with this disorder may also have more internal cancers. Down syndrome is a known genetic defect that is linked to leukemia.

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Defects of the immune system, including genetic diseases such as Wiskott-Aldrich syndrome and agammaglobulinemia, increase the risk of developing lymphoma. Other syndromes exist, though most of them are rare. Genetic Counseling and Testing Individuals with a strong family history of cancer or multiple types of cancer may want to find out about their genetic makeup. This knowledge may help the individual or family members in planning health care for the future. Since inherited mutations affect all cells of a person's body, they can often be identified by genetic testing on blood samples. Genetic counseling and testing may be recommended for some people with a strong family history of cancer. For more information on genetic testing, please call us at 1-800-ACS-2345 and request a copy of the American Cancer Society document, Genetic Testing What You Need to Know. Future Directions The Human Genome Project is an international program devoted to determining the complete DNA sequence in humans. Although all the genes have been listed, there is still a great deal to learn about what proteins each gene makes. Researchers need to find out how each gene fits into the bodys activities at the cellular level and the effect that activity has on diseases such as cancer.The hope is that it will provide a single reference to all human genetic information, including cancer genes and markers. The impact this project will have on the future of cancer is profound. Genetics Dictionary Chromosome (krom-o-some): structures that carry the genes, the basic units of heredity. Humans have 23 pairs of chromosomes, one member of each pair from the mother, the other from the father. Each chromosome can contain hundreds or thousands of individual genes. Gene: a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Genes contain instructions on how to make the proteins the body needs to function, when to destroy damaged cells, and how to keep the cells in balance.

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Hereditary cancer syndrome: conditions associated with cancers that occur in several family members because of an inherited, mutated (abnormal) gene. Oncogenes (on-ko-genes): genes that promote uncontrolled cell growth and multiplication. After activation, they can cause cells to grow too quickly and form tumors. Tumor suppressor genes: genes that monitor cell division, repair damaged DNA, or cause cells to die at the appropriate time. Alterations of these genes can lead to rapid cell growth and development of cancer.

Cancer Prevalence: Cancer prevalence is defined as the total number of people living with cancer at any point in time. It includes people diagnosed with cancer in the past (who are still alive) as well as people recently diagnosed. Cancer prevalence is not a measure of how common a cancer is. This number is reflected by cancer incidence, which is the number of people newly diagnosed with cancer in a given time period (usually a year). Prevalence is affected both by the incidence of a cancer and by how long people normally live with the disease. For example, lung cancer is the second most common cancer in both men and women, but lung cancer prevalence is not as high as that of some less common cancers because people with lung cancer tend not to live as long once diagnosed. Lifetime Probability of Developing or Dying From Cancer The lifetime probability (or risk) of developing or dying from cancer refers to the chance a person has, over the course of his or her lifetime (from birth to death), of being diagnosed with or dying from cancer. These risk estimates, like annual incidence and mortality data, provide another measure of the how widespread cancer is. Environmental Carcinogens Environmental factors can include smoking, diet, sun exposure, and infectious diseases, as well as chemicals and radiation in our homes and workplaces. Learn more about these risks and how you can reduce them. 39

What is a carcinogen? Cancer is caused by changes (mutations) in a cell's DNA -- its genetic "blueprint". Some of these changes may be inherited from our parents, while others may be caused by outside exposures, which are often referred to as environmental factors. Environmental factors can include a wide range of exposures, such as lifestyle factors (nutrition, tobacco use, physical activity, etc.), naturally occurring exposures (ultraviolet light, radon, infectious agents, etc.), medical treatments (chemotherapy, radiation, and immune system-suppressing drugs used after organ transplants, etc.), workplace and household exposures, and pollution. Substances and exposures that can lead to cancer are called carcinogens. Some carcinogens do not act on DNA directly, but lead to cancer in other ways. For example, they may cause cells to divide at a faster than normal rate, which could increase the chances that DNA changes will occur. Carcinogens do not cause cancer in every case, all the time. Substances labeled as carcinogens may have different levels of cancer-causing potential. Some may cause cancer only after prolonged, high levels of exposure. And for any particular person, the risk of developing cancer depends on many factors, including how they are exposed to a carcinogen, the length and intensity of the exposure, and the person's genetic makeup. How do researchers determine if something is a carcinogen? Testing substances or exposures to see if they can cause cancer is often difficult. It is not ethical to test a substance by exposing people to it and seeing if they get cancer from it. Therefore, scientists must resort to other types of tests, which may not always provide clear answers. Lab studies Scientists get much of their data about whether something might cause cancer from lab studies in cell cultures and animals. Because there are far too many substances (natural and man-made) to test each one in lab animals, scientists use knowledge about chemical structure, other types of lab tests, information about the extent of human exposure, and other factors to select chemicals for testing. For example, they can often get an idea about whether a substance might cause a problem by 40

looking at its chemical structure and comparing it to similar chemicals that have been better studied. Although it isn't possible to predict with certainty which substances will cause cancer in humans based on lab studies alone, virtually all known human carcinogens that have been adequately tested produce cancer in lab animals. In many cases, carcinogens are first found to cause cancer in lab animals and are later found to cause cancer in people. Most studies of potential carcinogens expose the lab animals to doses that are higher than common human exposures. This is so that cancer risk can be detected in relatively small groups of animals. For most carcinogens, it is assumed that those that cause cancer at larger doses in animals will also cause cancer in people. Although it isn't always possible to know the relationship between exposure dose and risk, it is reasonable for public health purposes to assume that lowering human exposure will reduce risk. Epidemiologic (population-based) studies Another important way to identify carcinogens is through epidemiologic studies, which look at human populations to determine which factors might be linked to cancer. Although these studies also provide useful information, they also have their limitations. Humans do not live in a controlled environment. People are exposed to numerous substances at any one time, including those they encounter at work, school, or home; in the food they eat; and the air they breathe. It's very unlikely they know exactly what they've been exposed to or that they would be able to remember all of their exposures if asked by a researcher. And there are usually many years (often decades) between exposure to a carcinogen and the development of cancer. Therefore, it can be very hard to single out any particular exposure as having a definite link to cancer. By combining data from both types of studies, scientists do their best to make an educated assessment of a substance's cancer-causing ability. When the available evidence is compelling but not felt to be conclusive, the substance may be considered to be a probable carcinogen. But in some cases there simply isn't enough information to be certain one way or the other. Who determines how carcinogens are classified?

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Several agencies (national and international) are responsible for determining the cancer-causing potential of different substances. International Agency for Research on Cancer The International Agency for Research on Cancer (IARC) is part of the World Health Organization (WHO). Its major goal is to identify causes of cancer. The most widely used system for classifying carcinogens comes from the IARC. In the past 30 years, the IARC has evaluated the cancer-causing potential of more than 900 likely candidates, placing them into one of the following groups: Group Group Group Group Group 1: Carcinogenic to humans 2A: Probably carcinogenic to humans 2B: Possibly carcinogenic to humans 3: Unclassifiable as to carcinogenicity in humans 4: Probably not carcinogenic to humans

Perhaps not surprisingly, based on how hard it can be to test these candidate carcinogens, most are listed as being of probable, possible, or unknown risk. Only a little over 100 are classified as "carcinogenic to humans." The Report on Carcinogens (RoC) identifies 2 groups of agents: "Known to be human carcinogens" "Reasonably anticipated to be human carcinogens"

Unlike the IARC's list, the RoC does not list substances that have been studied and found not to be carcinogens. Environmental Protection Agency The Integrated Risk Information System (IRIS), an electronic database that contains information on human health effects from exposure to various substances in the environment. The EPA uses a rating system similar to that of IARC when describing the cancer-causing potential of a substance: Group Group Group Group Group A: Carcinogenic to humans B: Likely to be carcinogenic to humans C: Suggestive evidence of carcinogenic potential D: Inadequate information to assess carcinogenic potential E: Not likely to be carcinogenic to humans 42

These lists include only those substances and exposures most likely to cause cancer, there are many others that have not been studied fully yet. Most of the agents on the list are connected only with certain kinds of cancer, not all typesThe lists themselves say nothing about how likely it is that an agent will cause cancer. Carcinogens do not cause cancer at all times, under all circumstances. Some may only be carcinogenic if a person is exposed in a certain way (for example, ingesting it as opposed to touching it). Some may only cause cancer in people who have a certain genetic makeup. Some of these agents may lead to cancer after only a very small exposure, while others might require intense exposure over many years. Again, you should refer to the agencies' reports for specifics. Even if a substance or exposure is known or suspected to cause cancer, this does not necessarily mean that it should be avoided at all costs. Although looking at the list below can tell you whether or not something may increase your risk of cancer, it is important to have an idea of what your risk is to begin with. Many factors can enter into this, including your age, gender, family history, and lifestyle factors (tobacco and alcohol use, weight, diet, physical activity level, etc.). As noted above, the type and extent of exposure to a substance may also play a role. You should consider the actual amount of increased risk when deciding if you should avoid an exposure. As an example, the lists below include many commonly used medicines, particularly some hormones and drugs used to treat cancer. For example, tamoxifen increases the risk of certain kinds of uterine cancer but can be very useful in treating some breast cancers, which may be more important for some women. If you have questions about a medicine that appears on one of these lists, be sure to ask your doctor. Known human carcinogens International Agency for Research on Cancer "Carcinogenic to humans" (Group 1) Agents and groups of agents 4-Aminobiphenyl

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Arsenic and arsenic compounds (Note: This evaluation applies to the group of compounds as a whole and not necessarily to all individual compounds within the group) Asbestos Azathioprine Benzene Benzidine Benzo[a]pyrene Beryllium and beryllium compounds N,N-Bis(2-chloroethyl)-2-naphthylamine (Chlornaphazine) Bis(chloromethyl)ether and chloromethyl methyl ether (technicalgrade) 1,3-Butadiene 1,4-Butanediol dimethanesulfonate (Busulphan; Myleran) Cadmium and cadmium compounds Chlorambucil 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MethylCCNU; Semustine) Chromium[VI] Ciclosporin Cyclophosphamide Diethylstilbestrol Dyes metabolized to benzidine Epstein-Barr virus Erionite Estrogen-progestogen menopausal therapy (combined) Estrogen-progestogen oral contraceptives (combined) (Note: There is also convincing evidence in humans that these agents confer a protective effect against cancer in the endometrium and ovary) Estrogens, nonsteroidal (Note: This evaluation applies to the group of compounds as a whole and not necessarily to all individual compounds within the group) Estrogens, steroidal (Note: This evaluation applies to the group of compounds as a whole and not necessarily to all individual compounds within the group) Estrogen therapy, postmenopausal Ethanol in alcoholic beverages Ethylene oxide Etoposide in combination with cisplatin and bleomycin Formaldehyde Gallium arsenide [Gamma Radiation: see X- and Gamma (g)-Radiation]

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Helicobacter pylori (infection with) Hepatitis B virus (chronic infection with) Hepatitis C virus (chronic infection with) Human immunodeficiency virus type 1 (infection with) Human papillomavirus types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66 (Note: The HPV types that have been classified as carcinogenic to humans can differ by an order of magnitude in risk for cervical cancer) Human T-cell lymphotropic virus type I Melphalan 8-Methoxypsoralen (Methoxsalen) plus ultraviolet A radiation Methylenebis(chloroaniline) (MOCA) MOPP and other combined chemotherapy including alkylating agents Mustard gas (Sulfur mustard) 2-Naphthylamine Neutrons Nickel compounds N'-Nitrosonornicotine (NNN) and 4-(N-Nitrosomethylamino)-1-(3pyridyl)-1-butanone (NNK) Opisthorchis viverrini (infection with) [Oral contraceptives, combined estrogen-progestogen: see Estrogen-progestogen oral contraceptives (combined)] Oral contraceptives, sequential Phosphorus-32, as phosphate Plutonium-239 and its decay products (may contain plutonium-240 and other isotopes), as aerosols Radioiodines, short-lived isotopes, including iodine-131, from atomic reactor accidents and nuclear weapons detonation (exposure during childhood) Radionuclides, a-particle-emitting, internally deposited (Note: Specific radionuclides for which there is sufficient evidence for carcinogenicity to humans are also listed individually as Group 1 agents) Radionuclides, b-particle-emitting, internally deposited (Note: Specific radionuclides for which there is sufficient evidence for carcinogenicity to humans are also listed individually as Group 1 agents) Radium-224 and its decay products Radium-226 and its decay products Radium-228 and its decay products Radon-222 and its decay products Schistosoma haematobium (infection with)

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Silica, crystalline (inhaled in the form of quartz or cristobalite from occupational sources) Solar radiation Talc containing asbestiform fibres Tamoxifen (Note: There is also conclusive evidence that tamoxifen reduces the risk of contralateral breast cancer) 2,3,7,8-Tetrachlorodibenzo-para-dioxin Thiotepa Thorium-232 and its decay products, administered intravenously as a colloidal dispersion of thorium-232 dioxide ortho-Toluidine Treosulfan Vinyl chloride X- and Gamma (g)-radiation

Mixtures Aflatoxins (naturally occurring mixtures of) Alcoholic beverages Areca nut Betel quid with tobacco Betel quid without tobacco Coal-tar pitches Coal-tars Herbal remedies containing plant species of the genus Aristolochia Household combustion of coal, indoor emissions from Mineral oils, untreated and mildly treated Phenacetin, analgesic mixtures containing Salted fish (Chinese-style) Shale-oils Soots Tobacco, smokeless Wood dust

Exposure circumstances Aluminum production Arsenic in drinking-water Auramine production Boot and shoe manufacture and repair Chimney sweeping Coal gasification Coal-tar distillation

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Coke production Furniture and cabinet making Hematite mining (underground) with exposure to radon Involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) Iron and steel founding Isopropyl alcohol manufacture (strong-acid process) Magenta production Painter (occupational exposure as a) Paving and roofing with coal-tar pitch Rubber industry Strong-inorganic-acid mists containing sulfuric acid (occupational exposure to) Tobacco smoking and tobacco smoke

Carcinogens "Known to be human carcinogens" Aflatoxins Alcoholic beverage consumption 4-Aminobiphenyl Analgesic mixtures containing phenacetin Arsenic compounds, inorganic Asbestos Azathioprine Benzene Benzidine Beryllium and beryllium compounds 1,3-Butadiene 1,4-Butanediol dimethylsulfonate (busulfan, Myleran) Cadmium and cadmium compounds Chlorambucil 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU) bis(chloromethyl) ether and technical-grade chloromethyl methyl ether Chromium hexavalent compounds Coal tar pitches Coal tars Coke oven emissions Cyclophosphamide Cyclosporin A (Ciclosporin) Diethylstilbestrol (DES) Dyes metabolized to benzidine Environmental tobacco smoke

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Erionite Estrogens, steroidal Ethylene oxide Hepatitis B virus Hepatitis C virus Human papilloma viruses: some genital-mucosal types Melphalan Methoxsalen with ultraviolet A therapy (PUVA) Mineral oils (untreated and mildly treated) Mustard gas 2-Naphthylamine Neutrons Nickel compounds Oral tobacco products Radon Silica, crystalline (respirable size) Solar radiation Soots Strong inorganic acid mists containing sulfuric acid Sunlamps or sunbeds, exposure to Tamoxifen 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); "dioxin" Thiotepa Thorium dioxide Tobacco smoking Vinyl chloride Ultraviolet radiation, broad spectrum UV radiation Wood dust X-radiation and gamma radiation

Probable carcinogens International Agency for Research on Cancer "Probably carcinogenic to humans" (Group 2A) Agents and groups of agents Acrylamide Adriamycin Androgenic (anabolic) steroids Aristolochic acids (naturally occurring mixtures of) Azacitidine Bischloroethyl nitrosourea (BCNU)

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Captafol Chloramphenicol a-Chlorinated toluenes (benzal chloride, benzotrichloride, benzyl chloride) and benzoyl chloride (combined exposures) 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) 4-Chloro-ortho-toluidine Chlorozotocin Cisplatin Clonorchis sinensis (infection with) Cyclopenta[cd]pyrene Dibenz[a,h]anthracene Dibenzo[a,l]pyrene Diethyl sulfate Dimethylcarbamoyl chloride 1,2-Dimethylhydrazine Dimethyl sulfate Epichlorohydrin Ethyl carbamate (urethane) Ethylene dibromide N-Ethyl-N-nitrosourea Etoposide Glycidol Indium phosphide IQ (2-Amino-3-methylimidazo[4,5-f]quinoline) Kaposi's sarcoma herpesvirus/human herpesvirus 8 Lead compounds, inorganic 5-Methoxypsoralen Methyl methanesulfonate N-Methyl-N-nitro-N-nitrosoguanidine(MNNG) N-Methyl-N-nitrosourea Nitrate or nitrite (ingested) under conditions that result in endogenous nitrosation Nitrogen mustard N-Nitrosodiethylamine N-Nitrosodimethylamine Phenacetin Procarbazine hydrochloride Styrene-7,8-oxide Teniposide Tetrachloroethylene Trichloroethylene 1,2,3-Trichloropropane Tris(2,3-dibromopropyl) phosphate

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Ultraviolet radiation A Ultraviolet radiation B Ultraviolet radiation C [Urethane: see Ethyl carbamate] Vinyl bromide (Note: For practical purposes, vinyl bromide should be considered to act similarly to the human carcinogen vinyl chloride.) Vinyl fluoride (Note: For practical purposes, vinyl fluoride should be considered to act similarly to the human carcinogen vinyl chloride.) Mixtures Creosotes Diesel engine exhaust High-temperature frying, emissions from Hot mate Household combustion of biomass fuel (primarily wood), indoor emissions from Non-arsenical insecticides (occupational exposures in spraying and application of) Polychlorinated biphenyls Exposure circumstances Art glass, glass containers and pressed ware (manufacture of) Carbon electrode manufacture Cobalt metal with tungsten carbide Hairdresser or barber (occupational exposure as a) Petroleum refining (occupational exposures in) Shiftwork that involves circadian disruption Sunlamps and sunbeds (use of) National Toxicology Program 11th Report on Carcinogens "Reasonably anticipated to be human carcinogens" Acetaldehyde 2-Acetylaminofluorene Acrylamide Acrylonitrile Adriamycin (doxorubicin hydrochloride) 2-Aminoanthraquinone o-Aminoazotoluene 1-Amino-2,4-dibromoanthraquinone

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1-Amino-2-methylanthraquinone 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Amitrole o-Anisidine hydrochloride Azacitidine (5-Azacytidine, 5-AzaC) Benz[a]anthracene Benzo[b]fluoranthene Benzo[j]fluoranthene Benzo[k]fluoranthene Benzo[a]pyrene Benzotrichloride Bromodichloromethane 2, 2-bis-(bromoethyl)-1,3-propanediol (technical grade) Butylated hydroxyanisole (BHA) Carbon tetrachloride Ceramic fibers (respirable size) Chloramphenicol Chlorendic acid Chlorinated paraffins (C12, 60% chlorine) 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea Bis (chloroethyl) nitrosourea Chloroform 3-Chloro-2-methylpropene 4-Chloro-o-phenylenediamine Chloroprene p-Chloro-o-toluidine and p-chloro-o-toluidine hydrochloride Chlorozotocin C.I. basic red 9 monohydrochloride Cisplatin Cobalt sulfate p-Cresidine Cupferron Dacarbazine Danthron (1,8-dihydroxyanthraquinone) 2,4-Diaminoanisole sulfate 2,4-Diaminotoluene Diazoaminobenzene Dibenz[a,h]acridine Dibenz[a,j]acridine Dibenz[a,h]anthracene

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7H-Dibenzo[c,g]carbazole Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,i]pyrene Dibenzo[a,l]pyrene 1,2-Dibromo-3-chloropropane 1,2-Dibromoethane (ethylene dibromide) 2,3-Dibromo-1-propanol Tris (2,3-dibromopropyl) phosphate 1,4-Dichlorobenzene 3,3-Dichlorobenzidine and 3,3-dichlorobenzidine dihydrochloride Dichlorodiphenyltrichloroethane (DDT) 1,2-Dichloroethane (ethylene dichloride) Dichloromethane (methylene chloride) 1,3-Dichloropropene (technical grade) Diepoxybutane Diesel exhaust particulates Diethyl sulfate Diglycidyl resorcinol ether 3,3-Dimethoxybenzidine 4-Dimethylaminoazobenzene 3,3-Dimethylbenzidine Dimethylcarbamoyl chloride 1,1-Dimethylhydrazine Dimethyl sulfate Dimethylvinyl chloride 1,6-Dinitropyrene 1,8-Dinitropyrene 1,4-Dioxane Disperse blue 1 Dyes metabolized to 3,3-dimethoxybenzidine Dyes metabolized to 3,3-dimethylbenzidine Epichlorohydrin Ethylene thiourea Di (2-ethylhexyl) phthalate Ethyl methanesulfonate Formaldehyde (gas) Furan Glasswool (respirable size) Glycidol Hexachlorobenzene Hexachlorocyclohexane isomoers Hexachloroethane

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Hexamethylphosphoramide Hydrazine and hydrazine sulfate Hydrazobenzene Indeno[1,2,3-cd]pyrene Iron dextran complex Isoprene Kepone (chlordecone) Lead and lead compounds Lindane and other hexachlorocyclohexane isomers 2-Methylaziridine (propylenimine) 5-Methylchrysene 4,4-Methylenebis(2-chloroaniline) 4-4-Methylenebis(N,N-dimethyl)benzenamine 4,4-Methylenedianiline and 4,4-methylenedianiline dihydrochloride Methyleugenol Methyl methanesulfonate N-methyl-N-nitro-N-nitrosoguanidine Metronidazole Michlers ketone [4,4-(dimethylamino) benzophenone] Mirex Naphthalene Nickel (metallic) Nitrilotriacetic acid o-Nitroanisole Nitrobenzene 6-Nitrochrysene Nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) Nitrogen mustard hydrochloride Nitromethane 2-Nitropropane 1-Nitropyrene 4-Nitropyrene N-nitrosodi-n-butylamine N-nitrosodiethanolamine N-nitrosodiethylamine N-nitrosodimethylamine N-nitrosodi-n-propylamine N-nitroso-N-ethylurea 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone N-nitroso-N-methylurea N-nitrosomethylvinylamine N-nitrosomorpholine

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N-nitrosonornicotine N-nitrosopiperidine N-nitrosopyrrolidine N-nitrososarcosine Norethisterone Ochratoxin A 4,4-Oxydianiline Oxymetholone Phenacetin Phenazopyridine hydrochloride Phenolphthalein Phenoxybenzamine hydrochloride Phenytoin Polybrominated biphenyls (PBBs) Polychlorinated biphenyls (PCBs) Polycyclic aromatic hydrocarbons (PAHs) Procarbazine hydrochloride Progesterone 1,3-Propane sultone beta-Propiolactone Propylene oxide Propylthiouracil Reserpine Safrole Selenium sulfide Streptozotocin Styrene-7,8-oxide Sulfallate Tetrachloroethylene (perchloroethylene) Tetrafluoroethylene Tetranitromethane Thioacetamide 4,4-Thiodianaline Thiourea Toluene diisocyanate o-Toluidine and o-toluidine hydrochloride Toxaphene Trichloroethylene 2,4,6-Trichlorophenol 1,2,3-Trichloropropane Ultraviolet A radiation Ultraviolet B radiation Ultraviolet C radiation

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Urethane Vinyl bromide 4-Vinyl-1-cyclohexene diepoxide Vinyl fluoride

Cancer Clusters What is a cancer cluster? Cancer clusters have received a good deal of attention in the media in recent years, both in the news and in Hollywood movies. More than 1,000 suspected cancer clusters are reported to state health departments each year. But what exactly is a cancer cluster? Many people tend to think of a cancer cluster as a higher than normal number of cases of cancer in a defined community. Cancer clusters are usually thought to be caused by some type of environmental pollutant. Scientists, however, usually define a cancer cluster a little differently, as a greater than expected number of cancer cases in a defined geographic area or group of people over a certain period of time. A cancer cluster almost always involves only one type of cancer. What are the characteristics of a true cancer cluster? There are some important points to know about cancer clusters. First, cancer is actually a group of more than 100 different diseases. Each type of cancer has its own risk factors and causes. This is why true cancer clusters very rarely involve more than one type of cancer. True clusters usually involve one of the following: several cases of a rare type of cancer larger than expected numbers of a more common type of cancer a type of cancer that is not usually seen in a particular group of people (for example, children getting a cancer usually seen in adults)

If the cluster includes cancers of many different sites or over a period of many years, it is very unlikely to be a true cluster caused by a single environmental agent. Most well-documented cancer clusters have not been found in the community. Rather, they have been seen in the workplace, where exposures to certain chemicals or other factors tend to be higher and 55

over longer periods of time. Also, the group of people being exposed is much better defined in workplace groups. In fact, the links between cancer and many cancer-causing agents (carcinogens) were first figured out from studies of workers in certain jobs. Lung, skin, and bladder cancers are the types of cancer most commonly linked with high level exposure to workplace carcinogens are. Other cancers such as leukemia, lymphoma, testicular, and brain cancer occasionally occur in clusters as well. Statistics can usually give an idea of a particular cancer cluster being strictly due to chance. But even statistics can't tell the whole story. The excess number of cases reported in a cancer cluster may look significant based on statistics, but this does not necessarily mean that the cancers are caused by something unique to that area. Some clustering of cancer cases can still happen by chance (see below), but people tend to notice and report situations where rates seem to be above average. Who investigates cancer clusters, and how is this done? People concerned about a possible cancer cluster often report it to a local or state health department. Procedures vary by state, but most health departments will first request more information, such as: the type(s) and number of cancers involved any suspected exposure(s) that might be causing these cases the area and time period in which the cases occurred specific information about each person thought to be affected specific information about the cancers themselves

At this point, as many as 4 out of 5 suspected clusters are found NOT to be true clusters. For example, the group of people may have different types of cancers, or the number of cases isn't greater than what would be expected, etc. If the health department feels that the potential cluster should be studied further, more information will be collected. Attempts may be made to contact patients or relatives to check information. Sometimes investigators will ask to see medical records. The health department may do a more in-depth statistical analysis on the number of cases in the affected area and surrounding regions. Scientists in the health department may also look at reports in the medical literature to see if similar clusters have occurred elsewhere in the past.

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Suspected cancer clusters can cause a great deal of concern and confusion in a community. It is very important that government agencies keep concerned members of the community informed from the start of and throughout the investigation. This should include giving people a realistic idea of what may or may not be found. What are the possible outcomes of a cluster investigation? A true cluster may not exist

In many cases, investigators can determine that a "cluster" of cancers isn't a true cluster. For example, the number of cases may not turn out to be higher than expected when other factors that could explain the increase (such as age, gender, and race/ethnicity) are taken into account. A cancer cluster may be found and the cause can be identified In some cases, especially when there may be an obvious potential cause, a true cancer cluster may be confirmed. At that point, steps can be taken to address it. A cancer cluster may be found, but no cause can be identified

Even if investigators believe that a true cluster may be present, it's important to realize that it's very rare that a cause is found. There are several reasons why this is the case. It is very hard to determine which of many exposures might be the cause: With rare exceptions, scientists don't have a way of telling what trigger (if any) may have caused cancer in any one person, whether it's part of a cluster or not. Humans are not like lab animals -- their environments are not strictly controlled. People are exposed to a wide array of natural and man-made substances during their lifetimes. Think about how hard it would be to test for everything you've been exposed to, even assuming you knew where to start. Investigators may have a few clear leads or starting points, but they need to look at all of the possibilities. Finding the single exposure that may be the cause can be like looking for the so-called needle in the haystack. There is often a long delay between exposure and cancer: In clusters where the cause was known (again, mostly from workplace cases), the time between exposure to the substance and the development of cancer has been anywhere from a few years to several decades. Exposures are 57

not likely to cause cancers right away. Again, it's not easy to study people and their environments. Suppose a group of people live in a community where there's a higher than expected number of cases of a certain type of cancer. If there is a potential cause, investigators first have to figure out when these people were exposed to it. Was it a single event or has it been ongoing? Was it 5 years ago, or 10, or 20? And what did the people with cancer have in common during that time? Added to this, some people would have moved into the community, while others may have moved away since then. Should the cases of people who moved into town in recent years be included? And can the people who moved away be tracked? The boundaries of the cluster area can be hard to define: Defining the geographic area is another issue that's not always as clear-cut as one might think it would be. Just how big should the "bull's eye" be drawn? Should it include only a local neighborhood where most of the cases occurred? Or should it also include the larger community, or even nearby communities? These areas may have cases that may or may not be related to the others. Not everyone who is exposed is likely to develop cancer: To compound the matter even further, people may be more or less prone to getting cancer based on their genes. It's unlikely that everyone exposed will develop cancer, and there may be others who were not exposed who develop the same cancer by chance. Scientists do their best to piece the puzzle together, but more times than not, they don't find a likely link. This doesn't necessarily mean that there isn't one; it may just be that one can't be teased out with the methods scientists have at the time. This may be an unsatisfactory answer for people in a community being affected, but it may be the case. Infectious Agents and Cancer Since the beginning of the 20th century, we have known that some infections play a role in cancer in animals. But only recently has infection with certain viruses, bacteria, and parasites been recognized as a risk factor for several types of cancer in humans. Worldwide, infections are linked to about 15% to 20% of cancers. In the United States and other developed countries, it is thought that fewer than 10% of all cancers are linked to infectious agents. In developing countries, infections can account for as much as 20% of all cancers. 58

Some infections may cause long-term inflammation, suppress a person's immune system, or directly affect a cell's DNA. Any of these pathways may lead to a higher risk of cancer. Even though the infections described below can raise a person's risk of certain types of cancer, most people with these infections never develop cancer. The risk of developing a cancer is also influenced by other factors. For example, infection with Helicobacter pylori (H. pylori) bacteria may increase your risk of developing stomach cancer, but what you eat, whether or not you smoke, and other factors also influence your risk. Although the infections that influence cancer risk are usually contagious (especially viral infections), cancer itself is not a contagious disease. A healthy person cannot get cancer from someone who has the disease. Viruses Viruses are very small organisms -- most cannot even be seen with an ordinary microscope. They are made up of a small group of genes (in the form of DNA or RNA) surrounded by a protein coating. Viruses cannot reproduce on their own. They need to enter a living cell and "hijack" the cell's machinery to make more viruses. Some viruses do this by inserting their own DNA (or RNA) into that of the host cell. When this insertion affects the host cell's genes, it may push the cell toward becoming cancerous. Several viruses are now known or suspected of being linked with cancer in humans. Our growing knowledge of the role of viruses as a cause of cancer may lead to vaccines that prevent or treat certain human cancers in the future. Human papilloma viruses (HPVs) HPVs are a group of over 100 related viruses that can cause warts on the skin, mouth, genital organs, and larynx. They are spread by contact (touch), including through sex. HPV infections are very common in people who are sexually active. There are no effective treatments for HPV other than removing or destroying cells that are known to be infected. Most genital HPV infections go away over time with the help of the body's immune system.

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Certain types of HPV are the main cause of cervical cancer, which is the second most common cancer among women worldwide. It is much rarer in the United States because of the use of the Pap test. This test can detect pre-cancerous changes in cells in the cervix that might be due to HPV infection, which can then be treated, if needed. This treatment can prevent the development of cancer. While nearly all women who develop cervical cancer shows signs of HPV infection, most women infected with HPV will not develop cervical cancer. Even though doctors can test women for HPV, there is no treatment for the HPV infection itself. If the HPV causes abnormal cells to start growing, these cells can be treated. Women with HPV infection may be checked for abnormal cells more often than those who don't have it. For more information, see the American Cancer Society document, Thinking About Testing for HPV?. HPVs also have a role in causing some cancers of the penis, anus, vagina, and vulva. They have also been linked to cancers of the mouth, throat, head, and neck. Again, while HPVs have been linked to these cancers, most people infected with HPV never develop cancer. Smoking and drinking, which are also linked with these cancers, may work together with HPV to increase cancer risk. Vaccines against the types of HPV that cause cancer are now under development. One of these vaccines (Gardasil) has been shown to help protect against infection from 2 of these HPV types, and is now approved for use in females aged 9 to 26. Because it is still fairly new, it is not yet known how well it will protect against cervical cancer. Further studies of this vaccine and others like it are still under way. Epstein-Barr virus (EBV) EBV is another type of herpes virus. It is probably best known for causing infectious mononucleosis, also known as "mono" or the "kissing disease." In addition to kissing, it can be passed from person to person by coughing, sneezing, or sharing drinking or eating utensils. Most people in the United States are infected with EBV before the age of 20, although not everyone develops the symptoms of mono. As with other herpes viruses, the virus remains in the body throughout life, but after the first few weeks of infection most people never have any other symptoms. EBV infects and stays in certain white blood cells in the body called B lymphocytes (also called B cells). Infection with EBV increases a 60

person's risk of getting nasopharyngeal cancer (cancer of the area in the back of the nose) and certain types of fast-growing lymphomas such as Burkitt lymphoma. It may also be linked to Hodgkin disease and some cases of stomach cancer. These cancers are more common in Africa and parts of Southeast Asia. Overall, very few people who have been infected with EBV will ever develop these cancers. Hepatitis B virus (HBV) and hepatitis C virus (HCV) HBV and HCV cause viral hepatitis, a type of liver infection. While other viruses can also cause hepatitis (hepatitis A virus, for example), only HBV and HCV can cause chronic (long-term) infections that increase a persons chance of developing liver cancer. In the United States, about 30% of liver cancers are related to HBV or HCV infection. This number is much higher in certain other countries, where both the infections and liver cancer are much more common. HBV and HCV are spread from person to person in much the same way as HIV (see section on HIV below) -- through sharing needles, unprotected sex, or childbirth. They can also be passed on through blood transfusions, although this has rarely happened in the United States since blood products began to be tested for these viruses. Of the 2 viruses, infection with HBV is more likely to cause symptoms, such as a flu-like illness and a yellowing of the eyes and skin (jaundice). But most people recover completely from HBV infection within a few months. Only a very small percentage goes on to become chronic carriers. These people have a higher risk for liver cancer. HCV, on the other hand, is less likely to cause symptoms. But most people with HCV develop chronic infections, which are more likely to lead to liver damage or even cancer. This means that many of the estimated 3.2 million people in the United States who have chronic HCV infection do not know they have it. While there are few drugs effective in treating hepatitis B or C, a vaccine is available to prevent HBV infection. In the United States, the vaccine is recommended for all children and for adults who are at risk, such as healthcare workers and injection drug users. Unfortunately, there is no vaccine to prevent HCV at this time. Human immunodeficiency virus (HIV)

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HIV, the virus that causes acquired immune deficiency syndrome (AIDS), does not appear to cause cancers directly. But HIV infection increases a person's risk of getting several types of cancer, especially some linked to other viruses such as HHV-8 (see section below) and HPV. HIV is acquired through intimate contact with blood, vaginal secretions, breast milk, or semen from an HIV-infected person. Known routes of spread include: unprotected sex (oral, vaginal, or anal) with an HIV-infected person injections with needles or injection equipment previously used on an HIV-infected person prenatal and perinatal (during birth) exposure of infants from mothers with HIV breast-feeding by mothers with HIV transfusion of blood products containing HIV (blood has been tested since 1985) organ transplants from an HIV-infected person (donors are now tested for HIV)

HIV is not spread by insects, through water, or by casual contact such as talking, shaking hands, hugging, sneezing, sharing dishes, sharing a bathroom or kitchen, sharing telephones, or sharing computers. HIV infects and destroys white blood cells known as helper T cells, which weakens the body's immune system. When the body is less able to fight off infections, other viruses such as HPV may be able to cause more damage to the cells. This damage may trigger cancer. Many scientists believe that the immune system is also important in attacking and destroying newly formed cancers. So a weak immune system may allow new cancers to survive long enough to become a serious, life-threatening tumor. HIV infection has been linked to a higher risk of developing of Kaposi sarcoma, invasive cervical cancer, and certain kinds of lymphoma, especially non-Hodgkin lymphoma and central nervous system lymphoma. Anti-HIV drugs may be used to reduce the risk of Kaposi sarcoma and cervical cancer. Other forms of cancer that may be more likely to develop in people with HIV infection include: 62

invasive anal cancer Hodgkin disease lung cancer cancer of the mouth and throat cancer of the testicles skin cancers, including basal cell, squamous cell, and even malignant melanomas

Human herpes virus 8 (HHV-8) HHV-8, also known as Kaposi sarcoma-associated herpes virus (KSHV), has been found in nearly all tumors in patients with Kaposi sarcoma (KS). KS is a rare, slow-growing cancer that often appears as reddishpurple or blue-brown tumors just underneath the skin. KS has been known to exist in central Africa and the Middle East for some time, but was rare in the United States until it started appearing in patients with AIDS in the early 1980s. The number of people with KS has dropped in the United States since peaking in the early 1990s, most likely due to better treatment of HIV infection. HHV-8 is transmitted sexually and appears to be spread by other means as well. Blood tests show less than 10% of the US population is infected with this virus. HHV-8 does not appear to cause disease in most healthy people. In the United States, almost all people who develop KS have other conditions that have affected their immune system, such as infection with the HIV or immune suppression after an organ transplant. HHV-8 is related to other herpes viruses, such as the viruses that cause cold sores and genital herpes, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). But these other viruses are not the same as HHV-8 and do not cause KS. Like other herpes virus infections, HHV-8 infections never go away, even when there are no signs of disease. Researchers are not yet sure how HHV-8 contributes to the development of KS. Because many more people are infected with HHV-8 than ever develop the disease, it is likely that other factors are also needed for KS to develop. As mentioned above, having a weakened immune system appears to be one such factor. HHV-8 infection has been linked to some rare blood cancers, such as primary effusion lymphoma. The virus has also been found in many people with multicentric Castleman disease, an overgrowth of lymph

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nodes that acts very much like lymphoma. Further study is needed to better understand the role of HHV-8 in these diseases. Human T-lymphotrophic virus-1 (HTLV-1) HTLV-1 has been linked with a type of lymphocytic leukemia and nonHodgkin lymphoma called adult T-cell leukemia/lymphoma (ATL). This cancer is found mostly in southern Japan, the Caribbean, Central Africa, parts of South America, and in some immigrant groups in the southeastern United States. In addition to ATL, the virus also causes a form of degenerative nerve disease called tropical spastic paraparesis (TSP), which is most common in Japan and in the Caribbean basin. HTLV-1 belongs to a class of viruses called retroviruses. These viruses use RNA (instead of DNA) for their genetic code. To reproduce, they must go through an extra step using an enzyme called reverse transcriptase. This allows them to change their RNA genes into DNA. Some of the new DNA genes can then become part of the chromosomes of the human cell infected by the virus. This can change the genes (cause genetic mutations) in human cells that normally control how often the cell divides. This change can sometimes cause cancer. Retroviruses have long been known to cause leukemia in some animals. HTLV-1 is something like HIV, since it is another human retrovirus. But HTLV-1 cannot cause AIDS. In humans, HTLV-1 can be spread in the same ways as HIV: unprotected sex with an HTLV-1-infected partner injection with a needle or injection equipment after an infected person has used it blood transfusion from an infected donor (blood donations are now tested for this virus in developed countries) from infected mother to child during pregnancy, childbirth, or breastfeeding

Not everyone exposed to the virus becomes infected. For example, mothers infected with HTLV-1 have about a 10% to 30% chance of passing on the virus to their children. Once infected, a person's chance of developing adult T-cell lymphoma can be up to about 5%, usually after a long period with no symptoms (20 or more years). Viruses with uncertain or unproven links to cancer in humans 64

Feline leukemia virus (FeLV) FeLV causes feline leukemia, a fatal disease in American domestic cats. A vaccine to protect cats against FeLV is available, and all healthy cats can be immunized against feline leukemia. FeLV has not been known to be transmitted to humans. Simian virus 40 (SV40) SV40 is a virus that usually infects monkeys. Some polio vaccines prepared between 1955 and 1963, which were produced from monkey cells, were found to be contaminated with SV40. Some recent studies have raised the possibility that infection with SV40 might increase a person's risk of developing mesothelioma (a rare cancer of the lining of the lungs or abdomen), as well as some brain cancers, bone cancers, and lymphomas. Scientists have found that intentional infection of some lab animals, such as hamsters, with SV40 causes mesotheliomas to develop. Researchers have also noticed that SV40 can cause mouse cells grown in the lab to become cancerous, and asbestos increases the cancercausing effect of SV40 on these cells. Other researchers have studied biopsy specimens of certain human cancers and found fragments that appear to be SV40 DNA. But not all researchers have found this, and fragments much like these can also be found in non-cancerous human tissues. So far, the largest studies looking at this issue in humans have not found any increased risk for mesothelioma or other cancers among people who got the contaminated vaccines as children. For example, the recent increase in lung mesothelioma cases has been seen mainly in men aged 75 and older, most of whom would not have received the vaccine. Another observation is that, among the age groups who were known to have gotten the vaccine, mesothelioma rates have actually gone down. And even though women were just as likely to have had the vaccine, many more men continue to be diagnosed with mesothelioma. But the peak age range for diagnosis of mesothelioma is 50 to 70 years. Some researchers have pointed out that this issue may remain unresolved until more of the people exposed to SV40 between 1955 and 1963 get into that age range.

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Recent findings have suggested that the number of people exposed to SV40 may have been underestimated in earlier studies. Some of the oral polio vaccine that was made in Eastern Europe and used throughout the world may have contained SV40 up until the late 1970s. Research into this important topic is still under way. Bacteria Helicobacter pylori (H. pylori) While stomach cancer is fairly rare in the United States, it is the fourth most common cancer worldwide. Long-term infection of the stomach with H. pylori may lead to chronic inflammation and damage to the inner layer of the stomach, including ulcers. Some of these changes could lead to cancer over time, especially cancer in the lower part of the stomach. H. pylori infection is also linked with some types of lymphoma of the stomach. More than half of all cases of stomach cancer are thought to be linked to H. pylori infection. But most people who have these bacteria in their stomachs never develop cancer. About 1 in 3 adults has evidence of infection with H. pylori, and the rate of infection is higher in older age groups. Researchers aren't exactly sure how H. pylori may be spread from one person to another, but a likely route of spread is through a fecal-oral route, such as through contaminated water sources. In fact, contaminated well water has been linked to H. pylori infection in the United States. Because the bacteria's DNA is found in saliva, it may also be transmitted from mouth to mouth. Other factors also play a role in whether or not someone develops stomach cancer. For example, nitrites are substances commonly found in cured meats, some drinking water, and certain vegetables. They can be converted by certain bacteria, such as H. pylori, into compounds that have been found to cause stomach cancer in animals. Antibiotics and other medicines can be used to treat H. pylori infections. It is not yet known if people with chronic H. pylori infection of their stomach lining but no symptoms should be treated for this infection. Some doctors believe that patients with H. pylori who are at high risk of stomach cancer should be treated whether or not they have symptoms. These issues are still being studied.

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Doctors have given antibiotics to patients who have had superficial stomach cancers removed in order to get rid of H. pylori infection. This seems to have prevented new stomach cancers in those patients. Chlamydia trachomatis Chlamydia trachomatis is a relatively common kind of bacteria that can infect the female reproductive system. It is spread by sexual contact. Although infection may cause symptoms, more than 2 out of 3 women have no symptoms. This means that most women with chlamydia do not know they are infected unless samples taken when they have a Pap test are also studied for this type of bacteria. It is very common in younger women who are sexually active, and may persist for years unless it is detected and treated. Some studies suggest that women whose blood test results show past or current chlamydia infection are at greater risk for cervical cancer than are women with a negative blood test. Studies have not shown that chlamydia by itself can cause cancer. But it may work with HPV in some way that promotes cancer growth. One possible explanation suggested by 2 recent studies is that chlamydia may affect how long cancer-promoting HPV stays in the cervix. Researchers found that women who had chlamydia along with HPV were more likely to still have HPV when they were re-tested later than the women who had not had chlamydia. Although further studies are needed to confirm these findings, there is already good reason to avoid this infection and to have it treated with antibiotics when it is found. Long-term chlamydia infection is known to be a cause of pelvic inflammation that can lead to infertility. Like other sexually transmitted diseases that irritate or ulcerate the genital area, chlamydia can also increase the risk of becoming infected with HIV during exposure to an HIV-infected sexual partner. Other bacteria Chlamydia psittaci is being studied as a possible cause of cancer. It is best known for causing a mild infection sometimes known as "parrot fever" when the germ is inhaled from dried bird droppings or feather dust. (This germ is not like the type of chlamydia discussed above and is not sexually transmitted.) Two recent studies have suggested that Chlamydia psittaci bacteria may also be involved in a rare cancer of the eyes known as ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. In some cases, this lymphoma started to improve when the patient was given an antibiotic to treat the bacteria, but this 67

did not happen in others. Further research is needed to learn more about the link between the bacteria and the cancer. Other studies have suggested that infection with Borrelia burgdorferi (the bacterium that causes Lyme disease) may be linked with MALT lymphoma of the skin. And Campylobacter jejuni may be linked with MALT lymphomas of the digestive tract. Further research is needed to clarify these links. Chlamydia pneumoniae is a type of bacteria that can cause lung infections (pneumonia). In several studies, more people with lung cancer had evidence of previous infection with this germ than those who did not have lung cancer. Even though it looks like there may be a link, these types of studies do not show that the bacteria caused the cancer. Studies are under way to explore the chance that this germ can increase the risk of lung cancer. Parasites Certain parasitic worms that can live inside the human body can also raise the risk of developing some kinds of cancer. While these organisms are not found in the United States, they can be a concern for people who live in or travel to other parts of the world. Opisthorchis viverrini and Clonorchis sinensisare liver flukes (a type of flatworm) that have been linked to increased risk of developing cancer of the bile ducts (the tubes that connect the liver to the intestines). These infections come from eating raw or undercooked fish. They are found mostly in East Asia and are rare in other parts of the world. Schistosoma haematobium is a parasite found in the water of developing countries of Africa and Asia. Infection with this parasite (an illness called schistosomiasis) has been linked to bladder cancer. Possible links to other types of cancer are now being studied as well. Radon What Is Radon? Radon-222 is a colorless, odorless, radioactive gas. It forms from the decay of naturally occurring uranium-238, which is found in soil and rock throughout the world. Radon is present both outdoors and indoors. Exposure in homes mostly results from radon-contaminated gas rising from the soil. This makes it an unusual indoor air pollutant in that it has 68

a natural source. Exposure to radon is also a known cause of lung cancer in underground miners of uranium and other ores. Thus, its presence in indoor air has raised concern that it may also be a cause of lung cancer for the entire population. Radon has a half-life of 3.8 days; that is, half of a given amount takes 3.8 days to decay. It breaks down into a series of solid elements called radon progeny. Several of these elements (such as polonium-218, polonium-214, and lead-214) emit radiation in the form of alpha particles. An alpha particle consists of 2 protons and 2 neutrons, like the nucleus of a helium atom, and carries a positive charge. Although alpha particles do not penetrate deeply into tissue (as gamma radiation can), they carry enough energy to permanently change DNA if they reach the nucleus of a cell. As a result, when inhaled radon progeny reach the lungs, the alpha particles can damage cells within the airways and thereby increase lung cancer risk. How Are People Exposed to Radon? A link between cancer and working in underground mines was suspected even before radon was identified as an element. In 1556, German scholar Georgius Agricola wrote in De re metallica about the high death rates of miners in the Carpathian Mountains of Eastern Europe. More than 300 years later, autopsy studies of miners in that region revealed a common cause of death to be chest tumors, which were later shown to be primary lung cancer. In the early 20th century, high levels of radon were found in mines in Germany and Czechoslovakia (now the Czech Republic), and researchers believed that this exposure led to the miners lung cancer. In the 1950s, radiation scientists recognized that tiny particles of radon progeny and not radon gas delivered the radiation dose that caused the cancer. Epidemiologic studies of radon-exposed miners during the 1950s and 1960s confirmed the connection between radon exposure and lung cancer (NRC, 1998). A recent concern is whether radon exposure might also cause lung cancer in the general population. Adults and children are exposed to radon in homes, commercial buildings, schools, and other places. The radon gas emitted by soil or rock enters the buildings through cracks in floors or walls; construction joints; or gaps in foundations around pipes, wires, or pumps. Without ventilation or another way of dissipating, radon can build up and reach rather high levels.

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Within buildings, radon levels are usually highest in the basement. This level is closest to the soil from which the radon-containing gas diffuses. Therefore, people who spend much of their time in basement rooms at home or at work would have a greater risk for exposure. Radon emitted into outdoor spaces generally disperses and does not reach high levels. Indoor exposure is usually far lower than the occupational exposure for miners. However, the range of levels in the most contaminated homes approaches levels found in mines and may exceed the exposure standards permitted for underground miners. Radon levels in the air are measured by units of radioactivity per volume of air. The most common concentration measure used is picocuries per liter (pCi/L). Background outdoor levels of radon range from near 0 to over 2 pCi/L. The US Environmental Protection Agency (EPA) has set an action level of 4 pCi/L as an annual average for homes and schools, and the National Council of Radiation Protection recommends a limit of no more than 8 pCi/L indoors. Radon concentration may also be expressed in units of becquerels per cubic meter (Bq/m3) or as a working level (WL), a unit applied previously to underground mines. Exposure to radon or radon progeny incorporates the time spent at different concentrations; one commonly used unit for exposure is the working level month, which refers to spending 1 working month of time at a concentration of 1 WL. The level of personal exposure to radon varies, depending on the concentration at home and any occupational exposure. Higher levels of radon exposure are more likely for people who: work in some underground mines (not only uranium but also some other types), in caves, or in uranium processing factories come in contact with phosphate fertilizers, which have high levels of radium (the immediate precursor of radon) live near uranium mines, although few facilities are now operating

Radon exposure can occur through drinking water, but this type of exposure is minimal. As the radon moves from the water to air, it can be inhaled. Water that comes from deep, underground wells in rock with high radium concentrations may have high levels of radon, whereas surface water (drawn from lakes or rivers) usually has very low radon levels. For the most part, water does not contribute much to the overall exposure to radon.

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Radon exposure can also occur from some building materials if they are made from radon-containing substances. Specific instances of higher levels have been linked to particular building materials. For example, in Sweden, wallboard made with phosphogypsum having a high concentration of radium led to elevated concentrations of radon. Such materials usually contribute significantly to radon exposure. Concerns about radon exposure from granite countertops have been raised periodically. Most health and radiation experts agree that while a small percentage of granite countertops may emit increased levels of radiation and radon, most countertops emit extremely low levels. Does Radon Cause Cancer? Radon is among the best studied of environmental carcinogens. Through epidemiologic, animal, and laboratory studies, weve come to understand how inhaling radon progeny can deliver a radiation dose to the lungs and how alpha particles emitted by radon progeny can damage the cells. Weve also learned more about the degree of lung cancer risk associated with radon exposure. This evidence is summarized in Health Effects of Exposure to Radon, the 1998 report of the National Research Councils Committee on the Biological Effects of Ionizing Radiation (BEIR) VI, often called the BEIR VI report.

What Do Epidemiologic Studies Show? The epidemiologic evidence on radon and lung cancer risk comes from (1) cohort studies of underground miners with rather high levels of radon exposure, (2) case-control studies that compare radon exposure of persons with lung cancer and appropriate controls from the general population, and (3) ecologic studies comparing lung cancer deaths or incidence across geographic areas with differing levels of radon exposure. The cohort studies provided the first evidence showing that radon is a cause of lung cancer. These studies have also been used for estimating the risk of radon exposure. Once the problem of indoor radon was widely recognized, the case-control and ecologic studies were initiated. Scientists have studied many groups of underground miners exposed to radon, including uranium miners in Czechoslovakia, France, Canada, Australia, and the US; fluorspar miners in Canada; iron miners in Sweden; and tin miners in China. To estimate lung cancer risk, 71

researchers gathered data from 11 cohort studies, including 68,000 miners with 2,700 deaths from lung cancer. They looked at how lung cancer risk varies with exposure to radon and other factors, including cigarette smoking. At all but the highest levels, risk increases as exposure increases. In those miners known to be nonsmokers, a direct relationship between lung cancer risk and exposure also exists. These studies of miners provide good information on the relationship between increasing radon exposure and lung cancer risk at high levels of exposure. However, average radon concentrations in the indoor air of most homes are considerably lower than those in uranium mines. The EPA set recommended levels for maximum concentration of radon in homes based on extrapolation from high occupational exposures to the generally much lower residential exposures. Researchers have subsequently confirmed the reliability of these risk estimates by combining the results of multiple studies of indoor radon exposures. The observed risk of lung cancer from indoor radon exposures approximates that which was predicted by studies of uranium miners exposed at much higher doses. What Do Animal and Laboratory Studies Suggest? Like the studies done with miners, experimental studies on animals have clearly shown a risk of lung cancer with exposure to radon. These animal studies revealed that breathing in radon and its progeny (chemical products of radon decay) significantly increased the incidence of respiratory tract tumors. Nonspecific effects on the lungs have also been reported. In laboratory studies using human cells, radon and its decay products induced chromosomal abnormalities and other signs of permanent cellular change. What Do the Experts Say? The National Toxicology Program (NTP) evaluates exposures that may be carcinogenic. Exposures that are thought to cause cancer are included in the Reports on Carcinogens, published every 2 years. Each exposure is assigned to 1 of 2 categories: "known to be human carcinogens" or "reasonably anticipated to be human carcinogens." The first category includes substances for which human studies (epidemiologic studies or experimental studies) provide "sufficient evidence" of carcinogenicity in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans or sufficient evidence of carcinogenicity in experimental 72

animals. Using this scheme, the NTP classifies radon as a "known human carcinogen. The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 1 of 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories; Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable because available evidence is limited or inadequate. Group 4 exposures are "probably not carcinogenic to humans," based on evidence suggesting lack of carcinogenicity in humans and in experimental animals. IARC rates radon as "carcinogenic to humans" (Group 1). The Environmental Protection Agency (EPA), through its Integrated Risk Information System, uses a classification scheme similar to that of IARC. It classifies exposures into 1 of 5 categories: (A) human carcinogen (B) probable human carcinogen (C) possible human carcinogen (D) not classifiable as to human carcinogenicity (E) evidence of noncarcinogenicity for humans

The EPA has not classified radon as to its carcinogenicity. The Agency for Toxic Substances and Disease Registry (ATSDR) has concluded that radon is carcinogenic. Does Radon Cause Any Other Health Problems?

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There is convincing evidence that radon causes lung cancer. Some studies of miners further suggest a connection between radon exposure and nonmalignant (non-cancerous) respiratory disease, especially pulmonary fibrosis (scar tissue formation in the lungs that leads to shortness of breathe). These effects appear primarily in miners with high levels of exposure. The patterns seen on radiographs are not typical of silicosis (a lung disease caused by overexposure to crystalline silica), which is also a problem in the uranium miners. Some evidence has also linked radon exposure with malignancies other than lung cancer. An analysis of the 11 cohort studies of miners found an increase in leukemia and in cancers of the stomach and liver. Risk for these cancers in the miners does not increase with the level of exposure, and these associations do not appear to be causal. Ecologic studies have linked radon with elevations of cancers other than lung cancer but without any consistent pattern. A recent case-control study of acute lymphocytic leukemia did not show an increased risk linked to radon exposure. Because radon is absorbed mainly through inhalation, and because alpha particles penetrate tissues only superficially, effects on tissues other than lung tissue would not be expected. What Should I Do If Ive Been Exposed to Radon? Concerned patients may ask their doctor about medical tests for radon exposure. At present, no test is sensitive enough to determine past levels of exposure. Researchers are evaluating some methods for estimating past exposure (for example, special counting of levels of radiation in the skull), but these lack the needed sensitivity for most exposures in the general population. For people exposed to higher levels of radon, it is especially important to quit smoking. Evidence has shown that the combined effect of cigarette smoking and radon exposure can cause lung cancer. For miners, the synergy between smoking and radon exposure has resulted in extremely high health risks. Radon is a naturally occurring environmental carcinogen. This makes radon the second-leading cause of lung cancer after cigarette smoking, although cigarettes account for far more cases than radon. Most radon-induced cases of lung cancer occur in smokers, reflecting synergy between smoking and radon exposure. Quitting smoking is an essential part of prevention, but the estimates of radon-caused lung cancer are also substantial. 74

Radon-induced lung cancer can be prevented by reducing radon levels in homes and other buildings. Approximately one-third of radon-induced lung cancer could be avoided if homes with radon concentrations exceeding 4 pCi/L (the EPA action level) underwent changes to reduce radon concentrations to below that level. However, eliminating all radon exposure is not possible. Diesel Exhaust Exposure to diesel exhaust is widespread in the modern world. Trucks, buses, trains, construction and farm equipment, generators, ships, and some cars have diesel engines. Exhaust from these engines brings a complex mixture of soot and gases to roadways, cities, farms, and other workplaces. Health concerns about diesel exhaust relate not only to cancer, but also to lung (respiratory) and heart diseases. What Is Diesel Exhaust? The exhaust from diesel engines is made up of both gases and soot, each of which is made up of thousands of different substances. The gas portion of diesel exhaust is mostly carbon dioxide, carbon monoxide, nitric oxide, nitrogen dioxide, sulfur oxides, and hydrocarbons, including polycyclic aromatic hydrocarbons (PAHs). The particulate portion of diesel exhaust, also known as soot, is mainly made up of elemental carbon, organic material (including PAHs), and traces of metallic compounds. So, PAHs are found in both the gases and the soot of diesel exhaust. How Are People Exposed to Diesel Exhaust? People are exposed to diesel exhaust by breathing in the soot and gases, rather than by eating contaminated foods or through skin absorption. Measuring exposure is difficult because diesel exhaust is chemically complex and many parts of it are also found in a lot of other sources. This has been, and remains, a major challenge in scientific studies. People may be exposed to diesel exhaust at work, through daily living, or on the way to school. At Work The amount and length of time people are exposed to diesel exhaust varies greatly. Those with the highest exposures include truck drivers, bridge and tunnel workers, mine workers, forklift drivers, railroad and 75

dock workers, and garage workers. Farm workers and car, truck, and bus maintenance garage workers may also spend a lot of time around diesel exhaust. Every Day The general public is also exposed to diesel exhaust, although less often and at much lowers levels than in the workplace. Exposures are highest where diesel traffic is heaviest, such as along major highways and in cities. Does Diesel Exhaust Cause Cancer? Background Information How Normal Cells Become Cancer Cells Cancer cells develop because of damage to DNA. DNA is in every cell and directs all the cell's activities. When DNA becomes damaged it is often able to repair itself. In cancer cells, the damage is not repaired. Carcinogens A substance that causes cancer is called a carcinogen (car-SIN-oh-gin). Some carcinogens do not act on DNA directly, but lead to cancer in other ways. For example, the carcinogen may cause cells to divide at a faster rate, which could increase the chances that DNA changes will occur. Carcinogens do not cause cancer in every case, all the time. Substances classified as carcinogens may have different levels of cancer-causing potential. Some may cause cancer only after prolonged, high levels of exposure. And for any one person, the risk of developing cancer depends on many factors, such as the length and intensity of exposure to the carcinogen, the person's overall health, and the persons family history. Evidence Two kinds of evidence tell us about the cancer-causing (carcinogenic) potential of diesel exhaust: 1. Studies of the parts of diesel exhaust, such as soot and PAHs 2. Studies of diesel exhaust itself 76

A full discussion of what is known about the parts of diesel exhaust, such as soot and PAHs, is beyond the scope of this article, but soot and PAHs have been classified as carcinogens. Evidence about diesel exhaust as a whole is presented here. What Do Epidemiologic Studies Suggest? Epidemiologic studies provide information about the possible causes of disease, occurrence of disease in a population or its subgroups, and trends in the frequency of disease over time. Epidemiologic studies of lung cancer risk in diesel-exposed workers have been done. Lung cancer is the major cancer thought to be linked to diesel exhaust. These studies face the usual challenges of such studies. For example, it is very hard to correctly define and measure work-place exposure. It is also difficult to take into account the impact of other risk factors, such as smoking. Epidemiologic studies of workers exposed to diesel exhaust have shown small but significant increases in risk of lung cancer. A case-control study found that railroad workers with at least 20 years of service were more likely to die from lung cancer than were members of the general population. Another study of railroad workers by the same researchers found that lung cancer risk increased with length of exposure to diesel exhaust; the relative risk was highest among workers with the longest exposure. Several studies of Teamsters also linked diesel exhaust exposure with lung cancer. Still another study of almost a half-million American men looked at the effect of work-place exposure to diesel exhaust on their risk of developing lung cancer. Men with the heaviest and most prolonged exposures, such as railroad workers, heavy equipment operators, miners, and truck drivers, had higher lung cancer death rates than unexposed workers. Although most studies have found a link between diesel exhaust exposure and lung cancer, many have not. Still, with more than 1 million exposed workers, diesel exhaust may pose a substantial health risk. The relationship between lung cancer and diesel exhaust in the general environment has been studied less than occupational exposures. What Do Animal and Laboratory Studies Suggest?

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In laboratory studies, diesel exhaust (as soot or chemical extracts) can cause changes in DNA. Several studies also provide proof that diesel exhaust can cause cancer in animals. For example, a long-term inhalation study in mice, rats, and hamsters exposed to diesel exhaust showed a higher rate of lung cancer in the exposed animals. However, the carcinogenic effects of diesel exhaust in animals may relate to soot overload in their lungs. If true, this would suggest that normal lung defenses must be overcome in order for diesel exhaust to cause cancer. What Do the Experts Say? Based on animal and human evidence, expert agencies have evaluated the potential of diesel exhaust to cause cancer. The International Agency for Research on Cancer The International Agency for Research on Cancer (IARC) also evaluates exposures that may cause cancer. IARC classifies exposures into 1 of 4 categories. Group-1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group-2 exposures are divided into 2 categories. Group-2A ("probably carcinogenic to humans") has stronger evidence, and Group-2B ("possibly carcinogenic to humans") has weaker evidence. Group-3 exposures are not considered classifiable because the available evidence is limited or inadequate. Group-4 exposures are "probably not carcinogenic to humans" based on evidence suggesting these substances do not cause cancer in humans or in experimental animals.

IARC puts diesel exhaust in Group-2A, as "probably carcinogenic to humans." The Environmental Protection Agency The Environmental Protection Agency (EPA) uses a classification system very similar to that of the IARC. EPA considers diesel exhaust "likely to be carcinogenic to humans." The EPA also reports that the fine particles that diesel exhaust contains "are a serious risk to public health. They pose a significant health risk because they can pass through the nose 78

and throat and become lodged in the lungs. Fine particles cause lung damage and premature death. They can also aggravate respiratory conditions such as asthma and bronchitis." Does Diesel Exhaust Cause Any Other Health Problems? Lung cancer is the main cancer to have been linked to diesel exhaust, but there is also suspicion that other cancers, especially those of the larynx, pancreas, bladder, and kidney, may be associated with diesel exhaust. Diesel exhaust is a major part of outdoor air pollution. As mentioned above, diesel exhaust is believed to play a role in other health problems, such as eye irritation, headache, lung damage, asthma and other lung diseases, heart diseases, and possibly immune system problems. What Should I Do If I Have Been Exposed to Diesel Exhaust? If you are or have been heavily exposed to diesel fumes, your risk of lung cancer may be increased. If you have been exposed to diesel fumes in the general environment, the increase in your risk is likely to be very small. If you have had exposure to high levels over a long period of time, your risk is higher. However, using study results to predict individual problems is not easy, so measuring the exact amount of an exposed persons risk is difficult. At Work If your workplace exposes you to diesel exhaust, there are many ways to reduce or prevent exposures. Some of these measures will also protect you from other chemical exposures that are likely to happen in the workplace. Engineering changes, such as ventilating the exhaust away from workers breathing zones, are important. Good work practices, such as changing clothes after work, washing hands regularly, and keeping food out of the work area, are also important. Finally, personal protective equipment, such as respirators, may be a key part of a workplace protective program. You should work with your employer to be sure that enough protection is in place. Every Day If you are exposed to diesel exhaust fumes in the general environment, you can take some of the same precautions. For example, you can avoid 79

spending time near large sources of diesel exhaust, such as behind trucks and buses. Over the last 7 years the EPA has enforced the Clean Air Act, which included reducing diesel emissions from cars and trucks by mandated changes in both engines and fuel. This has decreased public exposure to diesel exhaust. Cigarette smoking is a much more powerful risk factor for lung cancer than are diesel fumes. The two exposures combined, however, may increase risk to a greater extent than the sum of their individual risks. People with a history of diesel exhaust exposure should avoid any contact with tobacco smoke, either through smoking or through secondhand exposure. What's the Bottom Line? Prolonged exposure to diesel exhaust probably increases the risk of lung cancer and maybe other cancers, too. Parts of diesel exhaust, such as soot and PAHs, have been shown to cause cancer. As a result, several government and research organizations have stated that diesel exhaust probably causes cancer in humans. Another reason for limiting exposure is that diesel exhaust, like many other air pollutants, also causes lung, heart, and other health problems. Short-term exposure to diesel exhaust is very unlikely to affect anyone's risk of developing lung cancer. Secondhand Smoke What is secondhand smoke? Secondhand smoke is also known as environmental tobacco smoke (ETS) or passive smoke. It is a mixture of 2 forms of smoke that comes from burning tobacco: sidestream smoke: smoke that comes from the end of a lighted cigarette, pipe, or cigar mainstream smoke: smoke that is exhaled by a smoker

When non-smokers are exposed to secondhand smoke it is called involuntary smoking or passive smoking. Non-smokers who breathe in secondhand smoke take in nicotine and other toxic chemicals just like smokers do. The more secondhand smoke you are exposed to, the higher the level of these harmful chemicals in your body.

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Why is secondhand smoke a problem? Secondhand smoke causes cancer Tobacco smoke contains over 4,000 chemical compounds. More than 60 of these are known or suspected to cause cancer. Secondhand smoke causes other kinds of diseases and deaths Pregnant women exposed to secondhand smoke are also at increased risk of having low birth weight babies. Secondhand smoke may be linked to breast cancer An issue that is still being studied is whether secondhand smoke may increase the risk of breast cancer. Both mainstream and secondhand smoke contain about 20 chemicals that, in high concentrations, cause breast cancer in rodents. And we know that in humans, chemicals from tobacco smoke reach breast tissue and are found in breast milk. Any link between secondhand smoke and breast cancer risk in human studies is still being debated. This is partly because breast cancer risk has not been shown to be increased in active smokers. One possible explanation for this is that tobacco smoke may have different effects on breast cancer risk in smokers and in those who are exposed to secondhand smoke. Secondhand smoke kills children and adults who don't smoke, and makes others sick. Secondhand smoke causes premature death and disease in children and in adults who do not smoke. Children exposed to secondhand smoke are at an increased risk of sudden infant death syndrome (SIDS), acute respiratory infections, ear problems, and more severe asthma. Smoking by parents causes breathing (respiratory) symptoms and slows lung growth in their children. Secondhand smoke immediately affects the heart and blood circulation in a harmful way. Over a longer time it also causes heart disease and lung cancer. The scientific evidence shows that there is no safe level of exposure to secondhand smoke. 81

The only way to fully protect non-smokers from exposure to secondhand smoke indoors is to prevent all smoking in that indoor space or building. Separating smokers from non-smokers, cleaning the air, and ventilating buildings cannot keep non-smokers from being exposed to secondhand smoke.

Where is secondhand smoke a problem? There are 4 places where you should be especially concerned about exposure to secondhand smoke: Your workplace The workplace is a major source of secondhand smoke exposure for adults. Because there are no known safe levels, they recommend that exposures to secondhand smoke be reduced to the lowest possible levels. Secondhand smoke in the workplace has been linked to an increased risk for heart disease and lung cancer among adult non-smokers. Smoke-free workplace policies are the only way to do away with secondhand smoke exposure in the workplace. Separating smokers from non-smokers, cleaning the air, and ventilating the building cannot prevent exposure if people still smoke inside the building. An extra bonus besides protecting non-smokers is that workplace smoking restrictions may also encourage smokers to quit. Public places Everyone can be exposed to secondhand smoke in public places, such as restaurants, shopping centers, public transportation, schools, and daycare centers. Some businesses seem to be afraid to ban smoking, but there is no credible evidence that going smoke-free is bad for business. Public places where children go are a special area of concern. Your home Making your home smoke-free may be one of the most important things you can do for the health of your family. Any family member can develop health problems related to secondhand smoke. Children are especially sensitive to secondhand smoke. Asthma, lung infections, and ear infections are more common in children who are around smokers. Some of these problems can be serious and even life82

threatening. Others may seem like small problems, but they add up quickly: think of the expenses, doctor visits, medicines, lost school time, and often lost work time for the parent who must take the child to the doctor. Think about it: we spend more time at home than anywhere else. A smoke-free home protects your family, your guests, and even your pets. The car Cars are another place that you can be exposed to secondhand smoke. If someone smokes there, hazardous levels of smoke can build up quickly. Again, this can be especially harmful to children. In response to this fact encourage people to make their cars, as well as their homes, smoke-free. What about smoking odors? There is no research in the medical literature about the cancer-causing effects of cigarette odors. Research does show that secondhand tobacco smoke can get into hair, clothing, and other surfaces. Though unknown, the cancer-causing effects would likely be very small compared to direct exposure to secondhand smoke, such as living in a house with a smoker. Menopausal Hormone Replacement Therapy and Cancer Risk For decades, women have used hormone replacement therapy (HRT, also known as post-menopausal hormone therapy or PHT) to ease symptoms of menopause, such as hot flashes. Many doctors and their patients believed HRT had other health benefits, too. But recent research studies have led doctors to question some of these beliefs. Here we will discuss what is known about how hormone replacement therapy (HRT) can affect a woman's risk of getting certain cancers. We will not go into the possible effects of HRT on other diseases, such as osteoporosis (bone thinning), heart disease, and dementia. This is not meant to be a policy statement of the American Cancer Society -- it is a summary of published medical studies on the subject. Women who are thinking about using HRT are should talk with their doctors about the information covered here. Woman should also understand the risks and benefits of HRT and the follow-up they will need to have with their doctors if HRT is used. Based on this information, a woman and her doctor may decide that hormones are or 83

are not needed for a period of time to help with symptoms of menopause. Menopause, symptoms, and hormone replacement therapy Menopause is the time in a woman's life when her ovaries stop releasing eggs and start making smaller amounts of the 2 main female hormones, estrogen and progesterone. Over time, this results in the end of menstrual periods. Women who have their ovaries removed by surgery (oophorectomy) or whose ovaries stop working for other reasons also go through menopause, too, but much more suddenly. Lowered hormone levels cause the symptoms that are often linked to menopause -- hot flashes and night sweats, for instance. These symptoms tend to start early and fade away at some point, whether or not they are treated. Other symptoms, like dryness and thinning of vaginal tissues can start later and may worsen over time. Low estrogen levels also increase a woman's risk of other health problems, such as osteoporosis. Types of hormone replacement therapy The term hormone replacement therapy (HRT) is used to mean estrogen and progestin, or estrogen alone, given to a woman whose levels of these hormones are low due to menopause. Estrogen replacement therapy Estrogen replacement therapy (ERT) is used to raise estrogen levels in the body. CEE (conjugated equine estrogens) forms of ERT (such as Premarin) are most common and have been used for the longest time. Combined hormone replacement therapy Combined hormone replacement therapy uses both estrogen and progestin (progesterone-like hormone). Combined HRT can be given 2 ways: Continuous HRT involves giving the same dose of estrogen and progestin each day.

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Sequential (cyclical) HRT uses different amounts of the hormones during the month so that it is more like the natural menstrual cycle.

ERT and combined HRT are sometimes used to relieve symptoms of menopause. Some doctors believe hormone therapy can also lower a woman's risk of some other health problems linked to low estrogen levels. How hormone replacement therapy is given Both ERT and combined HRT may be given as a systemic therapy. This means that the hormones are given as pills or as a patch. They are absorbed through the digestive system, the mucous membranes, or the skin and reach all parts of the body through the bloodstream. As another option, hormone treatments may be used topically. This means they mainly reach nearby areas rather than the whole body. Hormones that are placed in the vagina can enter the bloodstream, but the amount that gets in depends on the type of hormone and the dose. Dry or thinned vaginal tissues respond to very small doses of estrogen. These smaller doses are placed inside the vagina in the form of creams, rings, or tablets that slowly release hormones to the vagina and nearby tissues. Even though tiny amounts of hormone may enter the blood, most of it stays in the vaginal tissues. This is considered topical use. HRT and endometrial (uterine) cancer risk ERT Using systemic estrogen (ERT) by itself increases a woman's risk of developing endometrial cancer (cancer of the lining of the uterus). Long-term use of vaginal creams, rings, or tablets containing estrogen may also increase estrogen levels in the body. The risk continues to be increased even after ERT is no longer used. For these reasons, estrogen alone is almost never given to women who have gone through menopause and who still have a uterus. Combined HRT For women who still have their uterus, studies show that combined HRT (progestin and estrogen) may help menopause symptoms without increasing the risk of endometrial cancer. 85

One study showed that about 1 in 9 women treated with estrogen alone for 3 years developed a type of pre-cancerous change in their endometrium called atypical hyperplasia. Women treated with both types of hormones did not develop this change any more often than women not taking any hormones. A woman who has had her uterus completely removed (total hysterectomy) is not in danger of developing endometrial cancer, regardless of whether she takes ERT or HRT. But because the only reason for giving progestin is to protect the endometrium, a woman without a uterus would most likely be given ERT alone. HRT and breast cancer risk Combined HRT Daily use of combined HRT increases a woman's chance of developing breast cancer by about 5% to 6% with each year of use. Out of 10,000 women who took combined HRT for a year, this would add up to about 8 more cases of breast cancer than in those who took no hormones. The longer HRT was used, the more the risk increased. In this study, women who took combined HRT also had a higher risk of having breast cancer detected at a more advanced stage and were more likely to have abnormal results on mammograms. Not all of the questions surrounding combined HRT and breast cancer risk have been answered. Most of the increased risk of breast cancer from combined HRT is thought to be due to the progestin. Doctors are now looking at whether the dose of progestin can be decreased to lower the risk of breast cancer while still protecting the endometrium. Women who no longer have a uterus (due to hysterectomy) should take ERT instead of combined HRT. These women do not need progestin to protect against uterine cancer and are increasing their risk of breast cancer by taking combined HRT. The risk of HRT applies only to current and recent users. A woman's breast cancer risk is thought to decrease after stopping HRT and return to that of the general population (the usual risk) within 5 years of stopping.

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ERT Women who had had a hysterectomy, and whose ovaries were either removed or had stopped working, those who were taking only estrogens did not have an increased risk of breast cancer. The British "Million Women Study," and many other studies like this, reported a very slight increase in breast cancer risk (about 1% to 3% increase per each year of use) among women who took ERT. HRT and ovarian cancer risk Ovarian cancer is so rare that it is hard to study whether something increases a woman's risk for it. Even when the relative risk (or probability) is found to be increased, a woman's absolute risk is still likely to be low. For example, a woman is much more likely to be affected by a 50% increase in her risk for breast cancer than by a 50% increase in her risk for ovarian cancer, because her risk for ovarian cancer is much lower to begin with. To put this another way, in a group of 100 women with a 12% risk of breast cancer and a 2% risk of ovarian cancer, you would expect about 2 cases of ovarian cancer and 12 breast cancers. A 50% risk increase in both cancers would mean there would be 18 women with breast cancer but only 3 with ovarian. So each woman's absolute risk of ovarian cancer would still be much lower than her risk of breast cancer. ERT Studies have shown that women who take ERT have higher risk for ovarian cancer compared to women who take no hormones after menopause. The risk of ovarian cancer increases the longer a woman uses ERT, particularly among those who have used ERT for more than 10 years. Combined HRT It's still not known if HRT increases the risk of ovarian cancer. In one recent study, women who took estrogen and progestin (either together or in cycles) did not have a higher risk for ovarian cancer unless they had previously taken estrogen without progestin. The WHI study found that continuous combined HRT may increase the risk of ovarian cancer slightly. But this finding may have been due to

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chance because of the small number of women who developed ovarian cancer during the study. HRT and colon cancer risk Combined HRT The WHI study found that combined HRT reduced the risk of colorectal cancer by about 40%. This effect seemed to fade when the women were checked a little more than 2 years after the HRT was stopped. This reduction has also been found in other studies like this. Of course, these results must be weighed along with the effects of HRT on the risk of other types of cancer, as well as its effects on non-cancerous conditions. ERT In the WHI group that took estrogen only, estrogen replacement therapy did not seem to have any effect on the risk of colorectal cancer. Conclusions The decision to use hormone replacement therapy (ERT or combined HRT) after menopause should be made by each woman and her doctor after weighing the possible risks and benefits. Factors to think about include the risk of breast, endometrial, and ovarian cancer the risks of other serious conditions affected by ERT or combined HRT not covered here, such as heart disease, stroke, and serious blood clots (DVT or deep vein thrombosis) Other medicines that may be used to treat menopausal symptoms or osteoporosis.

Other factors to consider include how severe the woman's menopausal symptoms are and the type and dose of the hormones the doctor recommends. If a woman and her doctor decide that ERT or combined HRT is the best treatment for certain symptoms of menopause or health problems, it is usually best to use it at the lowest dose that works for her and for as 88

short a time as possible. Other treatments for these symptoms and conditions should also be considered. It is important that any woman taking ERT or combined HRT be checked yearly by her doctor for any signs of cancer. All women should report any vaginal bleeding that happens after menopause to their doctors right away -- it may be a sign of endometrial cancer. Adding progestin to estrogen (combined HRT) reduces the risk of endometrial cancer, but may not eliminate it entirely. If you are using vaginal cream, rings, or tablets containing estrogen talk to your doctor about follow-up and the possible need for progestin treatment. For women who have had a total hysterectomy (removal of the uterus), progestin does not need to be added because there is no risk of endometrial cancer. Adding progestin does not protect against breast cancer and, in fact, raises the risk further, so ERT is a better option. In recent years, many over-the-counter "natural" products have been marketed to help with menopausal symptoms. These include certain vitamins, soy-based products, and herbal products (such as black cohosh and red clover). These products are considered dietary supplements (as opposed to drugs) and have not been evaluated for their safety or effectiveness. Some of the products have been tested, mostly in small clinical trials, but many of the tests had problems with the way they were done that could affect their outcomes. Dietary Supplements: How to Know What Is Safe What You Need to Know First If you are thinking about using dietary supplements such as vitamins, herbs, or any product made from plants (botanicals) as part of your cancer treatment, you need to consider your choice carefully. So it still falls to you, the consumer, to gather truthful information about using these products safely. Like drugs, dietary supplements have risks and side effects. They can usually be used safely within certain dosage guidelines. But, unlike drugs, dietary supplements are mostly "self-prescribed," with little or no input from informed medical sources like doctors or pharmacists. There is a lot of wrong information out there. Often, there is not enough 89

reliable information about the safe use and potential risks of dietary supplements. It is safe to assume that most people who suffered unexpected side effects, illnesses, or drug interactions from dietary supplements did not call a poison control center. That means that these numbers are likely to be a very low estimate of actual events. This is not to say that used properly, certain dietary supplements cannot reduce the risk of some diseases, relieve or reduce discomfort caused by certain drugs or conditions, or simply improve your quality of life. However, particularly in the case of people who are getting treatment for cancer, taking dietary supplements can be risky. For example, some dietary supplements can cause skin sensitivity and severe reactions when taken while receiving radiation treatments. Patients having radiation treatment should talk to their doctors before taking any supplement. Also, patients getting chemotherapy may be at higher risk for drug interaction if they take dietary supplements. Cancer experts often recommend that these patients avoid dietary supplements altogether. Keep in mind that most of what you hear or read about dietary supplements is based on anecdotal evidence -- that is, evidence based on people's (even doctors') personal experiences or opinions rather than objective, controlled scientific studies. Be skeptical of sources that make grand claims based on a few people's testimonials or vague references to "scientific proof." The rule "if it sounds too good to be true, it probably is" usually applies to such claims. Remember also that the makers and sellers of supplements have a vested interest in promoting their products. Look for evidence or research on the supplement from objective, third-party sources wherever possible. Regardless of your treatment, it is always safest to talk with your doctor about the exact amount of each supplement you plan to take before starting on a supplement regimen. Talking With Your Doctor Many doctors are just starting to learn about the uses, risks, and potential benefits of dietary supplements. In some cases, this can widen the gap between patient and doctor when it comes to using 90

supplements along with a mainstream treatment. This situation should improve as more studies are done and better information becomes available. Common Misconceptions About Dietary Supplements Megadosing: The "More Is Better" Myth Many people wonder why dietary supplements such as vitamins, herbals, and botanicals are sold over the counter or without a prescription from a doctor, while medications (or drugs) are more closely regulated and controlled. People often make the mistake of assuming that because supplements are sold over the counter, sometimes with little or no direction on the label, they are completely safe to take, even in high doses. In the 1990s there was a trend of "megadosing" antioxidants such as vitamin C, beta carotene, and vitamin E. Even though no scientific studies have ever proven that large doses of vitamin C can prevent or cure colds, many people still think this is true. You may have heard a number of claims about the benefits of taking large doses of certain vitamins. But the practice of using large doses of vitamins to fight disease in humans is not supported by the available scientific evidence. In fact, large doses of some vitamins or minerals can be dangerous and toxic. For example, too much vitamin C can interfere with the body's ability to absorb copper, a metal that is essential to our body chemistry. Also, too much phosphorous can inhibit the body's absorption of calcium. In addition, large doses of vitamins A, D, and K are not eliminated quickly by the body and can easily reach toxic levels when too much is taken. Talk with your doctor before taking large doses of any vitamin, mineral, or other supplement. Your doctor may be able to give you more information on safe dosages. Even when vitamin doses are not high enough to cause toxic effects, the overall impact on health may be negative. For example, several large studies found that, on average, people taking vitamin E supplements lived no longer than those who didn't. Some even died sooner, particularly of heart failure. The "Natural Is Safe" or "Natural Is Better" Myth In todays cultural climate, you will not find much support for the idea that a man-made or refined substance is better or safer than one sold in its unrefined, natural state. However, supplements that claim to be "all natural" are not always better or safer for people to take than refined or manufactured substances. Keep in mind that some of the most toxic 91

substances in the world occur naturally. Poison mushrooms, for example, are completely natural but not safe or helpful to humans. Many plants in nature are toxic, even deadly, if taken internally. Botanical supplements (such as garlic, ginger, ginkgo biloba, echinacea, and others) are made of plant material, so many of them are sold as "natural" products. However, plants are made up of many chemicals. Some of these chemicals can be helpful while others are poisonous or can cause allergies in humans. Botanicals that market themselves as "all natural" are not always the most helpful ones, since they are not refined to remove potentially harmful chemicals. Botanicals can contain any or all parts of the plant, including roots, stems, flowers, leaves, pollen, and juices. Different parts of plants can have very different effects on humans. For example, dandelion root is a laxative (causes bowel movements), while dandelion leaves contain a diuretic (chemical that increases urination). If you decide to use a botanical supplement, make sure you know what parts of the plant were used in its production. If you are unsure, contact the company and ask about how they make their supplement. Also, remember that safety and dose are related. The leaves or roots of some plants can be safely consumed in small amounts as an herb. But concentrated extracts sold as liquids or pills may contain the plant's chemicals in far greater amounts and may not be safe. The "It's Been Used for Thousands of Years, So It Must Be Good" Myth Knowing that a botanical has been used in folk or traditional medicine for thousands of years is helpful but is not convincing proof of safety. If small amounts of a plant caused painful or life-threatening side effects right away, its use is unlikely to have persisted in folk medicine or traditional medical systems. However, traditional medical systems of thousands or even hundreds of years ago did not have the scientific methods to detect long term side effects. So, if a plant seemed useful over the short term but actually increased the risk of chronic disease (like cancer, heart failure, or kidney failure) after years of use, those side effects would have not been noticed. It is also important to find out whether a plant is being used now like it was in its traditional use. For example, tea prepared from a certain plant might have been safely used in traditional Chinese medicine to treat occasional bouts of asthma when given by an experienced 92

practitioner. On the other hand, daily use of much higher doses taken in a concentrated form with no professional supervision might be quite unsafe. The "It Can't Hurt to Take Supplements with my Regular Medicines" Myth Many people also assume that dietary supplements can safely be taken along with any prescription drugs. This is also not true. For example, certain botanicals can block or speed up the body's absorption of some prescription drugs, causing the person to have too much or too little of the prescribed drug in their bloodstream. Most drug companies and producers of herbal supplements do not do research on possible drug interactions, so the risks of taking supplements with many medications are unknown. Talk with your doctor about any herbal supplements you wish to take. He or she can tell you of any known interactions with medicines you may be taking. Unfortunately, there are always new drugs and supplements for which interactions have not yet been found. Talk with your doctor or pharmacist about the chance of interactions if you are taking newer drugs or supplements. What Kinds of Problems Have There Been With Supplements and Herbs? Products such as herbs were sometimes contaminated with germs, pesticides, or toxic heavy metals. Others did not contain what was listed on the label at all. Still others contained more or less than the amount claimed on the label. Vitamin supplements, for example, were sometimes found to contain much less than the stated amounts on the labels. Some "herbal" supplements have been found to contain prescription drugs that were not listed on their labels. Some of these problems can cause serious health issues for the consumer. Currently, there are no guidelines in place for the production of dietary supplements, although this should be improving over the next few years. It is generally the manufacturer's responsibility to see that the supplements they produce are standardized, quality products that meet the specifications described on their label. Many manufacturers follow careful, consistent production standards and market only high-quality, correctly labeled supplements. However, some less scrupulous manufacturers make supplements that contain little or none of the products listed on the label. Some supplements contain a larger dose 93

than the label lists, possibly due to poor quality controls. There have even been reported cases of toxic products. Reading Dietary Supplement Labels Before you buy a supplement, look at the label carefully. It is easy to misread the claims that are being made about the product. The manufacturers of dietary supplements are allowed to make 4 kinds of claims on the labels of their products: nutritional claims, claims of well being, health claims, and structure or function claims. Nutritional claims: These are statements about the general effects dietary supplements, vitamins, and minerals have on diseases known to be caused by nutrient deficiency. For example, "vitamin C prevents scurvy." Claims of well being: These are just that-- statements such as "makes you feel better." Health claims: These are statements about known health benefits of certain compounds. For example, risk-reduction claims such as "folate may reduce the chance of pregnant women delivering an infant with neural tube defects" fall into this category. Structure or function claims: These are the most hotly debated and confusing to consumers. They are claims about the effect of the dietary supplement on the structure or function of the body .Dietary supplements may not make any claims regarding the treatment of disease. However, the following product descriptions are acceptable as structure or function claims for dietary supplements: The product's mechanism of action ("works as an antioxidant") The product's effects on cellular structure ("helps membrane stability") The product's effects on the body's physiology ("promotes normal urinary flow") The product's effects on chemical or laboratory parameters ("supports normal blood glucose") Claims of maintenance ("helps maintain a healthy circulatory system") Other non-disease claims ("helps you relax") Claims for common conditions and symptoms related to life stages ("reduces irritability, bloating, and cramping associated with premenstrual syndrome") 94

For example, many consumers believe that a statement such as "helps maintain vision acuity" means the product has been proven to prevent vision loss, or that a statement such as "helps maintain a healthy prostate gland" means the product has been proven to prevent or remove diseases such as prostate cancer. Do not assume that because a product claims to support or promote healthy body function that it prevents or reduces the risk of any disease, including cancer. Guidelines for Choosing Safe Dietary Supplement Products First, speak with your doctor about any supplement you might consider taking. He or she can probably tell you if the supplement has any risks to your health and if the supplement is safe to take with other medications you may be taking. If you are shopping for a botanical, make sure to find a product that uses only the effective part of the plant. Avoid botanicals that have been made using the entire plant, unless the entire plant is recommended. Remember that a product described as "natural" is not necessarily safer or more effective. Consider the name and reputation of the manufacturer or distributor. Is it a nationally known name? Large companies with a reputation to uphold are more likely to manufacture their products under strict, quality-controlled conditions. Does the label provide a way to contact the company if you have questions or concerns about their product? Reputable manufacturers will provide contact information on the label or packaging of their products. Contact the manufacturer and ask about their quality control procedures and manufacturing processes. Try to avoid mixtures of many different supplements. The more ingredients, the greater the chances of harmful effects. Avoid supplements priced significantly lower than similar products; they are likely to be of lower quality.

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Avoid products that claim to be "miracle cures," "breakthroughs," or "new discoveries," to have benefits but no side effects, or to be based on a "secret ingredient" or method. Such claims are almost always fraudulent, and the product may contain potentially harmful substances or contaminants. Avoid products that claim to be effective treatment for a wide variety of unrelated illnesses. If a supplement claims that it can diagnose, treat, cure, or prevent disease, such as "cures cancer," the product is being sold illegally as a drug. Avoid products that claim to be safe or effective based solely on testimonials.

Dietary Supplements: How to Know What Is Safe What You Need to Know First If you are thinking about using dietary supplements such as vitamins, herbs, or any product made from plants (botanicals) as part of your cancer treatment, you need to consider your choice carefully. Like drugs, dietary supplements have risks and side effects. They can usually be used safely within certain dosage guidelines. But, unlike drugs, dietary supplements are mostly "self-prescribed," with little or no input from informed medical sources like doctors, or pharmacists. There is a lot of wrong information out there. Often, there is not enough reliable information about the safe use and potential risks of dietary supplements. This is not to say that used properly, certain dietary supplements cannot reduce the risk of some diseases, relieve or reduce discomfort caused by certain drugs or conditions, or simply improve your quality of life. However, particularly in the case of people who are getting treatment for cancer, taking dietary supplements can be risky. For example, some dietary supplements can cause skin sensitivity and severe reactions when taken while receiving radiation treatments. Patients having radiation treatment should talk to their doctors before taking any supplement. Also, patients getting chemotherapy may be at higher risk for drug interaction if they take dietary supplements. Cancer

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experts often recommend that these patients avoid dietary supplements altogether. Keep in mind that most of what you hear or read about dietary supplements is based on anecdotal evidence -- that is, evidence based on people's (even doctors') personal experiences or opinions rather than objective, controlled scientific studies. Be skeptical of sources that make grand claims based on a few people's testimonials or vague references to "scientific proof." The rule "if it sounds too good to be true, it probably is" usually applies to such claims. Remember also that the makers and sellers of supplements have a vested interest in promoting their products. Look for evidence or research on the supplement from objective, third-party sources wherever possible. Regardless of your treatment, it is always safest to talk with your doctor about the exact amount of each supplement you plan to take before starting on a supplement regimen. Talking With Your Doctor Many doctors are just starting to learn about the uses, risks, and potential benefits of dietary supplements. In some cases, this can widen the gap between patient and doctor when it comes to using supplements along with a mainstream treatment. This situation should improve as more studies are done and better information becomes available. We encourage you to gather as much information as possible on the dietary supplement you are thinking about. Then, approach your doctor with the information you have, and ask for an open conversation. Ask for his or her professional opinion as to whether the treatment is safe and medically sound, and how it might be safely added to your cancer treatment. Radiation Radiation Exposure and Cancer Radiation is the emission (sending out) of energy from any source. The light that comes from the sun is a source of radiation, as is the heat that is constantly coming off our bodies. When talking about radiation, however, most people think of specific kinds of radiation such as that 97

produced by radioactive materials or nuclear reactions. Most forms of radiation have not been linked to cancer. Only high frequency radiation (ionizing radiation and ultraviolet radiation) has been proven to cause genetic damage, which can lead to cancer. The hazards of exposure to some kinds of radiation were recognized shortly after the discovery of the x-ray in 1895. Skin reactions were observed in many people working with early x-ray generators, and by 1902 the first radiation-caused cancer was reported in a skin sore. Within a few years, a large number of such skin cancers had been observed. The first report of leukemia (a cancer of the bone marrow) in radiation workers appeared in 1911. Marie Curie, the discoverer of radium, and her daughter are believed to have died of radiation-caused leukemia. Since that time, many studies have confirmed the cancercausing effects of some types of radiation. Ionizing Radiation Radiation can generally be defined as being ionizing or non-ionizing. Ionizing radiation consists of high-energy waves that are able to penetrate cells and can cause ionization in different parts of the cell. Ionization is the development of a positive charge in a molecule (group of atoms) that is normally neutral (without a charge). Ionized molecules are unstable and quickly undergo chemical changes. This can lead to the formation of free radicals that can damage the molecule or other molecules around it. One type of molecule that is sensitive to ionizing radiation is DNA, the part of the cell that contains the genes (blueprints) for each person's characteristics. Ionizing radiation can lead to a mutation (change) in a cell's DNA, which could contribute to cancer, or to the death of the cell. All cells in the body can be damaged by ionizing radiation. The amount of damage is related to the dose of radiation received by the cell. While the process of cellular change from radiation takes only a fraction of a second, other changes such as the beginning of cancer may take years to develop. Types of ionizing radiation include x-rays, gamma rays, cosmic rays, and particles given off by radioactive materials such as alpha particles, beta rays, and protons. These forms of radiation have different energy levels and can penetrate cells to different extents, but all are capable of causing ionization. People may be exposed to 3 main types of ionizing radiation: 98

Natural background radiation comes from cosmic rays from our solar system and radioactive elements normally present in the soil. This is the major contributor to worldwide radiation exposure. Non-medical synthetic radiation occurs as a result of above ground nuclear weapons testing that took place before 1962 as well as occupational and commercial sources. Medical radiation comes in the form of diagnostic x-rays and other tests, as well as from radiation therapy. Radiation therapy is currently used to treat some types of cancer and involves dosages many thousand times higher than those used in diagnostic x-rays.

Does Ionizing Radiation Cause Cancer? Ionizing radiation has been shown to induce (cause) cancer in many different species of animals and in almost all parts of the body. It is one of the few scientifically proven carcinogens (cancer-causing agents) in human beings, although it appears to be a relatively weak carcinogen compared to many chemical agents. Many years may elapse between the radiation exposure and the appearance of the cancer. The types of cancer that can be caused by radiation can also occur naturally (without increased exposure to radiation), but some occur more frequently as a result of radiation. For example, a higher percentage of small cell lung cancers occur in uranium miners as a result of exposure to alpha radiation (a form of highly ionizing radiation). Organs differ in their sensitivity to the effects of radiation. The thyroid gland and bone marrow are most sensitive to radiation, while the kidney, bladder, and ovary seem to be least affected. Some forms of leukemia, a type of cancer that arises in the bone marrow, appear to be the most common radiation-induced cancers. Evidence that ionizing radiation causes cancer comes from studies of atomic bomb survivors in Japan, persons exposed to large amounts of x-rays, and from certain occupational exposures, such as workers with lung exposure to alpha radiation. These studies, however, generally involved relatively high-dose exposure - greater than 10 centigray. (A centigray (cGy) is a standard unit of radiation dose.) Therefore, the risk

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estimates for lower doses of radiation have to be estimated from the high-dose data, and may not be accurate. Dose-Related Radiation Effects Ionizing radiation is probably the only carcinogen with evidence that its effects are related to dose exposure. The probability that cancer will result from radiation exposure increases as the dose increases. However, there is no evidence to suggest that the grade (tendency to grow and spread) of the resulting cancer is affected by the dose. In other words, higher doses of radiation do not cause more aggressive cancers. Low-Dose Radiation Exposure A number of studies over the past 20 years have looked at the impact of environmental radiation exposure in the dose range of 10 cGy or less. Careful analysis of this research revealed no significant increase in the incidence of all cancers combined, or of cancers in specific parts of the body. Research in this area is continuing. Types of Cancer Associated With Ionizing Radiation Leukemia was at one time thought to be the major cancer to arise from high-dose radiation exposure, based on the experience with people exposed to the atomic blasts in Japan. It is now known that other cancers can result from radiation exposure, although they may take longer to develop (usually at least 10 to 15 years). Leukemias, by contrast, begin appearing as early as 2 years after acute radiation exposure. Studies of the survivors of the atomic blasts have demonstrated that high-dose radiation (at least 100cGy) increases the risk of developing several types of cancer. For these survivors, the risk of developing leukemia is five and a half times greater than in the general public. Children appear to be twice as sensitive as adults to the leukemia-causing effects of radiation, and unborn children exposed to radiation in the uterus are even more sensitive.

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The risk for developing any type of cancer in those highly exposed to an atomic blast is about 50% higher than the risk in those not exposed. Female breast cancer risk is more than twice as high as normal, and women who are exposed when under the age of 20 are found to be at higher risk than older women. The risk of developing lung cancer is 50% higher, and the risk for multiple myeloma is more than twice as high as in the general population.

Some people serving in the armed forces were exposed to radiation in nuclear weapons testing during the Cold War era. Cancers Caused by Radiation Therapy Ionizing radiation is an effective way to treat certain kinds of cancer. During radiation therapy, high doses of ionizing radiation are directed at the cancer, resulting in the death of the cancer cells. However, this can lead to DNA mutations in cells that survive the radiation, which can eventually lead to the development of another cancer (called a second primary cancer). An increase in second primary tumors in the area being irradiated has been observed in patients with several types of cancer following radiation therapy and/or chemotherapy. Some studies have associated radiation therapy with an increased incidence of thyroid cancer and early-onset breast cancer. Overall, however, radiation alone does not appear to be a very potent cancer-causing agent in second tumors. This is probably due to the fact that it is often used in a localized area, which means fewer normal cells are exposed to radiation. However, treatment for Hodgkin disease, a type of lymphoma, often delivers lower radiation doses to many areas of the body. These treated areas include large amounts of normal tissue. Patients with Hodgkin disease who are treated with radiation therapy are at an increased risk for developing second primary tumors. When considering radiation exposure from radiation therapy treatment, the benefits generally outweigh the risks. However, some combinations of radiation therapy and chemotherapy are more risky than others. Additional research is needed in this area so that optimal treatment can

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be given that minimizes the risk of the development of secondary cancers. Genetic Susceptibility to Radiation-Caused Cancer Scientists are making great progress in understanding how certain changes in DNA can cause cells to become cancerous. DNA is the chemical that carries the instructions for nearly everything our cells do. We usually resemble our parents because they are the source of our DNA. However, DNA affects more than our outward appearance. Some genes (parts of DNA) contain instructions for controlling when our cells grow, divide, and die. Certain genes that promote cell division are called oncogenes. Others that slow down cell division, or cause cells to die at the right time, are called tumor suppressor genes. It is known that cancers can be caused by DNA mutations (changes) that "turn on" oncogenes or "turn off" tumor suppressor genes. Certain inherited DNA changes can lead to a high risk for developing cancer and are responsible for the cancers that run in some families. Now that specific genes have been discovered that are associated with cancer, there is renewed interest in whether some people are more likely to develop cancers when exposed to radiation. There are some rare cancers where the interaction between radiation and genetic factors can be seen. Children treated with radiation therapy for hereditary retinoblastoma, a malignant eye tumor, are at an increased risk for developing a certain type of bone cancer called an osteosarcoma. Similarly, people who have nevoid basal cell carcinoma syndrome, a type of skin cancer, are at high risk for development of basal cell cancers in irradiated areas. Non-Ionizing Radiation Non-ionizing radiation is low-frequency radiation that does not have enough energy to cause ionization in tissues, but may cause adverse health consequences in other ways. Common types of non-ionizing radiation include ultraviolet rays, visible light, electromagnetic fields, infrared radiation, microwaves, and radiofrequency radiation (radio waves). Electrical appliances, heaters, and cellular phones emit (send out) non-ionizing radiation waves. Of all the types of non-ionizing radiation, only ultraviolet rays have been established as a cancercausing agent. Ultraviolet (UV) Radiation 102

The sun is the major source of ultraviolet (UV) radiation. Most skin cancers are a direct result of sunlight exposure. Both basal cell and squamous cell cancers (the most common types of skin cancer) are found on sun-exposed parts of the body, and their occurrence is related to lifetime sun exposure. Melanoma, a potentially fatal type of skin cancer, is less dependent on sun exposure and can develop on any area of the body. If you live in the mid-United States, being in direct sunlight for 30 minutes creates a buildup of a lethal dose of UVR for human cells not protected by sunscreen. The only other exposure to a carcinogen approaching this level of exposure is cigarette smoke in very heavy smokers.

Ultraviolet radiation is divided into three wavelength ranges: UVA rays are involved in the aging of cells and produce some damage to DNA. UVB rays are in the wavelength range mainly responsible for direct damage to the DNA, and are thought to cause most skin cancers. UVC rays are not present in sunlight, but are present in mercury lamps.

While UVA and UVB rays make up only 1/10,000,000th of the sun's wavelengths, they are primarily responsible for the damaging effects of the sun on the skin. Electromagnetic Fields Electromagnetic radiation is produced by moving electric charges and may be of natural origin (the sun) or human origin (electronic devices or power lines). Electromagnetic fields have been the subject of much controversy. Recent extensive studies of electric utility workers showed a minimal increase in the risk of brain tumors and leukemia. However, either of these increases may have been due to chance. Results from studies on magnetic fields and childhood leukemia have been suggestive but inconsistent. While smaller studies have observed a link between cancer and activities such as the use of electric blankets and television watching,

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the most recent and largest study did not find a connection between electromagnetic fields and cancer. Additionally, in 1999 the National Institute of Environmental Health Sciences (NIEHS) released results of an extensive 6-year study stating that the evidence for a risk of cancer and other human disease from the electric and magnetic fields (EMF) around power lines is "weak" but could not totally be discounted, and efforts to reduce exposures when possible should continue. Video display terminals: Video display terminals (VDTs), or computer screens, give off several kinds of radiation, most of which is in the extremely low frequency (ELF) range. Questions have been raised about possible health problems associated with the use of VDTs, including cancer and birth defects. The amount of energy given off by VDTs is far below government exposure standards, and at this time the available evidence does not support links to either of these health problems. Research in this area continues. Other health-related issues linked to long-term use of VDTs may be of greater concern, including problems with vision, backaches and other muscle problems, and stress. The conflicting data concerning electromagnetic fields will undoubtedly continue to generate controversy. Clearly, the question of whether or not electromagnetic fields can cause cancer needs to be answered. Other Sources of Non-Ionizing Radiation Radiofrequency radiation (radio waves): Radiofrequency radiation is emitted from radio broadcast transmitters, citizen band radios, and heaters. Generally speaking, the potential risk from this type of radiation exposure is thought to be minimal. Microwaves: Microwaves have energy levels similar to radio waves and infrared waves but are of a different frequency. Microwave radiation is used not only in microwave ovens, but also in navigational technology such as radar. Many materials absorb microwave energy, causing them to become hot. This is how food is cooked in microwave ovens. Microwaves do not make food radioactive. When microwave ovens are used according to 104

instructions, there is no evidence that they pose a risk of radiation exposure to people. Exposure to high levels of microwaves can have effects on health. Such exposure can lead to a painful burn or to the development of cataracts in the lenses of the eyes. Because the testes are very sensitive to changes in temperature, exposure to high levels of microwaves can alter or kill sperm. These injuries are caused only by exposure to large amounts of microwave radiation, however, and the small amount that can leak from a microwave oven does not cause these problems. Some pacemakers can be affected if the person with the pacemaker gets too close to a microwave oven while it is on. This can happen with other kinds of electronic equipment as well. Radar and radar guns: Most forms of radar use waves in the microwave range. Questions have been raised about exposure to radar and the risk of developing cancer, such as in police officers who use radar guns in traffic enforcement. To date there is very little evidence to support such a connection, but studies to look at this possibility are ongoing, and governmental recommendations have been made to reduce any possible risk. Cellular phones: Cellular phones give off small amounts of low frequency electromagnetic radiation. People have raised questions about possible links between the use of cellular phones and cancer, brain cancer in particular. For more detailed information about cellular phones, refer to our document, "Cellular Phones." Cancer among Military Personnel Exposed to Nuclear Weapons In the period of time at the beginning of the Cold War between 1945 and 1962, several countries tested nuclear weapons in the open air. The United States tested weapons in the South Pacific as well as at the Nevada testing grounds. Military maneuvers involving about 200,000 people were conducted as part of many of these tests. In addition, thousands of workers who were employed at several nuclear weapons plant sites were exposed to radiation and other toxic substances. As we have learned more about cancers caused by radiation exposure questions have been raised about the types of exposures and their impact on military workers. What Is the Evidence? 105

There is little doubt that high-dose radiation exposure can cause cancer. Some issues, however, are not as clear, such as the amount of exposure required, and the types of cancer that radiation can cause. In the late 1970s, a higher than usual number of cases of leukemia (4 expected, 10 found) was seen among the 3,000 troops present at the "Smokey" nuclear test in Nevada in August 1957. The question arose as to whether these cases were caused by radiation from the nuclear tests. Although the rate of leukemia was higher than expected as of 1979, rates for all cancers combined were actually lower than expected, making the results difficult to interpret. Some cancers are known to have a long latency period that is, they do not appear until decades after the exposure. The reason for the high leukemia rates of the "Smokey" test remains unexplained. To date, follow-up of many other troops present at other tests have not shown an increased number of deaths from cancer. British troops present at similar tests have not shown high exposure levels or an increase in cancer deaths. A recent study compared about 1,000 veterans who received the highest doses of radiation to other veterans who were minimally exposed. The risk of dying from some blood-related cancers (certain leukemias and lymphomas) was more than 3 times higher in those exposed to radiation, and the risk of dying overall was also slightly higher (about 22%). However, the risk was not increased for other types of cancers known to be caused by radiation, and the overall risk of dying from any form of cancer was not higher. Again, these results are difficult to interpret, and radiation may only be one of a number of factors at work. Results are more clear-cut in other groups, such as in the survivors of the atomic blasts in Hiroshima and Nagasaki and those exposed to fallout from the Chernobyl nuclear plant in the former Soviet Union, where certain cancers such as leukemias and thyroid cancers were significantly more prevalent. Much of this may have to do with the high level of radiation exposure in these groups. What Has Been Done About These Exposures? While the scientific evidence is mixed, the government has passed several laws to compensate veterans exposed to radiation during 106

nuclear testing who later developed certain types of cancer or other diseases. The first major piece of legislation was passed in 1984 as the Veterans Dioxin and Radiation Exposure Compensation Act. Although at first limited to certain cancers, this law, after subsequent amendments covered all cancers and four non-cancerous conditions as potentially radiogenic (caused by radiation). When passed in 1984, it required that the veteran prove his or her radiation exposure was sufficiently high to have caused the cancer. The Radiation-Exposed Veterans Act was passed in 1988. It stated that to be compensated, a veteran has only to show he or she participated in a specified nuclear testing activity and now has a cancer that is caused by radiation (radiogenic), which developed in a reasonable time period after the exposure. These laws initially recognized only certain types of cancer as caused by radiation; however, in 1998 the Secretary of Veterans Affairs amended these regulations, stating that based on the available evidence, prostate cancer and any other cancers may be caused by ionizing radiation. Beryllium is a metal found in mineral rocks, coal, soil, volcanic dust and is purified for use in nuclear weapons and reactors. It is a known cancer-causing agent, but can also cause chronic beryllium disease, with respiratory symptoms, weakness, weight loss, and heart disease. Silicosis is also a lung disease cause by breathing in of silica dust, which leads to inflammation and scarring of lung tissue. Silica comes from a naturally occurring crystal found in rock beds during the mining process. Cellular Phones Cellular (cell) phones are a relatively new technology that became widely used in the United States only in the 1990s. Although they have been studied extensively, we don't yet have information on the potential health effects of very long-term use or usage by children. Cell phones wouldn't be expected to cause cancer because they don't emit ionizing radiation. Periodic reports exist that have observed an association between cell phone use and the risk of brain cancer, but these reports are primarily based on small studies in Sweden. But the weight of the evidence, which is based on larger studies, has shown no association between cell phone use and brain cancer. Studies currently in progress such as the 107

European Interphone Study will provide more information on this subject. For now, the Food and Drug Administration Center for Devices and Radiological Health and the Federal Communications Commission offers the following advice to people concerned about cell phone use and risk: If there is a risk from these products -- and at this point we do not know that there is -- it is probably very small. But if you are concerned about avoiding even potential risks, you can take a few simple steps to minimize your exposure to radiofrequency energy (RF). Since time is a key factor in how much exposure a person receives, reducing the amount of time spent using a wireless phone will reduce RF exposure. If you must conduct extended conversations by wireless phone every day, you could place more distance between your body and the source of the RF, since the exposure level drops off dramatically with distance. For example, you could use a headset and carry the wireless phone away from your body or use a wireless phone connected to a remote antenna. Background Recent media attention has focused on a possible link between cell phone use and brain cancer, originally because of a lawsuit that alleged such a link. Network news programs ran their own tests of cell phones, reporting to the public that some of them exceed the maximum level of emitted radiofrequency (RF) energy . Based on the large and still rapidly growing number of cell phone users, and the seriousness of brain tumors, this is clearly a topic of wide concern. This document summarizes what we now know about the carcinogenicity (cancer-causing potential) of using cell phones. How do cell phones work? Cell phones operate with radio frequencies (RF), a form of energy located on the electromagnetic spectrum between FM radio waves and the waves used in microwave ovens, radar, and satellite stations. Cell phones do not emit ionizing radiation, the type that damages DNA and is known to have the ability to cause cancer. Cell phone technology works on a system of geographically separated zones called "cells." Each cell has its own "base station" that both receives and emits radio waves. When a call is placed from a cell phone, a signal is sent from the cell phone antenna to that cells base station antenna. The base station responds to the cell phone signal by assigning 108

the phone an available RF channel. When the RF channel is assigned, radio signals are simultaneously received and transmitted, allowing voice information to be carried between the cell phone and the base. The base station transfers the call to a switching center, where the call can be transferred to a local telephone carrier or another cell phone.

There are 2 types of wireless phones: cordless mobile

Cordless phones, commonly used in homes, have base units that are plugged into telephone jacks and wired to a local telephone service; these are not considered "cell" phones. The question of health risks associated with cordless phones, which operate at 1/600 the power of cell phones, has not been raised. Mobile phones are also known as "cell phones." The antennas of these phones are integrated into the body of the phone. Because the antenna of a mobile phone is close to the phone users head, mobile phones pose greater RF exposure than the other types of cordless phones. How are people exposed? Many factors affect the amount of RF to which a person is exposed. The number of "cells" in a geographical area depends on the cell phone traffic in that area. For example, large cities may have many cells per square mile, whereas a less-populated, rural area may have a single large cell stretching over several square miles. The farther away a cell phone antenna is from its base station, the higher the power level needed to maintain the connection. Smaller cells are therefore associated with much lower exposures. Each geographical cell has a different number of available channels. Cell phones operate ideally with the least amount of interference from neighboring channels. To help achieve the best operation, cell phones automatically step down to the lowest power level available that still maintains a connection with the base station. On the other hand, any physical obstacle, such as buildings or trees, interfering with the connection forces the base station to increase the power sent to the 109

phone. Therefore, the amount of power sent from a base station to a particular cell phone can vary, even within a single call. Cell phone makers are required to report the specific absorption rate (SAR) of their product to the FCC. The SAR is the amount of RF energy absorbed from the phone into the user's local tissues. The upper limit of SAR allowed is 1.6 watts per kilogram (W/kg) of body weight. Exposure to RF also depends on the duration and frequency of cell phone use, with more use implying more exposure. Finally, older cell phones (analog models) involve higher exposure than newer, digital equipment. Do cell phones cause brain cancer? What studies in humans suggest Because widespread cell phone use is little more than a decade old, there has been limited opportunity to examine its long-term health effects. However, large case-control studies and cohort studies have compared cell phone use among brain cancer patients and people without brain cancer. In each of the case-control studies, patients with brain cancer were compared to people free of brain cancer, in terms of their past use of cell phones. If the patients reported more cell phone use than those in the study who did not have brain cancer, and if no other differences between the 2 groups could account for the brain cancers, these observations would provide evidence of a possible link between cell phones and brain cancer. The majority of case-control studies have yielded similar results: First, the patients with brain cancer did not report more cell phone use overall than the controls. This finding was true when all brain cancers were considered as a group, when individual types of brain cancer were considered, and when specific locations within the brain were considered. In fact, most of the studies showed a tendency toward a lower risk of brain cancer among cell phone uses, for unclear reasons. Second, none of the studies showed a "dose-response relationship" -- a tendency for the risk of brain cancer to increase with increasing cell phone use, which would be expected if cell phone use caused brain cancer. Third, the studies did not show a clear link between the side of the head on which the brain cancer occurred and the side on which the 110

cell phone was used (with the possible exception of the Swedish study). Recent results from the Swedish Interphone study of long-term cell phone use, using a population-based case control design indicate the same conclusions. There was no association with risk of any of the brain tumor types studied (glioma or meningioma), or with duration of use, side of use, or amount of use. Results of the long-term cohort study, which linked data on all of the 420,095 cell phone users in Denmark between 1982 and 2002 to the Danish Cancer Registry, agree with the findings of the case-control studies. Cell phone use, even for more than 10 years, was not associated with an increased risk of developing brain tumors or cancer overall, nor was there an association with any brain tumor subtypes or with tumors in any location within the brain. As in the case-control studies, no link was found between brain tumor risk and RF dose, as assessed by length of cell phone use, date since first subscription, age at first subscription, or type of cell phone used. However, these published studies have only limited ability to examine the association between cell phone use and specific subtypes of brain cancer. One subtype that has been studied is acoustic neuroma, a relatively rare, slow-growing tumor of the acoustic nerve (which transmits the sensation of hearing from the ear to the brain) that occurs in less than one adult per 100,000 people per year. At least 9 epidemiological studies have looked for an association between the use of cell phones and acoustic neuroma. Results of these studies have been inconsistent, due largely to variations in study design and statistical challenges posed by the rarity of these tumors. One of the largest and most recent studies analyzed data from the 5 northern European countries, and found no relation of acoustic neuroma risk with cell phone use, duration of use, or number of calls made. According to the researchers, "The study suggested there is no substantial risk of acoustic neuroma in the first decade after starting mobile phone use. However, an increase in risk after longer term use or after a longer lag period could not be ruled out." In summary, there is now considerable epidemiologic evidence that shows no consistent association between cell phone use and overall risk of brain cancer. Some uncertainty remains regarding a possible association with acoustic neuromas. Several large studies now in progress will add markedly to the evidence within a few years.

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What the animal and laboratory evidence suggests Most but not all laboratory studies have reported a lack of RF-induced DNA damage. No increase in spontaneous brain tumors was observed in 2 studies of rats exposed to RF. The risk of lymphoma after radiation in rodents genetically altered to be especially sensitive to cancer-causing influences was increased following whole-body RF exposure. What do expert agencies say? Based on animal and human evidence like the examples above, expert agencies have evaluated the cancer-causing potential of cell phone use. A recent consumer information document issued reaches the same conclusions: The available scientific evidence does not show that any health problems are associated with using wireless phones. There is no proof, however, that wireless phones are absolutely safe. Wireless phones emit low levels of radiofrequency energy (RF) in the microwave range while being used. They also emit very low levels of RF when in the stand-by mode. Whereas high levels of RF can produce health effects (by heating tissue), exposure to low-level RF that does not produce heating effects causes no known adverse health effects. Many studies of low level RF exposures have not found any biological effects. Some studies have suggested that some biological effects may occur, but such findings have not been confirmed by additional research. In some cases, other researchers have had difficulty in reproducing those studies, or in determining the reasons for inconsistent results. Do cell phones cause any other health problems? To date, no claims have been made that cell phones are responsible for any other health problems. A small epidemiologic study from Germany found an association between uveal melanoma (a rare form of eye cancer) and exposure to mobile phones and other RF-transmitting devices, but this has not yet been examined in other studies. However, evidence has shown that the use of cell phones while driving increases the risk of automobile crashes. Another concern, without much evidence one way or the other, is that cell phones may interfere with medical electronic devices such as pacemakers and insulin pumps. Can I do anything to lower my exposure to RF from cell phones?

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Cell phone users who wish to lower exposure to RF emissions from cell phones may choose to use a corded or cordless earpiece when using their phone. Using an earpiece moves the device away from the user's head, which decreases the amount of radiation that reaches the body. Cell phone users can also choose a phone with a low SAR value Since there are no known risks from exposure to RF emissions from wireless phones, there is no reason to believe that hands-free kits reduce risks. Hands-free kits can be used with wireless phones for convenience and comfort. These systems reduce the absorption of RF energy in the head because the phone, which is the source of the RF emissions, will not be placed against the head. On the other hand, if the phone is mounted against the waist or other part of the body during use, then that part of the body will absorb more RF energy. Some products that claim to shield the user from RF absorption use special phone cases, while others involve nothing more than a metallic accessory attached to the phone. Studies have shown that these products generally do not work as advertised. Unlike 'hands-free' kits, these so-called 'shields' may interfere with proper operation of the phone. The phone may be forced to boost its power to compensate, leading to an increase in RF absorption. Cellular Phone Towers What Are Cellular Phone Towers? The widespread use of cellular phones has led to the placement of cellular phone towers in many communities. These towers, also called "base stations," consist of radios, computerized switching equipment, and antennas that receive and transmit radiofrequency (RF) signals. When a person makes a cellular phone call, a signal is sent from the phones antenna to the base station antenna. The base station responds to this signal by assigning it an available radiofrequency channel. Transmission and reception of these radio signals transfer the voice information to the base station. Next, the voice signals are sent to a switching center, which transfers the call to its destination. Cellular phone towers are usually mounted either on top or on the side of existing structures, such as trees, water tanks, or tall buildings. The antennas need to be located high enough so they can adequately cover the area. Base stations usually range in height from 150-270 feet.

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Cellular phones operate at the radiofrequency (RF) part of the electromagnetic spectrum. This is non-ionizing radiation. Other examples of the non-ionizing part of the electromagnetic spectrum include AM and FM radio waves, microwaves, and infrared waves from heat lamps. Unlike x-rays and gamma rays (which are examples of ionizing radiation), radio waves have too little energy to break the bonds that hold molecules (such as DNA) in cells together. Similarly, since RF of this frequency contains relatively low energy, it does not enter tissues. At very high levels of exposure, RF can cause warming of tissues, much as a heat lamp does. The wavelength of cell phone waves is about one foot and the frequency is approximately 800 to 900 MHz, although newer models may use higher frequencies up to 2,200 MHz. How Are People Exposed to Radiofrequency Energy From Cellular Phone Towers? As people use cellular phones to make phone calls, signals are transmitted back and forth to the base station. The radio waves produced at the base station are emitted into the environment, where people can be exposed. The energy from a cellular phone antenna, like that of other telecommunication antennas, is directed toward the horizon (parallel to the ground), with some downward scatter. Base station antennas use higher power levels than other types of land-mobile antennas, but much lower levels than radio and television broadcast stations. The power density decreases with increasing distance from the antenna. As a result, the level of exposure to radio waves at ground level is very low compared to the level close to the antenna. Public exposure to radio waves from cellular phone antennas is slight for several reasons. The power levels are relatively low, the antennas are mounted at high above ground level, and the signals are transmitted intermittently, rather than constantly. Agencies such as the National Council on Radiation Protections and Measurements, the International Radiation Protection Association, the Institute of Electrical and Electronics Engineers, and the American National Standards Institute, have established guidelines for exposure to RF radiation originating from cellular communications base stations. These guidelines were designed to protect workers, as well as the public, from potentially harmful radio frequency. The recommended exposure limits are in the range of .41-.45 milliwatts per square centimeter (mW/cm2) for cellular radiofrequencies. 114

Exposures that exceed these recommended standards can sometimes be encountered on the rooftops of buildings where base stations are mounted. If this is the case, access to these areas should be limited. The power density inside buildings where a base station is mounted is typically 10 to 100 times lower than the level outside depending on the construction materials of the building. Wood or cement block reduces the exposure level of RF radiation by a factor of about ten. The power density behind an antenna is hundreds to thousands of times lower than in front. Therefore, if an antenna is mounted on the side of a building, the exposure level in the room directly behind the wall is typically well below the recommended exposure limits. Do Cellular Phone Towers Cause Cancer? Humans generate electromagnetic fields internally as well as externally. The simple collision between 2 molecules is an electrical event. Since there is electrical activity inside the human body, the question arises as to whether radio waves emitted by cellular phone towers can influence cell function, and in particular whether they can cause cancer. However, several theoretical considerations suggest that cellular phone towers are unlikely to cause cancer. First, the energy level of radio waves is relatively low. Electromagnetic energy comes in "packages" that are referred to as photons. Photon energy is measured in electron volts (eV), the energy gained by an electron after accelerating over 1 volt. The energy in the photons depends directly on the frequency, and decreases as one moves down the electromagnetic spectrum. X-rays have about 1,000 eV of energy, while the photon energy of radio waves from cellular phone towers is about one millionth of an eV, not enough to alter molecules in the body. A second issue has to do with wavelength. Radio waves have a wavelength of approximately 1 foot in air, and about 2 inches in body tissue. As a result, RF radiation can only be concentrated to about an inch or two in size. This makes it unlikely that the energy from radio waves could be concentrated on a small bit of tissue, affecting individual cells. A third issue has to do with the magnitude of exposure, Measurements taken around typical cellular phone towers show ground level power densities well below the recommended limits. Moreover, public exposure near cell phone towers is not significantly different than background 115

levels of RF radiation in urban areas from other sources, such as radio and television broadcast stations. For these reasons, cell phone antennas or towers are unlikely to cause cancer. What Does the Epidemiologic Evidence Say? No human studies have focused specifically on cellular phone towers or even on radio waves more generally. Several studies have looked at the effects of radio waves and microwaves combined; these have generally not shown any increase in cancer, except for a US Air Force study that suggested an increase in brain tumors in association with radiofrequency/microwave exposure. What Does the Animal Evidence Say? A number of animal studies have been conducted, generally showing no carcinogenic (cancer-causing) effect of radio waves. Several experiments have used exposure levels that cause a rise in tissue temperature, and even in these studies, there was no increase in DNA mutations or in cancer. A recent review concluded that: "The scientific evidence indicates that exposure to radiofrequency radiation fields is not mutagenic and is therefore unlikely to act as an initiator of carcinogenesis. What Do the Expert Agencies Say? The World Health Organization stated in 1993 that "the epidemiologic and comparative clinical studies do not provide clear evidence of detrimental health effects in humans from exposure to RF fields. Occupational exposure to RF will be at higher levels than that encountered by the general population, and, thus, there is less likelihood of health effects in the general population as a whole. The electromagnetic RF signals transmitted from base station antennas stations travel toward the horizon in relatively narrow paths. For example, the radiation pattern for an antenna array mounted on a tower can be likened to a thin pancake centered around the antenna system. The individual pattern for a single array of sector antennas is wedgeshaped, like a piece of pie. As with all forms of electromagnetic energy, the power decreases rapidly as one moves away from the antenna. Therefore, RF exposure on the ground is much less than exposure very close to the antenna and in the path of the transmitted radio signal. In 116

fact, ground-level exposure from such antennas is typically thousands of times less than the exposure levels recommended as safe by expert organizations. So exposure to nearby residents would be well within safety margins. When cellular and PCS antennas are mounted on rooftops, RF levels on that roof or on others near by would probably be greater than those typically encountered on the ground. However, exposure levels approaching or exceeding safety guidelines should be encountered only very close to or directly in front of the antennas. In addition, for sectortype antennas, typically used for such rooftop base stations, RF levels to the side and in back of these antennas are insignificant. Do Cellular Phone Towers Cause Any Other Health Problems? While high levels of radiofrequency waves can cause a warming of tissues, cellular phone towers do not yield exposure at levels sufficient to cause this effect. There is no evidence in published scientific reports that cell phone towers cause any other health problems. What Do I Do If Ive been exposed to Cellular Phone Towers? As noted above, cell phone towers pose little risk under ordinary conditions. There is no test to measure whether you have been exposed to RF radiation from cellular phone towers. However, if there is a cellular phone tower mounted near your home or office, you can ask a government agency or private firm to measure the radiofrequency field strength near the tower to ensure that it is within the acceptable range. If you have additional health concerns, please consult your doctor. The Bottom Line... Cellular phone towers, like cellular phones themselves, are a relatively new technology, and we do not yet have full information on health effects. In particular, not enough time has elapsed to permit epidemiologic studies. There are some theoretical reasons why cellular phone towers would not be expected to increase cancer risk, and animal studies of RF have not suggested a risk of cancer. People who are concerned can ask for measurements of RF near cellular phone towers to be sure exposures do not exceed recommended limits. Chemicals Find out how certain chemicals might increase your cancer risk.

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Benzene A colorless, flammable liquid with a sweet odor, Benzene is formed from natural processes, such as volcanoes and forest fires, and is also found in cigarette smoke. Asbestos A group of naturally occurring fibrous minerals used in insulation, roofing shingles, ceiling and floor tiles, textiles, and hundreds of other products. MTBE MTBE (methyl tertiary-butyl ether) is part of a group of chemicals known as a fuel oxygenates. Find out what the experts say about its carcinogenicity. Tetrachlorethylene Also known as perchlorethylene, perchloroethylene, or "perc, Tetrachloroethylene, this chemical has been produced commercially since the early 1900s, primarily for dry cleaning and textile processing. Lead A naturally occurring bluish-gray metal found in small amounts in the earths crust, as well as in plants, animals, air, water, dust, and soil. Arsenic Arsenic is known to cause cancer, as well as many other serious health problems. This document reviews the hazards of arsenic exposure and ways people can protect themselves from these hazards. Agent Orange and Cancer Some US soldiers were exposed to this chemical (used to cause the leaves to fall off plants) during the years of the Vietnam War. Water Fluoridation and Cancer Risk There's still controversy surrounding the possible health effects of drinking water fluoridation. Benzene 118

What Is Benzene? Benzene is a colorless, flammable liquid with a sweet odor. It is a volatile chemical that evaporates quickly. Benzene is formed from natural processes, such as volcanoes and forest fires, as well as from human activities. Benzene is even a component of cigarette smoke. Benzene is widely used in the United States and ranks among the top 20 chemicals produced. Benzene is primarily used as a solvent, as a starting material for the synthesis of other chemicals and as a gasoline additive. It is found in a number of hazardous waste sites in the United States identified by the Environmental Protection Agency (EPA). How Are People Exposed to Benzene? People are exposed to benzene in 3 ways: at work, in the general environment, and through the use of some consumer products. The greatest risk for exposure to high doses of benzene occurs from workplace exposures, but the most common exposure to lower doses of benzene occurs in the general environment. The 2 routes of exposure to benzene are inhalation and skin absorption. However since liquid benzene evaporates quickly, skin absorption, which requires contact with a source such as gasoline, is less common. Therefore, inhalation of contaminated air is the primary route of exposure. Occupational exposures. Workers in industries that make or use benzene may be exposed to high levels of this chemical. These industries include the rubber industry, oil refineries, chemical plants, shoe manufacturers, and gasoline related industries. Environmental exposures. Sources of benzene in the environment include gasoline, automobile exhaust fumes, cigarette smoke, emissions from coke ovens and other industrial processes, and waste water from certain industries. While benzene is commonly found in air in both urban and rural areas, the levels are usually very low. Areas of heavy vehicular traffic, gasoline stations, and areas near industrial sources may have higher air levels. Cigarettes have been found to release between 50 and 150 micrograms of benzene per cigarette, so smoking and second-hand smoke are important sources of exposure to benzene. Cigarette smoke accounts for about half of the US national exposure to benzene and for about 89% of benzene exposure among smokers. Secondhand smoke accounts for 10% of benzene exposure among 119

nonsmokers. Benzene has also been identified in contaminated water and food. Consumer products, some consumer household products, such as glues, cleaning products, detergents, art supplies, and paint strippers, contain benzene. Does Benzene Cause Cancer? The evidence linking benzene and cancer predominantly comes from studies of workers, and relates to leukemia, particularly with 2 types called acute myeloid leukemia (AML) and to a lesser degree, chronic lymphocytic leukemia (CLL). Leukemia is a cancer of blood-forming cells in the bone marrow. What Do the Epidemiologic Studies Say? A considerable number of human studies provide evidence linking benzene and cancer. Initially, increased risks of leukemia, chiefly AML, were reported among workers with high levels of benzene exposure in the chemical, shoemaking, and oil refining industries. More recently, studies have focused on workers with relatively lower exposure. Two examples are highlighted here. One is a study of approximately 750 Pliofilm rubber workers at three facilities in Ohio, whose causes of death were followed over three decades. This study had several strengths: relatively little exposure to dangerous chemicals other than benzene that might act as confounders (and create a false impression about benzene), a wide range of benzene exposures, and very complete follow-up. It showed an increase in leukemia and multiple myeloma (a cancer of immune system cells in the bone marrow) among exposed workers. Another important study was conducted by the National Cancer Institute (NCI) in collaboration with the Chinese Academy of Preventive Medicine. Investigators followed almost 30,000 workers exposed to benzene in 233 factories in China, and a similar group of unexposed control workers. The large sample size permitted elevated risks to be detected at low levels of exposure. This study suggested an increased risk of leukemia in workers exposed to less than 10 ppm (parts per million). These and other epidemiologic studies of benzene show a fairly consistent excess risk to exposed workers of leukemia, and suggestions of excesses in other blood and bone marrow cancers as well. 120

What Does the Animal and Laboratory Evidence Say? The human data are supported by animal studies. There is sufficient evidence for the carcinogenicity of benzene in experimental animals. Key animal studies support the finding of an excess risk of leukemia in humans from exposure to benzene by inhalation and ingestion. The details of these studies have been reviewed and found to support the association between benzene and cancer. Benzene has been shown to induce chromosomal aberrations, or changes, in mammalian cells in vitro (outside a living organism). In vivo (within a living organism) studies have shown that benzene exposure leads to chromosome changes in bone-marrow cells. Such changes are commonly found in human leukemia cells. What Do the Expert Agencies Say? Based on animal and human evidence like the examples above, expert agencies have evaluated the carcinogenicity of benzene. The National Toxicology Program (NTP) evaluates exposures that may be carcinogenic. Exposures that are thought to be carcinogenic are included in the Reports on Carcinogens, published every 2 years. Each exposure is assigned to one of two categories: "known to be human carcinogens," and "reasonably anticipated to be human carcinogens." The first category includes substances for which human studies (epidemiology studies and/or experimental studies) provide "sufficient evidence" of carcinogenicity in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans and/or sufficient evidence of carcinogenicity in experimental animals. Using this scheme, the National Toxicology Program classifies benzene a "known carcinogen. The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 1 of 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories. Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable, because available evidence is limited or inadequate. Finally, Group 4 exposures are 121

"probably not carcinogenic to humans," based on evidence suggesting lack of carcinogenicity in humans and in experimental animals. IARC rated benzene as "known to be carcinogenic to humans" (Group 1). The Environmental Protection Agency (EPA), through its Integrated Risk Information System, uses a classification scheme very similar to that of IARC. It classifies exposures into 1 of 5 categories: (A) Known human carcinogen, (B) Probable human carcinogen, (C) Possible human carcinogen, (D) Not classifiable as to human carcinogenicity, and (E) Evidence of noncarcinogenicity for humans. EPA classifies benzene as "a known carcinogen" (Group A). Does Benzene Cause Any Other Health Problems? Short-term effects. Short-term exposure (less than one year) to high doses (700-3,000 ppm) of benzene may cause drowsiness, dizziness, headaches, tremors, confusion, and/or unconsciousness. Consuming foods or fluids contaminated with high levels of benzene can cause vomiting, irritation of the stomach, dizziness, sleepiness, convulsions, and rapid heart rate. In extreme cases, death may occur after oral ingestion or inhalation of very high concentrations (approximately 10,000-20,000 ppm) of benzene. Long-term effects. Long-term and/or high level exposure (one year or longer) to benzene may interfere with normal blood cell production by hematopoietic (blood forming) cells in the b one marrow. This may result in anemia (decreased ability of blood to transport oxygen) and low white blood cell counts (decreased ability of blood to fight infections), and can even be life-threatening. There is some evidence that benzene may also be harmful to reproductive organs. What Should I Do If Ive been exposed to Benzene? Benzene can be measured in the blood or breath. A metabolite of benzene, called phenol, can be measured in the urine and can serve as an indicator of the presence of benzene. These tests are only useful for recent exposures to benzene. Also, these tests cannot predict health effects; they can only detect levels of exposure to benzene. If you are concerned about benzene exposure, there are several ways you can limit your exposure. First, if you are exposed on the job, try to prevent exposures through process changes (such as replacing the benzene with another solvent or enclosing the benzene source) or by using personal protective equipment. Second, if you are a smoker, stop 122

smoking. Smoking greatly increases the blood level of benzene. Third, avoid gasoline fumes by pumping gasoline carefully and choosing gas stations with vapor recovery systems that capture the fumes. Finally, use common sense when around any chemicals that might contain benzene. For example, avoid unnecessary skin contact with gasoline. Conclusion Benzene is considered a human carcinogen based on experimental and epidemiological data. Steps have been taken to limit exposures to benzene both occupationally and environmentally. The EPA regulates limits concentrations of benzene in drinking water to 5 ppb (parts per billion) with an ultimate goal of 0 ppb. The National Institute of Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration have limited occupational exposures to benzene to 1 ppm (part per million) during an average workday and also recommend personal protective equipment such as respirators. Asbestos What Is Asbestos? Asbestos is a group of naturally occurring fibrous minerals. These minerals, found in soil and rocks in many parts of the world, are made of magnesium, silicon, and other elements. Some asbestos fibers are curly (or "serpentine"). The most common asbestos in industrial use, known as chrysotile, or white asbestos, has curly fibers. Other asbestos fibers are straight and needle-like (or "amphibole"). These include amosite, crocidolite, tremolite, actinolite, and anthophyllite, Asbestos fibers are resistant to heat and many chemicals. As a result, asbestos has been used as an insulating material since ancient times. Since the industrial revolution, asbestos was used to insulate factories, schools, homes, and ships, to make automobile brake and clutch parts, roofing shingles, ceiling and floor tiles, cement, and textiles, and hundreds of other products. During the first half of the 1900s, growing evidence demonstrated that asbestos is a health hazard causing scarring of the lungs. In the early 1900s, exposure to asbestos dust in the workplace was not controlled. Beginning in England in the 1930s, steps were taken to protect workers in the asbestos industry by installing ventilation and exhaust systems. However, in the huge shipbuilding effort during World War II, large numbers of workers were exposed to high levels of asbestos. As asbestos-related cancers became better recognized in the second half of 123

the twentieth century, additional measures were taken to reduce exposure, and exposure standards were established. In addition to more careful handling, there has been a dramatic decrease in the import and use of asbestos since the mid-1960s, and alternative insulating materials have been developed. As a result, asbestos exposure has dropped dramatically in the United States. However, exposure continues in some other countries. And in this country, there is still a potential for exposure from asbestos that remains in place in older buildings, water pipes, and other settings. How Are People Exposed to Asbestos? People are exposed to asbestos mainly through inhaling fibers in the air they breathe. This may occur when mining and processing asbestos, producing asbestos-containing products, or installing asbestos insulation. It may also occur when older asbestos-containing materials begin to break down. In any of these situations, asbestos fibers tend to create a dust composed of tiny particles that can float in the air. In addition, asbestos can enter the body through ingestion. This may occur when people consume contaminated food or liquids (such as water that flows through asbestos cement pipes). It may also occur when people cough up asbestos they have inhaled, and then swallow their saliva. Many people are exposed to very low levels of naturally occurring asbestos in outdoor air as a result of erosion of asbestos-bearing rocks. The potential for such exposure is higher in areas where rocks have higher asbestos content. After the collapse of the World Trade Center in 2001, there was concern about the presence of asbestos in the dust. Recommendations were made for testing and cleaning of residences in Lower Manhattan to minimize any health risks from such exposures. However, the people with the heaviest exposure were those who worked in asbestos industries, such as shipbuilding and insulating. Many of these people recall working in thick clouds of asbestos dust, day after day. Family members of asbestos workers are also potentially exposed to higher levels of asbestos because the fibers are carried home on the workers clothing, and can then be inhaled by others in the household. Removing asbestos from homes and other buildings can cause some exposure, although modern asbestos abatement workers are trained to use appropriate protective equipment to minimize exposure.

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Exposure to asbestos-containing building material is also a concern, particularly in older buildings. If building materials like insulation and ceiling and floor tiles begin to decompose over time, asbestos fibers can be found in indoor air and may pose a threat to human health (EPA). There is no risk to human health if the asbestos is bonded into intact finished products, such as walls and tiles. As long as the material is not damaged or disturbed, for example by drilling or remodeling, there is no way for the fibers to be released into the air and inhaled. Maintenance workers who sweep up and dispose of the asbestos dust or handle damaged asbestos-containing building materials are often exposed to higher levels than other occupants of these buildings. Asbestos may be detected in the water supply as well as in the air. It may be released into the water through several sources, such as erosion or natural deposits, corrosion from asbestos-cement pipes, and the break down of roofing materials containing asbestos that are then transported into sewers. Although use of asbestos has declined in many developed countries, its use continues to present a hazard in other parts of the world. More than 70% of the worlds asbestos production is used in Eastern Europe, Latin America, and Asia. Does Asbestos Cause Cancer? Lung Cancer Inhalation of asbestos fibers has been proven to cause lung cancer. The connection between asbestos exposure and lung cancer was noted as early as 1925, and confirmed by many epidemiologic studies of asbestos-exposed workers over the next 70 years. All four main types of commercially used asbestos, chrysotile, amosite, anthophyllite, and mixtures containing crocidolite, are associated with an increased risk of lung cancer. An increase in lung cancer has also been observed after exposure to minerals containing tremolite and actinolite, and to tremolitic material mixed with anthophyllite and small amounts of chrysotile (IARC-Supp 17). Approximately 1 in 7 people who suffer from asbestosis, a lung disease caused by prolonged high exposure, eventually develop lung cancer, the higher the exposure to asbestos, the higher the risk of lung cancer. Smoking acts together with asbestos to greatly increase the risk of lung cancer. Asbestos workers who smoke face a much higher risk than asbestos workers who do not smoke. Evidence suggests that asbestos125

exposed workers who quit smoking can reduce their risk of developing lung cancer by as much as 50% within 5 years of quitting (NCI). Mesothelioma Mesothelioma is a rare form of cancer that affects the thin membranes lining the abdomen and chest. Mesothelioma is closely linked with asbestos; most cases of mesothelioma result from direct occupational asbestos exposure. However, mesotheliomas have been observed not only among workers who are occupationally exposed to crocidolite, amosite, and chrysotile, but also among their family members and people living in the neighborhoods surrounding asbestos factories and mines (IARC). It is estimated that one third of the mesothelioma cases in the United States may be due to non-occupational exposure such as these (IARC). Although scientists know that the risk of developing mesothelioma increases with the amount of asbestos exposure, there is no way to measure exactly the minimum amount of asbestos exposure that can lead to mesothelioma. However, mesothelioma is very rare in the general population of the United States. Unlike lung cancer, mesothelioma risk is not increased among smokers. Other Types of Cancer There is evidence that asbestos also causes other types of cancer, although the evidence is not as strong as for lung cancer and mesothelioma. Cancer of the larynx is one such cancer, although it has been difficult to separate the contributory role of asbestos from the strong effect of smoking. Many studies have also found an increase in stomach and colon cancer among workers in the asbestos industry, although this association is still debated. What Do Epidemiologic Studies Show? As explained above, much of the evidence about asbestos-associated cancers comes from epidemiologic studies. What Do Animal Studies Show? Tests on several different species, using several different methods of exposure, have confirmed that asbestos causes cancer in animals. 126

Inhalation exposure of asbestos has been tested in rats, intrapleural administration (injection into the chest cavity) in rats and hamsters; intraperitoneal (injection into the abdominal cavity) injection in mice, rats, and hamsters; and ingestion in rats and hamsters (IARC). All commercial forms of asbestos have produced tumors in animals. The size and shape of the asbestos fibers influence the incidence of tumors; smaller fibers less than 0.5 micrometers (um) in diameter (1 micrometer, or "micron", is 1 millionth of a meter) seem more hazardous, perhaps because they are more likely to reach the deepest parts of the lungs (IARC). A series of lifetime feeding studies have been done to determine if oral exposure to asbestos increases the risk of cancer. These studies reported that short-range (98% of fibers are shorter than 10 um) asbestos fibers did not significantly increase the tumor incidence in rats; however, the incidence of benign tumors of the large intestines in male rats increased when the animals were exposed to intermediate-range (65% of fibers are longer than 10 um) asbestos fibers (EPA). What Do the Expert Agencies Say? Based on animal and human evidence like the examples above, expert agencies have evaluated the cancer causing nature of asbestos. The National Toxicology Program evaluates exposures that may be carcinogenic (cause cancer). Exposures that are thought to be carcinogenic are included in the Reports on Carcinogens, published every 2 years. Each exposure is assigned to 1 of 2 categories: "known to be human carcinogens," and "reasonably anticipated to be human carcinogens." The first category includes substances for which human studies (epidemiology studies and/or experimental studies) provide "sufficient evidence" of carcinogenicity in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans and/or sufficient evidence of carcinogenicity in experimental animals. Using this scheme, the National Toxicology Program classifies asbestos as a known human carcinogen. The International Agency for Research on Cancer (IARC also evaluates exposures that may be carcinogenic. IARC classifies exposures into one of four categories:

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Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into two categories. Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable, because available evidence is limited or inadequate. Group 4 exposures are "probably not carcinogenic to humans," based on evidence suggesting lack of carcinogenicity in humans and in experimental animals.

IARC rated asbestos a known human carcinogen (Group 1). The Environmental Protection Agency, through its Integrated Risk Information System, uses a classification scheme very similar to that of IARC. It classifies exposures into 1 of 5 categories: (A) Human carcinogen (B) Probable human carcinogen (C) Possible human carcinogen (D) Not classifiable as to human carcinogenicity (E) Evidence of noncarcinogenicity for humans

EPA classified asbestos as a human carcinogen.

Does Asbestos Cause Any Other Health Problems? The major health problem caused by asbestos exposure, aside from cancer, is asbestosis. This is a scarring (or "fibrotic") disease of the lungs that develops when a person breathes high levels of asbestos over time. The principal symptoms of asbestosis are shortness of breath and cough. Asbestosis is a serious disease that can result in disability or death. It is most commonly found among asbestos workers. Asbestos can also result in scar-like tissue in the membranes around the lung, called pleural thickening, skin lesions like warts, and immunological effects. 128

What Should I do if Ive been exposed to Asbestos? If you have been exposed to asbestos, it is important to assess the amount of your exposure. If you were exposed only very briefly, or only at very low levels, your risk of a resulting disease is minimal. However, it you were exposed at high levels, you may be at increased risk of the diseases discussed above. You can protect your health in several ways: If you are a smoker, it is essential that you stop smoking. Get regular health checkups from a doctor experienced with asbestos-related diseases. People with heavy asbestos exposure often have periodic chest x-rays and lung function tests. It may be advisable for you to receive vaccines against flu and pneumonia. Discuss this with your physician. Get prompt medical attention for any respiratory illness.

How Can I Avoid Exposure to Asbestos? You should also avoid any future exposure to asbestos. If there is a possibility of on-the-job exposure, like renovating old buildings for example, then you should use all protective equipment, work practices, and safety procedures designed for working around asbestos (NCI). If you live in an older home, there may be asbestos-containing insulation or other materials. A knowledgeable expert can check your home to determine if there is any asbestos and if it poses any risk of exposure. This may involve testing the air for asbestos levels. You may then decide to have the asbestos removed from your home. You should hire a qualified contractor to perform this job to avoid contaminating your home further or causing any exposure to the workers. You should not attempt do remove asbestos-containing material yourself. What's the Bottom Line? Asbestos is well recognized as a carcinogen. It causes lung cancer, mesothelioma, and other cancers. The people at highest risk are those with very heavy exposure, usually over many years on the job. Smoking acts together with asbestos to greatly increase the risk of lung cancer. While asbestos use is much less common now than it was years ago, there is still a potential for exposure in older buildings and products. MTBE

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MTBE (methyl tertiary-butyl ether) is part of a group of chemicals known as fuel oxygenates. Oxygenates do not occur naturally in gasoline; they are added to increase gasolines oxygen content,to increase the octane rating, and help prevent engine knocking. MTBE and other oxygenates make gasoline burn better and decrease harmful carbon monoxide and other emissions from vehicles. The Clean Air Act The Clean Air Act Amendments of 1990 required oxygenates in fuel under certain circumstances, to help reduce carbon monoxide (CO) emissions. Accordingly, the United States Environmental Protection Agency (EPA) began the Oxygenated Fuel (Oxyfuel) Program in 1992. The Oxyfuel Program requires that gasoline have 2.7% oxygen by weight during fall and winter months. To meet this oxygen requirement, gasoline producers began adding oxygen-containing compounds, called oxygenates, to gasoline. When gasoline companies use MTBE to meet requirements, they must add MTBE to a final concentration of 15% by volume. Thus every liter of "gasoline" under the Oxyfuel program actually contains 150mL MTBE. In 1995, the EPA began the Reformulated Gasoline (RFG) Program to try to comply with the Clean Air Act. The RFG Program requires that gasoline have 2% oxygen by weight year-round in the most polluted metropolitan areas to help reduce smog and ozone. To meet RFG requirements, the MTBE concentration in gasoline must be 11% by weight. Thus, every liter of gasoline under the RFG program must have 110 mL of MTBE.

What's Happening Now? Since 1999, many areas have begun to phase out MTBE because of groundwater contamination. Then the Energy Policy Act of 2005 reduced the federal requirement for oxygen content in reformulated gasoline. Since that time state laws have been passed to ban MTBE in certain areas. California and New York, which together accounted for 40% of MTBE consumption in the US, banned the chemical starting January 1, 2004. As of September, 2005, twenty-five states had signed legislation banning MTBE. Today MTBE is commonly replaced with ethanol.

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Also in 2005, a number of petroleum companies announced their intent to remove MTBE from their gasoline in 2006. This decision to eliminate MTBE was driven by many things, including: state bans due to water contamination concerns continuing liability exposure from adding MTBE to gasoline perceived potential for increased liability exposure due to the elimination of the oxygen content requirement for reformulated gasoline included in the Energy Policy Act of 2005 tax subsidies for using ethanol

Problems with MTBE MTBE is much more soluble in water than are most other components of gasoline. It is also more resistant to biodegradation. As a result, it is more likely to contaminate public and private water wells and is harder to clean up once contamination occurs. This is a major problem with MTBE use. In September 1999, the EPA's Report of the Blue Ribbon Panel on Oxygenates in Gasoline stated that between 5% and 10% of community drinking water supplies located in areas that use a lot of MTBE contained detectable levels of MTBE. A report in March 2000 stated that more than 9,000 community water wells near leaking underground storage tanks in 31 states were contaminated with MTBE. This led to a great deal of public concern and media attention. In late March 2000, EPA administrator Carol Browner pledged to ban the use MTBE as a fuel additive. An EPA regulation now requires statistical sampling of small and medium public water systems to monitor and report the presence of MTBE in their water supplies. However, the maximum contaminant level of MTBE in drinking water has not yet been established by the EPA. How Are People Exposed to MTBE? According to the National Institute for Environment Health Sciences, exposure to MTBE from gasoline can occur in the following situations: Pumping gasoline into motor vehicles; Filling gasoline-powered home maintenance equipment such as lawn mowers; Living near bulk gasoline loading and unloading facilities; and Living near facilities that leak gasoline from the underground storage containers. 131

In most of these situations, the most important form of exposure is the inhalation of MTBE-contaminated air. However, it is also absorbed through the contact with the skin. And groundwater contamination can result in exposure from the tap water. The biggest cause of MTBE in ground and surface water is through leaking underground storage tanks and pipelines. Spills and emissions from marine engines into lakes and reservoirs also release MTBE into the environment. MTBE does not build-up in the body, but is broken down and exhaled or excreted. Does MTBE Cause Cancer? Though MTBE has been used as a fuel additive since 1979, there have been no long-term studies looking at the carcinogenicity of MTBE in workers or other people exposed to high concentrations. MTBE has been shown to cause lymphomas and leukemias in laboratory animals, as well as cancers of the kidney, liver, testicles, and uterus. In one study, rats and mice were exposed to various concentrations of MTBE vapors. After chronic inhalation of MTBE, female rats were found to have an excess number of liver tumors (hepatocellular adenomas) at the highest MTBE concentration (8,000 parts per million). Neither male rats nor mice of either sex were found to have any excess cancers at any concentration of MTBE. Another study examined the effect of long-term oral administration of various concentrations of MTBE.After chronic MTBE ingestion, male rats were found to develop Leydig interstitial cell tumors of the testes (a type of testicular cancer). A dose-response relationship was seen in female rats, whose risk for lymphomas and leukemias increased with increasing concentrations of MTBE. A second study of orally administered MTBE by the same researchers confirmed the results of the first. Male rats developed testicular cancer, and female rats developed leukemias and lymphomas depending on the dosages. Female rats were also found to develop uterine cancer at lower doses, a new finding that had not been observed in the first study. Finally, a 1997 study found that chronic inhalation of high levels of MTBE caused renal tubular cell neoplasms (a type of kidney cancer) in male rats and hepatocellular adenomas (liver cancer) in female mice. The same study found an increased risk of testicular cancer in male rats 132

and lymphomas and leukemias (combined) in female rats after chronic ingestion of MTBE. The authors of this study note that the development of these cancers requires chronic exposure to toxic doses of MTBE. They stated, "because of the intense odor and taste of MTBE, humans will not tolerate either air or water concentrations sufficient to produce [similar effects]." Relatively few laboratory studies have addressed the potential carcinogenicity of MTBE. One study funded by Exxon examined MTBE carcinogenicity using a variety of laboratory techniques, including a Drosophila test, tests on both mouse and rat bone marrow cells, and tests of liver cell DNA. Each of the tests produced a negative result. The researchers concluded that the "potential for in vivo mutagenic activity [of MTBE] was low." What Do the Expert Agencies Say? Based on animal and human evidence, expert agencies have evaluated the carcinogenicity of MTBE. The National Toxicology Program evaluates exposures that may be carcinogenic. Exposures that are thought to be carcinogenic are included in the Reports on Carcinogens, published every 2 years. In 1998 the National Toxicology Program Board of Scientific Counselors voted not to include MTBE on the list of compounds known to be human carcinogens and at this time it is still not included on their list. The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. In 1999 they concluded that there is inadequate human evidence, and limited animal evidence, for the carcinogenicity of MTBE, leading to overall classification of MTBE as "not classifiable as to its carcinogenicity to humans." In 2003, the IARC removed MTBE from its list of potential carcinogenic agents that should be re-evaluated in the future. The Environmental Protection Agency, through its Integrated Risk Information System, uses a classification scheme very similar to that of the IARC. It classifies exposures into one of five categories: (A) Human carcinogen, (B) Probable human carcinogen, (C) Possible human carcinogen, (D) Not classifiable as to human carcinogenicity, and (E) Evidence of non-carcinogenicity for humans. EPA classified MTBE as a possible human carcinogen (Group C).

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The National Toxicology Program Board of Scientific Counselors Report on Carcinogens Subcommittee (the External Peer Review Group) has voted not to include MTBE in the list of compounds known to be a human carcinogen. In general, there is no consensus within the scientific community as to the appropriate carcinogenicity classification for MTBE. But interest in MTBE remains and research continues. Does MTBE Cause Any Other Health Problems? There have been complaints of nausea; dizziness; lightheadedness; headaches; and eye, nose, and throat irritation in several areas where MTBE use is high. At this time, however, the evidence linking these symptoms to MTBE exposure is inconclusive. The health effects of short-term exposures to large amounts of MTBE in humans are not known. Animal studies have shown adverse effects on the nervous system ranging from hyperactivity and incoordination to convulsions and unconsciousness. Human health effects of long-term exposures to smaller amounts of MTBE have not been identified. Animal studies have shown kidney damage and adverse effects on fetal development, in addition to excess cancers as discussed above. As for the animal studies, the NIEHS notes that the levels of MTBE used for animal studies are many times higher than the levels seen for typical human exposures.

How Do I Know If I've been exposed to MTBE? There are many ways you can find out if your water contains MTBE. If you get your drinking water from a public water system, you can contact the system directly and ask whether they monitor for MTBE and what levels, if any, have been detected. If you have a private well, your local health department may be able to tell you if MTBE has been found in water in your area. What's the Bottom Line? Although there has been much concern about the adverse health effects related to MTBE exposure, there is still a great deal of uncertainty, about the acute effects and about MTBE's potential to cause cancer. The 134

EPA is sponsoring ongoing research to better define the effects of MTBE on human health. Meanwhile, the use of MTBE is being phased out because of its tendency to pollute water. What Is Tetrachlorethylene? Tetrachlorethylene, also known as perchlorethylene, perchloroethylene, or "perc," is a commonly used chlorinated solvent (a solvent is a substance, usually a liquid, capable of dissolving another substance). Tetrachlorethylene has been produced commercially since the early 1900s primarily for dry cleaning and textile processing. It has also been used for rubber coatings, solvent soaps, printing inks, adhesives, glues, sealants, polishes, lubricants, and silicones. Tetrachloroethylene has also been used in producing chlorofluorocarbons (refrigerants) and for degreasing metals. How Are People Exposed to Tetrachlorethylene? The highest exposures to tetrachloroethylene occur among dry cleaning and degreasing workers, who inhale it and absorb it through their skin. Oil and wax are used to shape and polish metal during the manufacturing process. Removing oil, wax, and related substances from the finished products is known as degreasing. Other workers may also be exposed to lower levels in similar ways. The permissible air concentration allowed by OSHA as an average over an 8-hour workday is 25 parts per million (ppm). People who live near dry cleaning or metal degreasing operations, consumers using coin-operated laundries where dry cleaning machines are present, and residents in buildings where dry cleaning shops are located can breathe in smaller amounts from time to time. People who live in communities that have drinking water contaminated by tetrachlorethylene can drink it, or inhale it while bathing or showering. Does Tetrachlorethylene Cause Cancer? Tetrachlorethylene has been suspected of causing several cancers, based on both human and animal evidence. The studies in humans were conducted in people exposed at work and in communities with contaminated drinking water. What Does the Epidemiologic Evidence Suggest? Two studies of dry cleaning workers with exposure to tetrachloroethylene were conducted. In each study, a subgroup of 135

workers could be identified which had been exposed only or predominantly to tetrachloroethylene, while other workers were exposed to more than one solvent. Both studies found approximately 2-fold excesses of esophageal cancer and cervical cancer in the total population, with similar risks in the smaller subgroups exposed solely or predominantly to tetrachloroethylene. Both studies also found significant excesses of lung cancer, although in one of the studies the risk was lower among workers exposed only to perchloroethylene. One of the studies also reported non-significant excesses of laryngeal cancer and Hodgkin disease. The contribution of cigarette smoking, alcohol consumption or socioeconomic factors to the observed excesses could not be evaluated. Three studies of workers exposed to tetrachloroethylene in other industries reported non-significant excesses of non-Hodgkin lymphoma. Other studies have examined the relationship between tetrachloroethylene in drinking water and cancer. Most of these studies have not found an increased risk of cancer associated with tetrachloroethylene-contaminated drinking water. Case-control studies of colorectal, lung, brain, pancreatic and breast cancer have been conducted in areas of Massachusetts where some drinking water supplies were heavily contaminated with tetrachloroethylene. Typical levels of tetrachloroethylene in some of these areas were as high as 1,600-7,500 ug/L, 320-1,500 times the current EPA standard for drinking water of 5 ug /L. The case-control studies found some evidence of increased lung, breast and colorectal cancer among residents with the highest exposure to tetrachloroethylene, estimated from information about their water supply. Overall, the findings of studies of cancer risks associated with exposure to tetrachloroethylene provide limited evidence for carcinogenicity in humans. In summarizing the evidence in 1995, the International Agency for Research on Cancer concluded that while there was evidence for consistently positive associations between tetrachloroethylene and risks for esophageal and cervical cancer and non-Hodgkin lymphoma, the possibility that these excesses were caused by other chemical exposures or behavioral risk factors could not be ruled out. What Does the Laboratory and Animal Evidence Suggest? Tetrachlorethylene is carcinogenic in animals, causing liver cancer in mice and mononuclear-cell leukemia in rats. What Do the Expert Agencies Say? 136

Based on animal and human evidence like the examples above, expert agencies have evaluated the carcinogenicity of tetrachloroethylene. The National Toxicology Program (NTP) evaluates exposures that may be carcinogenic. Exposures that are thought to be carcinogenic are included in the Reports on Carcinogens, published every 2 years. Each exposure is assigned a category: known to be human carcinogens, or reasonably anticipated to be human carcinogens. The first category includes substances for which human studies (epidemiology studies and/or experimental studies) provide sufficient evidence of carcinogenicity in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans and/or sufficient evidence of carcinogenicity in experimental animals. The National Toxicology Program classifies tetrachloroethylene as reasonably anticipated to be a human carcinogen, based on sufficient evidence for carcinogenicity in experimental animals. The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 1 of 4 categories: Group 1 exposures are those known to be carcinogenic to humans, usually based on sufficient human evidence, but sometimes based on sufficient evidence in experimental animals and strong human evidence. Group 2 exposures are divided into two categories. Group 2A (probably carcinogenic to humans) has stronger evidence, and Group 2B (possibly carcinogenic to humans) has weaker evidence. Group 3 exposures are not considered classifiable, because available evidence in limited or inadequate. Group 4 exposures are probably not carcinogenic to humans based on evidence suggesting lack of carcinogenicity in humans and in experimental animals.

Based on limited evidence in human studies and sufficient evidence in animal studies, IARC rated tetrachlorethylene as probably carcinogenic to humans (Group 2A).

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The Environmental Protection Agency (EPA) through its Integrated Risk Information System uses a classification scheme very similar to that of IARC. It classifies exposures into 1 of 5 categories: (A) Human carcinogen (B) Probable human carcinogen (C) Possible human carcinogen (D) Not classifiable as to human carcinogenicity (E) Evidence of noncarcinogenicity for humans

EPA considers the risk of tetrachlorethylene to be on a continuum between probable and possible (categories B and C). Does Tetrachlorethylene Cause Any Other Health Problems? Exposure to tetrachlorethylene may irritate the eyes, skin, nose, throat, and/or respiratory system. Other effects may include nausea, facial flushing, dermatitis (skin inflammation), heart arrhythmias (irregular heartbeat), and kidney and liver damage. As a nervous system toxin, tetrachlorethylene may cause headache, dizziness, visual disturbances, incoordination, drowsiness, numbness and tingling, fainting spells hallucinations, and even coma and death at very high doses. What Should I Do If I've been exposed to Tetrachlorethylene? If you work in a workplace with potential exposure to tetrachlorethylene, there are several ways to reduce or prevent exposure. Engineering changes, such as substituting safer materials for more hazardous materials, enclosing a process that may expose workers to hazards, or ventilating a work area, are important. Good work practices, such as changing clothes after work, washing work clothes regularly, and keeping food out of the work area, are also essential. Finally, personal protective equipment such as gloves and respirators may be an important part of a workplace protective program. The Occupational Safety and Health Administration (OSHA) has established a permissible exposure limit (PEL) of 25 ppm as an 8-hour time weighted average (TWA) with no short-term exposure limit (STEL) or ceiling permitted. You should work with your employer to make sure sufficient protection is in place. For more information on preventing or reducing occupational exposures for your current occupation, consult your companys safety and health manager. Additional information is available from the National Institute for Occupational Safety and Health. 138

Workplace and environmental exposure to perchloroethylene used in dry cleaning shops can be reduced by use of newer dry cleaning machines that control or eliminate the escape of perchloroethylene through the dry cleaning process. New methods of fabric cleaning which use water as a solvent in specialized machines are available in some areas. If you wear clothing that has been drycleaned, you may be exposed to levels of tetrachloroethylene that are slightly higher than what is normally found in the outdoor air; however, these amounts are not expected to be hazardous to the average persons health. Professional dry cleaners remove perchloroethylene from drycleaned clothes as part of the overall cleaning process. You cannot tell by odor alone if all of the tetrachloroethylene has been removed from your clothes. If you think all of the solvent was not removed, or if your newly drycleaned clothes smell like solvent, you should ask your cleaner to re-process your order or take them to another cleaner for re-cleaning. What's the Bottom Line? There is consistent evidence that tetrachlorethylene can cause cancer in animals. The human evidence is suggestive but limited, Because of the possibility that it is carcinogenic, and because it has other adverse health effects, you should limit your exposure to tetrachlorethylene as much as possible. Lead What Is Lead? Lead is a naturally occurring bluish-gray metal found in small amounts in the earths crust. Lead can also be found in plants, animals, air, water, dust, and soil. As an element, lead is indestructible. But lead compounds can be changed by air, sunlight, and water. Once lead is released into the air, it lasts, and can move from one medium to another. For example, lead in dust can be carried long distances, dissolved in water, and find its way into soil where it can remain for years. Like many metals, lead exists in different chemical forms. Metallic lead is the pure metal. Inorganic lead compounds, such as lead oxide and lead acetate are combinations of lead with other elements.

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Organic lead compounds, such as tetraethyl lead, those where lead is combined with carbon, are especially toxic.

Lead has many useful properties. It is soft and easily shaped, durable, resistant to some chemicals, and fairly common. Humans have used lead since early history. Lead is in batteries, paints, ceramics, and soldering and building materials. Until recently, lead was added to automobile gasoline. It has even been used in medicines and cosmetics. Because of its many uses, lead is now a common contaminant in waste sites. It is found in over half of the nations Superfund sites. Superfund is the federal government's program to evaluate and clean up uncontrolled or abandoned sites where hazardous waste is located and may pose a risk to local ecosystems or people. For more information about the Superfund program, visit their Web site: http://www.epa.gov/superfund/index.htm. How Are People Exposed to Lead? People are exposed to lead by swallowing or breathing it. In the past, when lead was added to gasoline, this was the major source of exposure. Automobile exhaust contained lead and people breathed it in contaminated air. Lead from automobile exhaust also contaminated soil near busy roadways and this soil continues to contaminate many yards. Since lead has been taken out of gasoline, the major source of exposure is old paint that contains lead. This can be found in older homes and on structures such as bridges. Although the amount of lead used in paint has been regulated since 1978, it is estimated that 38 million homes in the US still have lead paint. That's about 40% of all US housing. During renovation of an older home, (built before 1978) swallowing or breathing lead paint dust can increase your bodys lead content. Some children pick off the lead paint chips to chew on and swallow. More often, particles from worn painted surfaces mix with soil and household dust, and children unintentionally swallow lead from their contaminated toys or hands. Tap water that runs through old lead pipes and soldered joints in older homes can also be contaminated with lead. So can the water that runs through the water service lines that contain lead in many older US cities. The EPA estimates that 10% to 20% of human lead exposure comes from drinking water. Other sources of lead exposure include cosmetics (especially the Asian cosmetics surma and kohl), ceramics (especially imported hand-painted 140

ceramics which can contaminate food and drinks stored in and eaten from them), and bullets (which may expose people who prepare their own shot and/or who practice shooting in indoor firing ranges). Workers who make or recycle lead batteries, who process other metals that may be contaminated by lead, who weld or solder, and who repair automobile radiators may be exposed to lead. Occupations with Exposure to Lead Metal Workers Lead Burners Metal Grinders Pipe Cutters Scrap Metal Workers Glassmakers Solderers/Welders Battery Makers Bridge Deleaders Cable Makers/Splicers Ceramics Workers Brass and Bronze Workers Demolition Workers Firing Range Personnel Foundry Workers Gas Station Workers Glass Blowers/Stained Gun Makers Jewelers Painters/Pigment Makers Plumbers Radiator Repair Workers Smelters

Does Lead Cause Cancer? There is some evidence showing that lead may cause cancer, but this evidence is weak. Still, lead has been loosely linked with cancers of the lung and stomach, and more weakly linked to brain and kidney cancers. What Do Scientific Studies Show? Like most metals, it is difficult to evaluate lead's ability to cause cancer because it is found in so many forms. Most of the evidence linking lead exposure and cancer comes from studies of workers with high levels of occupational (work-related) exposure to inorganic lead. People who have worked in heavily lead-exposed industries have been found to have blood lead concentrations of 40 to 100 micrograms per deciliter (mcg/dL). In comparison, in 1991, the average blood lead concentration in US males in the general population was 4 mcg/dL (10 mcg/dL is considered a low lead level). In 2000, Steenland and Boffetta summarized results from 8 studies of workers exposed to lead, using standard methods to compute combined relative risk estimates for the cancer sites of concern. The results of their study are reviewed here. 141

Lung cancer All 8 studies of highly exposed workers reported results for lung cancer, with 2 showing an increased risk of lung cancer (at least 50% higher than people not exposed). In all studies combined, the risk was about 30% higher than in people not exposed. But, the results depended heavily on one study where a very high (3-fold) excess risk of lung cancer was found. Workers in the highest risk study may have been exposed to arsenic as well as lead in the early years of plant operation. Because arsenic is known to cause lung cancer, it is not clear whether the increase in lung cancer was due to lead, arsenic, or the combination of the two. More studies are being done to find out if lead or arsenic is responsible for the increase. Without the one highest risk study, all studies combined estimate the risk of workers exposed to lead at about 14% higher than unexposed persons. And, these studies could not determine whether this increase was because of lead exposure or if it happened because the lead-exposed workers tended to smoke more than the comparison groups. Stomach Cancer The combined analysis of 8 groups of lead-exposed workers showed a 34% increase in their risk of developing stomach cancer. A case-control study in one of the groups found that workers with the highest exposure levels were no more likely to develop stomach cancer than were workers with lower exposure levels. But many case-control studies in the general population found higher rates of stomach cancer among people who worked in jobs likely to have exposed them to high levels of lead. The evidence from studies does not agree, and stomach cancer among people exposed to lead is still a concern. Brain Cancer A case-control study of lead-exposed workers in Finland compared 26 patients who had brain cancer to 200 control subjects who did not, and found that the brain cancer patients had higher blood lead levels. In a death-certificate based study in the United States, researchers looked at the occupations of more than 27,000 people who died of brain cancer and more than 108,000 who died of other causes. The brain cancer cases were about twice as likely to have worked in an occupation that 142

exposed them to lead. When combined data from all 7 studies of brain cancer among lead-exposed workers was reanalyzed, it did not show evidence of increased risk. But this finding was limited by the small number of brain cancer cases available to study. More recently, a 2006 study found that brain cancer risk was highest among people with the highest likelihood and intensity of lead exposure, which gives further support to the link between lead exposure and brain cancer. And so, research continues and the link between lead exposure and brain cancer is still a concern. Kidney Cancer In animal studies, kidney cancer is the most common cancer linked to lead exposure. Still, the combined results from all 7 studies of leadexposed workers showed no evidence of an increased risk. Two of the studies did show about a 2-fold excess of kidney cancer, so kidney cancer remains a concern. Colon and Rectal Cancer A 1991 study found that workers in tetraethyl lead manufacturing industries were nearly 4 times as likely as unexposed people to develop rectal cancer, and workers with higher estimated exposure had higher risk. Less tetraethyl lead is produced today because it is no longer used as a gasoline additive. What Do Animal Studies Show? Lead by itself does not cause DNA mutations (changes) in animal cells. But studies suggest that lead exposure can interfere with repair of DNA damage caused by other chemicals. Lead acetate and lead phosphate, two inorganic lead compounds, cause kidney tumors in mice and rats. Most human exposures are to lead oxide and lead fumes, which have not been evaluated for carcinogenicity (the ability to cause cancer) in animals. What Do the Expert Agencies Say? National Toxicology Program The National Toxicology Program evaluates exposures that may be carcinogenic. Those that are thought to be carcinogenic are included in the Reports on Carcinogens, which is published every 2 years. Each exposure is assigned to a category: "known to be human carcinogens" 143

or "reasonably anticipated to be human carcinogens." The first category includes substances for which human studies show "sufficient evidence" of carcinogenicity in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans and/or sufficient evidence of carcinogenicity in experimental animals. Using this system, the National Toxicology Program classifies lead acetate and lead phosphate as "reasonably anticipated to be human carcinogens." International Agency for Research on Cancer The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories. Group 2A (probably carcinogenic to humans) has stronger evidence, and Group 2B (possibly carcinogenic to humans) has weaker evidence. Group 3 exposures are not considered classifiable, because available evidence in limited or there is not enough evidence. Group 4 exposures are "probably not carcinogenic to humans," based on evidence suggesting lack of carcinogenicity in humans and in experimental animals.

In 2006 the IARC rated lead and inorganic lead compounds as probably carcinogenic to humans (Group 2A). Environmental Protection Agency The Environmental Protection Agency (EPA), through its Integrated Risk Information System, uses a classification scheme very much like that of IARC. It classifies exposures in 5 categories: (A) Human carcinogen (B) Probable human carcinogen (C) Possible human carcinogen (D) Not classifiable as to human carcinogenicity (E) Evidence of non-carcinogenicity for humans The EPA has classified lead and lead compounds (inorganic) as probable human carcinogens. 144

Does Lead Cause Any Other Health Problems? Lead is a well-known toxin. Severe lead poisoning can cause death. One of lead's primary targets is the nervous system. It lowers intelligence, stunts growth, impairs hearing, and causes behavioral difficulties and learning disabilities in children. It also causes problems with mood and thinking in adults. Adults whose work exposes them to lead have been shown to develop nervous system problems even at relatively low blood lead levels. Lead harms the peripheral nerves causing weakness and sensory disturbances. Wrist weakness was a common symptom found among persons with severe lead poisoning in the early 20th century. Other forms of lead toxicity include: kidney damage, which can lead to high blood pressure and stroke bone marrow damage, which can cause anemia reproductive problems, such as miscarriage and stillbirth among exposed women low sperm counts and hormone disturbances in highly exposed men gastrointestinal symptoms such as nausea, constipation, and abdominal pain bone and joint pain

In fact, these other symptoms of lead toxicity are usually of greater concern than its ability to cause cancer, and are the reason to regulate exposure to lead. After lead enters the body, it travels in the blood reaching the soft tissues and bone. About 75% to 90% of lead in the body is found in the bones and teeth. Studies have shown that it can stay in the bones for decades. Then, when bone conditions such as osteoporosis cause loss of minerals from bones, lead can reenter the bloodstream and affect the nervous system and other organs, causing delayed side effects. Blood lead levels can show recent exposure to lead or lead released from bone. Bone lead levels show exposure over a lifetime. The amount of lead in bone can be measured using a method called x-ray fluorescence. What Should I Do If Ive been exposed to lead? Talk to a Doctor

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If you think you have been exposed to lead, it is important to look at the amount of your exposure. You can do this by having a doctor do a blood test. There are also other ways to measure long-term lead exposure, including chelation challenge testing and x-ray fluorescence. Ask your doctor about these tests. If a high level of lead is found in your blood there is a medical treatment, called chelation, (using a substance to bind with a metal so that it loses its toxic effect and/or is excreted). Although there is no convincing evidence that chelation helps with low-level lead exposure, many doctors recommend it. If you were only exposed for a short time, or only at very low levels, your blood lead level will most likely stay low, and you are not at risk of lead-related disease. But, if you were exposed at higher levels, you may have a higher risk of the health problems discussed above. Children are especially at risk for leads effects on the nervous system. If your blood lead level is increased, you should avoid any further exposure to lead. For example, a child who is exposed to lead from paint in an older home should not stay in the home until the lead is removed. Protect Yourself and Your Family Take the following steps to protect your health and the health of those around you: Avoid lead exposure at home by using lead-free paint, ceramics, and other products. Have leaded paint removed from your home by a qualified contractor. In older homes, built before about 1980, you should find out if the paint has lead in it. Wipe dust from floors, windowsills, and other surfaces with water and detergent. Cloths and sponges that have been used to clean lead dust shouldnt be used to wash dishes or wipe down food preparation areas. Move cribs and playpens away from areas where paint is chipped or peeling. Children should wash their hands often, especially before eating. Pacifiers and toys that children put in their mouths should be washed every day. If you live in a building with old pipes or an old hot water heater, use cold tap water for cooking and drinking. Run it for at least 30 seconds or until its as cold as it can get. 146

Any product labeled as containing lead should be kept out of the reach of children. Hands should be washed right after handling such products to avoid accidental ingestion. Nutrition plays a role in lead absorption, so make sure you and your children eat balanced diets with recommended amounts of iron, calcium, zinc, and vitamin C. The amount of lead absorbed also increases when your diet is high in fat or your stomach is empty.

Protect Yourself at Work If there is a possibility that you will be exposed to lead on your job, your employer should follow the requirements of the OSHA Lead Standard, which is intended to protect workers from the harmful effects of lead exposure. Precautions to minimize exposure to lead include using careful personal hygiene such as hand-washing, showering and changing clothes before leaving work, and not smoking or eating near work. Your employer is required to make facilities available to do this. The employer is also required to maintain air levels of lead below 50 g/m3 averaged over an 8 hour period, and to provide respirators if air levels are higher than this. The OSHA standard also requires free, full medical monitoring which includes blood lead levels if employees are exposed to lead levels above 30 g/m3 for more than 30 days per year. Arsenic Arsenic is known to cause cancer, as well as many other serious health problems. This document reviews the hazards of arsenic exposure and ways people can protect themselves from these hazards. What Is Arsenic? Arsenic is a naturally occurring element in the environment. It has no taste or smell. Although sometimes found in its pure form as a metal, arsenic is usually a part of chemical compounds. These compounds are usually divided into 2 general categories: inorganic compounds (combined with oxygen, iron, chlorine, and sulfur) organic compounds (combined with carbon and other atoms)

Arsenic-contaminated inorganic compounds are found in industry, in building products (arsenic-treated wood), and in arsenic-contaminated 147

water. This is the form of arsenic that tends to be more toxic and has been linked to cancer. Organic arsenic compounds in fish and shellfish may account for significant dietary intake of arsenic. These compounds are much less toxic than the inorganic arsenic compounds. Organic forms of arsenic have not been linked to cancer. Lead and copper ores are also commonly contaminated with small amounts of arsenic. How is Arsenic Used? Although arsenic is known to be a poison, arsenic compounds have many uses, such as: in wood preservatives (currently the major use) in insecticides and herbicides (although its use in U.S. agriculture ended in 1993) as a preservative in animal hides as an additive to lead and copper for hardening in glass manufacturing to take away the natural green color in some medicines (mostly for veterinary use) as arsine gas to enhance electrical junctions in semiconductors

In the 1800s and early 1900s, inorganic arsenic was commonly used as rat poison and in treating some human diseases, such as syphilis. A widely used arsenic compound, Fowlers solution (potassium arsenite), was prescribed for chronic infections, anemia, and skin diseases. Pentavalent arsenic is still used to treat advanced trypanosomiasis (a disease caused by parasites, which is rare in the United States but more common in Africa), and arsenic trioxide is being used today as a treatment for promyelocytic leukemia. How Are People Exposed to Arsenic? People may be exposed to arsenic in many ways. Very high doses have been used in murder or suicide attempts (see table below). Some jobs may lead to high exposures over long periods of time when workers breathe in or swallow dust that contains arsenic compounds. But such exposures are now rare in the United States. People who live near current or former industrial or agricultural sources of arsenic may have fairly high exposures from inhaling fumes or eating contaminated food. People who live in areas where arsenic is naturally high in drinking 148

water may take in high levels of arsenic over the course of a lifetime. Finally, low chronic exposures may occur through diet, especially among people who eat a lot of seafood. Exposure at Work Arsenic has not been produced in the United States since 1985. In the past, workers in smelters and in plants that made packaged or distributed pesticides that contained arsenic had high exposures from breathing in arsenic fumes and dust. Today workplace exposure to arsenic may still occur in the wood preservative industry. Workers in semiconductor manufacturing may be exposed to arsine gas. Regulations are in place to limit workplace exposure. Exposure in the Community Community exposure to arsenic may occur near previous or current industrial sources. Facilities such as wood preservative and glass factories may contaminate nearby air and soil. Communities near former smelters, or near fields or orchards where arsenic pesticides were used, may also have contaminated soil. Drinking Water Drinking water is an important and potentially controllable source of arsenic exposure. In fact, drinking water accounts for most human arsenic exposures worldwide. In parts of Taiwan and Japan, in the Ganges River delta (especially in Bangladesh), and in parts of western South America (in northern Chile, southwestern Bolivia, southern Peru, and Argentina), arsenic occurs naturally in drinking water at levels from several hundred to several thousand parts per billion (ppb). Playground Equipment Chromated copper arsenate (CCA) is a chemical preservative that protects wood from rotting. It has been used to pressure treat lumber used for decks, playgrounds (playsets), and other outdoor uses since the 1930s. In fact, starting in the 1970s, the majority of the wood used in residential settings was CCA-treated wood. In 2003 the EPA and CCA makers agreed to end the manufacture of CCA-treated wood for most consumer applications. However, this wood can still be found on playgrounds and there is no way to look at it and know whether or not it

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is CCA treated. If you are not sure if a playset is composed of CCAtreated wood, you should assume that it is. An individual childs risk from arsenic in CCA-treated playground equipment will vary depending on many factors, including the amount of arsenic released from the CCA-treated wood, the amount of arsenic picked up on the hands, the number of days and years the child plays on the wood, and the amount of arsenic transferred to the mouth by hand-to-mouth activity. Hand-to-mouth behavior is the primary source of exposure to arsenic from CCA-treated playground equipment. To reduce this, parents and caregivers should thoroughly wash childrens hands with soap and water immediately after playing on all pressuretreated wood playground equipment. It has also been suggested that children not eat while on wooden playground equipment. Calling the playset manufacturer might help you find out if the playset contains CCA-treated wood. If you decide to remove your CCA-treated wood playset, the EPA states that CCA-treated wood should never be burned in open fires, stoves, fireplaces, or residential boilers. Other Possible Sources of Arsenic Other potential exposures to arsenic are generally at lower levels and for shorter periods of time than those from past occupational exposures or from highly contaminated drinking water. Because arsenic is commonly used in wood preservatives, people can be exposed by breathing sawdust from cutting arsenic-preserved wood or breathing the smoke from burning this wood. Hazardous waste sites can be another source of arsenic exposure. Burning cigarette tobacco and fossil fuels (such as coal) also releases arsenic into the air. Arsenic in Food Finally, a low level of arsenic exposure is common in the diet. In fact, most meat and vegetables contain low levels of arsenic. The average U.S. diet contains about 50mg (micrograms) of arsenic (mostly organic) per day. Diets high in seafood can contain several times that amount of mostly the less dangerous organic forms of arsenic. Does Arsenic Cause Cancer? The study of the carcinogenicity (cancer-causing potential) of arsenic is unusual because most evidence comes from human studies. The first evidence linking arsenic with cancer came from case reports of skin 150

cancer after exposure to inorganic arsenic in medical treatments, drinking water, or pesticides. Studies were then done to look at the connection between arsenic and cancer. These studies fell into 2 broad categories: studies of lung cancer in highly exposed workers studies of lung, skin, and urinary tract cancers in communities with contaminated water

Breathing Arsenic-Contaminated Dust Many studies have looked at cancer occurrence among workers who manufactured pesticides containing arsenic and those who worked in mines and copper smelters. Their inhaled exposures were often very high -- the air concentrations of arsenic in smelters before the 1970s were commonly 50 to 100 times higher than the current occupational limit of 0.01mg/m3. Studies in the United States, Sweden, and Japan have given researchers solid evidence after following several thousand workers for as long as 40 or 50 years. Together, these studies consistently have shown up to a 10-fold increase in lung cancer risk with higher and more prolonged exposures. Other cancers have not been consistently linked to inhaled arsenic exposure. Drinking Arsenic-Contaminated Water Worldwide Studies of populations with high levels of arsenic in drinking water in West Bengal, Taiwan, Bangladesh, China, and Argentina have shown elevated risks of cancers of the urinary tract, lung, skin, and, less consistently, cancers of the colon and liver. Some of these studies reported an increased risk of transitional cell bladder cancer at levels of arsenic below the then current U.S. standard of 50 ppb (parts per billion). For example, a 2001 study from Taiwan compared the incidence of this cancer in communities with known levels of arsenic in their drinking water. The findings showed that the bladder cancer risk for residents of communities with levels above 100 ppb was 151

over 15 times that of people living in areas with levels no higher than 10 ppb. A series of studies in Crdoba, Argentina, divided that states 26 counties into 3 categories: high exposure, medium exposure, and low exposure. In the high-exposure area, elevated arsenic levels in drinking water averaged 178 ppb. The higher the level of arsenic people were exposed to, the more likely they were to develop bladder cancer, lung cancer, and kidney cancer. In the United States Another study looked at a population in Utah exposed to arsenic concentrations in drinking water that ranged as high as 166 ppb. There was no increase in cancers of the urinary tract, lung, or skin, as might have been expected. The only significant increase was of prostate cancer in men. This cancer had not previously been connected with arsenic in drinking water and the significance of this finding is unclear. However, this was a relatively small study in which fewer than 600 people were classified as highly exposed, so the ability to detect increases in cancer risk was limited. Also, this was a unique population of Mormons with little or no exposure to alcohol, tobacco, and caffeine, so the relevance of these results to other groups with less healthy lifestyles may be limited. For most Americans who are on piped or public water systems, drinking water is not a major source of arsenic. Even in those areas of the United States where exposure in well water is above the EPA's guideline of 10 g/L, studies to date have not found a significant link between arsenic exposure and cancer. What Do Animal and Laboratory Studies Suggest? Arsenic has not been found to cause cancer in laboratory studies. In fact, arsenic is highly unusual in this respect -- it causes cancer in humans but not in laboratory animals. However, arsenic compounds have been found to damage the DNA of animal cells grown in laboratory dishes. DNA damage was also seen in the white blood cells of smelter workers exposed to arsenic and in patients treated with arseniccontaining compounds. What Do the Experts Say?

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The National Toxicology Program (NTP) evaluates exposures that are thought to cause cancer. These exposures are included in the Reports on Carcinogens, which is published every 2 years. Each exposure is assigned to 1 of 2 categories: "known to be human carcinogens," or "reasonably anticipated to be human carcinogens." The first category includes substances for which human studies provide "sufficient evidence" of causing cancer (carcinogenicity) in humans. The second category includes substances for which there is limited evidence of carcinogenicity in humans and/or sufficient evidence of carcinogenicity in experimental animals. Using this system, the NTP classifies arsenic compounds as a known human carcinogen. The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 1 of 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories. Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable because available evidence is limited or inadequate. Group 4 exposures are "probably not carcinogenic to humans," based on evidence suggesting lack of carcinogenicity in humans and in experimental animals.

The IARC rates arsenic and arsenic compounds as carcinogenic to humans (Group 1). IARC notes that this evaluation applies to the group of chemicals as a whole and not necessarily to all the individual chemicals in the group. The Environmental Protection Agency (EPA), through its Integrated Risk Information System, uses a classification system very similar to that of IARC. It classifies exposures into 5 different groups: (Group (Group (Group (Group (Group A) human carcinogen B) probable human carcinogen C) possible human carcinogen D) not classifiable as to human carcinogenicity E) evidence of non-carcinogenicity for humans 153

The EPA classifies arsenic as a human carcinogen (Group A). Does Arsenic Cause Any Other Health Problems? Arsenic is an acute (short-term) and a chronic (long-term) toxin. Acute Exposure An acute exposure by breathing in arsenic may cause a sore throat and irritated lungs. Acute exposure by either breathing or swallowing arsenic can also damage nerves, the digestive system, and the skin. Acute exposure to arsenic-laced well water (typically containing more than 1,200 micrograms per liter [g/L]) is known to cause things like abdominal pain vomiting diarrhea muscular weakness and cramping arm and leg pain skin changes or rashes swelling of the eyelids, feet, and hands

An acute exposure to large amounts of arsenic can be fatal. Chronic Exposure Chronic exposure to lower levels of arsenic is called arsenicosis. It can also cause health problems, besides cancer, including headache confusion blood vessel disease (atherosclerosis) nerve damage leading to numbness and weakness (called peripheral neuropathy) worsening of the complications of diabetes high blood pressure (hypertension) irregular heartbeats liver and kidney damage a shortage of red and white blood cells

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Skin changes are a common outward sign of chronic arsenic exposure. The changes include a darkening of the skin and the appearance of keratoses (pre-cancerous skin growths), usually on the palms and soles. Some evidence shows that arsenic is associated with ischemic heart disease. Finally, evidence also suggests that arsenic may interfere with the function of some hormones. What Should I Do If I Think Ive been Exposed to Arsenic? Several laboratory tests are used to assess arsenic exposure. Tests of hair and fingernails can detect relatively high-level arsenic exposures during the previous 6 to 12 months, but these tests are hard to standardize. Blood tests for arsenic show only very recent exposures because arsenic is cleared from blood within a few hours. Because of this blood tests are not useful when looking for long-term exposure. Urine tests are the most reliable method for identifying low levels of arsenic exposure, but these too reflect recent exposures because most absorbed arsenic is excreted in urine within days. Doctors and patients should also be aware that a large part of the arsenic found in urine may be organic arsenic (the less dangerous form of arsenic) that comes from eating fish. Because arsenic exposure increases the risk of skin, bladder, kidney, and lung cancer, people who have been exposed should learn about other risk factors and prevention strategies for these cancers. Avoiding risk factors such as tobacco use and excessive sun exposure is especially important if you have been exposed to arsenic. You should tell your doctor about any signs and symptoms such as new skin bumps or sores, changes in old skin problems, blood in the urine, painful urination, or persistent or blood-tinged mucous production. If exposed to arsenic, you should ask your doctor about a proper schedule of skin examinations and also check your own skin each month. Based on the presence of other risk factors and the intensity and duration of arsenic exposure, your doctor might consider using other early detection testing, such as urine cytology (checking urine for cancer cells under a microscope), although available evidence does not firmly support such testing. How Can I Avoid Exposure to Arsenic? In Water

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If you are concerned about the level of arsenic in your drinking water, know that information on arsenic levels is available. For public water systems, you can check the Consumer Confidence Reports issued annually or look for information on-line at the EPAs Office of Water (http://www.epa.gov/safewater/arsenic/index.html) or at your state Environment Department. If you depend on private wells for water, you may have your water tested by private firms. If the level is unacceptably high, consider getting drinking water from another source. Remember that household water filters do not effectively remove arsenic. At Work If you currently work in an industry where arsenic exposure is a concern, the important ways to reduce or prevent exposures include: engineering changes, such as substituting safer materials for more hazardous materials, enclosing a process that may expose workers to hazards, or ventilating a work area good work practices, such as changing clothes after work, washing work clothes regularly, and keeping food out of the work area Personal protective equipment, such as gloves and respirators, as part of a workplace protective program

For more information on preventing or reducing occupational exposures, speak with your companys safety and health manager. In Wood Many, but not all, "pressure-treated" lumber products contain inorganic arsenic compounds that protect the wood against termites and fungi. Because relatively little arsenic escapes from the wood, these products have not been considered to be very dangerous. However, some scientists warn that it may be wise to use wood preservatives other than arsenic or to substitute wood with other building materials for childrens playground equipment. Some suggest that people (especially children) should avoid prolonged contact with dirt and sand beneath structures built with arsenic-treated wood. It is also recommended that anyone in prolonged contact with pressure treated wood, such as builders or children on a playground, thoroughly wash their hands with soap and water when done. Hand-to-mouth transfer is the most common way people are exposed to the arsenic in wood.

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People may also be exposed to dangerous levels of arsenic by inhaling sawdust during construction. Acidic solutions help release the arsenic compounds from the wood and are not recommended for washing decks and other structures made with such products. You should avoid burning arsenic-treated lumber in stoves or open fires because this also releases dangerous levels of arsenic in smoke and ashes. If you are concerned about arsenic exposures at work, from drinking water, from treated wood, or from other sources, you may contact specialists in environmental and occupational medicine. They can assess exposure levels, evaluate current health problems that may be related to the exposures, and give you information concerning future risk and how to minimize it.

Whats the Bottom Line? Many health problems have been linked to arsenic exposure. Strong scientific evidence shows that arsenic can cause cancer in humans. Inhaling arsenic increases the risk of lung cancer. Swallowing arsenic increases the risk of skin, bladder, and lung cancer. Based on this evidence, expert agencies have classified arsenic as a human carcinogen. Because of the cancer risk and other health hazards linked to arsenic, exposures to arsenic should be minimized. Agent Orange and Cancer About 3 million Americans served in the armed forces in Vietnam during the 1960s and early 1970s, the time of the Vietnam War. During that time, the military used large amounts of mixtures known as defoliants, which were chemicals that caused the leaves to fall off plants. One of these defoliants was Agent Orange, and some troops were exposed to it. Many years after US forces withdrew from Vietnam; questions still remain about the lasting health effects of those exposures, including increases in cancer risk. As the US veteran population ages, study results continue to emerge. This article offers a brief overview of the health evidence on Agent Orange and cancer. It is intended to help doctors, Vietnam veterans, and their family members understand our current state of knowledge. The evidence comes from several sources, including studies of:

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Vietnam veterans Workers exposed to herbicides or dioxins in occupational (workplace) settings (since dioxins contaminated the herbicide mixtures used in Vietnam) Vietnamese populations in the aftermath of the war

This article does not offer a complete review of all evidence it is meant to be a brief summary. It also introduces readers to benefits programs and other issues that arise in caring for cancer patients or others concerned about the risks from exposure to Agent Orange during military service.

Background During the Vietnam War, US military forces sprayed nearly 19 million gallons of herbicide on about 3.6 million acres of land in Vietnam and Laos to remove forest cover, destroy crops, and clear vegetation from the perimeters of US bases. This effort, known as Operation Ranch Hand, lasted from 1962 to 1971. Various herbicidal (plant-killing) formulations were used, but most were mixtures of 2 herbicides known as phenoxy herbicides because of their chemical structures: 2, 4-dichlorophenoxyacetic acid (2,4-D) 2, 4, 5-trichlorophenoxyacetic acid (2,4,5-T)

Each formulation was shipped in a chemical drum marked with an identifying colored stripe. The most widely used mixture contained equal parts 2, 4-D and 2, 4, 5-T. Because this herbicide came in drums with orange stripes, it was called Agent Orange. Today, Agent Orange is used to refer generally to all the phenoxy herbicides sprayed at the time. (Other types of herbicides were also used, including cacodylic acid and picloram.) The 2, 4, 5-T was contaminated with small amounts of dioxins, which were created unintentionally during the manufacturing process. Dioxins are a family of biologically active compounds formed during the manufacturing of paper and some other industrial processes. Because they can remain in the environment for years, they form part of a group of chemicals known as "persistent organic pollutants." The particular 158

dioxin present in Agent Orange, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, or TCDD, is unusually toxic. In studies that compared Vietnam veterans with veterans who had served at the same time elsewhere, TCDD (dioxin) levels were found to be elevated among those who had served in Vietnam, although the elevations diminished slowly over time. After a scientific report in 1970 indicated that 2, 4, 5-T could cause birth defects in lab animals, the use of 2, 4, 5-T in Vietnam was suspended. A year later, all military herbicide use in Vietnam ended. During the 1970s, veterans returning from Vietnam began to report skin rashes, cancer, psychological symptoms, birth defects and handicaps in their children, and other health problems. Some veterans were concerned that Agent Orange exposure might have contributed to these health problems. These concerns helped initiate a series of scientific studies, health care programs, and compensation programs directed to the exposed veterans. A large class-action lawsuit was filed in 1979 against the herbicide manufacturers, and was settled out of court in 1984. It resulted in the Agent Orange Settlement Fund, which distributed nearly $200 million to veterans between 1988 and 1996. Although there is now quite a bit of evidence available about the health effects of Agent Orange, many questions have not yet been answered. How Were People Exposed to Agent Orange? About 3 million people served in the US military in Vietnam during the course of the war, about 1.5 million of who served during the period of heaviest herbicide spraying from 1967 to 1969. Exposure to Agent Orange varied a great deal. Most of the large-scale spraying operations in Operation Ranch Hand were done with airplanes and helicopters. However, some herbicides were sprayed from boats or trucks, and some were applied by soldiers with backpack sprayers. Those who loaded airplanes and helicopters may have been exposed the most. Members of the Army Chemical Corps, who stored and mixed herbicides and defoliated the perimeters of military bases, probably also, had some of the heaviest exposures. Others with potentially heavy exposures included members of Special Forces units who defoliated remote campsites, and members of Navy river units who cleared base perimeters. 159

Exposures could have occurred through breathing the chemicals in, ingesting them in contaminated food or drink, or absorbing them through the skin. Other exposure pathways may have been possible as well, such as through the eyes or through breaks in the skin. One of the challenges in assessing the health effects of Agent Orange exposure is determining the amount of exposure any individual veteran received (or even what they were exposed to), as there is very little information of this type available.

Does Agent Orange Cause Cancer? Human Evidence Studies of Vietnam veterans potentially provide the most direct evidence of the health effects of Agent Orange exposure. However, because of the small number of highly exposed persons, these studies have yielded very limited information on cancer. The Vietnam Experience Study (VES), conducted by the Centers for Disease Control (CDC), was a study that compared about 9,000 Vietnam Army veterans with about 9,000 Vietnam-era Army veterans who served elsewhere. A related effort was the CDC Selected Cancers Study, a study conducted in 8 cancer registries that provided data on nonHodgkin lymphoma, sarcomas, and other cancers. In both of these studies, the number of veterans with heavy exposure to Agent Orange was too small to draw firm conclusions. The Department of Veterans Affairs, formerly the Veterans Administration (VA), also conducted a series of studies beginning in the 1980s. The VA studies ranged from large-scale studies to studies of specific subgroups of veterans. Both the CDC and the VA studies looked broadly at Vietnam veterans, without a special focus on Agent Orange exposure (although some VA studies focused on Chemical Corps veterans). In contrast, the Air Force Health Study specifically compared about 1,200 Ranch Hand veterans directly involved in herbicide distribution to 1,300 veterans not involved. This 20-year study, launched in 1982, 160

involved periodic physical exams, medical records reviews, and blood dioxin measurements. Although this study focused more directly on Agent Orange exposure, the relatively small number of subjects, and the even smaller number with elevated blood dioxin levels, greatly limited the studys power to detect increases in cancer incidence. At the state level, about a dozen states, mostly in the Midwest and Northeast, have conducted studies of their veterans, some of which have yielded cancer information. Finally, a series of studies of Australian Vietnam veterans has provided information on cancer risk. These studies, too, were limited by their small size, by the lack of detailed exposure assessment, and (at least initially) by the relatively young age of the veterans. As the veterans continue to age, additional research should yield more information about cancer risk. Because of the limits of the Vietnam veteran studies, studies of 3 other groups have provided important information on the potential cancercausing properties of Agent Orange exposure. Vietnamese soldiers and civilians exposed to the same herbicides as United States service personnel, often for more prolonged periods (although there have been few systematic health studies in these populations) Workers exposed to herbicides in other settings, such as herbicide manufacturing workers, herbicide applicators, farmers, lumberjacks, and forest and soil conservationists, who often had much higher serum dioxin levels than Vietnam veterans People exposed to dioxins after industrial accidents in Germany, Seveso (Italy), and California, and after chronic exposures at work and in the environment

Each of these populations differs from the Vietnam veterans in the characteristics of the people exposed, the nature of the dioxin exposures, and other factors such as diet and other chemical exposures. Based on this relatively large body of evidence, conclusions can be drawn about several cancers. Soft tissue sarcoma: Studies of Vietnam veterans have not demonstrated an increase in soft tissue sarcomas. In particular, no 161

association with soft tissue sarcoma was seen in the Ranch Hand study, in a study of over 10,000 Marines who had served in Vietnam, a large study of sarcoma patients in VA hospitals, the Selected Cancers Study, or studies of veterans in Michigan, Massachusetts, or other states. A study of Australian Vietnam veterans suggested a large increase in soft tissue sarcomas, but this finding was based on a mail survey of selfreported diagnoses. In a follow-up study designed to confirm the diagnoses, the excess of soft tissue sarcomas could not be verified. However, soft tissue sarcomas have been linked to phenoxy herbicide exposure by a series of studies in Sweden and by some studies of industrially exposed workers, many studies of farmers and agricultural workers show an increase in soft tissue sarcomas, which may relate to herbicide exposure. Soft tissue sarcomas have also been linked to dioxin exposure in a study of over 5,000 chemical manufacturing workers in the United States, in some other workplace studies, and in some studies of environmental exposures. Non-Hodgkin lymphoma: Most studies of Vietnam veterans have not shown an increase in non-Hodgkin lymphoma (NHL). The Selected Cancers Study showed that Vietnam service was associated with a 50% increased risk of NHL, but self-reported Agent Orange exposure was not linked with increased risk. Similarly, in the CDCs Vietnam Experience Study, there were 7 NHL deaths among about 8,000 Vietnam veterans and only 1 NHL death among about 8,000 non-Vietnam veterans. Based on military job titles, there was no suggestion that the 7 Vietnam veterans with NHL had sustained Agent Orange exposure. The Ranch Hand study showed no increase in NHL, nor did the VA mortality study of over 33,000 Army and Marine Vietnam veterans, a study of over 200 Vietnam veterans with NHL, or numerous state-level studies. A study of Australian Vietnam veterans suggested a large increase in NHL, but this finding was based on a mail survey of self-reported diagnoses. In a study that attempted to confirm the diagnoses, the number of NHL cases declined to the upper end of the expected range. Several other studies have found a link between phenoxy herbicide exposure (usually on the job) and NHL. Many other studies of farmers and agricultural workers also suggest this association, although welldesigned studies of herbicide production workers have generally found no link or report very small or uncertain associations based on very small numbers of cases. Hodgkin disease: Studies of Vietnam veterans have not demonstrated an increase in Hodgkin disease. In particular, the Ranch Hand study did 162

not show an increase in these tumors, nor did a study of over 33,000 Army and Marine Vietnam veterans, the Selected Cancers Study, a study of more than 250 Vietnam-era veterans with Hodgkin disease, or studies of veterans in Michigan, New York, or other states. However, Hodgkin disease was linked to phenoxy herbicide exposure in one study in Sweden. Another yielded similar results, although the numbers were small enough that they may have been due to chance, many studies of farmers and agricultural workers show an increase in Hodgkin disease, which may relate to herbicide exposure. The link between Hodgkin disease and dioxin exposure specifically is less clear. The large occupational study of over 5,000 chemical manufacturing workers in the United States did not show an increase in Hodgkin disease. The Seveso, Italy studies showed no cases of Hodgkin disease in the zone of greatest dioxin exposure, and a small excess of cases in the other zones. Other studies have given mixed results. Lung and other respiratory cancers: Studies of Vietnam veterans have not shown a consistent pattern of increases in respiratory cancers, such as those of the lung, trachea (windpipe), bronchus, and larynx (voice box). The VA studies did not reveal increased risk of death from these cancers in Vietnam veterans, nor did the study of Army Chemical Corps veterans. The Ranch Hand study suggested an increase in lung cancer, but this finding was based on only 10 deaths, and a high prevalence of smoking in the group being studied may have accounted for this finding. In studies of Australian Vietnam veterans, self-reports suggested an increase in lung cancer (120 cases versus 65 expected), but only 46 of these self-reported cases could be confirmed, actually suggesting a decreased risk of lung cancer. Most studies of workers with workplace herbicide exposure, such as herbicide manufacturing workers, herbicide applicators, farmers, and forest and soil conservationists have shown no excess risk of lung cancer. Similarly, follow-up of the Seveso accident has not shown a link between dioxin exposure and lung cancer, although follow-up of industrial accidents in Germany and California did suggest an increase in respiratory cancers, based on small numbers of cases. Chronic workplace exposures to dioxin have also been associated with increased risk of respiratory cancers among those with high exposures. Together, these data provide little support for the hypothesis that phenoxy herbicides increase the risk of lung cancer, but they suggest a possible association of dioxin exposure with lung cancer. 163

Prostate cancer: While the VA and Ranch Hand studies did not show an excess of prostate cancer, the Australian veterans study did show an excess, with 212 cases observed and 147 expected. Studies of other groups have yielded mixed results. Most studies of workers occupationally exposed to phenoxy herbicides do not show an excess of prostate cancer. However, there are exceptions. For example, recent studies of pesticide applicators in Florida (exposed to many agents other than herbicides) reported an approximate doubling of prostate cancer incidence and mortality. Follow-up of the Seveso accident revealed a small excess of prostate cancer (which may have been due to chance), as did a National Institute of Occupational Safety and Health (NIOSH) study of chronic dioxin exposure. However, followup of other acute dioxin exposure incidents showed no excess of prostate cancer. Overall, the evidence of an association between Agent Orange and prostate cancer is not strong. Multiple myeloma: None of the studies of Vietnam veterans is helpful in determining risk of multiple myeloma (a type of immune system cancer that affects the bones), because the numbers of cases have been consistently small. However, other studies of people exposed to pesticides, herbicides, and/or dioxins have been suggestive. For example, several studies of farmers and agricultural workers have reported a small increase in risk of multiple myeloma, although other studies show no excess risk. Follow-up of the Seveso accident shows a decreased risk of multiple myeloma among exposed males but an increased risk among females, a disparity that remains unexplained. Similarly, the NIOSH study of over 5,000 workers exposed to dioxins showed about a doubling of multiple myeloma risk, based on 10 cases. Overall, the evidence linking Agent Orange to multiple myeloma is sparse and indirect. Acute myelogenous leukemia (AML) in the children of veterans: Three studies have pointed to an association between paternal Agent Orange exposure and acute myeloid leukemia (also called acute myelogenous leukemia) in children.

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The first study, reported by the Childrens Cancer Study Group, compared more than 200 children with AML (cases) to a similar group of children without AML (controls). Children with AML were about 2 times more likely to have a father with long-term pesticide exposure in the workplace. As for maternal exposure, 7 mothers of children with AML and no control mothers reported such exposure. The risk was elevated for children diagnosed before the age of 6and for children who had sustained direct pesticide exposure. "Pesticides" in this study included both insecticides and herbicides, so it is not clear which agents were associated with the increased risk. The second study was a survey of nearly 50,000 Australian Vietnam veterans. This study also found about a 4-fold increase in AML among the children of Vietnam veterans. The risk of acute lymphocytic leukemia (ALL) was not increased in this study. The third study, a study of more than 1,800 cases of ALL and more than 500 cases of AML, was reported from the Childrens Cancer Group. Although a parents military service in general conferred no increased risk of childhood leukemia, service in Vietnam or Cambodia was associated with a 70% increased risk for AML (and no increased risk of ALL). Self-reported exposure to Agent Orange was not associated with increased risk. Gastrointestinal (GI) cancer: Cancers of the GI tract esophagus, stomach, pancreas, colon, and rectum -- have been extensively studied in Vietnam veterans, occupational groups with herbicide exposure, and people exposed to dioxins. These studies have yielded a fairly consistent pattern of no association between these exposures and any GI cancer. One case-control study in Hanoi suggested that former military service, presumably entailing Agent Orange exposure, was associated with increased risk of hepatocellular carcinoma (liver cancer), but the risk was far smaller than that associated with hepatitis B virus infection. Brain cancer: Similarly, there is a fairly consistent pattern suggesting no association between Vietnam service, occupational herbicide exposure, or dioxin exposure, and brain cancer. Other cancers: There is not enough evidence to draw conclusions regarding a link between Agent Orange exposure and other cancers, including cancers of the nose and nasopharynx (upper part of the throat), breast, cervix, endometrium (uterine corpus), ovaries, liver and bile ducts, bone, kidneys, urinary bladder, testicles, or skin, or 165

leukemias other than chronic lymphocytic leukemia (in veterans themselves, as opposed to their children). Animal and Laboratory Studies Herbicides such as 2, 4, 5-T and 2, 4-D are not considered highly toxic compounds, and high doses are required to cause effects in animals. These compounds have not been associated with cancer in animal studies. Studies of cells in lab dishes have also generally been negative, although 2, 4-D caused mutations (changes in DNA) in one study. Cacodylic acid is reported to cause lung and bladder tumors, to promote skin cancer in mice, and to cause DNA mutations in some laboratory tests. Picloram has caused increases in benign liver tumors and in benign thyroid tumors in rats, but has not caused DNA mutations in cells in lab dishes. 2, 3, 7, 8-TCDD (dioxin) is carcinogenic (cancer-causing) in animal tests, increasing a wide variety of tumors in rats, mice, and hamsters. In lab dish studies, dioxin does not seem to damage DNA directly, but helps tumors to grow instead. What Do the Expert Agencies Say? Institute of Medicine The "Agent Orange Act of 1991" directed the Secretary of Veterans Affairs to request the National Academy of Sciences (NAS) to review and evaluate the effects of Agent Orange exposure. The Institute of Medicine (IOM), part of the NAS, responded by forming the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The Committee has issued a series of studies, beginning with its 1994 Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. "sufficient evidence of an association" "limited/suggestive evidence of an association" "inadequate/insufficient evidence to determine whether an association exists" "limited/suggestive evidence of no association"

This framework provides a basis for government policy decisions in the face of uncertainty. As of the most recent update, the links between

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Agent Orange exposure and cancer were designated as shown. (Note that this table shows only cancers.) Institute of Medicine: Associations between Agent Orange and Cancer Sufficient evidence of an association Soft tissue sarcoma Non-Hodgkin lymphoma (NHL) Hodgkin disease Chronic lymphocytic leukemia (CLL) Limited/suggestive evidence of an association Respiratory cancers (lung, trachea, bronchus, larynx) Prostate cancer Multiple myeloma Inadequate/insufficient evidence to determine whether an association exist sliver and bile duct cancers nasal/nasopharyngeal cancer bone cancer breast cancer female reproductive cancers (cervical, uterine, ovarian) urinary bladder cancer Kidney cancer Testicular cancer Leukemia (other than CLL) Skin cancers Acute myelogenous leukemia (AML) in the children of veterans Limited/suggestive evidence of no association Gastrointestinal cancers (stomach, pancreas, colon, rectum) Brain tumors National Toxicology Program The US National Toxicology Program (NTP), formed from parts of several government agencies, evaluates exposures that may be carcinogenic (cancer-causing). Those exposures thought to be carcinogenic are included in the "Report on Carcinogens," published every 2 years. Each exposure is assigned to 1 of 2 categories: "known to be a human carcinogen" "reasonably anticipated to be a human carcinogen" The first category includes substances for which human studies provide "sufficient evidence" of cancer causation in humans. The second category includes substances for which there is limited evidence of 167

cancer causation in humans and/or sufficient evidence of cancer causation in experimental animals. The National Toxicology Program has not listed the phenoxy herbicides, including Agent Orange, as carcinogens, but 2, 3, 7; 8-TCDD (dioxin) is classified as "known to be a human carcinogen." International Agency for Research on Cancer The International Agency for Research on Cancer (IARC) also evaluates exposures that may be carcinogenic. IARC classifies exposures into 1 of 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories. Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable, because available evidence is limited or inadequate. Group 4 exposures are "probably not carcinogenic to humans" based on evidence suggesting lack of carcinogenicity in humans and in experimental animals.

IARC has not rated Agent Orange per se, but the phenoxy herbicides, including 2, 4-D and 2, 4, 5-T, are categorized as "possibly carcinogenic to humans" (Group 2B), and 2, 3, 7, 8-TCDD (dioxin) is categorized as "known to be carcinogenic to humans" (Group 1). Does Agent Orange Cause Any Other Health Problems? Vietnam service and Agent Orange exposure in particular have been extensively studied in relation to health problems other than cancer. High levels of dioxin exposure are associated with chloracne, an acnelike rash caused by exposure to high levels of chlorine-containing chemicals.

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Dioxin exposures are also linked to a condition called porphyria cutanea tarda (PCT), which can result in liver damage and hypersensitivity of the skin to light. This disorder has not been found in excess in Vietnam veterans, however. For other health effects, the evidence is more variable. There has been a good deal of concern about reproductive effects such as birth defects in the children of exposed veterans. Some data are suggestive, especially with regard to neural tube defects (such as spina bifida), but this is an area that continues to be marked by great uncertainty. There has also been concern about toxicity to the nervous system, including psychiatric illnesses and problems with the nerves responsible for movement and sensation, especially in the hands and feet. Again, these links are uncertain. Although the immune system is a target of dioxin, evidence to date has not demonstrated an increase in immune disorders in veterans. Some evidence exists of an association between Agent Orange exposure and diabetes. For other disorders asthma, GI disease, circulatory disorders, and others there is little solid evidence of a link with Agent Orange. Advice for Vietnam Veterans Vietnam veterans with Agent Orange exposure may be eligible for 3 kinds of benefits. Doctors who are familiar with these benefits can counsel their patients who are veterans accordingly. Agent Orange Registry The first benefit is the Agent Orange Registry, a health examination program administered by the VA since 1978. Veterans who participate in this program receive medical examinations, basic laboratory evaluations, and specialty referrals if appropriate. Disability Compensation

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The second benefit is disability compensation payments. Such payments are available to veterans with service-related illnesses or illnesses that were incurred or aggravated by military service. The amount of the payments is determined by the extent of disability. Because past Agent Orange exposure is difficult to quantify, the VA uses a presumption-based system. If a veteran served in Vietnam between 1962 and 1975 and becomes disabled with one of the conditions designated as Agent Orange-related, the VA classifies his or her disability as service-related. The diseases considered related to Agent Orange exposure correspond closely to the conditions found by the IOM to have "sufficient" or "limited/suggestive" evidence of an association. The cancers on the list include: Hodgkin disease Multiple myeloma Non-Hodgkin lymphoma Prostate cancer Cancer of the lung, bronchus, larynx, or trachea Soft tissue sarcoma (other than osteosarcoma, chondrosarcoma, Kaposi sarcoma, or mesothelioma) Chronic lymphocytic leukemia

(Some conditions other than cancer, such as diabetes, are also on this list.) Medical Benefits Third, some veterans qualify for medical care following Agent Orange exposure. According to the Veterans Health Care Eligibility Reform Act of 1996 (Public Law 104-262), the VA must provide its Medical Benefits Package including outpatient and inpatient medical care at VA facilities, prescription medications, and home health and hospice care to veterans with disorders associated with herbicide exposure in Vietnam (to the extent that Congress appropriates funds to provide this care). These disorders include the cancers presumed to be Agent Orangerelated, as well as any other disorder that a VA physician determines is possibly associated with Agent Orange exposure during service in Vietnam. Under this law, 2 categories of disability are excluded from care: 170

A disability that the VA determines did not result from Agent Orange exposures (such as appendicitis or an injury from an automobile crash) A disease that the National Academy of Sciences classifies as having limited/suggestive evidence of no association with Agent Orange (GI tumors and brain tumors).

Veterans may want to check the VA Web site or their local VA hospitals for further information on any of these Agent Orange-related benefits. Doctors should also provide medical advice and careful routine medical care to patients with a history of Agent Orange exposure. Because of the possibility of excess cancer risk, veterans should be advised to seek recommended cancer screening tests and should promptly seek medical evaluation of suspicious symptoms. Veterans should also be advised to quit smoking, to avoid exposures to other carcinogens, to eat a diet primarily from plant sources, and to maintain a healthy body weight. Veterans concerned about past exposure to Agent Orange may want to join a support group at the local VA hospital and/or consult an occupational and environmental medicine clinic. These clinics can help assess past exposures and any risk that may persist, and can recommend appropriate steps to health protection. They may be located through the Association of Occupational and Environmental Clinics at www.aoec.org. Water Fluoridation and Cancer Risk Introduction More than 60 years after it was first introduced in the United States, there is still controversy surrounding the possible health effects of drinking water fluoridation. Many people have strongly held views either for or against fluoridation. Concerns are based on everything from legitimate scientific research, to freedom of choice issues, to government conspiracy theories. This document is intended mainly to explore the possible link between fluoridation and cancer. It does not address in detail other possible health effects of water fluoridation (positive or negative), and is not intended as a position statement of the American Cancer Society. 171

What Is Fluoride? Fluorides are compounds that combine the element fluorine with another substance, usually a metal. Examples include sodium fluoride, stannous fluoride, and fluoride monofluorophosphate (MFP fluoride). Once in the body, fluorides are absorbed in the digestive tract. They travel through the blood and tend to collect in areas high in calcium, such as the bones and teeth. Where Is Fluoride Found? Some fluorides occur naturally in soil, air, or water, although the levels of fluoride can vary widely. Just about all water contains some level of fluoride. The major sources of fluoride for humans are water and other beverages, food, and fluoride-containing dental products (toothpastes, mouth rinses, etc.). Fluoridation of Drinking Water Water fluoridation in the United States began in 1945, after scientists noted that people living in areas with higher water fluoride levels had fewer cavities. The US Public Health Service (PHS) has, since 1962, recommended that public water supplies contain between 0.7 and 1.2 milligrams of fluoride per liter of drinking water (mg/L) to help prevent tooth decay. (Some natural water sources have fluoride levels within this range, or even higher.) Fluoridation is now used in the public drinking water supplied to about two thirds of Americans. The types of fluoride added to different water systems include fluorosilicic acid, sodium fluorosilicate, and sodium fluoride. The US Environmental Protection Agency (EPA) has set a maximum amount of fluoride allowable in drinking water of 4.0 mg/L. Long-term exposure to levels higher than this can cause a condition called skeletal fluorosis, in which fluoride accumulates in the bones. This can eventually result in joint stiffness and pain, and can lead to weak or brittle bones in older adults. 172

The EPA also set a secondary standard of no more than 2.0 mg/L to help protect children (under the age of 9) from dental fluorosis. In this condition, fluoride collects in developing teeth, preventing tooth enamel from forming normally and resulting in permanent staining or pitting of teeth. Does Fluoride Cause Cancer? Some people have raised questions about the safety and effectiveness of water fluoridation since it first began. Over the years, many studies have looked at the possible link between fluoride and cancer. Some of the controversy concerning the possible link stems from a study of lab animals reported by the US National Toxicology Program in 1990. The researchers found equivocal (uncertain) evidence of cancercausing potential of fluoridated drinking water in male rats, based on a higher than expected number of cases of osteosarcoma (a type of bone cancer). There was no evidence of cancer-causing potential in female rats or in male or female mice. More than 50 population-based studies looking at the potential link have been reported in the medical literature. Most of these have not found a strong link between water fluoride levels and cancer. Just about all of these have been retrospective (looking back in time). They have compared, for example, the rates of cancer in a community before and after water fluoridation, or compared cancer rates in communities with lower levels of fluoride in drinking water to those with higher levels (either naturally or due to fluoridation). Some factors are hard to control for in these types of studies, which means the conclusions reached by any single study must be interpreted cautiously. There are other issues that make this topic hard to study. For example, osteosarcoma is a rare cancer, which means it can be hard to gather enough cases to do large studies. Smaller studies can usually detect large differences in cancer rates between 2 groups, but they may not be able to detect a smaller difference. If fluoride increased the risk only slightly, it might not be picked up by these types of studies. Other questions could relate to the fluoride itself. If fluoridation is a risk factor, is the type of fluoride used important? And is there a specific level of fluoride above which the risk is increased? Small studies by themselves may not provide all of the answers, but taken as a whole they tend to have more weight. Several systematic 173

reviews over the past 20 years have looked at all of the studies published on this subject. In its review published in 1987, the International Agency for Research on Cancer (IARC), part of the World Health Organization, labeled fluorides as non-classifiable as to their carcinogenicity [ability to cause cancer] in humans. While they noted that the studies have shown no consistent tendency for people living in areas with high concentrations of fluoride in the water to have higher cancer rates than those living in areas with low concentrations, they also noted that the evidence was inadequate to draw conclusions one way or the other. In 1991, the United States Public Health Service issued a report on the benefits and risks of fluoride. When looking at a possible link with cancer, they first reviewed the results of studies done with lab animals. They concluded that the few studies available fail[ed] to establish an association between fluoride and cancer. They also looked at population-based studies, including a large study conducted by the National Cancer Institute. They concluded: Optimal fluoridation of drinking water does not pose a detectable cancer risk to humans as evidenced by extensive human epidemiological data available to date, including the new studies prepared for this report. The National Research Council (NRC), part of the National Academies, issued a report titled Health Effects of Ingested Fluoride in 1993. Its conclusion was that the available laboratory data are insufficient to demonstrate a carcinogenic effect of fluoride in animals. They also concluded that the weight of the evidence from the epidemiological [population-based] studies completed to date does not support the hypothesis of an association between fluoride exposure and increased cancer risk in humans. The report recommended that additional welldesigned studies be done to look at the possible link to cancers, especially osteosarcomas. In the United Kingdom, the National Health Service (NHS) Centre for Reviews and Dissemination, University of York, published a systematic review of water fluoridation in the year 2000. After searching through the medical literature, they included 26 studies in their analysis, all of which were considered to be of low to moderate quality. They concluded, Overall, no clear association between water fluoridation and incidence or mortality of bone cancers, thyroid cancer, or all cancers was found. However, they also noted, Given the level of interest surrounding the issue of public water fluoridation, it is surprising to find that little high quality research has been undertaken. 174

More recently, the US Centers for Disease Control and Prevention (CDC) has issued a statement on water fluoridation and osteosarcoma in response to an unpublished study that received extensive media coverage. It concluded, At this time, the weight of the scientific evidence, as assessed by independent committees of experts, comprehensive systematic reviews, and review of the findings of individual studies does not support an association between water fluoridated at levels optimal for oral health and the risk for cancer, including osteosarcoma. The National Research Council issued an update of its 1993 review in early 2006. While the review included some new data, the results of this report were essentially the same: On the basis of the committees collective consideration of data from humans, genotoxicity assays, and studies of mechanisms of actions in cell systems, the evidence on the potential of fluoride to initiate or promote cancers, particularly of the bone, is tentative and mixed. The report also noted that a large study, based out of the Harvard School of Public Health and due to be published soon, should add important information to the current body of research. The overall consensus among these reviews, based on the studies done to date, is that there is no strong evidence of a link between water fluoridation and cancer. However, several of the reviews note that further research, including better-designed studies, is needed to address this topic. Reducing Fluoride Exposure Even without fluoridation, the natural levels of fluoride in water in some places can be even higher than 4 mg/L. Community water systems in such areas are required to lower the fluoride level below the acceptable standard. Private water sources, however, may still be higher. For those concerned that they or their families may be exposed to excessive amounts of fluoride, there are some steps that can be taken to reduce exposure. First, people should know the level of fluoride in their drinking water. You can find out about the levels of certain substances detected in drinking water, including fluoride, by contacting your local community water system. Each system is also required to provide its customers with an annual report on water quality known as a Consumer 175

Confidence Report. Those who get their drinking water from a private source such as a well can consider having fluoride levels tested by a reputable laboratory. People who live in areas with high levels of fluoride in the water may want to consider using alternative sources of drinking water, such as bottled water. (Most bottled water contains at least some fluoride, with natural spring waters tending to be the lowest. You may want to contact the bottler to find out about fluoride levels.) There are also several methods to filter fluoride out of water, although these can be expensive. Parents with concerns should give their children only a pea-sized amount of toothpaste for brushing, and should do their best to ensure their children are not swallowing, as this can be a significant source of fluoride. Speak to your childs dentist before using toothpaste in children under 2 years of age. Low- and no-fluoride toothpastes and other dental products are also available. Consumer Products Are the products you use everyday linked to cancer? Find out what current research says. Antiperspirants Persistent internet email rumors have wrongly suggested that underarm antiperspirants cause breast cancer. Hair Dyes Does hair dye cause cancer? Find out what research suggests and what you can do to minimize your risk. Talcum Powder Studies of the personal use of talcum powder have shown inconsistent results, although there is some suggestion of an increase in ovarian cancer risk. Aspartame Aspartame is a low-calorie artificial sweetener that's added to many foods. Its role in cancer risk has been widely debated over the last few decades.

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Antiperspirants and Breast Cancer Risk The claims A persistent internet email rumor has suggested that underarm antiperspirants cause breast cancer. It also claims that Underarm shaving allows cancer-causing substances in antiperspirants to be absorbed through razor nicks. These substances are said to keep lymph nodes under the arm from removing cancer-causing toxins before they get to the breasts. Most breast cancers develop in the upper outer quadrant of the breast because that area is closest to the lymph nodes exposed to antiperspirants. (A quadrant is 1/4 of the breast, if you think of the breast as a circle. The upper outer quadrant of the breast is the part closest to where the arm is attached.) Men have a lower risk of breast cancer because they do not shave their underarms, and their underarm hair keeps chemicals in antiperspirants from being absorbed.

All of these claims are largely untrue. Our responses Do antiperspirants increase a person's risk of developing breast cancer? There is no good scientific evidence to support this claim. We do not find any strong epidemiologic studies in the available medical literature that report a scientific study that links breast cancer risk and antiperspirant use. In fact, a carefully-designed epidemiologic study of this issue published in 2002 compared 813 women with breast cancer and 793 women without the disease. The researchers found no link between breast cancer risk and antiperspirant use, deodorant use, or underarm shaving. Another study published in 2003 reported on responses from questionnaires sent out to women who had breast cancer. The researcher reported that younger women who were diagnosed with breast cancer said they used antiperspirant and shaved their underarms 177

earlier and more often than women who were diagnosed when they were older. But the study design did not include a control group of women without breast cancer and has been criticized by experts as not relevant to the safety of these underarm hygiene practices. It is probable that, in general, young women are more likely than older women to shave their underarms and use antiperspirants, whether or not they develop breast cancer later. For instance, most women born in the 1950s and 1960s may have started shaving earlier and using antiperspirants more often than women born in the 1930s and 1940s. Or, it is possible that many women shave and use antiperspirants less often as they get older. These are more likely explanations of the researcher's findings than the suggestion that these practices cause cancer. Of special note, the study asked about underarm products that the women were using at the time the questions were answered, not what they used before they developed breast cancer. Does using antiperspirant after shaving allow chemicals to enter the body from the armpit and increase breast cancer risk? Razor nicks may increase the risk of skin infection. If the underarm skin already has an infection, it is possible that some antiperspirants could cause slight irritation. But it is unlikely that this is a major source of carcinogens (cancer-causing substances) that ever reach the breast cells. Should I be concerned about parabens in antiperspirants? In 2004, a small study found traces of substances called parabens in some samples of breast cancer tumors. Parabens are used in some underarm products as preservatives and may have entered the breast through the underarms in these cases. A possible concern is that in other studies, parabens have been found to have weak estrogen-like properties. Estrogen is a female hormone known to cause breast cells (normal and cancerous) to grow and divide. Some conditions that increase the bodys exposure to estrogen (not having children, late menopause, obesity, etc.) have been linked to an increased risk of breast cancer.

But there are some important points to keep in mind about the 2004 findings: 178

The researchers looked only for the presence of parabens in breast cancer samples. The study did not show that parabens caused or contributed to breast cancer development in these cases -- it only showed that they were there. What this means is not yet clear. While parabens have weak estrogen-like properties, the estrogens that are made in the body are hundreds to thousands of times more potent. So, natural estrogens (or those taken as hormone replacement) are much more likely to play a role in breast cancer development. Parabens are widely used in shampoo, lotions, other cosmetics, and even foods. This study did not contain any information to help find the source of the parabens found in breast tissue.

So far, studies have not shown any direct link between parabens and breast cancer risk. What has been found is that there are many other compounds in the environment that also mimic naturally-produced estrogen. The bottom line is that larger studies are needed to find out what effect, if any, parabens might have on breast cancer risk. This topic will no doubt continue to receive scientific attention. Is it true that antiperspirants keep a person from sweating cancercausing toxins out through their underarm lymph nodes and these results in a build-up of these toxins in breast tissue? Lymph nodes help clear bacteria, viruses, and other possible threats from the body, but the lymph nodes do not release their by-products through sweating. Sweat glands are not connected to lymph nodes. Sweat glands are located in the skin, not in the lymph nodes. Most cancer-causing substances are removed by the kidneys (and released into urine) and by the liver (and released into bile, which mixes with and is eliminated with feces).

Are there lymph nodes in the upper outer quadrant where most breast tumors occur?

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Lymph nodes are located throughout the breasts and have an important role. The underarm (axillary) nodes filter most of the lymph flowing out of the breast before it goes back into the body's bloodstream. These nodes are under the arm and breast, near the upper outer quadrant of the breast, near the collarbone, and along the chest area under the breastbone. The breast quadrants are not actually all the same size. About half of all breast cancers develop in the upper outer part of the breast, probably because most breast tissue is located in this area. The number of breast cancers in the upper outer part of the breast is in proportion to the amount of breast tissue in that area. There is no evidence to suggest that the location of cancers within the breast is related to using antiperspirants or underarm shaving. Are men less likely to get breast cancer because antiperspirant gets caught in their underarm hair and is not absorbed by their skin? Men are much less likely than women to develop breast cancer, mostly because men have much less breast tissue than women. Women have about 100 times more breast tissue than men do and are about 100 times more likely to develop breast cancer. Hormones also play a role. Men with metabolic or genetic conditions that lead to increased estrogen (female hormone) levels have an increased risk of developing breast cancer. Underarm hair and antiperspirant absorption have not been linked to male breast cancer risk. Why does my doctor tell me not to use antiperspirant or deodorant on the day of my mammogram? The reason for this is that many of these products have aluminum, which is a metal and can show up on a mammogram as tiny specks in the area. These specks can look like micro calcifications, which are one of the things doctors look for as a possible sign of cancer. Avoiding the use of these products helps prevent any confusion when looking at the mammogram films. How did this rumor get started and spread?

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We don't know who started this rumor. Most people who forwarded the e-mail did so with good intentions. We do know that this rumor has been posted on some internet Web sites that sell deodorants that are not antiperspirants, so these people might benefit financially from spread of this misinformation. How can I learn more about breast cancer risk factors and ways to find breast cancer early, when treatment is most effective? Women concerned about breast cancer should know that their risk of breast cancer is much more likely to be affected by factors known to affect hormone levels in the body, such as obesity and hormone replacement therapy after menopause. Women who wish to reduce their risk of developing or dying from breast cancer should avoid hormone replacement therapy, maintain a healthy weight, exercise regularly, avoid drinking too much alcohol, and get regular mammograms. We can give you information about all aspects of cancer, from causes and prevention, to diagnosis and treatment. Hair Dyes About 7 out of 10 adult American women, as well as a small but increasing number of men, use hair dyes. You may have heard rumors about a link between using hair dye and getting cancer. Many studies have looked at hair dyes as a possible risk factor for various types of cancer. Here we will discuss what these studies show so that you can make choices that are comfortable for you. Types of Hair Dyes Hair dyes vary greatly in their chemical make-up. People are exposed to the chemicals through skin contact. There are 3 main types of hair dye: Temporary hair dyes cover the surface of the hair but do not penetrate into the hair shaft Last for 1 to 2 washings

Semi-permanent hair dyes do penetrate into the hair shaft 181

Typically last for 5 to 10 washings

Permanent hair dyes (two different kinds) cause lasting chemical changes in the hair shaft Are the most popular types of hair dyes, because the color changes last until the hair is replaced by new growth.

Oxidative hair dyes contain colored dye substances (such as pphenylenediamine or 2-nitro-p-phenylenediamine) and hydrogen peroxide. These substances go through a chemical reaction inside the hair to become a dye. Oxidative hair dyes are mixed just before they are used. Progressive hair dyes contain metal salts (such as lead acetate or bismuth citrate) as their active ingredients. They gradually change hair color by reacting with sulfur in the hair. Concern about cancer risk is largely limited to the semi-permanent dyes and the oxidative type of permanent dyes. Because dark brown and black dyes have higher concentrations of suspected cancer-causing substances (carcinogens), these products are of greatest potential concern. Does Hair Dye Cause Cancer? Two kinds of evidence tell us about the potential cancer risk of hair dyes -- epidemiologic studies and laboratory studies. Epidemiologic studies in humans give us information about the possible causes of disease, occurrence of disease in a population or its subgroups, and trends in the frequency of disease over time. Laboratory studies are most often done on animals. What Do the Experts Say? Based on animal and human evidence, expert agencies have looked at the possibility of hair dyes causing cancer. The International Agency for Research on Cancer (IARC) evaluates exposures that may be carcinogenic. IARC classifies exposures into one of 4 categories: Group 1 exposures are those "known to be carcinogenic to humans," usually based on "sufficient" human evidence, but 182

sometimes based on "sufficient" evidence in experimental animals and "strong" human evidence. Group 2 exposures are divided into 2 categories. Group 2A ("probably carcinogenic to humans") has stronger evidence, and Group 2B ("possibly carcinogenic to humans") has weaker evidence. Group 3 exposures are not considered classifiable because the available evidence is limited or inadequate. Group 4 exposures are "probably not carcinogenic to humans" based on evidence suggesting these substances do not cause cancer in humans or in experimental animals.

The IARC concluded in 1993, that the hairdressers and barbers probably are exposed to cancer causing substances (Group 2A), but that the evidence of increased cancer risk was limited. There was not enough evidence at that time for the IARC to evaluate the possible cancercausing risks of personal use of hair dyes. Since this IARC decision in 1993, many more studies have been done worldwide. What Do the Studies Suggest? Studies have looked at whether people who use hair dye products or people who regularly work with them have an increased risk of bladder cancer, leukemia, multiple myeloma, Hodgkin disease, non-Hodgkin lymphoma, lung cancer, breast cancer, oral cancer, and cervical cancer. The evidence from these studies remains quite inconsistent. Most of the available evidence does not support a link to cancer risk. Those studies that do show a link find that it is too weak to be considered a major public health concern. Studies such as these need to be repeated in larger groups of people so that experts can get a better look at possible problems linked to hair dye use. What Do Animal and Laboratory Studies Suggest? Some of the ingredients (such as 4-methoxy-m-phenylenediamine or 4MMPD, 4-MMPD sulfate, 4-chloro-m- phenylenediamine, 2,4toluenediamine, 2-nitro-p- phenylenediamine, 4-amino-2-nitrophenol, C.I. Acid Orange 3 and C.I. Disperse Blue 1) in hair dyes have been shown to cause cancer in laboratory animals. In these studies, however, animals were fed large amounts of the dyes over a long period of time. 183

Although studies have shown that some of the dye applied to an animal's skin is absorbed into the bloodstream, most have not found any association between skin application and cancer risk. Does Hair Dye Cause Any Other Health Problems? Some of the ingredients in hair dyes can cause allergic reactions leading to severe skin and eye irritation. Eye irritation can seriously affect vision and, very rarely, lead to blindness. For these reasons, it is recommended that users test these products on a small area of skin before using them on their hair and scalp. It is also for these reasons that these products should not be used to dye eyebrows. What Should I Do If I Have Been Exposed to Hair Dye? There are no current recommendations for special testing to look at exposure to hair dye ingredients. Other than recommendations that apply to everyone (having routine screening exams, eating a healthy diet, being physically active, etc.) no specific medical advice is needed for current or former hair dye users. What's the Bottom Line? Most of the available evidence does not show hair dyes to be a significant cancer risk factor. However, the findings of published studies remain inconsistent. The US Food and Drug Administration (FDA) provide some suggestions for people worried about hair dyes as a cancer risk factor (FDA, 1993), (FDA, 1997): Don't leave the dye on your head any longer than necessary. Rinse your scalp thoroughly with water after use. Wear gloves when using hair dye. Carefully follow the directions in the hair dye package. Never mix different hair dye products, because you may cause potentially harmful reactions. Be sure to do a patch test for allergic reactions before putting the dye in your hair. Do a patch test before every use. Never dye your eyebrows or eyelashes. Delay dyeing hair until later in life when it starts to turn gray. Consider using henna, which is largely plant-based, or hair dyes that are lead acetate-based.

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What Is Talc? Talcum powder is produced from talc, a magnesium trisilicate mineral, which in its natural form may contain asbestos, a known human carcinogen (any substance that causes cancer or helps cancer grow). Because of this association with asbestos, all home-use talcum products marketed after about 1973 baby powders, body powders, and facial powders have been required by law to be asbestos-free. Asbestos can cause lung cancer and mesotheliomas (cancers affecting the lining surfaces of the chest and abdominal cavities). Does Talc Cause Cancer in Animals? Experimental toxicology studies have suggested carcinogenicity (the ability of a substance to cause cancer) of inhaled, asbestos-free talc powder in some rodent species but not in others. Does Talc Cause Ovarian Cancer in Humans? It has been suggested that talcum powder may be carcinogenic to the covering layer of the ovaries through the migration of talcum powder particles (applied to the genital area, sanitary napkins, diaphragms, or condoms) through the vagina, uterus, and fallopian tubes to the ovary. Several epidemiologic studies have examined the relationship between talcum powder and cancer of the ovary. Findings are mixed, with some studies reporting a slightly increased risk and some reporting no association. A case-control study published in 1997 of 313 women with ovarian cancer and 422 without this disease found that the women with cancer were more likely to have applied talcum powder to their external genital area or to have used genital deodorant sprays. Women using these products had a 50% to 90% higher risk of developing ovarian cancer. Storing diaphragms with powder did not significantly increase cancer risk. Since many of these women might have used products with more asbestos contamination than that in current products, the ovarian cancer risk for current users is difficult to evaluate. One study has suggested that an increased risk, if it exists, might be confined to borderline and endometrioid (uterine-like) tumors and therefore might not affect the majority of ovarian cancers.

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A prospective study (considered to generally be the most informative) published in 2000 found no effect on ovarian cancer overall but a 40% increase risk in one type invasive serous cancers. A meta-analysis which reanalyzed data from 16 studies published prior to 2003 found a 33% increase in ovarian risk among talc users. However, women with the highest exposure were at no greater risk than those with lower exposure, leading the researchers to question whether the association they observed was truly valid. The most recent study of this subject found an overall 37% increased risk among talc users. It was interesting that the risk from talc use increased by 54% among women who had not had a tubal ligation (had their tubes tied) to prevent pregnancy, whereas talc had no impact on women whose tubes had been tied. Because tubal ligation is expected to block external carcinogens from reaching the ovaries via the vagina, uterus, and fallopian tubes, this finding provides some support for the idea that talc is a carcinogen. Does Talc Cause Lung Cancer in Humans? No increased risk of human lung cancer has been reported in association with the use of cosmetic talcum powder. Although some studies of talc miners and millers have suggested an increased risk of lung cancer and other respiratory diseases, others found no increase in lung cancer risk. And the industrial grade talc to which such workers are exposed contains varying amounts of silica and asbestos, unlike the purified talc sold to consumers. One study of pottery workers exposed to silica dust and nonasbestiform talc showed an excess risk of lung cancer, while other studies of occupational talc exposure have not found an increased risk. While experimental evidence suggests that some forms of silica may cause cancer in animals, observational studies in humans are not conclusive. Advice for People Concerned About Talc and Cancer Risk Studies of personal use of talcum powder have yielded inconsistent results, although there is some suggestion of an increase in ovarian cancer risk. No other forms of cancer appear to be associated with the use of talcum powder.

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However, only a very small minority of women who have used talcum powder will ever develop ovarian cancer. And it is impossible to say to what extend talc use had contributed to these cases. Until additional information is available about the safety of talc use, people who use powder may wish to consider avoiding these products or substituting cornstarch-based powders that contain no talc. There is no evidence at present linking cornstarch powders with any form of cancer. Aspartame What Is Aspartame? Aspartame, one of the most common artificial sweeteners used today, is sold as NutraSweet and Equal. It is used in many foods and beverages instead of sugar because it is about 200 times sweeter than sugar, has fewer calories than sugar, and it does not cause tooth decay. Aspartame is made up of three chemicals that are all naturally found in foods and can be found in the body. How Are People Exposed to Aspartame? People are exposed to aspartame through the foods they eat. Aspartame is commonly used as a tabletop sweetener, as a sweetener in prepared foods and beverages, and in simple recipes that do not require too much heating (since heat breaks down aspartame). FDA Approval In 1981, after careful review, the Food and Drug Administration (FDA) approved the use of aspartame. It was then used in many foods, such as cold breakfast cereals, chewing gum, dry drink mixes, instant tea and coffee, gelatins, puddings, fillings, non-dairy toppings, and as a tabletop sweetener. It was approved in 1983 for use in carbonated beverages and carbonated beverage syrups. Today it is found in even more food products.

How Much Aspartame is Safe?

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Who Decides Safe Levels? Two units of the United Nations, the World Health Organization (WHO) and the Food and Agriculture Organization (FAO), through their Joint Expert Committee on Food Additives (JECFA), recommend Acceptable Daily Intake (ADI) levels for many food additives. The ADI is the amount of an additive that, if eaten every day for the rest of a person's life, would be considered safe. In the US, the FDA sets ADI guidelines. How much is Safe? Animal studies in the 1970s found that rats could eat 4 grams of aspartame per kilogram of body weight without showing health problems. To be safe, the JECFA divided this dose by 100, and set the Acceptable Daily Intake of aspartame for humans at 40 milligrams per kilogram of body weight. The FDA now has stated that the acceptable daily intake of aspartame for humans is 50 milligrams per kilogram of body weight. This is equivalent to 3500 milligrams per day for a typical 70-kilogram (about 150 pounds) adult, far more than most adults take in daily. For comparison, a can of diet soft drink contains about 180 milligrams of aspartame. So a typical adult could drink 19 cans of diet soft drink each day before going over the recommended level. A 30-kilogram (66 pounds) child would have to drink more than 8 cans of diet soda daily to reach the ADI for aspartame. Does Aspartame Cause Cancer? Soon after aspartame was introduced to the market, its safety was questioned. Its role in cancer risk has been widely debated over the last few decades. Concerns still exist today and studies continue to look at the safety of aspartame and other artificial sweeteners. As recently as April 2007, the FDA released this statement: "Considering results from the large number of studies on aspartame's safety, including five previously conducted negative chronic carcinogenicity studies, a recently reported large epidemiology study with negative associations between the use of aspartame and the occurrence of tumors, and negative findings from a series of three transgenic mouse assays, FDA finds no reason to alter its previous conclusion that aspartame is safe as a general purpose sweetener in food."

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What Do the Experts Say? Aspartame has been approved for use as a sweetener by the FDA and by the Joint Expert Committee on Food Additives of the United Nations Food and Agricultural Organization, and the World Health Organization. They have concluded that aspartame does not cause cancer or other adverse health effects in the general population. Though research into a possible link between aspartame and cancer continues, no study to date has had results that change this conclusion. Does Aspartame Cause Any Other Health Problems? Phenylketonuria (PKU) People born with a rare genetic disorder called phenylketonuria or PKU cannot break down (metabolize) the amino acid phenylalanine. This amino acid occurs naturally and is found in aspartame. PKU is usually detected in babies by a routine blood test at birth. People with the disorder are placed on a phenylalanine-restricted diet and must avoid aspartame. Other Complaints The FDA received hundreds of complaints of various symptoms after aspartame was introduced. The most common symptoms were headache, dizziness, stomach (gastrointestinal) symptoms, and change in mood. Less often, seizures were reported. The symptoms did not follow any particular pattern and most were minor. The Centers for Disease Control and Prevention (CDC) concluded that "although it may be that certain individuals have an unusual sensitivity to the product, these data do not provide evidence for the existence of serious, widespread, adverse health consequences attendant to the use of aspartame." Claims are still made that aspartame is related to numerous health effects including: Alzheimer disease, birth defects, cancer, diabetes, Gulf War syndrome, attention deficit disorders, lupus, multiple sclerosis, and seizures. However, there is very little scientific evidence to support these claims. Human exposure studies done to date, in which volunteers eat known quantities of aspartame, have not shown any evidence of harm. Methanol, one of the breakdown products of aspartame, is toxic to humans when large doses are eaten and could possibly cause blindness 189

and even death. However, the amount of methanol produced when aspartame is broken down is minimal and well below the level that is a risk to human health. What Should I Do If Ive been exposed to Aspartame? You should be able to see if you have taken in aspartame by reading food and drink labels. If you have eaten food that contains aspartame and you are concerned about the possible health effects that may occur, talk with your health care provider. If you want to avoid aspartame, check all food labels before you buy or eat food or drink. What's the Bottom Line? Research on artificial sweeteners, including aspartame, continues today. Current evidence does not demonstrate any link between aspartame and an increased risk of cancer. Aspartame has not been linked with other health problems except among people with the genetic disorder, phenylketonuria. People with this disorder should avoid aspartame in their diet. Guidelines for the Early Detection of Cancer: The following cancer screening guidelines are recommended for those people at average risk for cancer (unless otherwise specified) and without any specific symptoms. People who are at increased risk for certain cancers may need to follow a different screening schedule, such as starting at an earlier age or being screened more often. Those with symptoms that could be related to cancer should see their doctor right away.

Cancer-related checkup For people aged 20 or older having periodic health exams, a cancerrelated checkup should include health counseling, and depending on a person's age and gender, might include exams for cancers of the 190

thyroid, oral cavity, skin, lymph nodes, testes, and ovaries, as well as for some non-malignant (non-cancerous) diseases. Special tests for certain cancer sites are recommended as outlined below. Breast cancer Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health. Clinical breast exam (CBE) should be part of a periodic health exam, about every 3 years for women in their 20s and 30s and every year for women 40 and over. Women should know how their breasts normally feel and report any breast change promptly to their health care providers. Breast self-exam (BSE) is an option for women starting in their 20s. Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram. Yearly MRI screening is not recommended for women whose lifetime risk of breast cancer is less than 15%.

Colon and rectal cancer Beginning at age 50, both men and women at average risk for developing colorectal cancer should use one of the screening tests below. The tests that are designed to find both early cancer and polyps are preferred if these tests are available to you and you are willing to have one of these more invasive tests. Talk to your doctor about which test is best for you. Tests that find polyps and cancer Flexible sigmoidoscopy every 5 years Colonoscopy every 10 years Double contrast barium enema every 5 years CT colonography (virtual colonoscopy) every 5 years

Tests that mainly find cancer 191

Fecal occult blood test (FOBT) every year Fecal immunochemical test (FIT) every year Stool DNA test (sDNA), interval uncertain Colonoscopy should be done if test results are positive. For FOBT or FIT used as a screening test, the take-home multiple sample method should be used. A FOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening.

People should talk to their doctor about starting colorectal cancer screening earlier and/or being screened more often if they have any of the following colorectal cancer risk factors: a personal history of colorectal cancer or adenomatous polyps a personal history of chronic inflammatory bowel disease (Crohns disease or ulcerative colitis) a strong family history of colorectal cancer or polyps (cancer or polyps in a first-degree relative [parent, sibling, or child] younger than 60 or in 2 or more first-degree relatives of any age) a known family history of hereditary colorectal cancer syndromes such as familial adenomatous polyposis (FAP) or hereditary nonpolyposis colon cancer (HNPCC)

Cervical cancer All women should begin cervical cancer screening about 3 years after they begin having vaginal intercourse, but no later than when they are 21 years old. Screening should be done every year with the regular Pap test or every 2 years using the newer liquid-based Pap test. Beginning at age 30, women who have had 3 normal Pap test results in a row may get screened every 2 to 3 years. Another reasonable option for women over 30 is to get screened every 3 years (but not more frequently) with either the conventional or liquid-based Pap test, plus the HPV DNA test. Women who have certain risk factors such as diethylstilbestrol (DES) exposure before birth, HIV infection, or a weakened immune system due to organ

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transplant, chemotherapy, or chronic steroid use should continue to be screened annually. Women 70 years of age or older who have had 3 or more normal Pap tests in a row and no abnormal Pap test results in the last 10 years may choose to stop having cervical cancer screening. Women with a history of cervical cancer, DES exposure before birth, HIV infection or a weakened immune system should continue to have screening as long as they are in good health. Women who have had a total hysterectomy (removal of the uterus and cervix) may also choose to stop having cervical cancer screening, unless the surgery was done as a treatment for cervical cancer or pre-cancer. Women who have had a hysterectomy without removal of the cervix should continue to follow the guidelines above.

Endometrial (uterine) cancer The American Cancer Society recommends that at the time of menopause, all women should be informed about the risks and symptoms of endometrial cancer, and strongly encouraged to report any unexpected bleeding or spotting to their doctors. For women with or at high risk for hereditary non-polyposis colon cancer (HNPCC), annual screening should be offered for endometrial cancer with endometrial biopsy beginning at age 35. Prostate cancer Both the prostate-specific antigen (PSA) blood test and digital rectal examination (DRE) should be offered annually, beginning at age 50, to men who have at least a 10-year life expectancy. Men at high risk (African-American men and men with a strong family of one or more first-degree relatives [father, brothers] diagnosed before age 65) should begin testing at age 45. Men at even higher risk, due to multiple firstdegree relatives affected at an early age, could begin testing at age 40. Depending on the results of this initial test, no further testing might be needed until age 45. Information should be provided to all men about what is known and what is uncertain about the benefits, limitations, and harms of early detection and treatment of prostate cancer so that they can make an informed decision about testing.

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Men who ask their doctor to make the decision on their behalf should be tested. Discouraging testing is not appropriate. Also, not offering testing is not appropriate. Imaging (Radiology) Tests What Are Imaging Tests? Imaging tests are studies that make pictures of what's going on inside your body. These tests use different forms of energy (x-rays, sound waves, radioactive particles, or magnetic fields) that are passed through the body. The changes in energy patterns caused by different body tissues can be detected by special devices, which change them into pictures. These pictures can show normal body structure and function as well as abnormalities caused by diseases such as cancer. Imaging tests are different from endoscopic tests (for example, colonoscopy or bronchoscopy), which use a flexible, lighted tube connected to a viewing lens or a video camera. Endoscopic tests allow doctors to look inside parts of the body as if they were looking with the "naked eye." What Are Imaging Tests Used For? Imaging tests are used for cancer in many ways: They are sometimes used in screening looking for cancer in its early stages, even though a person has no symptoms. A mammogram is an example of an imaging test used for cancer screening. They sometimes help predict whether a tumor is likely to be cancer and help doctors decide if you need to have a biopsy (taking a tissue sample to be looked at under the microscope). A biopsy is almost always needed to know for sure that a tumor is cancer. They sometimes help predict whether a tumor is likely to be cancer and help doctors decide if a biopsy (removal of a tissue sample for viewing under the microscope) is needed. However, a biopsy is almost always needed to say for sure that a tumor is cancer. They show exactly where the tumor is, even deep within the body, so that a sample of it can be taken for further study. 194

They help stage cancer (determining how far the cancer has spread). They can be used to plan treatment, such as when determining where the beams should be focused in radiation therapy. They can give a doctor an idea of how well treatment is working (that is, if a tumor has shrunken, stayed the same, or grown after treatment). They can help find out if a cancer has recurred (come back) after treatment.

Imaging tests are only part of the process of cancer diagnosis and management. A complete initial workup for your cancer also includes a careful medical history (interview about symptoms and risk factors) and physical exam, and possibly blood or other lab tests. Imaging tests may give important evidence that a lump or mass is present, but they usually cannot tell for sure if the lump is a cancer. For the doctor to make a diagnosis, a biopsy is almost always needed. In many cases, imaging tests make it possible to get a biopsy without the need for major surgery. Many doctors request x-rays or other images before treatment begins so that a record is available showing how things change over time. These studies are called baseline studies because they provide a basis of information that helps doctors evaluate the results of treatment or progression of the disease. Who Performs and Interprets Imaging Tests? A doctor, a certified technologist, or other health professional may perform an imaging test. Depending on the technology involved, the test may be done in a hospital, a special clinic or imaging center, or a doctor's office. In larger medical centers, imaging tests are usually done in the radiology department (even though some types of tests do not involve high-energy radiation). A radiologist, a doctor who specializes in imaging techniques, usually reads (interprets) the imaging test. The radiologist writes a report on the findings and sends the report to your doctor. A copy of the report

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will become part of your patient records. Your other doctors (oncologists, surgeons, etc.) may look at the images as well. Types of Imaging Tests The rest of this document explains some of the more common types of imaging tests, how they are done, and when they may be needed. Computed Tomography (CT) Scan Other Names CT scan, CAT scan, spiral CT, helical CT What Does It Show? Computed tomography or CT (also called CAT) scans show a slice, or cross-section, of the body. The image shows your organs and soft tissues more clearly than standard x-rays. Because the image is created by a computer, it can be enlarged to make it easier to read and interpret. Since the late 1970s, CT scans have been a very valuable technology in detecting cancer. CT scans can show a tumor's shape, size, volume, and location and can reveal the blood vessels that feed the tumor. Doctors often use CT scans to help them guide a needle to remove a tissue sample (called a CT-guided biopsy). They can also be used to guide needles into tumors for some types of cancer treatments, such as radiofrequency ablation (destroying a tumor using heat and ionic agitation). CT scans are especially effective in detecting and evaluating cancer in the liver, pancreas, adrenal glands, lungs, and bones. They are also used to provide information about cancer in the large and small intestines, esophagus, stomach, brain, prostate, or other organs. By comparing CT scans done over time, doctors can see how a tumor is responding to therapy or detect a possible recurrence after treatment. How Does It Work? CT scans use controlled amounts of x-rays beams of high-energy radiation that are passed through the body to create images. In a 196

way, CT scans are like ordinary x-ray tests (see Radiographic Studies below). But an x-ray test uses a broad beam of radiation aimed from only one angle. A CT scan uses a pencil-thin beam to create a series of pictures taken from different angles. Each angle produces a slightly different view of your internal organs and soft tissues. The information from each angle is fed into a computer, which calculates how the images overlap. The computer then creates a single black and white image that shows a slice of a specific area of your body (much like looking at a single slice from a loaf of bread). The image can be made clearer by the use of a special contrast dye, which can be swallowed as a liquid, injected into a vein, or infused as an enema. Because body tissues absorb this material differently, the resulting CT image will have greater contrast between types of tissues, allowing abnormalities such as tumors to be seen more clearly. In recent years, spiral CT (also known as helical CT) has become available. This type of CT scan uses a faster machine. The scanner part of the machine rotates around the body continuously, allowing doctors to collect the images much more quickly than standard CT. As a result, you do not have to hold your breath for as long while the image is taken. This lowers the chance of blurred images occurring as a result of breathing motion. It also lowers the dose of radiation received during the test. The slices it images are thinner, which yields more detailed pictures. Spiral CT is currently used to look at liver, pancreas, lung, and some other tumors. By placing spiral CT image slices on top of each other, doctors can create a 3-dimensional (3D) scan, which provides even more information about certain cancers. The 3-dimensional image can be rotated on a computer screen to allow for different views. Doctors are now taking this technology one step further in a technique called virtual endoscopy. They can view the inside surfaces of organs such as the lungs (virtual bronchoscopy) or colon (virtual colonoscopy, also called CT colonography) without actually having to insert anything into the body. They can manipulate the 3D images to create a black and white fly-through view on the computer screen, which looks as it would if they were performing an actual endoscopy. Studies are now under way to determine if these techniques are as good as conventional endoscopy. How Do I Prepare for the Test?

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CT scans are normally done on an outpatient basis, meaning that you do not need to be admitted to the hospital. In some cases, your doctor may tell you not to eat or drink for several hours before the exam or may require you to have an enema to cleanse the bowel and remove material that could interfere with viewing the abdominal area. Depending on the part of the body being studied, you also may need to drink contrast liquid or receive a contrast enema before the test. If a contrast material is to be injected into a vein, you may have an intravenous (IV) catheter inserted into an arm vein. You may be asked to undress, put on a robe, and remove any jewelry or other metal objects that may interfere with the image. If you are having a head CT scan, you should remove dentures, hearing aids, hair clips, and so on. What Is It Like Having the Test? A radiologic technologist conducts the CT scan. You lie on a thin, flat table connected to a scanner. The scanner is a large, doughnut-shaped machine. The table can slide back and forth inside the hole in the middle of the scanner. As the table moves into the opening, an x-ray tube rotates within the scanner, emitting thousands of tiny x-ray beams at specific angles. These beams pass through the body and are detected on the other side of the scanner. Each full rotation of the x-ray tube results in an image of a slice of the body. You may hear buzzing and clicking as the scanner switches on and off. During a head CT scan, your head will be held still with a special device. The test is painless but you may find it uncomfortable to hold still in certain positions for minutes at a time. You may also be asked to hold your breath, since chest movement can affect the quality of the image. If a spiral CT machine is used, the time you hold your breath is shortened. If you are given contrast material in a vein, you will probably have a scan first, then receive the injection, then undergo a second scan. How Long Does It Take? Depending on how much of your body your doctors want to examine and whether contrast material is used, a CT scan can take anywhere from 10 to 30 minutes. Spiral CT scans take less time. More time is 198

taken getting you into position and in giving contrast material than in actually taking the pictures. After the test, you may be asked to wait while the images are looked at to see if more images are needed. What Are the Possible Complications? About 5% of people have some type of reaction to the contrast dye. Possible symptoms include: Nausea wheezing Shortness of breath a metallic or bitter taste in the mouth a feeling of flushing or warmth that lasts for a few minutes itching or facial swelling that can last up to an hour

These symptoms usually are not serious, and most often they disappear on their own, but be sure to let your health care team know if you begin to have any of them. In rare cases, people have a severe allergic reaction that causes trouble breathing and requires treatment with medicines, such as epinephrine. If there is a risk that you might have an allergic response, you may be given a test dose of the contrast material first. Be sure to let your health care team know if youve had a reaction to contrast dye (or to seafood or iodine) in the past. What Else Should I Know About This Test? Although a CT scan is sometimes described as a "slice" or a "crosssection," no cutting or incisions are involved. The amount of radiation received during a CT scan is more than that with a standard x-ray. People who are very overweight may have trouble fitting into the CT scanner. Tell your doctor if you have an allergy or are sensitive to iodine, seafood, or contrast dyes. CT scans can cost up to 10 times as much as a standard x-ray.

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Magnetic Resonance Imaging (MRI) Other Names Magnetic resonance (MR), nuclear magnetic resonance (NMR) imaging What Does It Show? Like computed tomography (CT) scans, MRI displays a cross-section of your body. However, MRI uses powerful magnetic fields instead of radiation to create the images. An MRI scan can present cross-sectional slices (views) from several angles, as if someone were looking at a slice of your body from the front (frontal view), from the side (sagittal view), or from above your head (axial view). The procedure creates images of soft tissue parts of the body that would sometimes be hard to see using other imaging tests. MRI is especially valuable in detecting and localizing cancer in the brain and spinal cord, head, neck, and bones and muscles. Used with contrast agents, it is the best way to see brain tumors. Using MRI, doctors can sometimes tell a benign tumor from a malignant (cancerous) tumor. In recent years, MRI has become the main way to thoroughly evaluate the female reproductive system, and it is helpful in determining the stage of endometrial cancer before surgery. Another important use for MRI is looking for signs that cancer may have metastasized (spread) to the liver from another site in the body. MRI images can also help doctors plan treatment such as surgery or radiation therapy. Unlike x-rays or CT scans, MRI cannot detect calcifications (tiny mineral deposits that may suggest the presence of cancer) in tissues such as the breast. However, special MRI machines, now available in a few hospitals, are designed specifically for examining the breast. MRI is sometimes used along with mammograms or breast ultrasound to look for breast cancer, particularly in younger women or those with very dense breasts. At this time MRI is not recommended by itself for the early detection of breast cancer. How Does It Work? An MRI scanner is a cylinder that houses a very strong magnet weighing several tons. As you lie on a table within the scanner, the device 200

surrounds you with a powerful magnetic field. The magnetic force causes the nucleus (center) of hydrogen atoms in your body to line up in one direction. Once the atoms are "standing at attention," the MRI machine emits a burst of radio-frequency waves. These waves cause the hydrogen atom nuclei to change their alignment. When the nuclei return to their original position, they emit certain signals, which the scanner detects. Hydrogen nuclei in different tissues change alignment in different ways. A computer interprets the signals resulting from these changes and converts them into a 2- or 3-dimensional black and white image. Contrast materials can be injected through a vein to improve the quality of the image. Once absorbed by the body, these agents speed up the rate at which tissue responds to stimulation from magnetic and radio waves. As a result, the signals produce stronger and clearer images. How Do I Prepare for the Test? No special diet or preparation is needed before an MRI. Some tests require injection of a contrast medium prior to the imaging. If a contrast material is to be injected, you may have an intravenous (IV) catheter inserted into an arm vein. If being placed in an enclosed space such as the MRI scanner concerns you, you may need to take medicine to help you relax. Talking with the technologist or a patient counselor or getting a "tour" of the MRI machine before the test can be helpful. Ideally, you will be able to see and hear what's going on through the use of an intercom system. You will also have a call button should you need to speak with someone. In some cases, you can arrange to have the test done with an open MRI machine that allows more space around your body (see below). Before the test, you may need to undress and put on a gown. Be sure to remove any metal objects. Before the scan, the MR technologist will ask you if you have any metal in your body, such as surgical clips or staples, pacemakers, artificial joints, metal fragments, tattoos, permanent eyeliners, and so on. Some metallic objects will not cause problems, but others might. You may need to have an x-ray to check for metal objects if there is any doubt. What Is It Like Having the Test?

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MRI scans are usually done on an outpatient basis in a hospital or clinic. You will lie down on a flat table. The technologist sometimes attaches straps to help keep you from moving or pillows to hold you in position. The table then glides through an opening in the cylinder. The part of your body that is being examined will be positioned in the center of the device. The test is painless, but you have to lie still inside the cylinder, the surface of which is a few inches from your face. You may be asked to hold your breath during certain parts of the test. The machine may make loud, thumping noises, similar to the sound of hammering, as the magnet switches on and off. Some facilities allow you to wear earplugs or headphones during testing. Newer machines that are less restrictive may be easier to tolerate. These open MRI machines replace the cylinder with a larger ring. This design lessens the banging sound and the claustrophobic feeling of lying in an enclosed space. However, the device does not generate as powerful a magnetic field. While open MRI technology is improving, the images may not be as clear or detailed as they are with standard MRI. In some cases, this may require retesting on a standard MRI machine. How Long Does It Take? MRI scans can take a long time typically between 45 and 60 minutes and sometimes up to 2 hours. After the test, you may be asked to wait while the images are looked at to see if more images are needed.

What Are the Possible Complications? Some people have mild reactions to the contrast agents. Such reactions include: Nausea Pain at the injection site Headache that develops a few hours after the test is over

These symptoms are much less common with MRI contrast agents than with those used for CT scans, but be sure to let your health care team know if you experience any of them.

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Some people become very uncomfortable, even panicky, when lying inside the MRI scanner. What Else Should I Know About This Test? People who are overweight may have trouble fitting into the MRI machine. Some kinds of metallic surgical implants, such as pacemakers, certain types of surgical clips or staples, or implanted pumps, may cause problems due to the strong magnetic field. Your health care team will ask you questions about these before the procedure. If you have an implanted intravenous (IV) catheter or port for long-term delivery of medication, your doctor will need to determine whether you should have an MRI. If you have tattoos or permanent makeup (such as eyeliner), let the technician know so that they can take the needed precautions and ensure the best results. MRI does not involve exposure to radiation. The use of MRI during pregnancy has not been well studied. MRI is usually avoided in the first 12 weeks of pregnancy unless there is a strong medical reason to use it. Do not bring credit cards with you into the exam room the magnet could wipe out the information stored on the card. MRI is more expensive than a CT scan and may not be available in some areas.

Radiographic Studies (Regular X-rays and Contrast Studies) Other Names Radiographs, roentgenograms. What Do They Show? Radiographs, commonly known as x-rays, produce shadow-like images of certain organs or tissues. An abdominal x-ray may reveal tumors or other diseases in organs of the abdomen, including the intestines, 203

stomach, liver, spleen, and kidneys. A chest x-ray is used to detect lung diseases, including cancer. These tests, which produce a single image or series of still images, are sometimes referred to as standard radiographic studies. Mammography (a breast x-ray) is another form of radiographic study (for more information, see the section Mammography). Special types of x-ray tests may use dyes called contrast materials. For example, a lower gastrointestinal (GI) series, often called a barium enema exam, takes x-ray images after the bowel is filled with barium sulfate (a contrast material). Another contrast study, intravenous pyelography (IVP), examines the structure and function of the kidneys. With advances in technology, many contrast studies once commonly used for diagnosis are being replaced by other methods, such as CT or MRI scans (see separate sections). How Do They Work? A special tube inside the x-ray machine produces a controlled beam of radiation. Tissues in the body block (absorb) the radiation to varying degrees. Dense tissues such as bones block most radiation, but soft tissues, such as fat or muscle, block less. After passing through the body, the beam falls on a piece of film, where it casts a kind of shadow. Tissues that block high amounts of radiation, such as bone, show up as white areas. Soft tissues block less radiation and show up in shades of gray, and organs that are mostly air (such as the lungs) normally appear black. Tumors are usually denser than the tissue around them, so they are often noticeable as lighter shades of gray. Contrast studies provide some information that standard x-ray techniques cannot. During a contrast study, you receive a dose of a contrast material that outlines, highlights, or fills in parts of the body so that they show up more clearly on an x-ray image. The contrast material may be given by mouth, as an enema, as an injection, or through a catheter (thin tube) inserted into various tissues of the body. For most of these tests, the images can be captured either on x-ray film or digitally (on a computer). Test Name(s) Organs Studied

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Contrast Given by angiography, angiogram, arteriography, arteriogram arteries throughout the body, especially brain catheter in an artery intravenous pyelography (IVP) urinary tract (kidney, ureters, bladder) injection into vein lower GI (gastrointestinal) series, barium enema (BE), double-contrast barium enema (DCBE), air-contrast barium enema (ACBE) colon, rectum enema lymphangiography lymphography lymph nodes, small lymph vessels injection through lymph vessel upper GI series barium swallow esophagography eophagus, stomach, part of small intestine mouth How Do I Prepare for the Test(s)? Other than removing metal objects that might interfere with the image, no special preparation is needed before having a standard x-ray. Preparation for a contrast study depends on the specific test. You may be asked not to eat anything or to prepare in other ways before the test (see next section). The radiology center where you are having the test should supply you with instructions. Check with them first. Your doctor also may give you instructions. What Is It Like Having the Test(s)? Standard x-rays: Usually x-rays are taken by an x-ray technologist, not by a doctor. You undress to expose the part of the body that will be x-rayed, removing rings or other objects that may interfere with the image. You will be asked to sit, stand, or lie down, depending on what part of the body will be imaged. Your body is placed in contact with a flat box that contains the x-ray film. The technologist then moves the machine to aim the beam of radiation at the correct area. You may have protective shields placed over parts of your body near the area to be xrayed so that they are not exposed as well. Usually the technologist leaves the room to operate the machine by remote control. Your exposure to the ray is kept to an absolute minimum usually less than a second. You may hear a short buzzing sound while the machine is working. For a chest x-ray, views are taken from the front and the side. Your arms will be at your side during the front exposure and will be placed either above your head or in front of you during the side exposure. The technologist will tell you when to take a deep breath and hold still. During an abdominal x-ray, you lie down on a table. You may be asked 205

to change position if several views are needed. Again, you will need to hold your breath and lie still during the exposure. After the exposure, the technologist will return to the room to move the machine out of the way, remove any protective shields, collect the film, and help you back to the changing room where you can get dressed. Angiography: In the past, angiography was often used to stage (tell the extent of) cancers, but CT and MRI scans are now used more often for these purposes. Angiography is occasionally used to show surgeons the location of blood vessels next to a cancer so that the operation can be planned to limit blood loss. Angiography is still used a great deal to diagnose non-cancerous blood vessel diseases. These types of studies are done by a radiologist, a doctor who specializes in imaging, with the help of technologists. Your diet will be restricted before this exam. Usually you will receive a sedative to relax you before the test starts. As you lie still on the table, the skin over the injection site is cleansed and numbed. A catheter (thin plastic tube) is inserted into a blood vessel (usually the femoral artery at the top of the thigh) and moved forward until it reaches the area to be studied. The contrast dye is then injected rapidly, and a series of xray images is taken. When the pictures are finished, the plastic tube is removed. Firm pressure may be needed on the insertion site for a time to ensure there is no excessive bleeding from the site. You will also be asked to lie flat for up to several hours. In recent years, advances in technology have led to the development of less invasive forms of angiography. CT angiography captures images of blood vessels using a CT scanner instead of a standard x-ray machine. The contrast dye can be injected into a vein in the arm instead of having to insert a catheter into a major blood vessel, which means the test takes less time and involves fewer risks than standard angiography. Magnetic resonance angiography (MRA) is an MRI study of the blood vessels. It may be done with or without having a contrast dye injected into an arm vein, and is therefore also quicker and less invasive than standard angiography. Intravenous pyelography (IVP): This test is used to study kidney function and to look for tumors of the urinary tract. You will likely be asked to not eat or drink anything for about 12 hours before the test, and you will be given laxatives to cleanse the bowel. For the test itself, you lie on a table for a series of x-rays. Contrast material is then given through a vein in your arm. Your kidneys remove the 206

contrast material from the bloodstream, and it enters the urinary tract. Another series of x-rays is taken at intervals over the next 30 minutes or so. Pressure may be applied to the abdomen to improve the clarity of the image. Once the dye has reached the bladder, you will be asked to urinate while another x-ray is taken. Lower GI series (barium enema): This study is used to look at the lining of the colon (large intestine) and rectum. Your intake of food and liquid may be restricted a few days before the test. Laxatives and/or enemas are used to cleanse the colon (large intestine). For the test, you lie secured on a table, and a series of x-rays is taken. Then liquid barium is inserted through a small tube placed in your rectum. The liquid feels cool. More images are taken while the table tilts you into different positions. You have to lie still and hold your breath as each image is taken. After the test, you can go to the toilet to excrete the barium solution. To get clearer pictures, a "double-contrast" exam is often done. This exam uses a smaller quantity of thicker barium liquid, followed by an infusion of air into your bowel. This can cause a sense of fullness, along with an urge to empty your bowels. Upper GI series (barium swallow): This test is used to study the lining of the esophagus, stomach, and the duodenum (first part of the small intestine). You will likely be asked to not eat or drink for 8 to 12 hours before the exam. As with the lower GI series, you lie on a tilting table while a series of x-ray images is taken. You will need to swallow a barium mixture, which has a consistency similar to a milkshake, several times during the test. You may also be asked to swallow baking soda crystals to create gas in your stomach. Sometimes pictures are taken several hours later to assess the small intestine. After the test you may take a laxative to speed up removal of the barium from your body. Lymphangiography: Although not commonly used to detect cancer, a lymphangiogram may be helpful in planning treatment or monitoring a response to treatment for some types of cancer, such as lymphoma. In some cases, you may be asked to fast or have only a liquid diet before the test. For the test, a blue dye is injected into the skin between your toes to reveal the lymphatic vessels. After a numbing medicine is applied, an incision is made in the foot and a very thin catheter (tube) is 207

inserted into a lymphatic vessel. The contrast material is slowly injected and allowed to travel through the lymph system. This may take an hour or two. Then a series of x-rays are taken. You may be asked to return on the next day or two for more x-rays, but you will not need to have dye injected during these visits. How Long Do They Take? standard x-ray: About 5 to 10 minutes angiography: From 1 to 3 hours intravenous pyelogram: About 1 hour lower GI series: 30 to 45 minutes upper GI series: 30 minutes to 6 hours, depending on the part of the digestive system being tested lymphangiography: 2 to 5 hours, plus another 30 minutes each time during the next few days for repeat studies

What Are the Possible Complications/Side Effects? Standard x-rays: Complications are very unlikely. Angiography: You may have a warm or burning feeling as the dye is given. The contrast material may cause nausea, vomiting, flushing, itching, or a bitter or salty taste. In rare cases, people have a severe allergic reaction to the iodine in the contrast material.

There is a small risk of a blood clot forming on the end of the catheter, which could block a blood vessel. There is also a small risk of damage to the blood vessel from the tip of the catheter, which could lead to internal bleeding. A hematoma (a large collection of blood under the skin) may develop at the incision site if pressure is not kept on it long enough. (Possible complications of CT or MR angiography are less serious and are similar to those described in the sections on CT and MRI). Intravenous pyelogram (IVP): The test is generally safe, but it should not be given to people who are sensitive to contrast material with iodine. This causes some people to have nausea, vomiting, flushing, itching, or a bitter or salty taste. In rare cases, people have a severe reaction to the contrast material. Lower GI series (barium enema): The test is not painful, but it can be uncomfortable. Some patients have abdominal cramping. Many 208

elderly patients find the procedure tiring. The barium contrast material will make your stools a light color for a few days after the test and may cause constipation. Upper GI series (barium swallow): The barium mixture has the thickness of a milkshake and has a chalky taste. Baking soda crystals can cause gas and belching. After the test, your stools will be lighter in color for a few days, and you may be constipated. Lymphangiography: The injection can cause discomfort at and near the site of contrast dye injection. An allergic reaction to the dye is possible. The dye can change the color of urine, stool, or skin for the next 1 to 2 days. Changes in the color of the skin around the toes can last for several months.

What Else Should I Know About These Tests? X-ray studies expose the body to radiation, but modern x-ray equipment uses the minimum amount of radiation needed (See General Questions and Comments on Radiation Risk for more information.) A newer technology, digital radiology, produces images on computer screens rather than on film. The size and contrast of the images can be adjusted to make them easier to read, and they can easily be sent to computers in other medical offices or hospitals through electronic connections. If you are to have a test involving the use of a contrast dye, tell your doctor if you have a known allergy to contrast materials or to seafood (which contains high levels of iodine).

Mammography Other Names mammogram, digital mammography What Does It Show? A mammogram is an x-ray exam of the breast. It can detect and diagnose many cases of breast cancer.

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A mammogram is an effective screening tool. A screening mammogram is used to look for signs of breast disease when you do not have any breast symptoms. Many breast cancers take years to develop. A mammogram can detect cancer in its early stages, when treatment is most likely to be successful. A diagnostic mammogram is the imaging test used when you have breast symptoms or when abnormalities appear on a screening mammogram. Diagnostic mammograms may include additional views (images) of the breast that are not usually done on screening mammograms. Mammograms can't prove that an abnormal area is (or is not) cancer, but it can give information that shows whether further testing is needed. The 2 main types of breast abnormalities that can be found with a mammogram are calcifications and masses. Calcifications are tiny mineral deposits within the breast tissue, which look like small white spots on the films. They may or may not be caused by cancer. There are 2 types of calcifications: Macrocalcifications are coarse (larger) calcium deposits that are most likely changes in the breasts caused by aging of the breast arteries, old injuries, or inflammation. These deposits are related to non-cancerous conditions and do not require a biopsy (removing a sample of tissue for viewing under a microscope). Macrocalcifications are found in about half the women over 50, and in 1 of 10 women under 50. Microcalcifications are tiny specks of calcium in the breast. They may appear alone or in clusters. Microcalcifications seen on a mammogram are of more concern, but still usually do not mean that cancer is present. The shape and layout of microcalcifications help the radiologist judge how likely it is that cancer is present. In most instances, the presence of microcalcifications does not mean a biopsy is needed. In other cases, the microcalcifications look more suspicious and a biopsy is needed.

A mass, which may occur with or without calcifications, is another important change seen on mammograms. Masses can be caused by many things, including cysts (non-cancerous, fluid-filled sacs) and noncancerous solid tumors, but they could be cancer and usually should be biopsied if they are not cysts.

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A cyst cannot be diagnosed by physical exam alone, nor can it be diagnosed by a mammogram alone. To confirm that a mass is really a cyst, either breast ultrasound or removal of fluid with a thin, hollow needle (aspiration) is needed. If a mass is not a simple cyst (that is, if it is at least partly solid), then you may need to have more imaging tests. Some masses can be watched with periodic mammograms, while others may need a biopsy. The size, shape, and margins (edges) of the mass help the radiologist to determine whether cancer may be present.

Your prior mammograms may help show that a mass has not changed for many years, which would mean that the mass is likely a benign condition and a biopsy would not be needed. Having your prior mammograms available to the radiologist is very important. A mammogram may show something suspicious, but by itself it cannot prove that an abnormal area is cancer. If a mammogram raises a suspicion of cancer, tissue must be removed and looked at under the microscope to tell if it is cancer. This can be done with a needle biopsy or an open surgical biopsy. To get an accurate breast biopsy, enough cells or fluid must be removed from the suspicious area for the pathologist to study. It can be hard for a doctor to insert the needle precisely where the abnormality exists, especially if the lump cannot be felt. To improve accuracy, your doctor may use different imaging studies to guide the placement of the needle: Stereotactic mammography uses mammograms taken from 2 angles (a "stereo" view). A computer calculates the precise location of the mass or calcification and then guides the placement of the biopsy needle. Breast ultrasound can also be used to guide biopsy needles (see the section on Ultrasound).

A ductogram (galactogram) is a type of mammogram that is done after a contrast agent is inserted into a nipple duct with a thin tube. It is used to evaluate nipple discharge. How Does It Work?

A mammogram uses a machine designed specifically to examine your breast tissue. The machine takes a different form of x-ray and at lower 211

doses than a usual x-ray. Because these x-rays do not go through tissue easily, the machine has 2 plates that compress the breast to spread the tissue apart. This gives a more accurate image using less radiation. Digital mammography: Digital mammography (also known as fullfield digital mammography or FFDM) is similar to standard mammography in that x-rays are used to produce an image of the breast. The differences are in the way the image is recorded, viewed by the doctor, and stored. Standard mammogram images are recorded on large sheets of photographic film, whereas digital images are captured electronically and viewed on a computer screen. They are stored on a computer and their magnification, brightness, or contrast can be changed after the exam is done to help the doctor see certain areas more clearly. Digital images can be sent electronically from one location to another for remote consultation with breast specialists. While many centers do not offer the digital option at this time, it is expected to become more widely available in the future. Because digital mammograms cost more than standard mammograms, studies are now under way to determine which form of mammogram will benefit more women in the long run. Some studies have found that women who have digital mammograms have to return less often for additional imaging tests because of inconclusive areas on the original mammogram. A recent large study from the National Cancer Institute found that digital mammography was more accurate than film mammography in finding cancers in women younger than 50 and in women with dense breast tissue, although the rates of inconclusive results were similar between digital mammography FDM and film mammography. It is important to remember that standard film mammography is also effective for these groups of women, and that they should not skip their regular mammogram if a digital mammogram is not available. Over the past 2 decades, computer-aided detection and diagnosis (CAD) has been developed to help radiologists detect suspicious areas on mammograms. This is done most commonly with screen-film mammograms and less often with digital mammograms. Computers can help doctors identify abnormal areas on a mammogram by acting as a second set of eyes. For standard mammograms, the film is fed into a machine which converts the image into a digital signal that is then analyzed by the computer. Alternatively, the technology can be applied to an image captured with digital mammography. The computer then displays the image on a video screen, with markers 212

pointing to areas it "thinks" the radiologist should check especially closely. Early tests have found that CAD can help find some cancers that doctors might have otherwise missed. But doctors still disagree about how many cancers the device will pick up. Some doctors feel that the device is not as effective as simply having a second radiologist review the films. Others are concerned that the device may lead to unnecessary biopsies by falsely identifying benign abnormalities as being suspicious for cancer. Most breast specialists are encouraged by recent progress in computer-aided detection and look forward to more technical refinements and studies that help to clarify its role in breast cancer detection. A ductogram uses a contrast dye to outline a breast duct (a tube through which milk passes) on an x-ray. This allows a doctor to see any growths or other abnormalities within it that may be causing nipple discharge. How Do I Prepare for the Test? The best time to schedule a mammogram is one week after your period, when your breasts are likely to be less sensitive. Youll need to undress from the waist up for the exam, so you may want to wear a shirt or blouse and a skirt or pants, rather than a dress, to make undressing easier. No special preparation, such as diet restriction, is necessary. However, on the day of your mammogram, do not use deodorants, perfumes, powders, or ointments under your arms or on your breasts because these may interfere with the images. A screening mammogram usually requires 2 views of each breast one from the top and one from the side. You may need to have more images taken to include as much breast tissue as possible, especially if the mammogram is being used for diagnosis or for guiding the placement of a needle for biopsy or if you have breast implants. What Is It Like Having the Test? You will be asked to undress from the waist up and to remove any jewelry around your neck. Your breast will rest on a flat surface. The compression will feel tight, but it should not be very painful. You hold your breath while the technologist takes the picture.

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For a ductogram, the nipple is first cleaned and sterilized. The doctor then applies gentle pressure to look for discharge and find the opening of the duct. He or she then inserts a very thin tube into the nipple duct and slowly infuses a contrast dye. How Long Does It Take? The screening mammogram from start to finish takes about 15 to 20 minutes. A diagnostic mammogram, involving images from more angles or close-up views, takes a total of 30 to 45 minutes. The breast is compressed for only a few seconds of that time. Ductograms may take a little longer. What Are the Possible Complications? A mammogram involves low doses of radiation and is safe. The very low risk that cancer may result from exposure to radiation during a mammogram is far outweighed by the benefits of detecting an early cancer. Some women find that mammograms are painful, but for most the compression causes only temporary discomfort. There have been reports of breast implant ruptures during mammography, but these are very rare. Because ductograms involve the use of a contrast material, some women may have allergic reactions to them. In some cases the doctor may have trouble finding the opening of the duct, which may require probing the area or even rescheduling the exam a week or two later. What Else Should I Know About This Test? The American Cancer Society has developed guidelines for the early detection of breast cancer in women who are not having breast symptoms: Women 40 years of age and older should have a mammogram every year and a clinical breast exam (CBE) performed by a health care professional every year. They also have the option of performing a breast self-exam (BSE) every month. The CBE should be conducted close to and preferably before the scheduled mammogram.

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Women aged 20 to 39 should have a clinical breast exam by a health care professional every 3 years and have the option of performing breast self-exam every month. Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram. See Breast Cancer: Early Detection for more information on breast cancer risk.

Mammography alone cannot detect all cases of breast cancer. For this reason, mammograms should be used in addition to a clinical breast exam by a health care professional. Knowing how your breasts normally look and feel, and reporting any changes to your doctor, is also very important. To reduce the chance of discomfort during a mammogram, schedule the procedure for a week or so after your menstrual period, when your breasts are less likely to be tender. A negative mammogram (no sign of calcifications or masses) does not necessarily mean that cancer is not present or that cancer will not develop later. The need for a biopsy does not mean that you have cancer. About 70% to 80% of biopsies turn out to be benign (not cancer). If you have breast implants, find a radiologist who is experienced in performing mammograms on augmented breasts and let the facility know this ahead of time. Additional views may be necessary, so it may take longer. Nuclear Scans Other Names Nuclear imaging, radionuclide imaging, nuclear medicine scans What Do They Show? Nuclear scans provide images based on the bodys chemistry rather than on anatomy (as is the case with other imaging tests). They use substances called radionuclides (also known as tracers or

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radiopharmaceuticals) that release low levels of radiation. The small amount of radioactivity used is harmless. Inside the body, tissues affected by certain diseases such as cancer may absorb more or less of the tracer than normal tissues. Special cameras pick up the pattern of radioactivity to create images that show where the material has traveled and where it has accumulated. The scans show certain disorders of internal organs and tissues more accurately than standard x-ray images. If cancer is present, the tumor may show up on the image as a "hot spot" an area of increased uptake. Depending on the type of scan performed, the tumor may instead be a "cold spot" a site of decreased uptake. Nuclear scans are used to locate tumors, especially in the bones and thyroid gland. They are also used to study a cancer's stage (extent of its spread) and to decide if treatment is working. In the past, nuclear scans were often used to detect liver and brain tumors. Because of improvements in technology, a CT or MRI scan can now be done instead of a nuclear scan in many of these cases. Nuclear scans may not detect very small tumors, nor do they always distinguish between benign and malignant (cancerous) tumors. They are often used along with other imaging tests to give a more complete picture of what is going on. For example, bone scans that show "hot spots" on the skeleton are usually followed by x-rays of the affected bones, which are better at showing details of the bone structure. Nuclear scans have different names, depending on the organ involved. Some of the more commonly used nuclear scans (described in more detail below) include: Bone scans Gallium scans FDG PET scans

How Do They Work? The type of scan done depends on what organ or tissue the doctor wishes to study. In general you are given an oral or intravenous (IV) dose of a compound that emits small doses of radiation.

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Radionuclide scans: Because they evaluate more than just the anatomy of a tumor, radionuclide scans have uses other than simply creating images. There are several radionuclides now in use:

Gallium-67 is used to detect cancer in the lungs, in lymph nodes or in bone marrow (such as Hodgkin disease or non-Hodgkin lymphoma). Gallium can also be used for a whole body scan (also called a gallium scan). Technetium-99 is used in whole body scans, especially in bone scans that look for metastasis (spread) to bones from breast, lung, prostate, or other cancers. Technetium sestamibi (Miraluma) scans are being studied for their usefulness in breast cancer, as well as in determining the resistance of some tumors to chemotherapy. Thallium-201 scans, more commonly used in cardiology (the study of heart disease), are sometimes used to determine the effectiveness of treatment for brain or lung tumors and may be useful for detecting lymphomas, as well as thyroid and breast cancers. Radioactive iodine (iodine-123 or iodine-131) can be used to detect (and even treat) thyroid cancers and some neuroendocrine tumors, such as carcinoid tumors. These substances emit gamma rays, which can be detected by a special camera (known as a gamma camera, rectilinear scanner, or scintiscan). The signals are processed by a computer, which turns them into two- or three-dimensional (3D) images, sometimes with color added for extra clarity. A radiologist or a doctor who specializes in nuclear medicine interprets the image and sends a report to your doctor. A form of radionuclide scanning using a special gamma camera, called single-photon emission computed tomography (SPECT), has become available in recent years. It has better resolution than standard radionuclide scanning. Like a CT scan, SPECT uses a rotating camera to create 3D cross-sectional images, or "slices," of the body. However, this technique uses radioactive substances, rather than the x-rays used in CT scans. SPECT is often used to detect bone metastasis in patients with cancer. Positron emission tomography (PET) scans: Positron emission tomography (PET) is a technique that usually involves a form of radioactive sugar known as fluorodeoxyglucose (FDG). Cells of the body 217

absorb different amounts of the radioactive sugar, depending on how fast they are growing. Cancer cells, which grow quickly, are more likely to take up large amounts of FDG. The substance gives off tiny atomic particles called positrons, which run into electrons in the body, giving off gamma rays. A special camera detects these rays as they leave the body. By providing data on how active the cells in the body are PET scans can help identify which tumors are more aggressive and can distinguish tumors from normal tissue that has been affected by cancer treatment. PET scans are especially useful for studying the brain. The technique is still fairly new but is becoming more widely used in looking at cancers of the head and neck, thyroid, esophagus, breast, colon, rectum, ovary, and lung, as well as melanomas and lymphomas. A newer imaging machine combines PET scanning with CT scanning. PET/CT scanners provide more detailed information on the location of any increased cell activity, helping doctors to pinpoint the location of tumors. Use of monoclonal antibodies in nuclear scans: A special type of antibody produced in the lab called a monoclonal antibody can be designed to stick to substances found only on the surface of cancer cells. A radioactive substance is attached to the monoclonal antibody, which is then given into a vein. It travels in the bloodstream until it reaches the tumor. The antibody, still carrying its radioactive cargo, attaches to the surface of the tumor. This causes the tumor to light up when viewed through a special scanner. Monoclonal antibody scanning is sometimes used to evaluate cancers of the prostate (ProstaScint scan), colon (OncoScint, CEA-Scan), ovaries (OncoScint), breast, skin (melanoma), and other organs. How Do I Prepare for the Test? The steps to take in preparing for a nuclear scan depend on the type of test and the tissue that will be studied. Gallbladder, liver, or thyroid scans require that you don't eat or drink for 2 to 12 hours beforehand. In other cases, you may be asked to take a laxative or have an enema. You may need to avoid some medicines (prescription and over-thecounter) before the test, so be sure to check with your doctor or nurse. Your health care team will provide you with specific instructions.

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The radioactive material is given by mouth or by injection into a vein, usually a few minutes or several hours before the test. For example, in a bone scan, the dose is injected about 2 hours before the test begins. You will have to drink several glasses of water to flush out any of the radioactive material that is not absorbed by the bones. For gallium scans, on the other hand, the injection is given a few days before imaging. What Is It Like Having the Test? A nuclear scan can be done on an outpatient basis, but because of the special materials and equipment needed, the scans are usually done in the radiology or nuclear medicine department of a hospital. You lie on a table while the scanner moves back and forth. The technician may ask you to shift positions to allow different views to be taken. The test is not painful. However, you may become uncomfortable after lying on the table for a while. If you are having a brain scan, several sets of images may be needed. The first scans are taken as the radioactive material moves through the arteries into the brain. The second set, taken a few hours later, reveals the presence of the material in the brain itself. You will be asked to move your head into different positions. Similarly, a thyroid scan may require 2 sets of tests using oral doses of radioactive iodine. How Long Does It Take? A nuclear scan takes about 30 to 60 minutes, plus the waiting time after the radioactive material is given. For bone scans, the material takes 2 to 3 hours to be absorbed, and the scan itself takes another hour or so. Gallium scans take several days between the injection and the actual scanning. Results of nuclear scans are usually available within a few days. What Are the Possible Complications? Generally, nuclear scans are safe procedures. The doses of radiation are very small, and the radionuclides have a low risk of toxicity or allergy. Some people may experience pain or swelling at the site where the radioactive material is injected. Using a moist, warm cloth on the area can relieve symptoms. Rarely, some people will develop a fever or allergic reaction when given a monoclonal antibody.

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What Else Should I Know About This Test? The amount of radiation exposure from a nuclear scan is about the same as that from standard x-rays. The scanning machine itself does not emit radiation. The radioactive material used during the test is eliminated from the body within a few hours or a few days. Talk to your health care team about sexual activity or being close to children during this time. The day after a scan, to reduce your risk of exposure to radioactive material excreted in urine, you should flush the toilet immediately after you use it. Nuclear scans are not recommended for pregnant women or nursing mothers.

Ultrasound (US) Other Names ultrasonography, sonography, sonogram What Does It Show? An ultrasound machine produces images called sonograms by generating high-frequency sound waves that go through your body. As the sound waves bounce off your internal organs and tissues, they create echoes. Cysts (fluid-filled sacs) and solid tumors have different echo patterns than normal body tissues. Ultrasound is especially good at giving pictures of some diseases of soft tissues that do not show up as well on x-rays. Ultrasound is an excellent way to tell fluid-filled cysts from solid tumors because the echo patterns produced by these disorders look very different. In diagnosing breast masses, for example, ultrasound is often used to tell cysts from solid 220

tumors. Ultrasound can also be used to determine how deeply a tumor of the esophagus, rectum, or uterus has gone through the wall of the organ. However, ultrasound images are not as detailed as those from CT or MRI scans. Ultrasound alone cannot distinguish a benign tumor from a cancerous one. Its use is also limited in some areas of the body because the sound waves cannot go through air (such as in the lungs) or through bone. Doctors often use ultrasound to determine where to place a needle to obtain a biopsy (withdrawing fluid or tiny tissue fragments for viewing under a microscope). This procedure occurs in "real time" -- that is, the doctor can look at the ultrasound monitor while moving the needle and actually see the needle moving toward and into the tumor. For some types of ultrasound exams, the transducer (the wand that produces the sound waves and detects echoes) is placed on the skin surface. The sound waves pass through the skin and reach the internal organs. In other cases, to get the best images, the doctor must use a transducer that is inserted into a body opening, such as the esophagus, rectum, or vagina. Special ultrasound machines, known as Doppler flow machines, are able to show how blood is flowing through the vessels. This is important because blood flows differently through tumors than it does through normal tissue. Some of these machines make color images to increase the amount of information it contains. Unlike other forms of blood vessel imaging, color Doppler studies do not require contrast agents. Color Doppler has made it easier for doctors to determine if cancer has spread into blood vessels, especially in the liver and pancreas. How Does It Work? An ultrasound machine has 3 key parts: a control panel, a display screen, and a transducer, which looks somewhat like a microphone or a computer mouse. The doctor or ultrasound technologist passes the transducer over the part of the body being studied. The transducer emits sound waves and picks up the echoes. The computer inside the main part of the machine analyzes the signals and displays an image on a computer screen. The shape and intensity of the echoes depend on how dense the tissue is. For example, most of the sound waves pass right through a fluid221

filled cyst and send back very few or faint echoes, causing it to appear black on the display screen. But the waves will bounce off a solid tumor, creating a pattern of echoes that the computer will translate into a lighter colored image. How Do I Prepare for the Test? As a general rule, no preparation is needed. However, your doctor or nurse will give you specific instructions about steps to take before your test. Depending on the organ being studied, you may need to fast overnight, take a laxative, or have an enema. If you will have an abdominal ultrasound, you may need to drink a large amount of water just before the study to fill your bladder. This will create a better picture because sound waves travel better through fluid. What Is It Like Having the Test? Ultrasound tests can be done in a doctor's office, clinic, or hospital. You will lie down on a table. The technologist will apply a gel to the part of the skin over which the transducer will pass. The gel both lubricates the skin and enhances the transmission of the sound waves. The gel feels cool and slippery. If a probe is used, it will be covered with gel and inserted into the body opening. Such procedures are not painful, but they can cause you to feel pressure or discomfort. During the test the technologist or the doctor moves the transducer back and forth. You may be asked to hold your breath during the scan to prevent excess movement. The operator may adjust knobs or dials to increase the depth to which the sound waves are sent. You may feel slight pressure from the transducer, but you will not hear the highfrequency sounds. How Long Does It Take? An ultrasound exam usually takes 20 to 30 minutes. The length of time depends on the type of exam and the ease or difficulty in finding any abnormalities of the organs being studied. What Are the Possible Complications? Ultrasound is a very safe procedure with a low risk of complications. Good images are harder to obtain in people who are obese. What Else Should I Know About This Test? 222

Ultrasound does not use radiation. Ultrasound costs much less than CT or MRI. The quality of the results depends to a large extent on the skill of the technologist or doctor operating the transducer, which is not the case with CT or MRI. Newer forms of ultrasound can provide 3D images. Contrast agents that may be used to enhance the quality of the picture are currently being studied.

Categories of Some Common Imaging Tests Angiogram: see Radiographic Studies Arteriogram: see Radiographic Studies Angiogram Barium enema: see Radiographic Studies Lower GI Series Barium swallow: see Radiographic Studies Upper GI Series Bone scan: see Nuclear Scans Gastrointestinal series: see Radiographic Studies Upper and Lower GI Series Positron emission tomography (PET): see Nuclear Scans Pyelography, intravenous (IVP): see Radiographic Studies SPECT: see Nuclear Scans X-ray: see Radiographic Studies General Comments on Radiation Risk In large doses, radiation can cause severe tissue damage and increase a person's risk of later developing cancer. Although the low doses of radiation used for imaging tests can increase a person's cancer risk slightly, it is important to put this risk into perspective. How Much Does an Imaging Test Increase a Person's Yearly Exposure to Radiation?

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Many people do not realize that we are constantly exposed to radiation from a variety of sources, including radioactive materials in our environment and cosmic rays from outer space. The average person is exposed to about 3 millisieverts (mSv) of radiation from natural sources over the course of a year. (A millisievert is a measure of radiation exposure.) Much of this is due to radon, a naturally occurring gas whose levels vary across the country. Because the earth's atmosphere blocks some cosmic rays, living at a higher altitude increases a person's exposure. For example, residents in Denver, Colorado have an annual exposure level of about 5 mSv. A round-trip airline flight across the United States increases exposure by about 0.03 mSv. A single chest x-ray exposes the patient to about 0.1 mSv, which is about the radiation dose people are exposed to naturally over the course of about 10 days. Some other imaging tests involve higher exposures. A lower GI series exposes a person to about 4 mSv while a CT scan of the abdomen exposes a person to about 10 mSv. (MRI and ultrasound exams do not expose a person to radiation.)

How Much Does the Additional Radiation Exposure Increase a Person's Cancer Risk? Unfortunately this is a hard question to answer. Most studies on the subject have looked at people exposed to higher doses of radiation, such as uranium miners and atomic bomb survivors. The risk from lowlevel radiation exposure is not easy to calculate from these studies. Researchers have estimated that radiation exposure from the average diagnostic x-ray may increase cancer risk very slightly (likely on the order of hundredths to thousandths of one percent). Of course, this can be affected by the type of test done, the area of the body exposed, and other factors. Because of this very small but real effect, and the fact that radiation exposure from all sources can add up over ones lifetime, imaging tests involving radiation should not be done without a valid medical reason. In many cases, other imaging tests such as ultrasound or MRI that do not involve radiation may be used. But when there is a reason to believe that an x-ray test or CT scan is the best way to diagnose cancer or 224

other diseases, the benefit to the patient is virtually certain to exceed the risk posed by the small dose of radiation. How Imaging Tests Are Used in Specific Cancers Many different methods are used to obtain images, including x-rays, ultrasound, magnetic resonance imaging (MRI), nuclear medicine scans, and so on. The approach your health care team recommends may depend on a number of factors: The location and type of the tumor; some imaging studies work better for certain organs or tissues If a biopsy (tissue sample) is needed The balance between any risks or side effects and the potential benefits The costs

The following table lists the imaging tests that may be used for various types of cancers. Other types of tests, such as endoscopy (inspection of body organs or cavities using a flexible, lighted tube), may be used in addition to or in place of those listed. Tests are chosen based on the extent and type of cancer. If you have questions about a test that your health care team has advised for you, ask them to explain the purpose of the test. Table 2: Common Uses of Imaging Tests in Oncology Bladder and Ureter Detection: Intravenous pyelogram Staging: MRI or CT of pelvis Chest x-ray

Breast Screening: Mammogram (screening) Ultrasound or MRI (together with mammogram in some younger women or those with dense breast tissue)

Detection: 225

Mammogram (diagnostic) Ultrasound (distinguish solid masses from cysts) MRI Nuclear scans (under investigation)

Image-guided biopsy: Stereotactic mammography Ultrasound

Staging: Chest x-ray Nuclear scan (bone scan) CT or MRI of abdomen and/or head

Brain & Spinal Cord Detection: MRI (usually preferred) CT

Imaging-guided biopsy: CT Staging: CT or MRI Colon and Rectum Screening: Lower GI series (barium enema with air contrast) Detection: Lower GI series (barium enema with air contrast) Staging: Chest x-ray CT of abdomen and chest Ultrasound (with rectal probe to check depth of rectal cancer invasion) MRI (rectal cancer)

Endometrium (Lining of Uterus) Staging:

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MRI (Usually surgery is performed for primary staging of the cancer; but MRI provides added information about involvement of lymph nodes) Ultrasound with vaginal probe (to estimate depth of invasion within uterus)

Esophagus Detection: Upper GI series (barium swallow) Staging: Ultrasound with esophageal probe (to estimate depth of tumor invasion and assess nearby lymph node involvement) CT of chest and abdomen

Head and Neck Staging: CT or MRI (evaluate size of tumor and spread to nearby soft tissue, bone, blood vessels, etc.) Kidney Detection: Intravenous pyelogram Staging: CT Chest x-ray CT of abdomen and chest MRI (to check for cancer spread into nearby veins)

Liver Detection: CT MRI Ultrasound

Image-guided biopsy: CT Ultrasound

Staging: 227

 Lung

CT MRI

Detection: Chest x-ray CT

Image-guided biopsy: CT Fluoroscopy (continuous x-ray)

Staging: CT of chest, head, abdomen MRI

Non-Hodgkin Lymphoma & Hodgkin Disease Detection: CT MRI

Image-guided biopsy: Ultrasound CT

Staging: CT MRI Lymphangiogram (rarely done)

Soft Tissue (Muscle, Tendons, Fat) Detection: CT 228

MRI

Image-guided biopsy: CT Staging: CT of chest, head, abdomen Ovary Detection: Ultrasound MRI CT

Staging: CT, MRI, or PET may be done before surgery. Staging is done during surgery.

Pancreas Detection/diagnosis: CT MRI Ultrasound

Image-guided biopsys Staging: CT Prostate Detection: Ultrasound with rectal probe Image-guided biopsy: Ultrasound with rectal probe Staging: Bone scan CT or MRI Monoclonal antibody nuclear scan (ProstaScint)

Stomach Detection/diagnosis: Upper GI series (barium swallow with double contrast) Staging: 229

Ultrasound CT Chest x-ray

Thyroid Detection/diagnosis: Image-guided biopsy: Staging: Nuclear medicine CT Nuclear medicine scans Ultrasound

CT = Computed tomography MRI = Magnetic resonance imaging PET= Positron emission tomography GI = Gastrointestinal Screening tests refer to procedures used to find a disease, such as cancer, in people who do not have symptoms of that disease. Detection refers to diagnostic procedures used if you have some indication (such as symptoms, abnormal physical exam results, or abnormal results from screening tests) that a disease such as cancer may be present. Imaging tests for detection can help find a mass or other abnormality of tissue and can often predict whether it is likely to be a cancer or some other type of disease. However, in almost all cases, a tissue sample (biopsy) must be viewed under the microscope to be sure if a cancer is present. Image-guided biopsy refers to use of imaging tests to help guide a biopsy needle into the area of abnormal tissue. An image-guided biopsy can often provide tissue for study without the need for surgery. Staging is the process of determining how far a cancer has grown and spread. Imaging tests are often used to estimate the size of a cancer; to find out how far it has spread in the organ in which it started; and to see whether it has spread to nearby tissues and organs, nearby lymph nodes, or distant organs. Most of the tests listed in this section are used to look for metastases in distant organs or tissues. For instance, men with prostate cancer often have bone scans to see if the cancer has spread to bones.

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Selection of imaging tests for staging will depend on the doctor's impression of how far the cancer is likely to have spread, as well as symptoms. People with larger cancers and those that have already spread to lymph nodes may need tests such as nuclear scans, CT scans, or MRI to look for distant metastases. People with bone pain, neurologic symptoms (such as numbness, paralysis, problems with balance or coordination, etc.), or other symptoms suggesting distant metastasis will have more extensive evaluation by imaging tests. On the other hand, these tests may not be done in people without symptoms of metastasis who have small tumors that appear localized. Questions That People Ask About Cancer What is cancer? Cancer is not just one disease. It is a group of diseases, and so far, more than 100 different types of cancer have been identified. All forms of cancer cause cells in the body to change and grow out of control. Most types of cancer cells form a lump called a tumor. Cells from the tumor can break away and travel to other parts of the body. There they may continue to grow and form more tumors. This process of spreading is called metastasis. Even when cancer spreads somewhere else in the body, it is still the same kind of cancer, and is still named after the part of the body where it started. For example, if lung cancer spreads to the bones, it is still lung cancer not bone cancer. In that case, it may be said that the person has lung cancer with bone metastases. Some cancers, such as cancers of the blood, do not form a tumor. Cancer of the blood is called leukemia. Not all tumors are cancer. A tumor that is not cancer is called benign (be-nine). Benign tumors do not grow and spread the way cancer does. They are usually not a threat to life. Another word that also means cancerous is malignant. So a tumor that is cancer is called a malignant tumor. What causes cancer? Some kinds of cancer are caused by things people do. For example, smoking can cause cancers of the lungs, mouth, throat, bladder, kidneys and several other organs, as well as heart disease and stroke. 231

While not everyone who smokes gets cancer, smoking increases a person's chance of getting the disease. Drinking a lot of alcohol has also been shown to increase a person's chance of getting cancer of the mouth, throat, and some other organs. This is especially true if the person drinks and smokes. Radiation can cause cancer. For example, people exposed to nuclear fallout have a higher cancer risk than those who were not exposed. Rarely, radiation treatment for one type of cancer can cause another cancer to grow many years later. This is why doctors and dentists use the lowest possible doses of radiation for x-rays and scans (much lower than that used for cancer treatment). Too much exposure to sunlight without any protection can cause skin cancer. Melanoma is a very serious form of cancer that is linked to sunlight and tanning bed exposure. About 1 in 20 cases of cancer is caused by genes that are inherited from parents. No one knows the exact cause of most cases of cancer. We know that certain changes in our cells can cause cancer to start, but we don't yet know exactly how this happens. Many scientists are studying this problem. Can injuries cause cancer? It is a common myth that injuries can cause cancer. The fact is that a fall, a bruise, a bone fracture, or other such injury cannot cause cancer. Sometimes a person might visit the doctor for what is thought to be an injury and cancer is found at that time. But the injury did not cause the cancer; it was already there. It also sometimes happens that a person will remember an injury that happened long ago in the place cancer was found. Rarely, burn scars can be the site of cancer many years after the burn has healed. Most often, skin cancer is the type that grows in a burn scar. Is cancer caused by stress? Researchers have done many studies to see if there is a link between personality, stress, and cancer. No scientific evidence has shown that 232

someone's personality or outlook can significantly affect their cancer risk. However, there are many factors that come into play when looking at the relationship between stress and cancer. While it is known that stress affects the immune system, so do many other factors. Despite many studies, a link between psychological stress and cancer has not been proven. Looking at the studies that have been done, it seems they sometimes come to opposite conclusions. In a large Danish study, people who reported major stressors in their lives did not appear to have a seriously increased risk for any type of cancer. A study that looked at women with major life stressors, such as divorce or the death of someone close, found a slight increase (about 1/3 higher than average) in breast cancer compared to women without these stressors. In the area of day-to-day stress, another study showed higher breast cancer risk linked to stress. Yet another found that women reporting higher day-to-day stress actually were less likely to be diagnosed with breast cancer within the next 18 years. It is difficult to explain these differences. Some of the differences may be related to the groups that were studied, while others may be explained by the way the study was done. Chance may have played a role. All that can be said for now is that a consistent link between stress and risk of cancer has yet to be found. Is cancer contagious? In the past, people often stayed away from someone who had cancer. They were afraid they might "catch" the disease. But cancer is not like the flu or a cold. You cannot "catch" cancer from someone who has it. You will not get cancer by being around or touching someone with cancer. Don't be afraid to visit someone with cancer. They need the support of their family and friends. Can cancer be prevented? Smoking and drinking alcohol cause some people to get certain types of cancer. These cancers might be prevented by not using tobacco or alcohol. It is best to never use tobacco at all and to stay away from secondhand smoke. Cigarettes, cigars, pipes, and oral tobacco products cause cancer and should not be used. People who already smoke should try to quit. Former smokers have less risk of cancer than do people who continue to smoke. 233

You can lower your chances of getting skin cancer by staying in the shade as much as you can; wearing a hat, shirt, and sunglasses when you are in the sun; and using sunscreen with a sun protection factor (SPF) of 15 or higher. We know that our diet (what we eat or don't eat) is linked to some types of cancer, although the exact reasons are not yet clear. The best advice is to eat a lot of fresh fruits and vegetables, focus on whole grain pastas and breads, and cut down on high-fat foods. It is also good to limit how much red and processed meats (such as bacon, lunch meats, and hot dogs) you eat, and use low-fat dairy products. To find cancer early, adults should have regular tests, called screening examinations. Talk to your doctor about which screening tests might be right for you. If cancer is found early, it can often be treated successfully. How many people alive today have ever had cancer? Today there are more than millions of people alive in the world who have had some type of cancer. Some of these people have been cured; others still have the disease. Years ago, most people who had cancer did not live very long. That is not the case any more. Every year more and more people survive cancer. This is especially true of children with cancer. The survival rates are different for people with different types of cancers. Some types of cancer grow very slowly. Some respond to treatment very well. Others grow and spread faster and are harder to treat. If you know someone who has cancer, keep in mind that what happens to them could be very different from what happens to someone else with another type of cancer. What are the different types of cancer treatment? Surgery, chemotherapy, and radiation are the 3 main types of cancer treatment, and a person with cancer may have 1, 2, or all 3 of these treatments. Surgery is often the first treatment option considered if the cancer is in the form of a tumor that can be removed from the body. Sometimes

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only part of the cancer can be removed. Radiation or chemotherapy might be used to shrink the cancer before or after surgery. Doctors use chemotherapy to kill cancer cells. The term chemotherapy (often shortened to "chemo") refers to the use of medicines to kill cancer cells. Usually, the drugs are given intravenously (into a vein) or taken by mouth. Chemotherapy drugs then go throughout the body in the bloodstream, reaching cancer cells that may have metastasized (spread) from the tumor. Radiation therapy involves treatment with high energy rays (such as xrays) to kill or shrink cancer cells. The radiation may come from outside the body (external radiation) or from radioactive materials placed directly in the tumor (internal or implant radiation). The procedure for getting external radiation is similar to that of getting an x-ray and is painless, although side effects may occur. Other kinds of treatment you might hear about include hormone therapy, stem cell or bone marrow transplant, and immunotherapy. Hormone therapy is sometimes used to treat specific kinds of prostate and breast cancers. Immunotherapy is treatment designed to boost the cancer patients own immune system to help fight the cancer. What are the side effects of cancer treatment? The type of treatment a person receives depends on the type and stage of the cancer, the age of the patient, and his or her medical history and general health. Each drug or treatment plan has different side effects. It is hard to predict what side effects will occur, even if patients receive the same treatment. Some effects can be severe and others fairly mild. While it is true that some people have a tough time with cancer treatment, there are also many who manage quite well throughout treatment. Short-term (and often treatable) side effects of chemotherapy can include nausea and vomiting, loss of appetite, hair loss, and mouth sores. Because chemotherapy can damage the blood-producing cells of the bone marrow, patients may have low blood cell counts. This can lead to: increased chance of infection (due to a shortage of white blood cells) bleeding or bruising after minor cuts or injuries (due to a shortage of blood platelets) anemia (due to low red blood cell counts), which can cause fatigue, shortness of breath, and other symptoms 235

For these reasons, oncologist must work carefully with the patient to manage the side effects of chemotherapy. Because everyone's body is different, each person will respond differently to chemotherapy drugs. Most of the side effects of chemotherapy will go away after treatment ends. For example, hair lost during treatment always grows back after treatment. In the meantime, most patients are able to use wigs, scarves, or hats to cover, warm, or protect their heads. Radiation treatments are much like x-rays and do not cause any pain. The most common side effects are skin irritation and fatigue. Fatigue is especially common when treatments go on for several weeks. Fatigue is a feeling of extreme tiredness and low energy, which often does not improve with rest. People also report sometimes that their fatigue is made worse by the daily trips to the hospital to get their radiation treatments. Is cancer treatment worse than cancer? This is a belief that can be dangerous to some people. Those who think this is true might not follow important treatment recommendations that can save their lives. It is easy to understand one of the sources of this belief. Often people diagnosed with cancer have never had any symptoms or pain, or any problems they've had have been fairly small. In the early stages of cancer, symptoms tend to be minor, if there are any at all. It is only after the treatment starts that they start to feel sick. It is true that chemotherapy, radiation, and surgery can cause distressing symptoms. However, the side effects fade after the treatment is over, and the treatment can be life-saving. Of course, there are some situations in which a person in very poor health may not be able to take cancer treatment. Or due to age and other medical conditions, a person might decide not to be treated for cancer, even knowing that it will cause death. This is a person's choice, as long as the person is a competent adult who is able to handle his or her affairs. The person who is thinking of refusing treatment must also clearly understand the likely outcomes of both treatment and non-treatment before making a decision to refuse treatment. Later in the course of 236

cancer, when more serious symptoms start, curative treatment may no longer be an option. Cancer kills by invading the intestines, lungs, brain, liver, kidneys, or other vital organs, or by interfering with a body function that is necessary for life. Untreated cancer commonly causes death. In contrast, cancer treatment is usually fairly short term and can save lives. Even when it cannot cure, treatment can often prolong life. And medical care can always be used to make a person more comfortable by reducing pain and other symptoms caused by the cancer or its treatment. There are times when every cancer patient questions their commitment to the difficult journey of treatment and its side effects. Sometimes they can get discouraged by the uncertainty of treatment and wonder if it's worth it. This is normal. It may help to remember that every year, cancer treatments get more and more effective, and doctors are learning better ways to work with patients to control treatment side effects too. Coping with Cancer in Everyday Life Almost 11 million Americans alive today have faced a diagnosis of cancer. Some of them have just been diagnosed or are going through treatment, while others no longer have active symptoms of cancer or are thought to be cured. No 2 people with cancer are alike -- just as no 2 friends or family members are alike.Each person has his or her own way of coping with cancer. Here we will review how some people facing cancer have dealt with their feelings and their individual situations. This information comes from many people who have shared their thoughts and feelings about coping with cancer. They've shared because they believe it's helpful to hear from others who have been "in their shoes." The Emotional Impact of a Cancer Diagnosis When you are told you have cancer, the diagnosis affects not only you, but also your family and friends. Making Informed Decisions

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Learning all they can about you and your cancer is the first step your doctor will take. Telling Your Family and Friends People who have been told they have cancer may wonder who to tell and how they should tell them. For the Person Who Has Cancer People facing cancer often find themselves facing the possibility of their own death. For Spouses, Family, and Friends Friends and families may also have a hard time adjusting to the cancer diagnosis. Finding Support Support can come from family and friends, as well as from health professionals, support groups, or your place of worship.

Life after Cancer Although each person with cancer looks forward to getting back to "normal" life, the process can be challenging. Additional Resources Find resources for coping with cancer in everyday life. People who are at increased risk for certain cancers may need to follow a different screening schedule, such as starting at an earlier age or being screened more often. Those with symptoms that could be related to cancer should see their doctor right away. Cancer-related checkup For people aged 20 or older having periodic health exams, a cancerrelated checkup should include health counseling, and depending on a 238

person's age and gender, might include exams for cancers of the thyroid, oral cavity, skin, lymph nodes, testes, and ovaries, as well as for some non-malignant (non-cancerous) diseases. Special tests for certain cancer sites are recommended as outlined below. Breast cancer * Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health. * Clinical breast exam (CBE) should be part of a periodic health exam, about every 3 years for women in their 20s and 30s and every year for women 40 and over. * Women should know how their breasts normally feel and report any breast change promptly to their health care providers. Breast self-exam (BSE) is an option for women starting in their 20s. * Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram. Yearly MRI screening is not recommended for women whose lifetime risk of breast cancer is less than 15%. Colon and rectal cancer Beginning at age 50, both men and women at average risk for developing colorectal cancer should use one of the screening tests below. The tests that are designed to find both early cancer and polyps are preferred if these tests are available to you and you are willing to have one of these more invasive tests. Talk to your doctor about which test is best for you. Tests that find polyps and cancer * * * * flexible sigmoidoscopy every 5 years* colonoscopy every 10 years double contrast barium enema every 5 years* CT colonography (virtual colonoscopy) every 5 years*

Tests that mainly find cancer 239

* fecal occult blood test (FOBT) every year*,** * fecal immunochemical test (FIT) every year*,** * stool DNA test (sDNA), interval uncertain* *Colonoscopy should be done if test results are positive. **For FOBT or FIT used as a screening test, the take-home multiple sample method should be used. A FOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening. People should talk to their doctor about starting colorectal cancer screening earlier and/or being screened more often if they have any of the following colorectal cancer risk factors: * a personal history of colorectal cancer or adenomatous polyps * a personal history of chronic inflammatory bowel disease (Crohns disease or ulcerative colitis) * a strong family history of colorectal cancer or polyps (cancer or polyps in a first-degree relative [parent, sibling, or child] younger than 60 or in 2 or more first-degree relatives of any age) * a known family history of hereditary colorectal cancer syndromes such as familial adenomatous polyposis (FAP) or hereditary nonpolyposis colon cancer (HNPCC) Cervical cancer * All women should begin cervical cancer screening about 3 years after they begin having vaginal intercourse, but no later than when they are 21 years old. Screening should be done every year with the regular Pap test or every 2 years using the newer liquid-based Pap test. * Beginning at age 30, women who have had 3 normal Pap test results in a row may get screened every 2 to 3 years. Another reasonable option for women over 30 is to get screened every 3 years (but not more frequently) with either the conventional or liquid-based Pap test, plus the HPV DNA test. Women who have certain risk factors such as diethylstilbestrol (DES) exposure before birth, HIV infection, or a weakened immune system due to organ transplant, chemotherapy, or chronic steroid use should continue to be screened annually.

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* Women 70 years of age or older who have had 3 or more normal Pap tests in a row and no abnormal Pap test results in the last 10 years may choose to stop having cervical cancer screening. Women with a history of cervical cancer, DES exposure before birth, HIV infection or a weakened immune system should continue to have screening as long as they are in good health. * Women who have had a total hysterectomy (removal of the uterus and cervix) may also choose to stop having cervical cancer screening, unless the surgery was done as a treatment for cervical cancer or precancer. Women who have had a hysterectomy without removal of the cervix should continue to follow the guidelines above. Endometrial (uterine) cancer The American Cancer Society recommends that at the time of menopause, all women should be informed about the risks and symptoms of endometrial cancer, and strongly encouraged to report any unexpected bleeding or spotting to their doctors. For women with or at high risk for hereditary non-polyposis colon cancer (HNPCC), annual screening should be offered for endometrial cancer with endometrial biopsy beginning at age 35. Prostate cancer Both the prostate-specific antigen (PSA) blood test and digital rectal examination (DRE) should be offered annually, beginning at age 50, to men who have at least a 10-year life expectancy. Men at high risk (African-American men and men with a strong family of one or more first-degree relatives [father, brothers] diagnosed before age 65) should begin testing at age 45. Men at even higher risk, due to multiple firstdegree relatives affected at an early age, could begin testing at age 40. Depending on the results of this initial test, no further testing might be needed until age 45. Information should be provided to all men about what is known and what is uncertain about the benefits, limitations, and harms of early detection and treatment of prostate cancer so that they can make an informed decision about testing. Men who ask their doctor to make the decision on their behalf should be tested. Discouraging testing is not appropriate. Also, not offering testing is not appropriate.

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The Complete Guide Nutrition and Physical Activity This document is a condensed version of the article describing the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines, which are updated every 5 years. The guidelines were developed by the American Cancer Society 2006 Nutrition and Physical Activity Guidelines Advisory Committee and approved by the American Cancer Society National Board of Directors on May 19, 2006. The full article, written for heath care professionals, is published in the September/October 2006 issue of CA: A Cancer Journal for Clinicians, and is available for free online at: http://caonline.amcancersoc.org/content/vol56/issue5/. Nutrition and physical activity guidelines for cancer prevention: summary ACS recommendations for individual choices Maintain a healthy weight throughout life. * Balance calorie intake with physical activity. * Avoid excessive weight gain throughout life. * Achieve and maintain a healthy weight if currently overweight or obese. Adopt a physically active lifestyle. * Adults: Engage in at least 30 minutes of moderate to vigorous physical activity, above usual activities, on 5 or more days of the week; 45 to 60 minutes of intentional physical activity are preferable. * Children and adolescents: Engage in at least 60 minutes per day of moderate to vigorous physical activity at least 5 days per week. Eat a healthy diet, with an emphasis on plant sources. * Choose foods and drinks in amounts that help achieve and maintain a healthy weight. * Eat 5 or more servings of a variety of vegetables and fruits each day. * Choose whole grains over processed (refined) grains. * Limit intake of processed and red meats. If you drink alcoholic beverages, limit your intake.

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* Drink no more than 1 drink per day for women or 2 per day for men. ACS recommendation for community action Public, private, and community organizations should work to create social and physical environments that help people adopt and maintain healthful nutrition and physical activity behaviors. * Increase access to healthful foods in schools, worksites, and communities. * Provide safe, enjoyable spaces for physical activity in schools. * Provide for safe, physically active transportation (such as biking and walking) and recreation in communities. ACS nutrition and physical activity guidelines for cancer prevention Maintain a healthy weight throughout life. * Balance calorie intake with physical activity. * Avoid excessive weight gain throughout life. * Achieve and maintain a healthy weight if currently overweight or obese. Being overweight or obese is clearly linked with an increased risk of developing several types of cancer: * * * * * breast (among women who have gone through menopause) colon endometrium (uterus) esophagus kidney

Obesity also likely raises the risk of other cancers: * * * * * * * * cervix gallbladder Hodgkin lymphoma multiple myeloma ovary pancreas thyroid aggressive forms of prostate cancer

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Some studies have shown a link between losing weight and lowering the risk of getting certain cancers such as breast cancer. While research in this area is still going on, people who are overweight or obese are encouraged to lose weight. A healthy weight depends on a person's height, so recommendations for a healthy weight are often expressed in terms of body mass index (BMI). BMI is a measure of body fat based on height and weight. Individuals should strive to maintain a healthy weight. Adult BMI chart The way to achieve a healthy body weight is to balance energy intake (food and drink) with energy used (physical activity). The healthiest way to reduce calories is to reduce intake of added sugars, saturated and trans fats, and alcohol, which provide a lot of calories, but few or no essential nutrients. Calorie intake can also be reduced by decreasing the size of food portions (see table below) and limiting the intake of foods and drinks that are high in calories, fat, and/or refined sugars, and which provide few nutrients. Examples include fried food, cookies, cakes, candy, ice cream, and sweetened soft drinks. What counts as a serving? Fruits 1 medium apple, banana, orange cup of chopped, cooked, or canned fruit cup of 100% fruit juice Vegetables 1 cup of raw, leafy vegetables cup of other cooked or raw vegetables, chopped cup of 100% vegetable juice Grains 1 slice of bread 1 ounce of ready-to-eat cereal cup of cooked cereal, rice, or pasta Beans and nuts cup of cooked dry beans 2 tablespoons of peanut butter 1/3 cup nuts 244

Dairy foods and eggs 1 cup of milk or yogurt 1 ounces of natural cheese 2 ounces of processed cheese 1 egg Meats 2-3 ounces of cooked, lean meat, poultry, or fish Note that foods listed as "cooked" should be measured after cooking. Adopt a physically active lifestyle. * Adults: Engage in at least 30 minutes of moderate to vigorous physical activity, above usual activities, on 5 or more days of the week; 45 to 60 minutes of intentional physical activity are preferable. * Children and adolescents: Engage in at least 60 minutes per day of moderate to vigorous physical activity at least 5 days per week. Usual activities are those that are done on a regular basis as part of one's daily routine. These activities include those done at work (such as walking from the parking garage to the office), at home (such as climbing a flight of stairs), as well as those that are part of daily living (such as dressing and bathing). Usual activities are typically brief and of low intensity. Intentional activities are those that are done in addition to these usual activities. Moderate activities are those that require effort equal to a brisk walk. Vigorous activities generally use large muscle groups and cause faster heart rate, deeper and faster breathing, and sweating. Examples of moderate and vigorous intensity physical activities Moderate Activities Vigorous Activities Exercise and Leisure Walking, dancing, leisurely bicycling, ice-skating or roller-skating, horseback riding, canoeing, yoga Jogging or running, fast bicycling, circuit weight training, aerobic dance, martial arts, jump rope, swimming Sports Volleyball, golfing, softball, baseball, badminton, doubles tennis, downhill skiing Soccer, field hockey or ice hockey, lacrosse, singles tennis, racquetball, basketball, cross-country skiing Home Activities Mowing the lawn, general lawn and garden maintenance Digging, carrying and hauling, masonry, carpentry

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Occupational Activity Walking and lifting as part of the job (custodial work, farming, auto or machine repair) Heavy manual labor (forestry, construction, fire fighting) Physical activity may reduce the risk of several types of cancer: * * * * breast colon endometrium (uterus) prostate

The benefits of a physically active lifestyle go far beyond lowering cancer risk. They include lower risk of heart disease, high blood pressure, diabetes, and osteoporosis (bone thinning). Tips on how to be more active * Use stairs rather than an elevator. * If you can, walk or bike to your destination. * Exercise at lunch with your co-workers, family, or friends. * Take an exercise break at work to stretch or take a quick walk. * Walk to visit co-workers instead of phoning or sending an email. * Go dancing with your spouse or friends. * Plan active vacations rather than sit-down trips. * Wear a pedometer (a device that counts each step taken) every day and increase your daily steps. * Join a sports team. * Use a stationary bicycle or treadmill while watching TV. * Plan your exercise routine to gradually increase the days per week and minutes per session. * Spend time playing with your kids. Eat a healthy diet, with an emphasis on plant sources. Choose foods and beverages in amounts that help achieve and maintain a healthy weight. * Pay attention to standard serving sizes (see table above), and read food labels to become more aware of the number of actual servings you eat. * Eat smaller portions of high-calorie foods. Be aware that "low-fat" or "nonfat" does not mean "low-calorie" and that low-fat cakes, low-fat cookies, and other low-fat foods are often high in calories. 246

* Switch to vegetables, fruits, and other low-calorie foods and beverages to replace calorie-dense foods and beverages such as French fries, cheeseburgers, pizza, ice cream, doughnuts and other sweets, and regular sodas. * When you eat away from home, choose food low in calories, fat, and sugar, and avoid large portion sizes. Eat 5 or more servings of vegetables and fruits each day. * * * * Include vegetables and fruits at every meal and for snacks. Eat a variety of vegetables and fruits each day. Limit French fries, snack chips, and other fried vegetable products. Choose 100% juice if you drink vegetable or fruit juices.

Choose whole grains over processed (refined) grains and sugars. * Choose whole grain rice, bread, pasta, and cereals. * Limit intake of refined carbohydrates (starches), such as pastries, sweetened cereals, and other high-sugar foods. Limit intake of processed meats and red meats. * Choose fish, poultry, or beans instead of beef, pork, and lamb. * When you eat meat, choose lean cuts and eat smaller portions. * Prepare meat by baking, broiling, or poaching, rather than by frying or charbroiling. If you drink alcoholic beverages, limit your intake. People who drink alcohol should limit their intake to no more than 2 drinks per day for men and 1 drink a day for women. The recommended limit is lower for women because of their smaller body size and slower breakdown of alcohol. A drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits. Alcohol is a known cause of cancers of the: * * * * * mouth pharynx (throat) larynx (voice box) esophagus liver 247

* breast Alcohol may also increase the risk of colon and rectum cancer. Diet and physical activity factors that affect risks for select cancers Bladder cancer The major risk factors for bladder cancer are tobacco smoking and being exposed to certain industrial chemicals. Some research suggests that drinking more fluids and eating more vegetables may lower the risk of bladder cancer. Brain tumors There are no known nutritional risk factors for brain tumors. Breast cancer The risk of breast cancer is increased by several factors that cannot be easily changed: * * * * having your first period before age 12 not having children or having your first birth after age 30 late age at menopause family history of breast cancer

But other factors may raise breast cancer risk as well. Both increased body weight and weight gain during adulthood are linked with a higher risk of breast cancer after menopause. Alcohol also increases risk to some extent, especially in women whose intake of folate is low. Moderate to vigorous physical activity may lower breast cancer risk. Greatly lowering fat intake may also lower breast cancer risk, although a recent major study found that this effect may be very small. The best advice to reduce the risk of breast cancer is to: * Engage in moderate to vigorous physical activity 45 to 60 minutes on 5 or more days a week. * Reduce lifetime weight gain by limiting your calories and getting regular physical activity. * Avoid or limit your intake of alcoholic beverages.

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Colorectal cancer The risk of colorectal cancer is higher for those with relatives who have had colorectal cancer. Risk is also increased by long-term tobacco use and possibly excessive alcohol use. Risk may be decreased by use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS, such as aspirin, ibuprofen, naproxen, and drugs like them) and hormone replacement therapy after menopause (postmenopausal). But neither aspirin-like drugs nor hormones after menopause are currently recommended to prevent colorectal cancer because of their potential side effects. Some studies show a lower risk of colon cancer among those who are moderately active on a regular basis, and more vigorous activity may even further reduce the risk of colon cancer. Obesity raises the risk of colon cancer in both men and women, but the link seems to be stronger in men. Diets high in vegetables and fruits have been linked with lower risk, and diets high in processed meats and/or red meats have been linked with a higher risk of colon cancer. Several studies have found that calcium, vitamin D, or a combination of the two may help protect against colorectal cancer. But because of the possible increased risk of prostate cancer with high calcium intake, it may be wise for men to limit their daily calcium intake to less than 1,500 mg per day until further studies are done. The best advice to reduce the risk of colon cancer is to: * * * * * * Increase the intensity and duration of physical activity. Limit intake of processed and red meats. Get the recommended levels of calcium. Eat more vegetables and fruits. Avoid obesity. Avoid excess alcohol.

In addition, it is very important to follow the American Cancer Society guidelines for regular colorectal screening because finding and removing polyps in the colon can prevent colorectal cancer. Endometrial cancer The major risk factors for the most common type of endometrial cancer (cancer of the lining of the uterus) involve excess exposure of the endometrium to estrogen, for instance: 249

* * * *

estrogen therapy after menopause certain types of birth control pills polycystic ovarian syndrome obesity

There is strong evidence of a link between obesity and endometrial cancer. Studies have also suggested lower endometrial cancer risk with high physical activity levels. Vegetable and fiber intake may lower risk, whereas red meat, saturated fat, and animal fat may increase risk. The link to weight is thought to result from the increase in estrogen levels that happens when women are overweight after menopause. At this time, the best advice to reduce the risk of endometrial cancer is to maintain a healthy weight through diet and regular physical activity, and to eat a plant-based diet rich in vegetables, whole grains, and beans. Kidney cancer The causes of kidney cancer are not clear, but the best-known risk factors that can be changed are obesity and tobacco smoking. Studies looking for links between specific parts of the diet and kidney cancer have not shown clear results. The best advice to lower risk for kidney cancer is to maintain a healthy weight and avoid tobacco use. Leukemias and lymphomas There are no known nutritional risk factors for leukemias or lymphomas. Lung cancer More than 85% of lung cancers result from tobacco smoking, and another 10% to 14% may be linked to radon exposure. Many studies have shown that the risk of lung cancer is lower among both smokers and nonsmokers who eat at least 5 servings of vegetables and fruits a day. Although healthful eating may reduce the risk of lung cancer, the risks from tobacco remain high. Using high-dose beta-carotene and/or vitamin A supplements has increased (not decreased) lung cancer risk among smokers (see beta-carotene under the section "Common questions about diet and cancer).

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The best advice to reduce the risk of lung cancer is to avoid tobacco use and secondhand smoke. Avoid radon exposure. Eat at least 5 servings of vegetables and fruits every day. Mouth, throat, and esophagus cancers Tobacco (including cigarettes, chewing tobacco, and snuff) and alcohol, and especially the combination of the two, increase the risk for cancers of the mouth, larynx (voice box), pharynx (throat), and esophagus. Obesity raises the risk for cancer in the lower esophagus and at the junction of the esophagus and stomach (likely due to increased acid reflux). There is some evidence that very hot beverages and foods may increase the risk of oral and esophageal cancers, likely as a result of the damage heat can cause. Eating the recommended amounts of vegetables and fruits probably reduces the risk of oral and esophageal cancers. The best advice to reduce the risk of these cancers is to: * * * * Avoid all forms of tobacco. Restrict alcohol intake. Avoid obesity. Eat at least 5 servings of vegetables and fruits each day.

Ovarian cancer The causes of ovarian cancer are not well understood. Family history is a risk factor, but fewer than 10% of ovarian cancers are inherited. There are no clearly proven nutritional risk factors for ovarian cancer -studies of vegetables, fruits, and dairy products have not found clear links. Moderate alcohol intake may lower risk. The roles of obesity and physical activity in ovarian cancer risk are unclear. Pancreatic cancer Tobacco smoking, adult-onset diabetes, and impaired glucose tolerance (sometimes called "pre-diabetes," or "borderline diabetes") all increase the risk for pancreatic cancer. Some studies have linked obesity, physical inactivity (both factors strongly linked to diabetes and prediabetes), and diets high in processed and red meats with increased pancreatic cancer risk. Some studies have also found high fruit and vegetable intake to be linked with a reduced risk. But none of these links has been clearly proven.

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The best advice to reduce the risk of pancreatic cancer is to: * * * * Avoid tobacco use. Maintain a healthful weight. Remain physically active. Eat 5 or more servings of vegetables and fruits each day.

Prostate cancer Prostate cancer is related to male sex hormones, but just how nutritional factors might increase risk remains unclear. Several studies suggest that diets high in certain vegetables (including tomatoes, cruciferous vegetables, soy, beans, and other legumes) or fish may be linked with decreased risk. There is some evidence that foods or supplements containing antioxidant nutrients, such as vitamin E, selenium, beta-carotene, and lycopene, may lower prostate cancer risk. However, a recent large study found no benefit from vitamin E or selenium supplements. Several studies have found that eating large amounts of red meats or dairy products may be linked with increased risk of prostate cancer. A high calcium intake, mainly from supplements, has also been linked to an increased risk for more aggressive types of prostate cancer. Although the link between obesity and prostate cancer risk is not clear, recent studies suggest that being overweight is linked to a worse outcome in men already diagnosed with prostate cancer. Exercise, especially vigorous exercise, may offer some benefit for prostate cancer. For now, the best advice to reduce the risk of prostate cancer is to: * Eat 5 or more servings of a wide variety of vegetables and fruits each day. * Limit intake of red meats and dairy products. * Maintain an active lifestyle and healthy weight. Stomach cancer Many studies have found that a high intake of fresh fruits and vegetables is linked with a lower risk of stomach cancer, while a high intake of salt-preserved foods is linked with a higher risk. There is also convincing evidence that chronic stomach infection by the bacterium Helicobacter pylori raises the risk of stomach cancer. Rates of stomach

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cancer have also likely been reduced by refridgeration and better food preservation, which allow fresh foods to be eaten all year long. The number of stomach cancer cases in most parts of the world is falling. While stomach cancer is fairly rare in the United States, the incidence of cancers in the first part of the stomach (the top, or the cardia) has risen in recent years. This may be due at least in part to increases in gastric reflux, which has been linked to obesity. At this time, the best advice to reduce the risk of stomach cancer is to: * Eat at least 5 servings of vegetables and fruits daily. * Reduce intake of foods that are preserved with salt. * Maintain a healthy weight. Common Questions About Diet and Cancer Because people are interested in the relationship that specific foods, nutrients, or lifestyle factors have to specific cancers, research on health behaviors and cancer risk is often reported on the news. No one study, however, provides the last word on any subject, and single news reports may put too much emphasis on what appear to be contradictory or conflicting results. In brief news stories, reporters cannot always put new research findings in their proper context. Therefore, it is rarely, if ever, advisable to change diet or activity levels based on a single study or news report. The following questions and answers address common concerns about diet and physical activity in relation to cancer. Alcohol Does alcohol increase cancer risk? Yes. Alcohol raises the risk of cancers of the mouth, pharynx (throat), larynx (voice box), esophagus, liver, and breast, and probably of the colon and rectum. People who drink alcohol should limit their intake to no more than 2 drinks per day for men and 1 drink per day for women. A drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits. The combination of alcohol and tobacco increases the risk of some cancers far more than the effect of either drinking or smoking alone. Regular intake of even a few drinks per week is linked to a higher of breast cancer in women, especially in women who do not get enough folate. Women at high risk of breast cancer may want to consider not drinking any alcohol.

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Antioxidants What are antioxidants, and what do they have to do with cancer? The body seems to use certain nutrients in vegetables and fruits to protect against damage to tissues that happens constantly as a result of normal metabolism (oxidation). Because such damage is linked with increased cancer risk, the so-called antioxidant nutrients are thought to protect against cancer. Antioxidants include vitamin C, vitamin E, carotenoids, and many other phytochemicals (chemicals from plants). Studies suggest that people who eat more vegetables and fruits, which are rich sources of antioxidants, may have a lower risk for some types of cancer. Clinical studies of antioxidant supplements are currently under way but have not yet proven to reduce cancer risk from vitamin or mineral supplements (also see entries for: beta-carotene, lycopene, vitamin E, supplements). To reduce cancer risk, the best advice at present is to get your antioxidants through food sources, rather than supplements. Aspartame Does aspartame cause cancer? Aspartame is a low-calorie artificial sweetener that is about 200 times sweeter than sugar. Current evidence does not show any link between aspartame use and increased cancer risk. People with the genetic disorder known as phenylketonuria should avoid foods and drinks that contain aspartame. Beta-carotene Does beta-carotene reduce cancer risk? Because beta-carotene, an antioxidant chemically related to vitamin A, is found in vegetables and fruits, and because eating vegetables and fruits is linked with a reduced risk of cancer, it seemed to make sense that taking high doses of beta-carotene supplements might reduce cancer risk. But the results of 3 major clinical trials show this is not the case. In 2 studies in which people were given high doses of betacarotene supplements in an attempt to prevent lung cancer and other cancers, the supplements were found to increase the risk of lung cancer in cigarette smokers, and a third found neither benefit nor harm from them. Therefore, eating vegetables and fruits that contain beta-carotene

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may be helpful, but high-dose beta-carotene supplements should be avoided. Bioengineered foods What are bioengineered foods, and are they safe? Bioengineered foods are made by adding genes from other plants or organisms to make a plant more resistant to pests and slow spoilage. Some genes improve flavor, nutrient composition, or make the food easier to transport. In theory, these added genes might create substances that could cause harmful reactions among sensitized or allergic individuals. But there is no evidence at this time that the substances found in bioengineered foods now on the market are harmful or that they would either increase or decrease cancer risk because of the added genes. Calcium Is calcium related to cancer? Several studies have suggested that foods high in calcium might help reduce the risk for colorectal cancer, and that using calcium supplements modestly reduces the formation of colorectal adenomas (polyps). But there is also evidence that a high calcium intake, mainly through supplements, is linked with increased risk for prostate cancer, especially for prostate cancers that are more aggressive. In light of this, both men and women should try to get the recommended levels of calcium, mainly from food sources. Recommended intake levels of calcium are 1,000 mg/day for people ages 19 to 50 years and 1,200 mg/day for people older than 50. Dairy products are excellent sources of calcium, as are some leafy vegetables and greens. People who get much of their calcium from dairy products should select low-fat or nonfat choices to reduce their intake of saturated fat. Cholesterol Does cholesterol in the diet increase cancer risk? Cholesterol in the diet comes only from foods with animal sources -meat, dairy products, eggs, and animal fats such as butter or lard. Although some of these foods (for example, processed and red meats) are linked with higher risk of certain cancers, at this time there is little evidence that this increased risk is specifically related to cholesterol. 255

Lowering blood cholesterol reduces heart disease risk, but there is no evidence that lowering blood cholesterol affects cancer risk. Coffee Does drinking coffee cause cancer? Caffeine may worsen symptoms of fibrocystic breast lumps (a type of benign breast disease) in some women, but there is no evidence that it increases the risk of breast cancer or other types of cancer. The link between coffee and cancer of the pancreas, which got a lot of attention in the past, has not been confirmed by recent studies. There does not appear to be any link between coffee drinking and cancer risk. Fat Will eating less fat lower cancer risk? There is little evidence that the total amount of fat a person eats affects cancer risk. But diets high in fat tend to be high in calories and may contribute to obesity, which in turn is linked with an increased risk of several types of cancer. There is evidence that certain types of fats, such as saturated fats, may increase cancer risk. There is little evidence that other types of fat (omega-3 fatty acids, found mainly in fish), monounsaturated fatty acids (found in olive and canola oils), or other polyunsaturated fats reduce cancer risk. Fiber What is dietary fiber, and can it prevent cancer? Dietary fiber includes a wide variety of plant carbohydrates that humans cannot digest. Specific categories of fiber are "soluble" (like oat bran) or "insoluble" (like wheat bran and cellulose). Soluble fiber helps to reduce blood cholesterol, which lowers the risk of coronary heart disease. Good sources of fiber are beans, vegetables, whole grains, and fruits. Links between fiber and cancer risk are weak, but eating these foods is still recommended. These foods contain other nutrients that may help reduce cancer risk and have other health benefits. Fish Does eating fish protect against cancer?

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Fish is a rich source of omega-3 fatty acids. Studies in animals have found that these fatty acids suppress cancer formation or slow down cancer growth, but there is limited evidence of a possible benefit in humans. While eating fish rich in omega-3 fatty acids is linked with a reduced risk of heart disease, some types of fish (large predatory fish such as swordfish, tilefish, shark, and king mackerel) may contain high levels of mercury, polychlorinated biphenyls (PCBs), dioxins, and other environmental pollutants. Women who are pregnant, breast-feeding, or planning to become pregnant, and young children should not eat these fish. People should vary the types of fish they eat to reduce the chance of exposure to toxins. Research has not yet shown whether taking omega-3 or fish oil supplements produces the same possible benefits as eating fish. . Fluorides Do fluorides cause cancer? Extensive research has looked at the effects of fluorides given as dental treatments or added to toothpaste, public water supplies, or foods on cancer risk. Fluorides have not been found to increase cancer risk. Folate What is folate, and can it prevent cancer? Folate is a B vitamin found in many vegetables, beans, fruits, whole grains, and fortified breakfast cereals. Since 1998, all grain products in the United States have been fortified with folate. Too little folate may increase the risk of cancers of the colon, rectum, and breast, especially in people who drink alcoholic beverages. Current evidence suggests that to reduce cancer risk, folate is best obtained by eating vegetables, fruits, and enriched grain products. Food additives Do food additives cause cancer? Many substances are added to foods to preserve them and to enhance color, flavor, and texture. New additives must be cleared by the Food and Drug Administration (FDA) before entering the food supply. 257

Rigorous testing in animals to look for any effects on cancer is done as part of this process. Additives are usually present in very small quantities in food, and no convincing evidence has shown that any additive at these levels causes human cancers. Garlic Can garlic prevent cancer? The health benefits of the allium compounds contained in garlic and other vegetables in the onion family have been publicized widely. Garlic is currently under study for its ability to reduce cancer risk. There is not enough evidence at this time to support a specific role for this vegetable in cancer prevention. Genetics If our genes determine cancer risk, how can diet help prevent cancer? Damage to the genes that control cell growth can be either inherited or acquired during life. Certain types of mutations or genetic damage can increase the risk of cancer. Nutrients in the diet can protect DNA from being damaged. Physical activity, weight control, and diet might delay or prevent the development of cancer in people with an increased genetic risk for cancer. The interaction between diet and genetic factors is an important and complex topic, and a great deal of research is under way in this area. Irradiated foods Do irradiated foods cause cancer? No. Radiation is used more often to kill harmful organisms on foods in order to extend their "shelf life." Radiation does not stay in the foods after treatment, and eating irradiated foods does not appear to increase cancer risk. Lycopene Will lycopene reduce cancer risk? Lycopene is the red-orange carotene pigment found mainly in tomatoes and tomato-based foods and to a lesser extent in pink grapefruit and watermelon. Several studies have reported that intake of tomato 258

products reduces the risk of some cancers, but whether lycopene is the nutrient responsible is uncertain. Even if lycopene in foods is linked with lower risk for cancer, it can't be concluded that high doses taken as supplements would be either more effective or safe. Meat: cooking and preserving Should I avoid processed meats? Some studies have linked eating large amounts of processed meat to increased risk of colorectal and stomach cancers. This connection may or may not be due to nitrites, which are added to many luncheon meats, hams, and hot dogs to maintain color and to prevent bacterial growth. Eating processed meats and meats preserved by methods involving smoke or salt increases exposure to potential cancer-causing agents and should be reduced as much as possible. How does cooking meat affect cancer risk? Adequate cooking is required to kill harmful germs in meat. But some research suggests that frying, broiling, or grilling meats at very high temperatures forms chemicals that might increase cancer risk. Although these chemicals can damage DNA and cause cancer in animals, it is not clear how much they (as opposed to other substances in meat) may contribute to the increased colorectal cancer risk seen in people who eat large amounts of meat in some studies. Techniques such as braising, steaming, poaching, stewing, and microwaving meats produce fewer of these chemicals. Obesity Does being overweight increase cancer risk? Yes. Being overweight or obese is linked with an increased risk of cancers of the breast (among women after menopause), colon, endometrium, esophagus, kidney, and possibly other sites as well. Although research on whether losing weight reduces cancer risk is limited, some research suggests that weight loss does reduce the risk of breast cancer. Because of other proven health benefits, people who are overweight are encouraged to lose weight. Avoiding excessive weight gain in adulthood is important not only to reduce cancer risk but also to reduce the risk of other chronic diseases. Olive oil 259

Does olive oil affect cancer risk? Intake of olive oil is linked with a reduced risk of heart disease, but is most likely neutral with respect to cancer risk. Although olive oil is a healthy alternative to butter and margarine, it is still a dense source of calories and should be used in moderation. Organic foods Are foods labeled "organic" more effective in lowering cancer risk? The term organic is popularly used to designate plant foods grown without pesticides and genetic modifications. At this time, no research exists to demonstrate whether such foods are more effective in reducing cancer risk than are similar foods produced by other farming methods. Pesticides and herbicides Do pesticides in foods cause cancer? Pesticides and herbicides can be toxic when used improperly in industrial, agricultural, or other occupational settings. Although vegetables and fruits sometimes contain low levels of these chemicals, overwhelming scientific evidence supports the overall health benefits and cancer-protective effects of eating vegetables and fruits. At present there is no evidence that residues of pesticides and herbicides at the low doses found in foods increase the risk of cancer, but fruits and vegetables should be washed thoroughly before eating. Physical activity Will increasing physical activity lower cancer risk? Yes. People who engage in moderate to vigorous levels of physical activity are at a lower risk of developing colon and breast cancer than those who do not. Risk is lowered whether or not the activity affects the person's weight. Data for a direct effect on the risk of developing other cancers is more limited. Even so, obesity and being overweight have been linked to many types of cancer, and physical activity is a key factor in reaching or staying at a healthy body weight. In addition, physical activity has helpful effects against heart disease and diabetes. Phytochemicals 260

What are phytochemicals, and do they reduce cancer risk? The term phytochemicals refers to a wide variety of compounds made by plants. Some of these compounds protect plants against insects or perform other important functions. Some have either antioxidant or hormone-like actions both in plants and in the people who eat them. Because consuming vegetables and fruits reduces cancer risk, researchers are looking for specific compounds responsible for the helpful effects. At this time, no evidence has shown that phytochemicals taken as supplements are as good for you as the vegetables, fruits, beans, and grains from which they are extracted. Saccharin Does saccharin cause cancer? No. In rats, high doses of the artificial sweetener saccharin can cause bladder stones to form that can lead to bladder cancer. But saccharin does not cause bladder stones to form in humans. Saccharin has been removed from the list of established human carcinogens by the US National Toxicology Program. Salt Do high levels of salt in the diet increase cancer risk? Studies in other countries link diets that contain large amounts of foods preserved by salting and pickling with an increased risk of stomach, nasopharyngeal, and throat cancer. No evidence suggests that moderate levels of salt used in cooking or in flavoring foods affect cancer risk. Selenium What is selenium, and can it reduce cancer risk? Selenium is a mineral that contributes to the body's antioxidant defense mechanisms. Animal studies suggest that selenium protects against cancer. One study has shown that selenium supplements might reduce the risk of lung, colon, and prostate cancer in humans. But repeated and well-controlled studies are needed to confirm whether selenium is helpful in preventing these cancers. High-dose selenium supplements are not recommended, as there is only a narrow margin between safe 261

and toxic doses. The maximum dose in a supplement should not exceed 200 micrograms (this is 2/10th of a milligram) per day. Soy products Can soy-based foods reduce cancer risk? Soy-derived foods are an excellent source of protein and a good alternative to meat. Soy contains several phytochemicals, some of which have weak estrogen activity and appear to protect against hormone-dependent cancers in animal studies. At this time there is little data showing that soy supplements can help reduce cancer risk. High doses of soy could possibly increase the risk of estrogen-responsive cancers, such as breast or endometrial cancer. Women with breast cancer should take in only moderate amounts of soy foods as part of a healthy, plant-based diet. They should not ingest very high levels of soy in their diet or take concentrated sources of soy such as soy-containing pills or powders, or supplements containing high amounts of isoflavones. Sugar Does sugar increase cancer risk? Sugar increases calorie intake without providing any of the nutrients that reduce cancer risk. By promoting obesity and elevating insulin levels, high sugar intake may indirectly increase cancer risk. White (refined) sugar is no different from brown (unrefined) sugar or honey with regard to their effects on body weight or insulin. Limiting foods such as cakes, candy, cookies, sweetened cereals, and high-sugar beverages such as soda can help reduce sugar intake. Supplements Can nutritional supplements lower cancer risk? There is strong evidence that a diet rich in fruits, vegetables, and other plant-based foods may reduce the risk of cancer. But there is no proof at this time that supplements can reduce cancer risk. Some high-dose supplements may actually increase cancer risk. Can I get the nutritional effects of vegetables and fruits in a pill?

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No. Many healthful compounds are found in vegetables and fruits, and these compounds most likely work in together to produce their helpful effects. There are also likely to be important compounds in whole foods that are not included in supplements, even though these compounds have not been identified. The small amount of dried powder in the pills that are sold as being equivalent to vegetables and fruits often contains only a small fraction of the levels contained in the whole foods. Food is the best source of vitamins and minerals. Supplements, however, may be helpful for some people, such as pregnant women, women of childbearing age, and people whose dietary intakes are restricted by allergies, food intolerances, or other problems. If a supplement is taken, the best choice is a balanced multivitamin/mineral supplement containing no more than 100% of the "Daily Value" of most nutrients. Tea Can drinking tea reduce cancer risk? Some researchers have suggested that tea might protect against cancer because of its antioxidant content. In animal studies, some teas (including green tea) have been shown to reduce cancer risk, but findings from human population studies are mixed. At this time, tea has not been proven to reduce cancer risk in humans. Trans-saturated fats Do trans-saturated fats increase cancer risk? Trans-saturated fats are made when oils such as margarines or shortenings are hydrogenated to make them solid at room temperature. Recent evidence shows that trans-fats raise blood cholesterol levels. Their relationship to cancer risk has not been determined, but people are advised to eat as few trans-fats as possible. Vegetables and fruits Will eating vegetables and fruits lower cancer risk? In most of the studies looking at large groups of people, eating more vegetables and fruits has been linked to a lower risk of lung, oral, esophageal, stomach, and colon cancer. Because we don't know which of the many compounds in these foods are most helpful, the best advice 263

is to eat 5 or more servings of an assortment of colorful vegetables and fruits each day. (This means at least 5 servings of fruits and vegetables when added together, for instance, 4 servings of vegetables plus 1 serving of fruit. What are cruciferous vegetables, and are they important in cancer prevention? Cruciferous vegetables belong to the cabbage family and include broccoli, cauliflower, Brussels sprouts, and kale. These vegetables contain certain compounds thought to reduce the risk for colorectal cancer. The best evidence suggests that eating a wide variety of vegetables, including cruciferous and other vegetables, reduces cancer risk. Is there a difference in nutritional values among fresh, frozen, and canned vegetables and fruits? Yes, but they can all be good choices. Fresh foods are usually thought to have the most nutritional value. But frozen foods can often be more nutritious than fresh foods because they are often picked ripe and quickly frozen (whereas fresh foods may lose some of their nutrients in the time between harvesting and eating). Canning is more likely to reduce the heat-sensitive and water-soluble nutrients because of the high heat that must be used. Be aware that some fruits are packed in heavy syrup, and some canned vegetables are high in sodium (salt). Choose vegetables and fruits in a variety of forms, and pay attention to the label information. Does cooking affect the nutritional value of vegetables? Boiling vegetables, especially for long periods, can leach out their content of water-soluble (B and C) vitamins. Microwaving and steaming are the best ways to preserve these nutrients in vegetables. Should I be juicing my vegetables and fruits? Juicing can add variety to the diet and can be a good way to consume vegetables and fruits, especially if chewing or swallowing is a problem. Juicing also helps the body absorb of some of the nutrients in vegetables and fruits. But juices may be less filling than whole vegetables and fruits and often contain less fiber. Fruit juice in particular can account for quite a few calories if large amounts are

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drunk. Commercially juiced products should be 100% vegetable or fruit juices. They should also be pasteurized to kill harmful germs. Vegetarian diets Do vegetarian diets reduce cancer risk? Vegetarian diets include many healthful features. They tend to be low in saturated fats and high in fiber, vitamins, and phytochemicals. It is not possible to conclude at this time, however, that a vegetarian diet has any special benefits for the prevention of cancer. Diets including lean meats in small to moderate amounts can also be healthful. Strict vegetarian diets that avoid all animal products, including milk and eggs, should be supplemented with vitamin B12, zinc, and iron (especially for children and women after menopause). Vitamin A Does vitamin A lower cancer risk? Vitamin A (retinol) is obtained from foods in 2 ways: it can be preformed from animal food sources (retinol) and made from beta-carotene in plant-based foods. Vitamin A is needed to maintain healthy tissues. Vitamin A supplements, whether in the form of beta-carotene or retinol, have not been shown to lower cancer risk, and high-dose supplements may, in fact, increase the risk for lung cancer in current and former smokers. And retinol can cause serious p roblems if too much is taken. Vitamin C Does vitamin C lower cancer risk? Vitamin C is found in many vegetables and fruits, especially oranges, grapefruits, and peppers. Many studies have linked intake of foods rich in vitamin C to a reduced risk for cancer. But the few studies in which vitamin C has been given as a supplement have not shown a reduced risk for cancer. Vitamin D Does vitamin D lower cancer risk? There is a growing body of evidence from studies that observie large groups of people (not yet tested in clinical trials) that vitamin D may 265

have helpful effects on some types of cancer, including cancers of the colon, prostate, and breast. Vitamin D is obtained through skin exposure to ultraviolet (UV) radiation and through diet, particularly products fortified with vitamin D such as milk and cereals, and supplements. But many Americans do not get enough vitamin D. The current national recommended levels of intake of vitamin D (200 to 600 IU per day) may not be enough to meet needs, especially among those with little sun exposure, the elderly, people with dark skin, and breastfed babies who only take in breast milk. More research is needed to define the best levels of intake and blood levels of vitamin D for cancer risk reduction, but recommended intake is likely to fall between 200 and 2,000 IU, depending on age and other factors. To reduce the health risks linked with UV radiation exposure while getting the most potential benefit from vitamin D, a balanced diet, supplementation, and limiting sun exposure to small amounts are the preferred methods of obtaining vitamin D. Vitamin E Does vitamin E lower cancer risk? Alpha-tocopherol is the most active form of vitamin E and is a powerful antioxidant. In one study, male smokers who took alpha-tocopherol had a lower risk of prostate cancer compared with those who took a placebo. But several other studies have not found the same link. While studies now under way will help clarify this, the promise of alpha-tocopherol for reducing cancer risk appears to be dimming. Water and other fluids How much water and other fluids should I drink? Drinking water and other liquids may reduce the risk of bladder cancer, as water dilutes the concentration of cancer-causing agents in the urine and shortens the time in which they are in contact with the bladder lining. Drinking at least 8 cups of liquid a day is usually recommended, and some studies show that even more may be helpful. Bone Marrow and Peripheral Blood Stem Cell Transplants This document will give you an overview of bone marrow transplants and other types of stem cell transplants that are used to treat cancer. If you would like more details about donating stem cells or having a stem 266

cell transplant, please contact the organizations listed in the "Additional resources" section. Stem cells are cells in the bone marrow that make all of the body's blood cells. Stem cell transplants are used to restore the stem cells when the bone marrow has been destroyed by disease, chemotherapy, or radiation. Depending on the source of the stem cells, this procedure may be called a bone marrow transplant, a peripheral blood stem cell transplant, or a cord blood transplant. The first successful bone marrow transplant was done in 1968. It was not until nearly 20 years later that stem cells taken from circulating (peripheral) blood were transplanted with success. More recently, doctors have begun using cord blood from the placenta and umbilical cords of newborn babies as another source of stem cells. Today tens of thousands of patients have had stem cell transplants. This has lead to better care for transplant patients and helped doctors know more about which patients are likely to have better results after transplant. What Are Stem Cells? All of the blood cells in our bodies start out as young (immature) cells called hematopoietic (blood-forming) stem cells. Learn about the different types of stem cells and where they are found in the body. Reasons for Stem Cell Transplants Stem cell transplants can be an important part of cancer treatment. Learn how stem cell transplants can be used to treat cancer or to replace bone marrow that has been destroyed. Types of Stem Cell Transplants The type of transplant depends on where the stem cells come from. Learn the differences between the three types of stem cell transplants. Sources of Stem Cells for Transplants There are 3 possible sources of stem cells to use for transplants. Learn how stem cells can be extracted from bone marrow, circulating blood and umbilical cord blood. Which Stem Cell Source Is Best? All 3 sources of stem cells can be used for the same goal. Learn about the advantages and drawbacks to each of the sources. Allogeneic Transplant: Importance of a Matched Donor A working immune system recognizes cells coming from other people as foreign. Learn how doctors try to find the best match possible to avoid possible complications with allogeneic stem cell transplants. The Donor Experience

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People usually volunteer to become stem cell donors either because they have a family member in need of a match or because they want to help people they don't know. Learn what to expect from the donor experience. The Transplant Process There are several steps in the transplant process, no matter what type of transplant you are going to have. Learn what to expect from the transplant process. Problems in the Post-Transplant Period Stem cell transplants have certain risks. Learn about possible problems and what to look out for after a transplant. What Questions Should I Ask My Doctor? Good communication with your doctor is important. Learn some questions you may want to ask before agreeing to a transplant. Issues Related to Stem Cell Transplants There are a number of issues related to stem cell transplantation. Learn what issues you should take into account as you make your treatment decisions. Additional Resources Find additional resources for Bone Marrow & Peripheral Blood Stem Cell Transplants. What Are Stem Cells? Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process

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Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References All of the blood cells in our bodies start out as young (immature) cells called hematopoietic (blood-forming) stem cells. Even though they are often called "stem cells" these cells are not the same as the embryonic stem cells studied in therapeutic cloning and other types of research. Stem cells mostly live in the bone marrow (the spongy inner part of certain bones), where they divide to make new blood cells. Once blood cells mature they leave the bone marrow and enter the bloodstream. A small number of stem cells are also found in the bloodstream. These are called peripheral blood stem cells. Stem cells make the 3 main types of blood cells: red blood cells, white blood cells, and platelets. Red blood cells (erythrocytes) Red blood cells (RBCs) carry oxygen from the lungs to all of the cells in the body, and then bring carbon dioxide back from the cells to the lungs to be exhaled. A lab measurement of the blood called the hematocrit shows how much of your blood is made up of RBCs. The normal range is about 35% to 50% for adults. People whose hematocrit is below this level have a condition called anemia. This can make them look pale and feel cold, tired, and short of breath. White blood cells (leukocytes) White blood cells (WBCs) fight infections caused by bacteria, viruses, and fungi. There are different types of WBCs. The most important in fighting infections are called neutrophils. When your neutrophil count drops below 1,000 per cubic millimeter (1,000/mm3), a condition called neutropenia, your risk of infection increases. The danger is greatest at levels below 500/mm3.

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Stem cells also make white blood cells called lymphocytes. These are immune cells that can make antibodies and help fight infections. They are also responsible for a person's ability to reject cells that are transplanted from someone else. Lymphocytes develop from the earliest stage of stem cells. Platelets (thrombocytes) Platelets are fragments of cells that seal damaged blood vessels and help blood to clot, both of which are important in stopping bleeding. A normal platelet count is usually between 150,000/mm3 and 450,000/mm3. A person whose platelet count drops below 150,000/mm3 is said to have thrombocytopenia. People with this condition may bruise more easily, bleed longer, and have nose bleeds or bleeding gums. Spontaneous bleeding (bleeding with no known injury) can happen if a person's platelet count drops lower than 20,000/mm3. Testing Biopsy and Cytology Specimens for Cancer Waiting out a possible cancer diagnosis can be a very stressful experience. But better understanding the tests doctors use to diagnose and classify cancer may relieve some of your stress. Learning about the testing process can also help you understand how results of these tests affect treatment options. They can also help you work together with your doctors to make informed decisions about your treatment. Much of the testing process takes place "behind the scenes." You will have a chance to meet and ask questions of most of your health care team, which may include a surgeon, medical oncologist, radiation oncologist, oncology nurses, and others. You will be able to see at least parts of what these professionals do. On the other hand, you rarely meet

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the pathologists, histotechnologists, cytotechnologists, and medical laboratory technologists whose work can tell you whether your biopsy is malignant (cancerous) or benign (non-cancerous). This document follows a tissue or cell sample as it goes through the steps of the diagnostic process, starting when the doctor removes the sample. It then explains what is done to the sample in the laboratory during the testing process, including some new ways that the sample may be tested. Finally, this document explains what type of information the pathology report contains. Along the way, it explains how the pathology information affects treatment decisions, and defines some of the medical terms used in these reports. How Is Cancer Diagnosed? A diagnosis of cancer is nearly always based on an expert looking at cell or tissue samples under a microscope. The procedure that takes a sample for this testing is called a biopsy, and the tissue sample is called the biopsy specimen. The testing process is sometimes referred to as pathology. Lumps that might be malignant (cancerous) can be found by imaging (radiology) studies

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or felt as masses (lumps) during a physical exam, but they still must be sampled and looked at under a microscope to find out what they are. Not all lumps are malignant. In fact, most tumors are benign (not cancer). A cancerous tumor is able to spread into surrounding tissues and even to distant parts of the body. A benign tumor can not do this. Types of Tissue and Cell Samples Tissue or cell samples can be removed from almost any part of the body. How this is done depends on where the tumor is and what type of cancer is suspected. For instance, the methods used for skin biopsies clearly need to be different from the procedures for brain biopsies. Overview of Biopsy Types Some types of biopsies involve operations to remove an entire organ. These types are done only by surgeons. Other types of biopsies are less invasive and may remove tumor samples through a thin needle or through an endoscope (a flexible lighted tube). These biopsies are often done by surgeons, but can also be done by other doctors. The most common biopsy types used in cancer diagnosis are discussed in this section. For more

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complete information, refer to the diagnosis section of American Cancer Society documents on specific types of cancer. Needle Biopsy There are 2 types of needle biopsies: * fine needle biopsy (also called fine needle aspiration) * core needle biopsy (also called core biopsy) Fine needle aspiration (FNA) uses a very thin needle and a syringe to withdraw a small amount of fluid and very small pieces of tissue from the tumor mass. The doctor can aim the needle while feeling a suspicious tumor or area near the surface of the body. If the tumor is deep inside the body and cannot be felt, the needle can be guided while being watched by imaging procedures such as an ultrasound or a computed tomography (CT) scan. The main advantages of FNA are that it does not require an incision (cutting through the skin) and that in some cases it is possible to make a diagnosis the same day. The disadvantage is that sometimes this needle cannot remove enough tissue for a definite diagnosis. Although FNA is a type of biopsy, it is also classified as a cytology test (see next section). The needles used for a core biopsy are slightly larger than those used in FNA. They

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remove a small cylinder of tissue (about 1/16 inch in diameter and 1/2 inch long). The core needle biopsy is done using local anesthesia (numbing medicine) in the doctor's office or clinic. Like FNA, a core biopsy can sample tumors that can be felt by the doctor as well as smaller ones that must be seen using imaging studies. Doctors sometimes use special vacuum tools to get larger core biopsies from breast tissue. (For more information, see the American Cancer Society document, For Women Facing a Breast Biopsy.) Processing core biopsy samples usually takes longer than processing FNA biopsies. Excisional or Incisional Biopsy With this type of biopsy, a surgeon cuts through the skin to remove the entire tumor (excisional biopsy) or a small part of a large tumor (incisional biopsy). This often can be done using local anesthesia or regional anesthesia (numbing medicine). If the tumor is inside the chest or abdomen, general anesthesia is used (the patient is asleep). Endoscopic Biopsy This is done using a thin, flexible lighted tube that has a lens or a video camera. If a video camera is used, it is connected to a screen that allows the doctor to clearly see 274

any masses in the area. The endoscope can be passed through a body opening to look at suspicious areas in the swallowing tube (esophagus), stomach, intestine, urine tube (urethra), bladder, uterus (womb), or breathing tubes (bronchi). Advantages of endoscopy include the chance to see the cancer directly and the ability to take a small tissue sample through the endoscope to find out if cancer is present and, if so, the cell type. Laparoscopy, Thoracoscopy, and Mediastinoscopy Laparoscopy is similar to endoscopy but is used to look inside the abdomen and remove tissue samples. A small incision is made in the abdomen then the endoscope is passed through this opening to see the inside. Similar procedures to look inside the chest are called thoracoscopy and mediastinoscopy. Laparotomy and Thoracotomy A laparotomy is a type of surgery that involves an incision into the abdomen, usually a vertical incision from upper to lower abdomen. This may be done when there is uncertainty about a suspicious area that cannot be diagnosed by less invasive tests. During the laparotomy, a biopsy of a suspicious area can be taken and the doctor can

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look at its location and size. The areas nearby can be checked to see if they are involved. General anesthesia is used for this technique. A similar operation which opens the chest is called thoracotomy. Skin Biopsies There are several ways to take a biopsy of the skin. Doctors choose the one best suited to the type of skin tumor suspected. Shave biopsies remove the outer layers of skin and are fine for some basal cell or squamous cell skin cancers, but they are not recommended for suspected melanomas of the skin. Punch biopsies or excisional biopsies remove deeper layers of the skin, and can find out how deeply a melanoma has gone into the skin -- an important factor in choosing treatment for that type of cancer. Sentinel Lymph Node Mapping and Biopsy This is a way for the surgeon to choose which lymph nodes to remove for an excisional biopsy. Sentinel node mapping and biopsy has become a common way to find out whether the cancer has spread to the lymph nodes (especially melanoma and breast cancer). This procedure can find the lymph nodes that drain lymph fluid from the area where the cancer started. If the cancer has spread, these lymph nodes are usually the 276

first place it will go. That is why these lymph nodes are called "sentinel" nodes (meaning that they stand watch over the tumor area, so to speak). To find the sentinel lymph node (or nodes), the doctor injects a small amount of slightly radioactive material into the area of the cancer. By checking various lymph node areas with a machine that detects radioactivity (like a Geiger counter), the doctor can find the group of lymph nodes the cancer is most likely to travel to. Then the doctor injects a small amount of a harmless blue dye into the site of the cancer. After about an hour, a surgeon makes a small incision in the lymph node area that was found with the radioactive test. Those lymph nodes are then checked to find which one(s) turned blue or became radioactive. When the sentinel node has been found, it is removed (an excisional biopsy) and looked at under a microscope. If the sentinel node does not contain cancer cells, no more lymph node surgery is needed because it is very unlikely the cancer would have spread beyond this point. If cancer cells are found in the sentinel node, the rest of the lymph nodes in this area are removed and looked at as well. This is known as a lymph node dissection.

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Overview of Cytology Types Diagnosing diseases based on looking at single cells and small clusters of cells is called cytology or cytopathology. It has become more important in cancer diagnosis over the past few decades. While the pieces of tissue in biopsy samples may be as small as 1/16 inch or much larger (several inches), the individual cells and the cell clusters in cytology samples are usually too small to see without a microscope. Sometimes, as in some FNA samples, only one drop of blood or tissue fluid (containing tiny fragments of the tumor) is taken. On the other hand, some pleural fluid (from around the lung) or peritoneal fluid (from inside the abdomen) cytology samples may include a quart or more of fluid. A cytology specimen usually: * * * * is easier to get causes less discomfort to the patient is less likely to result in serious complications costs less than a tissue biopsy

The disadvantage is that, in some cases, a tissue biopsy result is more accurate, but in many cases, the cytology fluid may be just as accurate. Sometimes an excisional biopsy is the only treatment needed to remove a cancer -- which is an obvious advantage. In other cases, a cancer might be better treated by chemotherapy or radiation therapy, and 278

surgery might be done after these treatments. For those types of cancer, a cytology sample, endoscopic biopsy, or incisional biopsy might be a better choice. As you can see, choices of tests are not simple -- the doctors consider many factors about the specific type of cancer that is suspected and what organ is affected. Cytology tests may be used in two ways -- for diagnosis or for screening. A diagnostic test is only used for people who have signs, symptoms, or some other reason to suspect that a particular disease such as cancer is likely to be present. A diagnostic test finds out if a disease is present and, if so, it precisely and accurately classifies the disease. A screening test is used to find people who might have a certain disease even before they develop symptoms. A screening test is expected to find nearly all people who are likely to have the disease, but the screening test does not prove that the disease is present. That means a diagnostic test is used if a screening test is positive (that is, if something is found on the screening test). Some cytology tests, such as the Pap test, are mainly used for screening but in many cases can accurately identify cancers (see

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"Scrape or Brush Cytology" below). A biopsy is generally done to be sure of any abnormal finding before surgery or radiation is started. Fine Needle Aspiration (FNA) Biopsy FNA is sometimes considered a cytology test and is sometimes called a biopsy. It is discussed in this document in the previous section, "Overview of Biopsy Types." Body Fluids This term refers to fluid from cavities and spaces in the body. These fluids can be tested to see if cancer cells are present. Some of the body cavity fluids tested in this way include: * urine * sputum (phlegm) * spinal fluid, also known as cerebrospinal fluid or CSF (from the space surrounding the brain and spinal cord) * pleural fluid (from the space around the lungs) * pericardial fluid (from the sac that surrounds the heart) * ascitic fluid, also known as ascites or peritoneal fluid (from the space in the abdomen or chest) Scrape or Brush Cytology Another cytology technique is to gently scrape or brush some cells from the organ or tissue being tested. The best-known cytology test that samples cells in this way is the

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Pap test. Pap test samples are taken by using a small spatula and/or brush to remove cells from the cervix (lower part of the uterus or womb). Other areas that can be brushed or scraped include the esophagus, stomach, bronchi (breathing tubes that lead to the lungs), and mouth. What happens to biopsy and cytology specimens after they are removed from the patient? Routine Biopsy Processing for Histology There are standard procedures and methods that are used with nearly all types of biopsy samples. These procedures are the usual ways that a sample is prepared for use by the doctor. Additional procedures, which are described later in this document, may also be done on certain types of samples (such as lymph nodes and bone marrow). After the doctor gets the biopsy specimen, it is placed in a container with formalin (a mixture of water and formaldehyde) or another fluid to preserve it. The container is labeled with the patient's name and other identifying information (hospital number and birth date, for example), site of biopsy (exactly where on the body it was taken from), and then sent to the pathology lab with a paper called a pathology requisition form. This 281

form also identifies who submitted the biopsy, the date the biopsy was obtained, and certain clinical history (information about the patient's symptoms, other abnormal test results, and what type of disease the doctor expects the biopsy may show). Next the pathologist or an assistant looks at the specimen without a microscope. How the whole sample looks before further processing is called the "gross description" and includes the tissue sample's size, color, consistency, and other characteristics. The lab staff may even take a picture of the sample as part of the record. The gross examination is important since the pathologist often sees features that suggest cancer. This will help the pathologist decide which parts of a large biopsy are the most critical to study under a microscope. For small biopsies, for example, like a punch biopsy or a core needle biopsy, the entire specimen may be looked at under a microscope. The tissue to be looked at under the microscope is placed into small containers called cassettes. The cassettes hold the tissue securely while it is processed, and help keep small samples from getting lost. After processing, which may take a few hours but is usually done overnight, the tissue sample is placed into a mold with hot 282

paraffin wax. The wax cools to form a solid block that protects the tissue. This paraffin wax block with the embedded tissue is placed on an instrument called a microtome, which the histotechnologist uses to cut very thin slices of the tissue. These thin slices of the specimen are placed on glass slides, and dipped into a series of stains or dyes to change the color of the tissue. The color makes cells more distinctive when viewed under a microscope. For most biopsy specimens, routine processing as described above is all that is required. At this point (usually the day after the biopsy was performed), the pathologist looks at the tissue under a microscope. Looking at the solid specimens in this way is called histology, which is the study of the structures of cells and tissues. Intra-operative Consultation (Frozen Section) Sometimes a surgeon needs information about a tissue sample during surgery, so that decisions can be made about immediate surgical treatment. The surgeon cannot wait until the next day as is the case for routine biopsies. He or she will request an intra-operative (during surgery) pathology consultation. This consultation is often called a frozen section exam.

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When a frozen section exam is performed, fresh tissue is sent from the operating room directly to the pathologist. Because the patient is often under general anesthesia it is important that the tissue be looked at as quickly as possible. This usually takes 10 to 20 minutes. The fresh tissue is grossly examined by the pathologist to decide which part of the tissue sample should be looked at under the microscope. Instead of processing the tissue in wax blocks, the tissue is quickly frozen in a special solution that forms what looks like an ice cube around the tissue sample. It is then thinly sectioned (sliced) on a refrigerated microtome, quickly stained (dipped in a series of dyes), and .looked at under the microscope. Although the frozen sections usually do not display features of the tissue as clearly as sections of tissue embedded in wax, they are usually provide enough information to help the surgeon decide what type of operation, if any, is best for the patient. Frozen sections are often used to evaluate how completely a cancer has been removed. For example, if a lobe of a lung is removed due to cancer, the surgeon will want to know whether the bronchial (breathing tube) margin (the edge of the removed tissue) is

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cancer-free. A slice from the edge of the tissue that was removed is then sent for a frozen section diagnosis. If there is no cancer in that margin, additional surgery usually is not necessary. But if cancer cells are found, it is assumed that some cancer cells are still present in the tissue left in the patient. So the surgeon will usually remove more tissue, in order to try to get all the cancer cells and reduce the chance of cancer growing back. If it is not possible to remove more tissue, there may be other options such as radiation to destroy the remaining cancer cells. Intra-operative consultations do not always provide a definite answer. In some cases, a piece of tissue will require routine or even special processing to arrive at a clear answer. In such cases, the surgeon will usually close the surgical incision. When the results are available in a few days, another operation may be needed. Cytology Specimen Processing Processing of cytology specimens depends greatly on their type. Some specimens are smeared directly on glass microscope slides by the doctor who obtains the sample. The slides, which are called smears, are then sent to the cytology lab where they are dipped into a series of stains (colored dyes), similar to those used for biopsy samples. Other 285

specimens, such as body fluids, cannot be easily placed on a glass microscope slide because they are too dilute (there are too few cells in a large volume of fluid). Several methods are used in cytology labs to concentrate the cells on a glass slide before staining. After processing and staining, the samples are examined under a microscope by a cytotechnologist, who can locate abnormal cells and mark their location with a special pen. A pathologist will then review the marked cells and decide on a diagnosis. What do doctors look for under the microscope? General Principles Over a hundred years ago, scientists realized that various tissues and organs look different from each other under a microscope. This is because they are formed by different cell types and because the cells are arranged differently. Even more importantly, it was discovered that the usual appearance of each type of tissue or organ is changed by certain diseases such as cancer. During the past century, this science, known as pathology, has been greatly refined. Most tissue and cell samples are looked at by pathologists (doctors who specialize in

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diagnosing diseases by laboratory tests). Sometimes, other doctors will also examine specimens or tissues of organs related to their area of expertise. For example, hematologists often examine blood and bone marrow samples from their patients, and some dermatologists will examine their patients skin biopsy specimens. The details of how doctors can tell normal tissue from cancer, and recognize the different types of cancer, are the subject of many thousands of pages of medical textbooks and journals. Some features that doctors look for under a microscope are important only when found in 1 or 2 types of tissue, while others will be more important if found in almost all tissues. There a few general concepts that can be explained in less technical terms and can help you to better understand how doctors decide whether cancer is present. * The overall size and shape of cancer cells are often abnormal. They may be either smaller or larger than normal cells. Normal cells often have certain shapes that help them better perform their roles in the body. Cancer cells usually do not function in a useful way and their shapes are often distorted. Unlike normal cells that tend to have the

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same size and shape, cancer cells often are very different in their sizes and shapes. * The size and shape of the nucleus of a cancer cell is often abnormal. The nucleus is the center of the cell that contains the cell's DNA (deoxyribonucleic acid). The nucleus is surrounded by cytoplasm. Some types of cells can be imagined as looking like a fried egg, in which the central yolk represents the nucleus and the surrounding white is the cytoplasm (this is only a way of imagining cells, and does not truly reflect what cells are made of). Cancer cells typically have a nucleus that is larger than that of a normal cell. And, like the overall cell size and shape, the size and shape of the cell nucleus is generally similar among normal cells of each tissue but can vary greatly among cancer cells. Another feature of the nucleus of a cancer cell is that it appears darker when seen under a microscope after being stained with certain dyes. The nucleus from a cancer cell is larger and has a darker shade because it often contains too much DNA. * Cancer cells do not relate to each other normally. Normal tissues are formed by a very orderly arrangement of cells. The arrangement of normal cells reflects the function of each tissue. For instance, cells can form glands that produce substances that are

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taken to other parts of the tissue. Gland tissue in the breast is organized into lobules, which, during breast-feeding can produce milk, and ducts that carry milk from the lobules to the nipple. Cells of the stomach also form glands, to produce enzymes, acid, and mucus that digest the food and protect the stomach lining from digesting itself. When cancers develop in the breast, stomach, and many other tissues, the cancer cells do not form glands as they should. Sometimes the cancer cells form abnormal or distorted glands. Sometimes they form cell clumps that do not look like glands at all. Another feature that shows abnormal interactions by cancer cells is that cancer cells invade other tissues. Normal cells stay where they belong within a tissue. The ability of cancer cells to invade reflects the fact that their growth and movement is not coordinated with their neighboring cells. This ability to invade is how cancer spreads to and damages nearby tissues. And, unlike normal cells, cancer cells can metastasize (spread through blood vessels or lymph vessels) to distant parts of the body. Knowing this helps doctors recognize cancers under a microscope, because finding cells where they don't belong is a useful clue that they might be cancerous.

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Classification of Various Types of Cancer There are several basic kinds of cancers, which doctors can further classify into hundreds or even thousands of types, based on how they look under a microscope. Cancers are named according to which type of normal cells and tissues they most closely resemble. For example, cancers that look like glandular tissues are called adenocarcinomas. Other cancers that resemble certain immune system cells are called lymphomas, and those that look like bone or fat tissue are osteosarcomas and liposarcomas, respectively. Grading a Cancer In addition to identifying the cell type or tissue a cancer looks like, doctors decide how close that resemblance is -- the grade of the cancer. Cancers that look more like normal tissues are called low grade, and those that do not resemble normal tissues are high grade. A high-grade cancer tends to grow and spread more quickly than a low-grade cancer. Patients with high-grade cancers tend to have a poorer prognosis (outlook). Special Studies in Cancer Diagnosis Although the type and grade of a cancer is usually clear when it is seen under a

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microscope after routine processing and staining, this is not always the case. Sometimes the pathologist may need extra laboratory methods to make a diagnosis. Histochemical Stains These tests use a different chemical dyes that are attracted to certain substances found in some types of cancer cells. An example is the mucicarmine stain, which is attracted to mucus. Droplets of mucus inside a cell that are exposed to this stain will appear pink-red under a microscope. This stain is useful if the pathologist suspects, for example, an adenocarcinoma (a glandular type of cancer) in a lung biopsy. Adenocarcinomas can produce mucus, so finding pink-red spots in lung cancer cells will tell the pathologist that the diagnosis is adenocarcinoma. Besides being helpful in sorting out different kinds of tumors, other types of special stains are used in the laboratory to identify microorganisms (germs) like bacteria and fungi in tissue sections. This is important to people with cancer that may develop infections as a side effect of chemotherapy, radiation, or even because of the cancer itself. It is also important in cancer diagnosis because some infectious diseases cause

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lumps to form which might be confused with a cancer at first, until these histochemical (cell-affecting) stains prove that the patient has an infection and not cancer. Immunohistochemical Stains Immunohistochemical or immunoperoxidase stains are another very useful category of special tests. The basic principle of this method is that an antibody will attach itself to certain substances called antigens. Each type of antibody recognizes and attaches to antigens that fit it exactly. Certain types of normal cells and cancer cells contain unique antigens, which can be recognized by specific antibodies. If cells have a specific antigen, they will attract the antibody that fits the antigen. To find out if the antibodies have been attracted to the cells, chemicals will be added that cause the cell to change color only if a certain antibody (and, therefore, the antigen) is present. Immunohistochemical stains are very useful in identifying certain types of cancers. For example, a routinely processed biopsy of a lymph node may contain cells that clearly appear cancerous, but the pathologist cannot tell whether the cancer started in the lymph node or whether it started elsewhere in the body and spread to the lymph nodes

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later. If the cancer started in the lymph node, the diagnosis would be lymphoma. If the cancer started in another part of the body and spread to the lymph node, it might be metastatic cancer. This distinction is of great importance to the patient and the doctor, since treatment depends on the type of cancer as well as other factors. There are hundreds of antibodies used for immunohistochemical tests by laboratories at cancer centers. Some are quite specific, meaning that they react only with one type of cancer. Others may react with a few types of cancer, so several antibodies may be tested to decide what type of cancer it is. By looking at these results along with the cancer's appearance after the biopsy specimen is processed, its location and other information about the patient (age, gender, etc.), it is often possible to classify the cancer in a way that can help the oncologist select the best treatment. Although immunohistochemical stains are used most often to classify cells, they can also be used to detect or recognize cancer cells. When a large number of cancer cells have spread to a nearby lymph node, these cells are usually recognized easily when the pathologist looks at the lymph tissue under the microscope using routine stains.

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However, if there are only a few cancer cells in the node, recognizing the cells using only routine stains can be very difficult. This is where immunohistochemical stains can help. Once the pathologist knows the kind of cancer to look for, he or she can choose one or more antibodies known to react with those cells. More chemicals are added so that the cancer cells will change color, which makes them clearly stand out from the normal cells around them. Immunohistochemical stains are generally not used for looking at tissue from lymph node dissections (which remove a large number of nodes), but they are sometimes used in sentinel lymph node biopsies (see the section "Sentinel Lymph Node Mapping and Biopsy"). Another specialized use of imunohistochemical and immunocytochemical stains is to help distinguish lymph nodes that contain lymphoma from those that are swollen from growth of non-cancerous lymphocytes (usually as a response to infection). Certain antigens are present on the surface of immune system cells called lymphocytes. Benign lymph node tissue contains many different types of lymphocytes with a variety of antigens on their surface. In contrast, cancers such as lymphoma start with a single

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abnormal cell, so that the cancer cells that grow from that cell typically share the chemical features of the first abnormal cell. This is especially useful in the diagnosing lymphoma. If most of the cells in a lymph node biopsy have the same antigens on their surface, this result supports a diagnosis of lymphoma. Electron Microscopy The typical medical lab microscope uses a beam of ordinary light to view specimens. A much more complex, larger, and more expensive instrument called an electron microscope uses beams of electrons. The electron microscope's magnifying power is about 1,000 times greater than that of an ordinary light microscope. This degree of magnification is rarely useful in deciding whether a cell is cancerous. But it sometimes helps find very tiny details of a cancer cell's structure that provide clues to the exact type of the cancer. For instance, melanoma, a highly aggressive cancer of the skin, is known to look like other types of cancer when seen under the ordinary light microscope. Although there are some exceptions, melanomas usually can be recognized by certain immunohistochemical stains. In such exceptional cases, the electron microscope may be

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used to identify tiny bodies located in melanoma cells called melanosomes. This helps to establish the type of cancer, which helps the oncologist choose the best treatment for the patient. Flow Cytometry This test is often used to test the cells from bone marrow, lymph nodes, and blood samples. It is very accurate in finding out the exact type of leukemia or lymphoma a person has. It also helps to tell lymphomas from non-cancerous diseases of lymph nodes. A sample of cells from a biopsy, cytology specimen, or blood specimen is treated with special antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of cells that contain the antigens that fit with it. If the sample contains those cells, the laser will cause them to give off light that is then measured and analyzed by a computer. Analyzing cases of suspected leukemia or lymphoma by flow cytometry uses the same principles explained in the section on immunohistochemistry. Finding the same substances on the surface of most cells in the sample suggests that they came from a single abnormal cell, and are therefore likely to be a cancer. On the other hand, finding 296

several different cell types with a variety of antigens means that the sample is less likely to contain leukemia or lymphoma. Flow cytometry can also be used to measure the amount of DNA in cancer cells. Instead of using antibodies to detect protein antigens, cells can be treated with special dyes that react with DNA. In this way, one can measure the ploidy of cancer cells, which reflects the amount of DNA they contain. If there's a normal amount of DNA, the cells are said to be diploid. If the amount is abnormal, then the cells are described as aneuploid. Aneuploid cancers of most (but not all) organs tend to be more aggressive than diploid ones. Another use of flow cytometry is to measure the S-phase fraction, which is the percentage of cells in a sample that are in a certain stage of cell division called the synthesis (or S) phase. The more cells that are in the S-phase, the faster the tissue is growing and the more aggressive the cancer is likely to be. Image Cytometry Like flow cytometry, this test uses dyes that react with DNA. But instead of suspending the cells in a stream of liquid and analyzing them with a laser, image cytometry uses a 297

digital camera and a computer to measure the amount of DNA in cells on a microscope slide. Like flow cytometry, image cytometry can determine the ploidy of cancer cells. Cytogenetics Normal human cells contain 46 chromosomes (pieces of DNA and protein that control cell growth and function). Some types of cancer have a unique type of abnormal chromosome. Recognizing them helps to identify those types of cancer. This is especially useful in diagnosing some lymphomas, leukemias, and sarcomas. Even if a patient is known to have a certain type of cancer, cytogenetic studies may help predict the outlook for survival. Sometimes the studies can even help predict which chemotherapy drugs the cancer is likely to respond to. Several types of chromosome changes can be found in cancer cells: * A translocation means part of one chromosome has broken off and is now located on another chromosome. * An inversion means that part of a chromosome is upside down (now in reverse order) but still attached to the right chromosome. * A deletion indicates part of a chromosome has been lost. * An addition happens when all or part of a chromosome has been duplicated, and too many copies of it are found within the cell. 298

Cytogenetic testing usually takes about 3 weeks, because the cancer cells must grow in lab dishes for about 2 weeks before their chromosomes are ready to be looked at under the microscope. Fluorescent in situ hybridization (FISH) is a newer test that is similar to cytogenetic testing. It can find most chromosome changes that can be seen under a microscope in standard cytogenetic tests. It can also find some changes too small to be seen with usual cytogenetic testing. FISH uses special fluorescent dyes that only attach to specific parts of certain chromosomes. FISH can find chromosome changes such as translocations, which are important to help classify some kinds of leukemia. This test can also recognize when there are too many copies of a certain gene (gene amplification), which can help choose the best treatment for some women with breast cancer. Unlike standard cytogenetic tests, it is not necessary to grow cells in laboratory dishes before doing FISH. That means FISH results are available much sooner, usually within a few days. Molecular Genetic Studies DNA and RNA tests can be used to find most of the translocations that are found by

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cytogenetic tests. They can also find some translocations involving parts of chromosomes too small to be seen with usual cytogenetic testing under a microscope. This type of advanced testing can help classify some leukemias and, less often, some sarcomas and carcinomas. These tests are also useful after treatment to find small numbers of remaining leukemia cancer cells that may be missed under a microscope. Molecular genetic tests can also identify mutations (abnormal changes) in certain areas of DNA that are responsible for regulating cell growth. Some of these mutations may cause cancers to be especially aggressive in growing and spreading. In some situations, identifying certain mutations can help doctors choose treatments that are more likely to work. Certain substances called antigen receptors appear on the surface of immune system cells called lymphocytes. Normal lymph node tissue contains lymphocytes with many different antigen receptors, which help the body respond to infection. Some types of lymphoma and leukemia, however, start from a single abnormal lymphocyte, so all their cells have the same antigen receptor. Lab tests of the DNA on each cell's antigen

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receptors are a very sensitive way to diagnose and classify these cancers. Some gene mutations can be inherited from parents and cause a person to have a greater risk of developing certain cancers. Unlike acquired gene mutations that only affect the abnormal cells of the tumor, inherited mutations affect all cells of a person's body. These inherited mutations can often be identified by genetic testing on blood samples. Genetic counseling and testing may be recommended for some people with a strong family history of cancer. Because these tests do not analyze the cancerous tissue, they are not discussed further in this document. For more information, see the American Cancer Society document, Genetic Testing: What You Need to Know. Polymerase chain reaction (PCR) is a very sensitive molecular genetic test for finding specific DNA sequences, such as those occurring in some cancers. Reverse transcriptase PCR (RTPCR) is a method for detecting small amounts of RNA, a substance related to DNA that is needed for cells to produce proteins. There are specific RNAs for each protein in our body. RTPCR can be used to find and classify cancer cells. RTPCR tests to detect cancer cells look for the RNA sequences that are responsible for

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making substances found in cancer cells but not in most normal cells. An advantage of this test is that it can detect very small numbers of cancer cells in the blood or tissue samples that would be missed by other tests. RTPCR is already used routinely for detecting certain kinds of leukemia cells that remain after treatment, but its value for more common types of cancer is less certain. The disadvantage is that doctors are not always sure whether having a few cancer cells in the bloodstream or a lymph node means that a patient will actually develop distant metastases that grow enough to cause symptoms or affect survival. In treating patients with most common cancer types, it is still uncertain whether recognizing a few cancer cells with this test should be a factor in choosing treatment options. RTPCR can also be used to sub-classify cancer cells. Some RTPCR tests measure levels of one or even several RNAs at the same time. By comparing the levels of important RNAs, doctors can sometimes predict whether a cancer is likely to be more or less aggressive than would be expected based on its microscopic appearance alone. Sometimes these tests can help predict whether a cancer will respond to certain

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treatments. Gene expression microarrays are miniaturized devices that are similar in some ways to computer chips. The advantage of this technology is that relative levels of hundreds or even thousands of different RNA molecules from one sample can be compared at the same time. Recent studies have found that this information can sometimes help predict a patient's prognosis or response to certain treatments. Although this is a very active area of research, doctors are still conducting studies to learn how this information should guide their treatment recommendations. For now, most cancer treatment guidelines do not recommend routine use of these tests. How long does biopsy and cytology testing take? The uncertainty you feel waiting for biopsy and cytology test results can be a source of much anxiety. Not knowing when the results will be ready and not understanding why testing sometimes takes longer than expected can cause extra concern. Routine biopsy and cytology results may be ready as soon as 1or 2 days after the sample is received in the laboratory. But there are many reasons why some cases take considerably longer to complete.

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Often, there are "technical" reasons for delays in reporting. For example, bone and other hard tissues that contain lots of calcium need to be specially handled. These tissues must be treated with strong acids or other chemicals to remove the minerals so that the tissue becomes soft enough to be thinly sectioned (sliced) on the microtome. Another technical reason for delay is that the formalin solution used for preserving tissues takes longer to penetrate samples with lots of fatty tissue (such as breast biopsies). An extra day of fixation (formalin treatment) is sometimes necessary. Large samples, such as those resulting from removal of an entire organ, might also require more than one day for the formalin to penetrate the tissue. If formalin does not completely penetrate the sample, cells may appear disturbed under the microscope and testing is more difficult and/or less accurate. For most large samples, only selected areas are processed and examined under the microscope. After the first sections of tissue are seen under the microscope, the pathologist may want to look at more sections for an accurate diagnosis. In these cases, processing of extra pieces of tissue may be needed. Or the lab may need to make more

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slices of the tissue that has already been embedded in wax blocks. Either of these situations can add 1or 2 days to the testing time. Although most cancers can be found by looking at routinely stained sections, other studies such as those already described may be needed for some specimens. For example, histochemical stains or immunoperoxidase stains usually delay a case for another day. Other advanced studies like flow cytometry, electron microscopy, and molecular pathology techniques can take even longer, sometimes days, before results are ready. Another important reason for delaying a pathology report is that the pathologist may seek a second opinion from an expert. Unlike some chemical tests done in the laboratory that measure the amount of a specific substance or look at whether a substance is present or absent, testing tissue or cell samples for cancer is based on the professional opinion of the pathologist who looks at the sample under the microscope. Although the abnormal features of some cancers are obvious, some cases have features that are very difficult to recognize. Also, pathologists are often understandably reluctant

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to diagnose certain very rare types of cancer without a second opinion from an expert who specializes in that area. There are pathology experts specializing in almost every organ system (digestive, head and neck, breast, bone, reproductive, etc.). When difficult or rare cases are encountered, slides are usually sent to experts by overnight mail. Such review can delay the case for several more days. Finally, patients should realize that delays might occur for reasons that are neither technical nor medical. For example, entering the report into the computer takes time. Some labs send results directly to doctors office computer systems or fax machines, but a hospital mail system or US mail is still often used and can delay the results. What can you do to learn more about your pathology results? Pathology results have a key role in making decisions about treatment, and many patients want to learn more about their test results. You should feel free to ask your doctors to explain these results in a way that you can understand. You will want to focus on how the results influence treatment options and help predict your outlook for survival. Some pathologists will speak with you to help you understand your pathology reports.

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But some other pathologists believe that your oncologist, primary care doctor, or other doctors are better able to explain the results because they know more of your overall medical situation. Also, doctors who already know you well are often best able to discuss the complex personal issues affected by your pathology results. You may request copies of your pathology reports, and you may find it useful to keep a folder or notebook with your pathology, radiology, and other test results. If you see more doctors in the same hospital where your cancer was diagnosed, the new doctors will have access to the original pathology report and other medical records. If consulting doctors (such as those sought for second opinions) practice at other facilities, it is usually necessary to send copies of pathology reports and other medical records. Usually you can simply sign a release form to have the copies sent, but it is helpful if you keep an original copy to share with the new doctor in case a report is not available. You will always want to get back the original for those times you may need it again. Some cancer centers have a policy requiring that microscope slides of the patient's cancer be reviewed by the pathologists at their own institution. Some pathology

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laboratories will give copies of microscope slides to you if you are about to visit another cancer center for a second opinion or consultation. Other laboratories prefer to mail the slides directly to the consulting cancer center's pathology department. If you or your doctors have any concerns about your pathology diagnosis, you can have your microscope slides reviewed by a consulting pathologist for a second opinion. Your oncologist or surgeon or the pathologist who first looked at your biopsy or cytology sample can often suggest a consultant with special qualifications in examining samples such as yours. Or you can have your slides sent to the pathology department of a medical school or cancer center you have confidence in. What information is included in a pathology report? The pathology report of surgical specimens is often quite long and complex. It is typically divided into a number of subheadings. Patient, doctor, and specimen identification: The general identifying information includes the patient's name, medical record number issued by the hospital, the date when the biopsy or surgery was performed and the unique number of the specimen issued in the laboratory.

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Clinical information: The next portion of the report often contains information about the patient provided by the doctor who removed the tissue sample. Such information may include a pertinent medical history and special requests made to the pathologist. For example, if a lymph node sample is being removed from a patient already known to have cancer in another organ, the doctor will note the type of the original cancer. This information is often useful in guiding the pathologist's selection of special studies that may be needed to find out whether any cancer in that lymph node is a metastasis from the prior cancer or is a new cancer that started in the lymph node. Gross description: The next part of the report is called the gross description. The medical meaning of "gross" differs from the common use of the word, and refers to features that can be identified without a microscope (by simply looking at, measuring, or feeling the tissue). For a small biopsy, this description is a few sentences listing its size color, and consistency. This section also records the number of tissue-containing cassettes submitted for processing. Larger biopsy or tissue specimens, for example, a mastectomy for breast cancer, will 309

have much longer descriptions including the size of the entire breast, size of the cancer, how close the cancer is to the nearest surgical margin or edge of the specimen, how many lymph nodes were found in the underarm area, and the appearance of non-cancerous breast tissue. A summary of exactly where tissue was taken from for processing is included. For cytology specimens, the gross description is very short and usually notes the number of slides or smears made by the doctor. If the sample is a body fluid, its color and volume are noted. Microscopic description: This description records what the pathologist saw under the microscope. The appearance of the cancer cells, how they are arranged together, and the extent to which the cancer penetrates nearby tissues in the specimen are usually included in the microscopic description. For typical cases of common cancers or for benign tissues, a microscopic description may not be included in the report. Results of any additional studies (histochemical stains, flow cytometry, etc.) performed in the case are noted in the microscopic description or in a separate section.

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Diagnosis: The most important part of the pathology report is the final diagnosis. It is, in essence, the "bottom line" of the testing process, although this section may appear at the bottom or the top of the page. The patient's doctor relies upon this final diagnosis to help in choosing the best treatment options for the patient. If the diagnosis is cancer, this section will note the exact type of cancer that is present and will usually include the cancer's grade. Comment: After the final diagnosis is made, the pathologist may wish to add more information for the doctors taking care of the patient. The comment section is often used to clarify a concern or recommend further testing. Summary: Some pathology reports for cancers contain a summary of findings most relevant to making treatment decisions.

Staging Staging is the process of finding out how much cancer there is in the body and where it is located. It is how the doctor learns the stage of a person's cancer. Doctors use this information to plan treatment and to help find out a person's outlook (prognosis).

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Cancers with the same stage usually have similar outlooks and are often treated the same way. The cancer stage is also a way for doctors to describe the extent of the cancer when they talk with each other about a person's case. Why is staging needed? Doctors need to know the amount of cancer and where it is in the body to make sure a person gets the best possible treatment. For example, the treatment for early stage breast cancer may be surgery and radiation, while a more advanced stage of breast cancer may need to be treated with chemotherapy, too. Doctors also use the stage to help predict the course a cancer is likely to take. What is the doctor looking for when staging cancer? For most cancers, the stage is based on 3 main factors: * the original (primary) tumor's size and whether or not the tumor has grown into nearby areas * whether or not the cancer has spread to the nearby lymph nodes * whether or not the cancer has spread to distant areas of the body Some cancers of the blood, such as leukemias, are not staged in this way because they are assumed to be in all parts of the body. Cancers in or around the brain are also not

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staged using the TNM system, since these cancers can disrupt vital brain and body functions before they even begin to spread. What does staging involve? Doctors gather different types of information about a cancer to figure out its stage. Depending on where the cancer is located, the physical exam may give some clue as to the extent of the cancer. Pictures taken during tests like x-rays, CT scans, and MRIs may also provide information about how much and where cancer is in the body. Taking out tumors or pieces of tumors and looking at them under the microscope (biopsy) is needed to confirm the diagnosis of cancer, but it can also help stage the cancer. Samples can be removed either during surgery or during less invasive biopsy procedures. The different techniques used to remove and examine samples are described in our Surgery document. Types of staging There are different types of staging. Clinical staging is done at the time of diagnosis, before any treatment is given. It is an estimate how much cancer there is based on the physical exam, imaging tests (x-rays,

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CT scans, etc.), and sometimes biopsies of affected areas. For some cancers the results of other tests, such as blood tests, are also used in staging. The clinical stage is a key part of deciding the best treatment to use. It is also the baseline used for comparison when looking at the cancer's response to treatment. Pathologic staging can only be done on patients who have had surgery to remove the cancer or to look at how much cancer is in the body. It combines the results of clinical staging with the results from the surgery. In some cases, the pathologic stage may be different from the clinical stage (for example, if the surgery shows the cancer has spread more than it was thought to have spread before surgery). The pathological stage gives the health care team more precise information that can be used to predict treatment response and outcomes (prognosis). Restaging is not common, but it may be done to find the extent of the cancer if it comes back (recurs) after treatment. This is done to help decide what the best treatment option would be at this time. Restaging is discussed further in the section "A cancer's stage does not change." The TNM staging system

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At one time there were many different systems used to stage cancers, and sometimes different systems were used to stage the same type of cancer. But many of these systems did not give doctors very useful information. The American Joint Committee on Cancer (AJCC) developed the TNM classification system as a tool for doctors to stage different types of cancer based on certain standards. It has replaced many of the older staging systems. In the TNM system, each cancer is assigned a T, N, and M category. The T category describes the original (primary) tumor. The tumor size is usually measured in centimeters (2 and 1/2 centimeters is about 1 inch) or millimeters (10 millimeters = 1 centimeter). * TX means the tumor can't be measured. * T0 means there is no evidence of primary tumor (it cannot be found). * Tis means the cancer is in situ (the tumor has not started growing into the structures around it). * The numbers T1, T2, T3, and T4 describe the tumor size and/or level of invasion into nearby structures. The higher the T number, the larger the tumor and/or the more it has grown into nearby tissues. 315

The N category describes whether or not the cancer has spread into nearby lymph nodes. * NX means the nearby lymph nodes cannot be evaluated. * N0 means nearby lymph nodes do not contain cancer. * The numbers N1, N2, and N3 describe the size, location, and/or the number of lymph nodes involved. The higher the N number, the more the lymph nodes are involved. The M category tells whether there are distant metastases (spread of cancer to other parts of body). * MX means metastasis can't be evaluated. * M0 means that no distant metastases were found. * M1 means that distant metastases were found (the cancer has spread to distant organs or tissues). Each cancer type has its own version of this classification system, so letters and numbers don't always mean the same thing for every kind of cancer. For example, for some cancers, classifications may have subcategories, such as T3a and T3b, while others may not have an N3 category. Stage grouping

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Once the T, N, and M have been learned, they are combined, and an overall "stage" of 0, I, II, III, or IV is assigned. (Sometimes these stages are subdivided as well, using letters such as IIIA and IIIB.) For example, a T1, N0, M0 breast cancer would mean that the primary breast tumor is less than 2 cm across (T1), does not have lymph node involvement (N0), and has not spread to distant parts of the body (M0). This would make it a stage I cancer. A T2, N1, M0 breast cancer would mean that the cancer is more than 2 cm but less than 5 cm across (T2), has reached only the lymph nodes in the underarm area (N1), and has not spread to distant parts of the body. This would make it a stage IIB cancer. Stage 0 is carcinoma in situ for most cancers. This means the cancer is at a very early stage, is only in the area where it first developed, and has not spread. Not all cancers have a stage 0. Stage I cancers are the next least advanced and often have a good prognosis (outlook for survival). As the stage number goes up the cancers are more advanced (bigger and more widespread), but in many cases they can still be treated. Other staging systems

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Staging systems other than the TNM system are often used for Hodgkin disease and other lymphomas, as well as for some childhood cancers. The International Federation of Gynecologists and Obstetricians (FIGO) has a staging system for cancers of the female reproductive organs. The TNM stages closely match the FIGO stages, which makes it fairly easy to convert stages between these 2 systems. Other, older staging systems (such as the Dukes system for colorectal cancer) may still be used by some doctors. If your doctor uses another staging system, you may want to find out if the stage can be converted into the TNM system. This will often help if you want to read more about your cancer and its treatment, since TNM is more widely used. A cancer's stage does not change An important point some people have trouble understanding is that the stage of a cancer does not change over time, even if the cancer progresses. A cancer that comes back or spreads is still referred to by the stage it was given when it was first found and diagnosed. For example, if a woman were first diagnosed with "stage II breast cancer" and the cancer went away with treatment but now has come back and spread to the bones, the 318

cancer is called "stage II breast cancer with recurrent disease in the bones." If the breast cancer did not respond to treatment and spread to the bones it is called "stage II breast cancer with metastasis in the bones." In either case, the original stage does not change and this is not called "stage IV breast cancer." A stage IV breast cancer refers to a cancer that has already spread to a distant part of the body when it is first diagnosed. A person keeps the same diagnosis stage, but more information is added to the diagnosis to explain the current disease status. This is important to understand because survival statistics and information on treatment by stage for specific cancer types refer to the stage when the cancer was first diagnosed. The survival statistics related to stage II breast cancer that has recurred in the bones may not be the same as the survival statistics for stage IV breast cancer. Still, restaging may be done to measure the cancer's response to treatment or to assess cancer that has come back (recurred) and will need more treatment. This often means going through the same process that was done when the cancer was first diagnosed: exams, imaging tests, biopsies, and possibly surgery to restage the cancer. If the cancer 319

is restaged, the stage will be recorded with a lower-case "r" before the restaged categories. A restaging process that finds T2, N3, M1, for instance, would be written rT2, rN3, rM1. The stage grouping IV would be written stage rIV rather than stage IV, to note that it is different from the stage at diagnosis. The original stage at diagnosis always stays the same. Restaging is not often done in cancer treatment, but it is more common in clinical trials. What else can affect prognosis? Your outlook (prognosis) is affected by the type of cancer you have, but it is also strongly affected by the cancer's stage. For some cancers, another important factor that is considered along with stage is tumor grade. Grade Tumor grade describes how different the cancer cells look when compared to normal ones. The grade is assigned after the doctor looks at a biopsy of the cancerous tissue. Tumor grade is taken into account when making treatment decisions and is another factor that affects prognosis for some kinds of cancer. The grade of the cancer reflects how abnormal the cancer cells look under the microscope. Grading is done by a 320

pathologist who compares the cancer cells from the biopsy to how normal cells look in the same area. (A pathologist is a doctor who is specially trained in diagnosis and classification of diseases by lab tests, such as looking cells under a microscope.) Grade is important because cancers with more abnormal-looking cells tend to grow and spread faster. Higher grade cancers (meaning that the cancer cells look very different from normal cells) usually have a worse prognosis, and sometimes need different treatments. The American Joint Committee on Cancer (AJCC) recommends the following cancer grading classifications: * GX Grade cannot be assessed * G1 Well-differentiated (the cancer cells look a lot like normal cells) * G2 Moderately well-differentiated (cancer cells look somewhat like normal cells) * G3 Poorly differentiated (cancer cells don't look much like normal cells) * G4 Undifferentiated (the cancer cells don't look anything like normal cells) The lower the cancer grade the better the prognosis. G1 cancers are linked to the best outcomes. G4 is linked to the worst outcomes, and G2 and G3 fall in between.

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There are problems with grading, though. For example, many different grade levels may be found in one tumor or the tumor grade may change with time. There are also several grading systems for different types of cancer, such as the Gleason grades for prostate cancer or the Kernohan grades for brain tumors. Each grading system divides cancer cells into those with the most abnormal cells, the least abnormal cells, and those in between. Generally, whatever grading system is used, the lower numbers indicate less aggressive cancers while the higher numbers suggest faster cancer cell growth and spread. Along with stage and grade, your outlook is also influenced by the treatment you get, your general health, and many other factors that your doctor will take into account. Finding out more about your type of cancer If you are looking for details on staging or grading for a certain type of cancer, you can find this information in each of our documents on specific cancer types. You can get any of these cancer site documents on our Web site or by calling our tollfree number below.

Surgery

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Surgery is the oldest form of cancer treatment. It also has a key role in diagnosing cancer and finding out how far it has spread (staging). Advances in surgical techniques have allowed surgeons to successfully operate on a growing number of patients. Today, less invasive operations often can be done to remove tumors while saving as much normal tissue and function as possible. Surgery offers the greatest chance for cure for many types of cancer, especially those that have not spread to other parts of the body. Most people with cancer will have some type of surgery. Why is surgery used for cancer? Surgery can be done for many reasons. Some types of surgery are very minor and may be called procedures, while others are much bigger operations. The more common types of cancer surgeries are reviewed here. Preventive (prophylactic) surgery Preventive surgery is done to remove body tissue that is likely to become cancerous (malignant), even though there are no signs of cancer at the time of the surgery. For example, pre-cancerous polyps may be removed from the colon. Sometimes preventive surgery is used to remove an entire organ when a person has an 323

inherited condition that puts them at a much higher risk for having cancer some day. For example, some women with a strong family history of breast cancer are found to have a change (mutation) in their DNA in a breast cancer gene (BRCA1 or BRCA2). Because their risk of getting breast cancer is high, these women may want to consider prophylactic mastectomy (the breasts are removed before cancer is found). Diagnostic surgery This type of surgery is used to get a tissue sample to tell whether or not cancer is present or to tell what type of cancer it is. The diagnosis of cancer is often made by looking at the cells under a microscope. Many methods are used to get a sample of cells from a suspicious-looking area. These are described in the section, "Surgery to diagnose and stage cancer." Staging surgery Staging surgery is done to find out how much cancer there is and how far it has spread. While the physical exam and the results of lab and imaging tests can help figure out the clinical stage of the cancer, the surgical stage (also called the pathologic stage) is usually a more exact measure of how far the cancer has spread. For more information, 324

please see the American Cancer Society document called Staging. Examples of surgical procedures commonly used to stage cancers, such as laparotomy and laparoscopy, are described in the section, "Surgery to diagnose and stage cancer." Curative surgery Curative surgery is done when a tumor appears to be confined to one area, and it is likely that all of the tumor can be removed. Curative surgery can be the main treatment for the cancer. It may be used alone or along with chemotherapy or radiation therapy, which can be given before or after the operation. Sometimes radiation therapy is actually used during an operation. This is called intraoperative radiation therapy. Debulking (cytoreductive) surgery Debulking surgery is done to remove some, but not all, of the tumor. It is done when removing all of the tumor would cause too much damage to an organ or near-by tissues. In these cases, the doctor may remove as much of the tumor as possible and then try to treat what's left with radiation therapy or chemotherapy. Debulking surgery is commonly used for advanced cancer of the ovary. Palliative surgery

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This type of surgery is used to treat complications of advanced cancer. It is not intended to cure the cancer. Palliative surgery can also be used to correct a problem that is causing discomfort or disability. For example, some cancers in the abdomen may grow large enough to block off (obstruct) the intestine. If this happens, surgery can be used to remove the blockage. Palliative surgery may also be used to treat pain when the pain is hard to control by other means. Supportive surgery Supportive surgery is used to help with other types of treatment. For example, a vascular access device such as a port-a-cath can be surgically placed into a large vein. The port can then be used to give treatments or draw blood for testing, instead of having needles put in the arms. Restorative (reconstructive) surgery This type of surgery is used to change the way a person looks after major cancer surgery or to restore the function of an organ or body part after surgery. Examples include breast reconstruction after mastectomy or the use of tissue flaps, bone grafts, or prosthetic (metal or plastic) materials after surgery for oral cavity cancers. For more information on

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these types of reconstructive surgery, please see the American Cancer Society documents Breast Reconstruction after Mastectomy and Oral Cavity and Oropharyngeal Cancer. Surgery to diagnose and stage cancer A biopsy is a procedure done to remove a tissue sample so that it can be looked at under a microscope. Some biopsies may need to be done in surgery, but many types of biopsies involve removing tumor samples through a thin needle or an endoscope (a flexible lighted tube). Biopsies are often done by surgeons, but they can be done by other doctors, too. Some of the more common ways to do a biopsy are reviewed here. Fine needle aspiration biopsy Fine needle aspiration (FNA) uses a very thin needle attached to a syringe to pull out a small amount of tissue from a tumor. If the tumor cant be felt near the surface of the body, the needle can be guided into the tumor by looking at it with an imaging method such as an ultrasound (US) or CT (computed tomography) scan. The main advantage of FNA is that no surgical incision (cutting through the skin) is needed. A drawback is that in some cases the needle cant take out enough tissue for a

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definite diagnosis. A more invasive type of biopsy may then be needed. Core needle biopsy This type of biopsy uses a slightly larger needle to take out some of the tissue. A core biopsy can be aspirated (removed) with a needle if the tumor can be felt at the surface. Core biopsies can also be guided by imaging methods if the tumor is too deep to be felt. The advantage of core biopsy is that it usually collects enough tissue to find out whether or not the tumor is cancer. Excisional or incisional biopsy For these biopsies a surgeon cuts through the skin to remove the entire tumor (excisional biopsy) or a small part of the tumor (incisional biopsy). They can often be done with local or regional anesthesia. This means numbing medicine is used just in the area where the biopsy will be done. If the tumor is inside the chest or abdomen, general anesthesia (drugs that put you into a deep sleep) may be needed. Endoscopy This procedure uses a thin, flexible tube with a viewing lens or a video camera and a fiber optic light on the end. If a video camera is used, it is connected to a television screen. This allows the doctor to clearly see any tumors in the area. Endoscopes can be 328

passed through natural body openings to look at areas of concern in places such as the following: * * * * * * * * throat (pharyngoscopy) voice box (laryngoscopy) esophagus (esophagoscopy) stomach (gastroscopy) small intestine (duodenoscopy) colon (colonoscopy or sigmoidoscopy) bladder (cystoscopy) respiratory tract -- windpipe, bronchi, and lungs (bronchoscopy)

Some of the advantages of endoscopy are: * The doctor can look right at the tumor and get a good idea of where it is and how big it is. * A biopsy can be taken through the scope to find out if the tumor is cancer. * An open surgical incision or general anesthesia is usually not needed. Local numbing medicines are needed before some types of endoscopy. Medicines may also be given to make you sleepy. Ultrasonography Ultrasound devices can be attached to the end of some endoscopes. This allows doctors to look at the layers of the esophagus (swallowing tube), bronchus (main breathing tube), and parts of the large intestine (bowel). Nearby lymph nodes can be seen, too.

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Using the ultrasound pictures to guide it, a needle can be placed through the endoscope and cells can be collected from lymph nodes that do not look normal. Laparoscopy, thoracoscopy, or mediastinoscopy Laparoscopy is much like endoscopy, but a small incision is made in the skin of the abdomen (belly). A thin tube called a laparoscope is then put through the incision and into the abdomen to look for possible areas of cancer that can be biopsied. When this type of procedure is done to look inside the chest it is called a thoracoscopy or mediastinoscopy. Open surgical exploration (laparotomy, thoracotomy, or mediastinotomy) When less invasive tests do not give enough information about a suspicious area in the abdomen, a laparotomy may be needed. In this procedure, a surgeon makes an incision, usually from the bottom of the sternum (breastbone) down to the lower part of the abdomen (belly), which allows him to look directly at the area in question. The location and size of the tumor and the surrounding areas can be seen and biopsies can be taken, if needed. Because this is a major surgical procedure, general anesthesia (medicines that put you in a deep sleep) is needed. An operation much like this can be done to 330

open and look inside the chest. It is called a thoracotomy. If lymph nodes near the trachea are swollen, a mediastinotomy is done. General anesthesia (medicines that put you in a deep sleep) is used for this procedure. A special scope (mediastinoscope) is put in the body through a small incision above the top of the sternum (breastbone) and biopsies are collected from the areas of concern. Special surgery techniques When most people think of surgery, they picture a doctor using a scalpel and other surgical instruments to remove, repair, or replace parts of the body affected by disease. But newer techniques, using different types of instruments, have expanded the concept of what surgery is. Some of these newer techniques are described below. Laser surgery A laser is a highly focused and powerful beam of light energy which can be used for very precise surgical work, such as repairing a damaged retina in the eye. It can also be used to cut through tissue (instead of using a scalpel) or to vaporize (burn and destroy) cancers of the cervix, larynx (voice box), liver, rectum, or skin. Some surgeries can be made less invasive by using laser light. For example, with fiber 331

optics the light can be directed inside the body without having to make a large incision. Lasers are also used in a type of surgery called photoablation or photocoagulation. This means lasers are used to destroy tissue or to seal tissues or vessels. This type of surgery is often used to relieve symptoms, such as when large tumors block the windpipe or esophagus, causing problems with breathing or eating. Cryosurgery Cryosurgery involves the use of a liquid nitrogen spray or a very cold probe to freeze and kill abnormal cells. This technique is sometimes used to treat precancerous conditions, such as those affecting the cervix. Cryosurgery is also being studied as a treatment for some cancers, such as those of the prostate. Electrosurgery High-frequency electrical current can be used to destroy cells. It is used for some cancers of the skin and mouth. Mohs surgery Mohs micrographic surgery, also called microscopically controlled surgery, is a technique to remove certain skin cancers by shaving off one thin layer at a time. After

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each layer is removed, a specially trained dermatologist (skin doctor) or a pathologist (doctor who specializes in diagnosing and classifying diseases by lab tests) looks at the tissue layer under a microscope. When all the cells look normal under the microscope, the surgeon stops removing layers of tissue. This technique is used when the extent of the cancer is not known or when as much healthy tissue as possible needs to be preserved (as in cancers around the eye). It is done under local anesthesia by a specially trained surgeon. Chemosurgery is an older name for this surgery and refers to certain chemicals put on the tissue before it is removed. Mohs surgery does not involve use of cancer chemotherapy drugs. Laparoscopic surgery A laparoscope is a long, narrow, flexible tube placed through a small incision (cut) to look inside the body. It is sometimes used to take biopsy samples. In recent years, doctors have found that by creating some small holes and using special instruments, the laparoscope can be used to perform surgery without making a large incision. This can help reduce blood loss during surgery and pain afterwards. It can also shorten hospital

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stays. Laparoscopic surgery is commonly used today to remove gallbladders and to repair hernias. The role of laparoscopic surgery in cancer treatment is not yet clear. Doctors are now studying whether it is safe and effective to use laparoscopic surgeries for many cancers of the bladder, colon, prostate, and kidney, among others. It may prove to be as safe and effective as standard surgery while being less invasive. Some studies have hinted at this being the case. But larger, long-term studies still need to be completed. Thorascopic surgery A thoracoscope is a narrow, rigid tube with a camera connected at one end that can be placed through a small incision (cut) into the chest after the lung is collapsed. This allows the doctor to see inside the entire chest. Any areas of concern on the lining of the chest wall can be biopsied, fluid can be drained, and small tumors on the surface of the lung can be removed with small stapling devices. This less-invasive approach has also been used to remove parts (lobes) of the lung that contain cancer. Studies have shown that for early stage lung cancer, results are much like removing part of the lung by doing an open thoracotomy (incision in the side of the chest).

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Other forms of surgery Newer ways to remove or destroy cancer tumors are always being explored. Some methods are beginning to blur the lines between what we commonly think of as "surgery" and other forms of treatment. Researchers are testing many new techniques, using things such as high intensity focused ultrasound (HIFU); microwaves or radio waves (radiofrequency ablation, or RFA); or even magnets in an attempt to get rid of unwanted tissue. While promising, these techniques are still largely experimental. As doctors learn how to better control the energy waves used in radiation therapy, some newer radiation techniques that are almost as effective as surgery have been found. By using radiation sources from different angles, stereotactic radiation therapy delivers a large precise radiation dose to a small tumor area. The doses are so exact that the term stereotactic surgery is sometimes used, even though no incision (cut) is actually made. In fact, the machines used to deliver this treatment have names like Gamma Knife and CyberKnife, although no actual knife is involved. The most common site being treated with this technique is the brain, but it is also being used in head, neck, lung, and spine

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tumors. Researchers are looking for ways to use it to treat other types of cancer, too. Questions to ask your doctor about surgery Before having surgery, find out all you can about the benefits, risks, and side effects of the operation. Answers to the following questions will help you feel more comfortable with your decision. * Why am I having this operation? What are the chances of its success? * Is there any other way to treat this cancer? * Other than my cancer, am I healthy enough to go through the stress of the surgery and the anesthesia? * Are you certified by the American Board of Surgery and/or Specialty Surgery Board? * How many operations like this have you done? What is your success rate? Are you experienced in operating on my kind of cancer? * Exactly what will you be doing in this operation? What will you be taking out? Why? * How long will the surgery take? * Will I need blood transfusions? * What can I expect after the operation? Will I be in a lot of pain? Will I have drains or catheters? How long will I be in the hospital after the surgery?

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* How will my body be affected by the surgery? Will it work or look different? Will any of the effects be permanent? * How long will it take for me to recover? * What are the possible risks and side effects of this operation? What is the risk of death or disability with this surgery? * What will happen if I choose not to have the operation? * What are the chances that the surgery will cure my cancer? * Do I have time to think about my options or get a second opinion? Getting a second opinion One of the ways to find out whether a suggested operation is the best choice for you may be to get the opinion of another surgeon. Your doctor should not mind this. In fact, some insurance companies require you to get a second opinion. You may not need to have tests done again because you can often bring the results of your original tests to the second doctor. Check with your insurance company before planning surgery and before getting a second opinion. Get all of the information you need to feel sure you are making the right choice for your situation. Making an informed decision about your health is almost always better than making a quick one. 337

What will surgery be like? Your experience with surgery can depend on many factors, including the disease being treated, the type of operation being done, and your overall health. There are probably as many different surgical techniques as there are diseases to treat, so each case is different. It's not possible to get into the specifics of each type of operation here, but if you would like more detail it can be found in the treatment sections of the American Cancer Society documents on specific types of cancer. Still, some parts of the surgical experience are common to most operations. They include pre-operative testing and preparation, the surgery itself (usually including some type of anesthesia), and a recovery period. Planning and preparation Both you and your doctor have things to do before surgery to make sure you have the best chance for a good outcome. As much as is possible, you need to know what to expect and be comfortable that the decision you've made is the best one for you. People differ about how involved they want to be in the decision-making process. But knowing

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as much as you can about what lies ahead can, at the very least, help reduce your stress level. It is not unusual for patients to wait several weeks after learning they have cancer to have surgery. You have time--time to learn more about your cancer, time to talk to others who have been through it, time to explore your treatment options, time to organize your thoughts, and time to find the right health care team for you. You also may want a second opinion. Insurance pre-approval for the surgery may be needed and this, too, takes time. In almost all cases, the time needed to prepare for surgery should have no impact on the positive outcome of the surgery. If you do have some type of urgent medical symptom, surgery will be scheduled as soon as possible. Informed consent Informed consent is one of the most important parts of your preparation for surgery. It is a process during which you are told about all aspects of the treatment before you give your doctor written permission to do the surgery. Although the details may vary from state to state, the informed consent form usually states that your doctor has explained these things:

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* * * * * * *

your condition and why surgery is an option the goal of the surgery how the surgery is to be done how it may benefit you what your risks are what side effects to expect what other treatment options you have

When you sign the consent form you are saying that you have received this information and you are willing to have the surgery. It is important that you read the consent form and understand each of the above issues before signing it. Make sure your doctor answers all of your questions and that you understand the answers. Having a family member or friend go over it with you may also be helpful. Pre-operative testing Many tests are usually needed in the days or weeks before your surgery, especially if a major operation is planned. These tests are done to make sure your body is able to go through surgery and anesthesia. They may also be done to help doctors better understand your condition and to help them plan the surgery. Not all of the tests listed here may be needed (especially if you are having a minor procedure in a doctor's office). The tests most often used include: * Blood tests to measure your blood counts, your risk of bleeding or infection, and how

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well your liver and kidneys are working. Your blood type may also be checked in case you need blood transfusions during the operation. * Urine test (urinalysis) to look at kidney function and check for infections. * Chest x-ray and EKG (electrocardiogram) to check how well your lungs and heart are working. * Other tests as needed, such as CT scans to look at the size and location of tumors and see whether or not the cancer has spread to nearby tissues. Your doctor will also ask you questions about high blood pressure, heart disease, diabetes, and other conditions that could affect surgery. It is important that you let your doctor know about any allergic reactions you've had in the past. If you are going to have general anesthesia (be put into a deep sleep), you will probably also see an anesthesiologist (doctor who specializes in giving anesthesia). Other specialists may be consulted or other tests done if you have any other problems that could affect the surgery. Your surgeon may also change some of the medicines you take and ask you to stop smoking, stop drinking alcohol, try to improve your diet, and actively exercise before surgery. 341

Preparing for surgery Depending on the type of operation you have, there may be things you need to do to be ready for surgery. Emptying your digestive tract (stomach and bowels) is important if you will be asleep during surgery. Vomiting while under anesthesia can be very dangerous because the vomit could get into the lungs and cause an infection. For this reason, you will be asked to not eat or drink anything starting the night before the surgery. You may also be asked to use a laxative or an enema to make sure your intestines are empty. You may need to have an area of your body shaved to keep hair from getting into the incision. The area will be cleaned before the operation to reduce the risk of infection. Other special preparations may also be needed. It is normal to be anxious about surgery and anesthesia. Let your doctors know about these fears. They may give you medicine to help you relax before surgery. The operation Again, although each type of surgical procedure is different, they usually have certain factors in common. Anesthesia 342

Anesthesia is the use of drugs to make the body unable to feel pain for a period of time. Depending on the type and extent of the operation, you may or may not need drugs to make you sleep. In some cases, you may have an option as to which type of anesthesia you prefer. * Local anesthesia is often used for minor surgeries, such as biopsies near the body surface. Medicine is injected into the site beforehand to numb the nerves that cause pain. You stay awake and usually feel only pressure during the procedure. * Topical anesthesia is a type of local anesthesia that is rubbed or sprayed onto a body surface instead of being injected. It is sometimes used in the throat before endoscopy. * Regional anesthesia (a "nerve block") affects a larger area of the body while still allowing you to stay awake. It usually involves injecting medicine into an area around the spinal cord, which affects certain nerves coming out of it. But it may also involve injecting medicine around nerves in the arms or legs. The location of the injection determines the area affected. Medicine may be given as a single injection or as a

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continuous infusion. While you do stay awake, you may be given something to help you relax. * General anesthesia puts you into a deep sleep for the surgery. It is commonly started by having you breathe into a face mask or by injecting a drug into a vein in your arm. Once you are asleep, an endotracheal (ET) tube is placed in your throat to make it easy for you to breathe. Your vital signs (heart rate, breathing rate, and blood pressure) will be closely watched during the surgery. A doctor or nurse who specializes in giving anesthesia watches you throughout the procedure and until you wake up. They also take out the ET tube once the operation is over. Recovery If you had local anesthesia, you may be allowed to go home shortly after the surgery. People who get regional or general anesthesia are taken to the recovery room to be watched closely while the effects of the anesthesia wear off. This may take several hours. People waking up from general anesthesia often feel "out of it" for some time. Things may seem hazy or dream-like for a while, and you may not feel like you are fully awake until the next day.

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Your recovery right after surgery depends on many factors, including your state of health before the operation and how extensive the operation was. You will get pain medicine while in the hospital, and will be given a prescription for pain medicine to take at home if you need it. Throughout your hospital stay, be aware that there are many different medicines available to help you control your pain. If you have pain that is holding up your recovery, be sure to let your health care team know. Your throat may be sore for a while from the ET tube. You may also have a catheter (tube) draining urine from your bladder into a bag. This may be taken out soon after surgery, but may need to be put back in if you have trouble urinating on your own. You may also have a tube or tubes (called "drains") coming out of the incision site. Drains allow the excess fluid that collects at the surgery site to leave the body. Your doctor will likely take them out once they stop collecting fluid, usually a few days after the operation. This may be done while you are still in the hospital or later at the doctor's office. You may not feel much like eating or drinking, but this is an important part of the

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recovery process. Your health care team may start you out with ice chips or water at first. They will check that you are urinating normally at this time and may want to measure the amount of urine you make by having you go in a special container. The digestive tract (stomach and intestines) is one of the last parts of the body to recover from the effects of anesthesia. Signs of stomach and bowel activity need to return before you will be allowed to eat. Along with checking your surgical scar and other parts of your body, your doctor will use a stethoscope to listen for bowel sounds in your abdomen and will ask if you have passed gas. You will likely be on a clear liquid diet until this happens. Once it does, you may be allowed to try solid foods. Your health care team will probably try to have you moving as soon as possible after surgery. They may even have you out of bed and walking the next day. While this may be difficult at first, it helps speed your recovery by getting the digestive tract moving. It also helps get your circulation going and prevents blood clots from forming in your legs. Again, be sure to let your team know if you are having a lot of pain, so they can give you medicine to control it.

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Your team may also encourage you to do deep breathing exercises. This helps fully inflate the lungs and reduces the risk of pneumonia. Once you are eating and walking, you may start hearing about plans for going home. Of course, this will depend upon other factors too, such as the results of the surgery and tests done afterward. Your doctor will want to make sure you are well enough to be home. Before leaving, be sure that you understand the following: * what kind of wound care you need to do at home * what to look for that might need attention right away * what your activity limits are (driving, working, lifting, etc.) * other restrictions (diet, those related to pain medicine, etc.) * what medicines to take and how often to take them, including pain medicines * who to call with questions or problems that may come up * whether you should be doing anything in terms of rehabilitation (exercises or physical therapy) * when you are due to see your doctor again You may need help at home for a while after surgery. If family members or friends are unable to do all that is needed, your team may be able to arrange to have a nurse or nurse's aide visit you at home for a short while.

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Other parts of recovery may be more long-term in nature. Wounds heal at different rates in different people. Some operations, such as a mastectomy (breast removal), may result in permanent changes to your body. Others, such as a limb amputation or an ostomy (opening in the abdomen connected to the end of your intestine) affect how your body works, and you may need to learn new ways of doing things. Fully understanding the result of the operation before it is done is an important part of helping you adjust to the changes that have been made to your body. Be sure that all of your questions are answered up front. Get as specific as you need to with your questions, and make sure your health care team gives specific answers, too. What are the risks and side effects of surgery? There are risks that go with any type of medical procedure and surgery is no exception. Of course, there are risks with almost everything we do in life. What is important is whether or not the benefits outweigh the possible risks. Doctors have been performing surgeries for a very long time. Advances in surgical techniques and in our understanding of how to prevent infections have made modern surgery safer and less invasive than it has ever been. Still, there is always a degree of 348

risk involved, no matter how small. Before you decide to have any medical procedure done, it is important that you understand the risks. Different procedures have different kinds of risks and side effects. This section is not meant to provide a list of all of the possible complications of every type of surgery. Be sure to discuss the details of your case with your doctor, who can give you a better idea about what your actual risks are. During surgery Possible complications during surgery may be caused by the surgery itself, the anesthesia, or an underlying disease. Generally speaking, the more complex the surgery the greater the risk. Minor operations and biopsies usually pose less risk than major surgery. Pain at the site of the incision is the most common problem. Infections at the site and reactions to local anesthesia are also possible. Complications in major surgical procedures are not common, but can include: * Bleeding during surgery that may cause you to need blood transfusions. Doctors try to minimize this risk by checking your blood counts beforehand and being careful when

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working near blood vessels. Still, some operations involve a certain amount of controlled blood loss. If you have concerns, you can to talk to your doctor about banking some of your own blood in the weeks before surgery so it can be given back to you during the operation if needed. (This is called autologous transfusion.) For more information, see the American Cancer Society document, Blood Product Donation and Transfusion. * Damage to internal organs and blood vessels during surgery. Again, doctors are careful to allow as little damage as possible. * Reactions to anesthesia or other medicines. Although rare, these can be serious because they can cause dangerously low blood pressures. Your doctors will watch your vital signs throughout the procedure to look for this. * Problems with other organs, such as the lungs, heart, or kidneys. These are very rare but can happen and can be life-threatening. They are more likely to happen to people who already have problems with these organs. This is why doctors get a complete patient history to look at possible risks before an operation is done. After surgery

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Some problems after surgery are fairly common, but are not usually life-threatening. * Pain is probably the most common side effect. Almost everyone has some level of pain after surgery. Some pain is normal, but it should not be allowed to delay your recovery. There are many ways of dealing with surgical pain. Medicines for pain range from aspirin and acetaminophen (Tylenol) to stronger drugs, such as opioids like codeine and morphine. * Infection at the site of the wound is another possible problem. Although doctors take great care to reduce this risk by cleaning the area and keeping the area around it sterile, infections do happen. Antibiotics, either as a pill or given through a vein in your arm (IV), are able to treat most infections. Other problems are rare, but may be more serious. * Pneumonia can occur, especially in patients with reduced lung function, such as smokers. Doing deep breathing exercises as soon as possible after surgery helps lessen this risk. * Other infections can develop within the body, especially if the digestive tract was opened during the operation. Doctors take great care to try to make sure this does not

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happen. But if it does, powerful antibiotics will be used to treat it. * Bleeding can happen either internally (inside the body) or externally (outside the body). It can occur if a blood vessel was not sealed off during surgery or if a wound opens up. Serious bleeding may cause the person to need another operation to find the source of the bleeding and stop it. * Blood clots can form in the deep veins of the legs after surgery, especially if a person stays in bed for a long time. Such a clot could become a serious problem if it were to break loose and travel to another part of the body, such as a lung. This is why you will be encouraged to get out of bed and sit, stand, and walk as soon as possible. * Slow recovery of other body functions, such as movement in the intestines, can sometimes become serious problems, too. Getting out of bed and walking around as soon as possible after surgery can decrease this risk. Other life-threatening complications are very rare and difficult to predict, but sometimes do happen. Your surgical team will take many steps to avoid possible complications. This includes things like shaving and cleaning the area before cutting the skin to avoid infection, use of special leg pumps and low-dose blood thinners to avoid clots, and 352

respiratory therapy to prevent pneumonia. Long-term side effects depend on the type of procedure done. For example, people who are having colorectal cancer surgery may need a colostomy (an opening in the abdomen to which the end of the colon is attached). Men undergoing radical prostatectomy (removal of the prostate) are at risk for losing control of urination or becoming impotent. Your doctor should talk to you about all of these long-term outcomes before surgery. You can get more information on any possible long-term effect by calling the American Cancer Society at 1-800-ACS-2345. Does surgery cause cancer to spread? In nearly all cases, surgery does not cause cancer to spread, but there are some important exceptions. Doctors who are experienced in taking biopsies of cancers and treating them with surgery are very careful to avoid these situations. The chances of a needle biopsy causing a cancer to spread are very low. In the past, larger needles were used for biopsies, and the chance of spread was higher. Most types of cancers can be safely sampled by an incisional biopsy, but there are a few exceptions, such as certain tumors in the eyes or in the testicles. For these types of 353

cancer, doctors may treat without a biopsy or may recommend removing the entire tumor if it is likely to be cancerous. In some cases a needle biopsy can be safely used, and then if the tumor is found to be cancer, the whole tumor is removed by surgery. One common myth about cancer is that it will spread if it is exposed to air during surgery. Some people may believe this because they often feel worse after the operation than they did before. It is normal to feel this way when beginning to recover from any surgery. Cancer does not spread because it has been exposed to air. If you delay or refuse surgery because of this myth, then you may be harming yourself by passing up effective treatment. The best chance of a cure from most types of cancer is to remove all of the cancer as soon as possible after diagnosis. If you have a solid tumor, sometimes surgery alone will provide a cure, but often chemotherapy, radiation therapy, or biologic therapy is also needed. Your health care team will discuss your best treatment options with you. If you have any concerns about surgery and cancer spread, discuss this issue with the people who know your situation best--your surgeon and other members of your cancer 354

care team. You can also call 1-800-ACS-2345 any time you have questions or need help. The American Cancer Society has information, resources, and support available on cancer-related topics. Talking With Your Doctor Patients who have good relationships with their doctors tend to be more satisfied with their care -- and to have better results. Here are some tips to help you and your doctor become partners in improving your health care. Getting Your Needs Met A good relationship between you and your doctor is an important part of good health care. You must be able to communicate well with each other so that your needs are met. Ask Yourself, "How Much Do I Want to Know?" Don't be afraid to tell your doctor how much--or how little--information you want. Sharing Information Everyone has a different style of sharing information. Be sure to set your own parameters. Remembering What Your Doctor Says Here are some tips for keeping track of what your doctor tells you. Asking Questions This list will help guide discussions with your doctor. The Doctor-Patient Relationship A good doctor-patient relationship is a two-way street. Here are some ways you can hold up your end of the bargain. 355

If You Have a Problem Talking with Your Doctor If you have a problem talking with your doctor, there are often ways to improve the situation. Here are some ideas. Changes in the Doctor-Patient Relationship You may end up changing doctors at some point, or if you stay at a hospital, many people may be involved in your care. Here's a list of some information you should always have at the ready. Additional Resources Looking for more information on this topic? We can help. Browse this list of related resources. Getting Your Needs Met Cancer treatment often means that you will have more than one doctor. You may even have a team of doctors, nurses, and other people involved in your care. Although you may get information from several people, it's a good idea to choose one doctor to be the one you turn to with your questions. This doctor may or may not be the one you see most often. You should be the one to make this choice. We offer the following information to help you make the choice that's right for you. You should feel at ease with your doctor. Sometimes, it takes a little time and work before you feel at ease. You will want to take the time to ask your questions and make

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your concerns known. Likewise, your doctor must take the time to answer your questions and listen to your concerns. If you and your doctor feel the same way about sharing information and making choices, you probably have a good relationship. Ask Yourself, "How Much Do I Want to Know?" You may want to know a lot of medical details about your illness. Some people feel more in control of what is happening to them when they know all of the facts. Decide how much detail about your diagnosis and treatment would be helpful, and let your doctor know. You may want only small amounts of information. It disturbs some people to be told too many details. They may want simple directions -- what pill to take or what their treatment will be and when it will be done. They feel overwhelmed by medical details and would rather leave most decisions to the doctor. Don't be afraid to tell your doctor how much or how little information you want. Sharing Information Everyone has a different style of sharing information. That's why the perfect doctor for one person may not be a good match for another. Think about what you value in a doctor. Some people want a doctor who will share information in a clinical and

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business-like manner. They expect their doctor to be the medical expert rather than a friend. Other people want their doctors to have an excellent "bedside manner." They value a doctor who can address both their emotional health and medical needs. Many people whose illnesses require treatment over a long period of time prefer this kind of friendly relationship with their doctor. After you have thought through what you want as a patient, the next step is to look at how you talk with the doctor you have chosen. Remembering What Your Doctor Says It's hard to understand complex information when you are anxious or afraid. Even if the doctor is thorough in explaining things, you may not hear or remember what is being said. There are several ways to make sure you remember everything your doctor tells you. Decide which way will be best for you. * Take notes to help you recall what your doctor says. * Ask if you can record your talk for later review. * Have a family member or friend there with you. He or she can remind you of questions you want to ask and help you remember what the doctor said. It may also be easier to have this person talk to your family about your medical status. This will help your family feel included without your having to deal with many questions. You may 358

want their help in making decisions; so keeping them up-to-date may be in your best interest. Sometimes, without realizing it, doctors use terms their patients don't understand. If you don't understand something, ask your doctor to explain it to you. The Doctor-Patient Relationship A good doctor-patient relationship is a two-way street. Here are some ways you can help keep up your end of the relationship: * Tell your doctor about any changes in your body and how it is working -- from sleep and bowel habits to headaches. Make notes so you can report these accurately to your doctor. * Ask your doctor what changes you should call about right away and which ones would merit an emergency call during times when the office is closed. * Discuss your concerns about how cancer will affect your lifestyle. Be honest about your habits -- even if they're habits, such as smoking, that you're not proud of. Never hold back information. Something you think is minor could affect your treatment. Or something you think is serious might be easily relieved. * Make a list of all your questions, and take it with you to your doctor visits. Don't be ashamed or shy about asking these questions. There is no such thing as a "dumb"

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question. Refer to the list of questions above for some ideas, and then add your own. * Be sure your doctor has a copy of your most recent instructions on how to care for you if you become unable to make decisions for yourself (advance directives). For more information, see the American Cancer Society document Advance Directives. Second opinions Because cancer treatment is so complex, some people don't even know where to start with asking questions. But they may wonder whether another doctor might offer something different in the way of treatment. You may find that you want to talk with another doctor who can look at test results, who can talk with you about your personal situation, and maybe give you a different take on it. Some people find it hard to tell their doctors that they'd like a second opinion. It may help you to know that it is common for patients to seek a second opinion, and most doctors are comfortable with the request. In fact, some insurance companies require you to get one before you start treatment. If you feel unsure on how to begin, here are some ideas you can consider to help bring it up with your doctor. * "Before we start treatment, I'd like to get a second opinion. Will you help me with

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that?" * "If you had my type of cancer, who would you see for a second opinion?" * "I think that I'd like to talk with another doctor to be sure I have all my bases covered." * "I'm thinking of getting a second opinion. Can you recommend someone?" You can ask your doctor to refer you to someone, as suggested above. You may also want to look at the American Cancer Society document Choosing a Doctor and a Hospital for other ideas. Once you have decided who you will see for your second opinion, ask that your medical records, original x-rays, and test results be shared with the referral doctor, so you won't have to repeat them. This is usually arranged with the office staff. You will need to sign a release of information form. Or you may want to take copies of your medical records to the new doctor yourself. The Doctor-Patient Relationship A good doctor-patient relationship is a two-way street. Here are some ways you can help keep up your end of the relationship: * Tell your doctor about any changes in your body and how it is working -- from sleep and bowel habits to headaches. Make notes so you can report these accurately to your doctor.

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* Ask your doctor what changes you should call about right away and which ones would merit an emergency call during times when the office is closed. * Discuss your concerns about how cancer will affect your lifestyle. Be honest about your habits -- even if they're habits, such as smoking, that you're not proud of. Never hold back information. Something you think is minor could affect your treatment. Or something you think is serious might be easily relieved. * Make a list of all your questions, and take it with you to your doctor visits. Don't be ashamed or shy about asking these questions. There is no such thing as a "dumb" question. Refer to the list of questions above for some ideas, and then add your own. * Be sure your doctor has a copy of your most recent instructions on how to care for you if you become unable to make decisions for yourself (advance directives). For more information, see the American Cancer Society document Advance Directives. Second opinions Because cancer treatment is so complex, some people don't even know where to start with asking questions. But they may wonder whether another doctor might offer something different in the way of treatment. You may find that you want to talk with another doctor who can look at test results, who can talk with you about your personal 362

situation, and maybe give you a different take on it. Some people find it hard to tell their doctors that they'd like a second opinion. It may help you to know that it is common for patients to seek a second opinion, and most doctors are comfortable with the request. In fact, some insurance companies require you to get one before you start treatment. If you feel unsure on how to begin, here are some ideas you can consider to help bring it up with your doctor. * "Before we start treatment, I'd like to get a second opinion. Will you help me with that?" * "If you had my type of cancer, who would you see for a second opinion?" * "I think that I'd like to talk with another doctor to be sure I have all my bases covered." * "I'm thinking of getting a second opinion. Can you recommend someone?" You can ask your doctor to refer you to someone, as suggested above. You may also want to look at the American Cancer Society document Choosing a Doctor and a Hospital for other ideas. Once you have decided who you will see for your second opinion, ask that your medical records, original x-rays, and test results be shared with the referral doctor, so you won't

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have to repeat them. This is usually arranged with the office staff. You will need to sign a release of information form. Or you may want to take copies of your medical records to the new doctor yourself. If You Have a Problem Talking with Your Doctor If you have a problem talking with your doctor, there are often ways to improve the situation. Try working out your concerns before deciding the situation is hopeless. First, state your concern as honestly and openly as possible. Here are some opening statements you may want to consider: * "Im concerned that we aren't communicating well, and here's why ..." * "I need to be able to talk with you about _________, and I feel like I can't. Can we discuss this?" * "I realize that you're very busy, but I need to discuss _________ with you. Can we schedule a time to do that?" * "I'm having trouble understanding ___________. Can you help me?" If you need more details after your doctor answers a question, say so. Sometimes it's even helpful to ask the same question again in a different way. Unless you tell your doctor that you don't understand something, he or she will usually assume that you do.

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There's nothing wrong with telling your doctor that you don't understand. If you want to learn more about your cancer treatment, ask your doctor to suggest some reading materials. Learning more about your treatment can help you become more actively involved in it. If you are unable to work out the problem during regular visits with your doctor, ask for a special visit to discuss it. If the issue concerns your cancer treatment, go to the meeting with as much information as possible. You can call us at 1-(800) ACS2345 for more information about your type of cancer and its treatment. Always tell your doctor where you get your information and then ask for his or her opinion. Even if you feel frustrated or angry, try to avoid being hostile toward your doctor. Often people become defensive and withdraw when they feel attacked -- a response that will be not be helpful in the long run. State your concerns and questions clearly and honestly, without accusing. What should you do if you feel you have done your part but the situation has not improved? You might consider talking with a third party about the problem. The head nurse or your family doctor might be willing to discuss the matter with the doctor. 365

Sometimes this is less stressful than facing the doctor directly, and their help could improve the situation. If not, it may be time to find a new doctor. Don't stay with a doctor only to protect his or her feelings. Just because you were referred to the doctor does not mean you can't decide to change on your own. It's your body and you have the right to find the best doctor for you. Changes in the Doctor-Patient Relationship If you are in the hospital, your relationship with your doctor will change somewhat. Many other people will be involved in your care during your stay at the hospital. Your doctor may not be the only one making treatment decisions. Sometimes hospital policies and routines clash with your own, and will take some adjustment on your part. In the hospital, you will also be surrounded by activity, which can be stressful in itself. Some of this can't be avoided, but you can bring up problems with the nurses who are caring for you. They can offer ideas about ways to deal with these changes, and how the staff can help meet your needs. Keep in mind that your doctor may also be able to help you solve problems that might come up as you adjust to 366

hospital routines and practices. If you have a problem with your doctor while you are in the hospital, there are other people who may be able to help. Speak to a nurse or a social worker, or ask if the hospital has a patient service representative on staff. They can provide support and help you organize your thoughts before talking with your doctor. With your permission, they might even speak directly with your doctor. People who have cancer are likely to want to build a good relationship with their doctors. Building this relationship doesn't just happen -- it takes care and effort on both sides. Chances are you'll both benefit from it. Information from your doctor that you will need later At some point--even if you don't change doctors before or during treatment--you are likely to find yourself in the office of a new doctor. It is important that you be able to give your new doctor the exact details of your diagnosis and treatment. Make sure you have the following information handy and always keep copies for yourself: * a copy of your pathology report from any biopsy or surgery * if you had surgery, a copy of your operative report * if you were hospitalized, a copy of the discharge summary that every doctor must prepare when patients are sent home from the hospital 367

* finally, since some cancer-treatment drugs can have long-term side effects, a list of your drugs, drug doses, and when you took them You can usually ask your treating doctor's office staff for copies. Keep in mind that doctors sometimes move and offices can close, so ask for your records sooner rather than later. If the treatment or test took place in a hospital, you will need to contact their medical records department to see how to get these records. This is the kind of information you will want to keep the rest of your life, since almost any doctor you see in the future will need it. Understanding Chemotherapy: A Guide For Patients And Families You've been told you have cancer. You've studied your treatment options and you and your doctor have agreed that chemotherapy is your best choice. Now you may have questions about your treatment. The American Cancer Society knows you may have concerns about chemotherapy, and we have answers to your questions. Remember that, along with reading about your treatment, you can also count on your doctor and nurse to answer your questions. At the end of this document you will find a glossary that gives definitions of some of the 368

words and terms used by your health care team. The words that are in italic type the first time they are used are also in the glossary. You can use the glossary to help you better understand the talks you have with your health care team. Open and honest talks with your cancer care team are the best way to understand what is going on with you, your body, and the cancer. General Questions and Answers About Chemotherapy Managing Side Effects Glossary of Chemotherapy Terms General Questions & Answers About Chemotherapy Chemotherapyis the use of medicines or drugs to treat disease. Many times this treatment is called just "chemo." Surgery and radiation therapy remove, kill, or damage cancer cells in a certain area, but chemo works throughout the whole body. Chemo can kill cancer cells that have metastasized or spread to parts of the body far away from the primary (original) tumor. What Is Chemotherapy and How Does It Work? What Is the Goal of Chemotherapy? Will Chemotherapy Be My Only Treatment for Cancer?

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A Checklist of Questions to Ask Your Doctor or Nurse Should I Get a Second Opinion? Where Will I Get Chemotherapy? How Often Will I Receive Chemotherapy Treatment? How Long Will It Last? How Will the Chemotherapy Treatment Be Given to Me? Does Chemotherapy Hurt? What Are Clinical Trials? Can I Take Other Medicines While I Am Getting Chemotherapy? Can I Be Around My Family and Friends While I Am Getting Chemotherapy? How Can I Protect Myself and Those I Live With While I Am Getting Chemo? Will I Be Able to Work During Treatment? How Will I Know If My Chemotherapy Is Working? How Do I Give My Permission for this Treatment? How Do I Pay for My Chemotherapy? What Is Chemotherapy And How Does It Work? Chemotherapy is the use of medicines or drugs to treat disease. Many times this treatment is called just "chemo." Surgery and radiation therapy remove, kill, or damage cancer cells in a certain area, but chemo works throughout the whole body. Chemo can

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kill cancer cells that have metastasized or spread to parts of the body far away from the primary (original) tumor. More than 100 chemo drugs are used in many combinations. A single chemo drug can be used to treat cancer. But for the most part, the drugs work better when used in certain combinations. Your chemo treatment will likely include more than one drug. This is called combination chemotherapy. A combination of drugs with different actions can work together to kill more cancer cells. It can also reduce the chance that the cancer may become resistant to any one chemo drug. You and your doctor will decide what drug or combination of drugs you will get. Your doctor will choose the doses, how the drugs will be given, and how often and how long you will get treatment. All of these decisions will depend on the type of cancer, where it is, how big it is, and how it is affecting your normal body functions and overall health. What Is the Goal of Chemotherapy? Depending on the type of cancer and its stage of development, chemo can be used to: * cure the cancer * keep the cancer from spreading * slow the cancer's growth

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* kill cancer cells that may have spread to other parts of the body from the original tumor * relieve symptoms caused by cancer Your doctor will talk to you about the goal of your chemo before you start treatment. Will Chemotherapy Be My Only Treatment For Cancer? Sometimes chemo is the only treatment you will need. More often, chemo is used along with surgery or radiation therapy or with both. Here's why: * Chemo may be used to shrink a tumor before surgery or radiation therapy. * It may be used after surgery or radiation therapy to help kill any remaining cancer cells. * It may be used with other treatments if your cancer returns. When chemo is given after surgery to kill any cancer cells that may still be present, it is called adjuvant therapy. When chemo is used to shrink a tumor before surgery or radiation therapy, it is called neoadjuvant therapy. A Checklist of Questions to Ask Your Doctor or Nurse Before choosing chemo as a treatment option, you should understand the expected benefits, side effects, and risks. Consider asking your doctor or nurse the questions

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below. It may help you to write down questions to take with you to your next visit. Our information and the information you get from your doctor should give you what you need to know about your treatment and give you a good idea of the expected outcome. * What is the goal of chemo for my cancer? * What are the chances that the chemo will work? * After chemo, will I be cured, in remission, or relieved of my symptoms? * Are there other ways to get to the same goals? * How will I know if the chemo is working? * If the chemo does not work, are there other treatments for me? * What are the risks and side effects of the chemo I will be taking? How do side effects of this chemo compare with side effects of other treatments? * How will I get the chemo, how often, and for how long? * Where will I be given the drugs? * What can I do to get ready for treatment and decrease the chance of side effects? * Will I need to change my diet in any way? My activities? My work? Exercise? Sexual activities? * Will I also need surgery, radiation, or both? If so, when and why? What results can I expect from each type of treatment?

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* If I have chemo after surgery or radiation, will it kill any remaining cancer cells? Could chemo be used alone? * Could I take part in a clinical trial? * How much will chemo cost? Will my health insurance cover it? * If the insurance company asks for a second opinion, or if I would like to get one, can you suggest someone for me to see? Here are some tips to help you remember your doctor's answers: * Take notes during your visits. Don't feel shy about asking your doctor to slow down if you need more time to write. Ask questions if you don't understand something. * If you can, use a tape recorder during your visit so you won't miss anything. * Consider taking a friend or relative with you to help you understand what your doctor says during your visit and to refresh your memory afterward. You might want to look at our booklet, After Diagnosis: A Guide for Patients and Families for more information you and your family will need to know. Should I Get a Second Opinion? One way to find out if a suggested treatment is the best one for you is to get the opinion of at least one other doctor before starting your treatment. Your doctor should not mind if

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you get a second opinion. In fact, some insurance companies require you to get one. Often, the results of any tests you have already had can be sent to the second doctor, so you wont have to repeat any of them. If your insurance is provided by a managed care group, such as a health maintenance organization (HMO), find out if the company covers second opinions before you get one. Where Will I Get Chemotherapy? The place you get your treatment depends on which chemo drugs you are getting, the drug doses, your hospital's policies, your insurance coverage, what you prefer, and what your doctor recommends. You may be treated with chemo: * * * * * at home in your doctor's office in a clinic in your hospital's outpatient department in a hospital

Some of these settings may have private treatment rooms, while others treat many patients together in one large room. It is important to be in a setting that is comfortable for you. Talk to your doctor ahead of time so that you know what to expect your first day. How Often Will I Receive Chemotherapy Treatment and How Long Will It Last? 375

How often you get chemo and how long your treatment lasts depend on the kind of cancer you have, the goals of the treatment, the drugs being used, and how your body responds to them. You may get treatments daily, weekly, or monthly, but they are usually given in on-and-off cycles. These breaks allow rest periods so that your body can build healthy new cells and regain its strength. Many people wonder how long the actual drugs stay in their body and how they are removed. Most chemo drugs are broken down by your kidneys and liver and then removed from your body through your urine or stool. The time it takes your body to get rid of the drugs depends on many things including the type of chemo you get, other medicines you take, your age, and your kidney and liver functions. Your doctor will tell you if you will need to take any special precautions because of the drugs you are getting. If your cancer returns, chemo may be used again. This time you may be given different drugs to relieve symptoms or to slow the cancers growth or spread. Side effects may be different, depending on the drug, the dose, and how it is given.

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How Will the Chemo Be Given to Me? Most chemo drugs are given to you through a tiny plastic tube, or catheter, which is put into a vein in your forearm or hand. This method is called intravenous, or IV. Intravenous drugs are given in these ways: * The drugs can be given quickly through IV tubing right from a syringe over a few minutes; this is called an IV push. * An IV infusion can last 30 minutes to a few hours. A mixed drug solution flows from a plastic bag. * Continuous infusions are sometimes needed and can last from 1 to 7 days. Catheters and needles can scar or weaken veins with ongoing chemo. Another option is the central venous catheter (CVC). The CVC is a catheter that placed in the chest or upper arm area during surgery. It can stay in place to give access to a large vein. Blood can be drawn from these catheters. Drugs can be injected directly into the CVC, or through an IV connected to the CVC. Many different kinds of CVCs are available. Many people talk about this option with their doctor even before starting treatment. Some find out during treatment that they need a CVC because their hand and arm veins are not

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good enough to complete the planned chemo. Your doctor can help you decide if you need a CVC, and the right type of CVC for you. Depending on the drugs and where the cancer is located, your chemo also may be given in one or more of these ways: * Orally or PO This means by mouth. You swallow the drug in a pill, capsule, or liquid form just as you do other medicines. This method is usually more convenient and may be less expensive because the drugs can be taken at home. If you take chemo drugs by mouth, it is very important to take the exact dosage, at the right time, for as long as it has been prescribed for you. For more information please call us and ask for Oral Chemotherapy: What You Need to Know. * Intravenous or IV The chemo is injected through a needle or catheter into a vein. * Intrathecal or IT The drug is injected into the spinal canal. You may either get an injection directly into your spine or into a long-term catheter and port that is put under the skin on your head during surgery. This is called an Omaya reservoir. The port is a small drum-like device that has a small tube attached to it. The tube goes in to the cerebrospinal fluid (CSF) in your spinal canal.

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* Intra-arterial The chemo drug is injected directly into an artery to treat a single area (such as the liver, an arm, or leg). This method limits the effect of the drug on other parts of the body. * Intracavitary Chemo drugs are given through a catheter into the abdominal cavity (the space around the bowels and other organs in the belly) or chest cavity (the space around the lungs and other organs in the chest). * Intramuscular or IM The drug is injected through a needle into a muscle. * Intralesional The drug is injected through a needle directly into a tumor in the skin, under the skin, or in an internal organ. * Topical The medicine is put right on to an area of cancer on the skin. Oral Chemotherapy: What You Need to Know Today, thanks to progress in cancer treatments, there are many types of chemotherapy (chemo) that can be taken as a liquid, tablet, or capsule. Oral chemo is any drug you are taking by mouth to treat your cancer. Oral chemo does not need to be injected into the body. Chemo taken by mouth is as strong as the other forms and works just as well. One of the best ways you can help fight your cancer is by taking your chemo exactly as your 379

doctor or nurse tells you to. Some chemo drugs are never taken by mouth because the stomach can't absorb them. Others may cause harm when swallowed. In fact, most chemo drugs are injected through an IV (intravenous) line into a person's vein. The chemo you take by mouth is easier, because it often can be taken at home. You don't need to go into a hospital or clinic for every treatment. Sometimes chemo is given in cycles. This cuts down on the harm to healthy cells and allows the drugs to kill more cancer cells. Your doctor will decide if you need to get your treatment every day, every week, every few weeks, or every month. Are you ready to start your oral chemo? Here are some things about oral chemo that you may want to talk about with your doctor or nurse: * What is the name of the chemo? Is there more than one name for the same drug? * What do you expect it to do? How might it make me feel? * Are the directions for taking the drugs easy to follow? * How are my chemo drugs taken? * What if I have trouble swallowing and keeping down the pills? Can they be opened, broken, or crushed? * When should I take it? * Is it safe to take it with other drugs, food, vitamins, herbs, supplements, or other 380

treatments you use? * What should I do if I miss a dose? * How should I store it? * What are the likely side effects? How should I report them if I have them? How can I get in touch with you if I have trouble late at night or over the weekend? * How long will I need to take the oral chemo? * Will my insurance pay for oral chemo? * Will my other health problems stop me from being able to follow your instructions? Is there a chance my other health problems could make me forget to take my oral chemo? * Will you be calling me to find out how I am doing with the chemo? How often will you need to see me in the office? Before starting oral chemo, discuss any concerns or questions you have with your doctor or nurse. Get answers to all of your questions about oral chemo before you start taking it. How do I take my oral chemo? You should have exact instructions on how much and when to take your chemo. Take it all just the way your doctor or nurse has told you to. Be sure to tell your doctor or nurse about any problems you have taking your chemo. For instance, if you are throwing up or feel sick to your stomach, you may feel too sick to take your chemo. Or, if you are 381

throwing up, you may not be able to keep your chemo down and may throw up your treatment dose. Your doctor needs to know about any problems so he or she can tell you about whether or not you need changes in your treatment plan. Oral chemo doses are set up so that you will have constant levels of the drugs in your body to kill the cancer cells. Not taking your chemo as it needs to be taken can affect how well the treatment works, and it can even allow the cancer to grow. Sometimes changes may be needed, but do not make any changes unless your doctor tells you to do so. Even after you start feeling better you may still have cancer cells in your body that must be kept under control with chemo. Will I still need to see my doctor? Even though you will be able to take your oral chemo at home, you will still need to see your health care team. They will watch for changes in the cancer and see how you are doing with your chemo plan. Blood tests and scans will be done to see how your body and the cancer respond to the chemo. If you miss a dose or are late with one, tell your doctor or nurse about it. Your doctor needs to know about this when looking at your

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response to the treatment. It may also help the doctor decide whether to change the dose or timing of the medicine. What can I expect from oral chemo? The side effects of any form of chemo vary from drug to drug and from person to person. Your doctor or nurse may not be able to predict what side effects you will have. Some oral chemo drugs can upset your stomach (nausea) or cause you to throw up (vomit). They can cause loose or watery bowel movements (diarrhea), hair loss, mouth sores, skin changes, low blood counts, and other possible side effects. This is because oral chemo is a systemic treatment just like the IV form of chemo. That means it goes through your whole body to kill cancer cells wherever they might be. But when it does that, it also can harm healthy, normal cells and cause side effects. Make sure you know what side effects to look for before you start chemo. Also ask if there are any side effects that you should call the doctor or nurse about right away. Telling your doctor or nurse about side effects as soon as they happen can help make sure that the problem does not become dangerous to you. Your doctor may have to change the dose you are taking or give you other drugs to help you feel better. If you are 383

in doubt about a side effect and can't get in touch with your doctor, don't take your chemo until you get further advice. Taking chemo at home gives you more freedom to carry on with your daily life without the trouble of frequent treatment visits. Although you may not be seeing your doctor and nurses very often, be sure to call them with any questions or concerns you might have. The success of oral chemo depends a lot on youit is important to take the right dose of the drug, on schedule, exactly as you were told. Your team is there to help you do thisthey want you to succeed. Does Chemo Hurt? You already know how it feels to take a pill or rub a medicine on your skin. And you've probably felt the slight but brief discomfort of an injection before. IV medicines should not hurt after the first needle stick to put in the catheter. If you feel pain, burning, coolness, or anything unusual while you are getting chemo, tell your doctor or nurse right away. What Are Clinical Trials?

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Clinical trials are carefully designed research studies that test promising new cancer treatments. You may want to talk to your doctor about this option. Patients who take part in research studies will be the first to benefit from these treatments. These patients can make an important contribution to medical care because the study results will also help other patients. In a clinical trial, you get either standard treatment or an experimental treatment. Studies are never done to see if you would recover from cancer without treatment at all. As in any other medical treatment, you are free to withdraw from a clinical trial at any time and seek other treatment options. Clinical Trials: What You Need to Know On this page: Why do we need clinical trials? What happens before clinical trials? What are the phases of clinical trials? Who sponsors clinical trials? Who conducts them? Should I think about taking part in a clinical trial? What's out there? Finding clinical trials What about cost? Will my insurance cover it? What would taking part in a clinical trial involve?

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What if I'm not eligible for a clinical trial? Additional resources References Deciding whether or not to take part in a clinical trial can be hard for a person with cancer. Clinical trials are studies in which people volunteer to test new drugs or procedures. Doctors use clinical trials to learn whether a new treatment is safe and eff-ective in humans. These studies are necessary for developing new treatments for serious diseases such as cancer. The doctors in charge of a clinical trial don't know ahead of time how things will turn out. If they did, there would be no need for the study in the first place. Because of this, there's no simple answer to the question, "Should I take part?" Most people don't pay much attention to clinical trials until they have a serious illness like cancer. Medical breakthroughs (the results of clinical trials) often make the news, but you usually don't hear about clinical trials themselves unless something has gone wrong in one of them. The media is quick to report an instance when a volunteer in a study is harmed. Although it is very rare, people have been harmed, and have even 386

died, while taking part in clinical trials. Reports of these tragic outcomes are important, because they help to expose problems in the system. These problems can then be corrected so that they don't happen again. Because of bad outcomes in the past, there are laws, requirements, and procedures in place to protect the rights and the health of human volunteers. What you usually don't hear about in the news are the thousands of people who are helped each year because they decided to take part in a clinical trial, not to mention the millions who will benefit from others' participation in clinical trials. There is no right or wrong choice when it comes time to decide on taking part in a clinical trial. The decision is a very personal one and depends on many factors, including the benefits and risks of the study, what the person hopes to achieve by taking part, and other preferences and priorities. Knowing all you can about clinical trials in general -- and ones you are looking at in particular -- can help you feel better about your decision. If you do decide to take part, knowing what to look for and what to expect ahead of time can be helpful.

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This guide will address many basic questions and concerns so that you will be better prepared to discuss the subject with your doctor and family. It should help you decide which questions you need to ask and what the answers may mean for you. But in the end, only you can decide if taking part in a clinical trial is right for you. One last note: this guide focuses on studies for people who are being treated for cancer. But most of the information here applies to other types of clinical trials as well. Return to Top of Page Why do we need clinical trials? Clinical trials show us what works (and what doesn't) in medicine. They are the best way for doctors to learn what is safe and effective in treating diseases such as cancer. Some doctors and scientists conducted what would now be considered clinical trials as far back as the late 1700s, but clinical trials were not used widely until the middle of the 20th century. Up until that time, doctors relied on their own experience in particular cases and on the teachings of those who came before them. Progress was slow, and there were very few medicines that could even be tested. With the discovery of the first antibiotics and other drugs, doctors needed a reliable way

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to tell what worked from what didn't. They also needed ways to find out which of the countless remedies available at that time were safe for people to use. So they developed studies that tested and compared treatments in certain groups of people. The results of these early clinical trials proved to be more useful than relying on whether or not something worked in one person or a few people. In the United States, new drugs and medical devices (but not dietary supplements) must be approved by the Food and Drug Administration (FDA) before they can be advertised or sold to the general public. The FDA began overseeing the safety of new treatments in the late 1930s, but didn't require proof of effectiveness until the early 1960s. Today, new drugs and medical devices must go through several phases of clinical trials (discussed later) before being approved for use. Based on what we have learned about cancer in recent years, researchers can now develop new treatments in a more logical way and much faster than in the past. But it's still a hard process that takes a long time. Clinical trials are only a small part of the research that goes into developing a new treatment. Drugs of the future, for example, first have to be discovered, purified, 389

described, and tested in labs (in cell and animal studies) before ever reaching human clinical trials. About 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. On average, a new cancer drug has at least 6 years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. It takes an average of 8 years from the time a cancer drug enters clinical trials until it is approved. Why so long? To be sure it is safe and effective, researchers look at each new treatment in several different studies. Only certain people are eligible to take part in each clinical trial. And cancer clinical trials take years to complete. It takes months, if not years, to see if a cancer treatment works in any one person. The biggest barrier to completing studies is that not enough people take part in them. Fewer than 5% of adults (less than 1 in 20) with cancer will take part in a clinical trial. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 600 cancer medicines were being tested in clinical trials in 2006. Not all of them

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will prove to be useful, but those that are may be delayed in getting approved because the number of adult volunteers for clinical trials is so low. The main reason people give for not taking part in a clinical trial is that they didn't know the studies were an option for them. But there are many other reasons. Some people may want to take part but aren't eligible. Some people are uncomfortable with the idea of being a "subject" in a study. Others worry that they won't be treated fairly or could be harmed by an unproven treatment. Certainly these are understandable concerns. We have addressed them in more detail in the section, "Should I think about taking part in a clinical trial?" One of the most important points in deciding if a clinical trial can be done is whether or not it would be ethical to ask patients to volunteer for the experimental treatment. Has the study been designed, as much as possible, to make sure the people involved will be safe? Would the participants receive a treatment that is at least as good as, and maybe even better than, what they would get if they did not volunteer for the study? Scientific panels are set up to review and approve all clinical trials to make sure questions like

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these are answered before the researchers are allowed to enroll patients. Return to Top of Page What happens before clinical trials? Clinical trials are medical research studies involving people. They are done only after "pre-clinical" studies suggest that the proposed treatment is likely to be safe and effective in people. Pre-clinical studies, also called laboratory studies, include: Cell studies: These are often the first tests done on a new form of treatment. To see if it might work, researchers look for effects of the new treatment on cancer cells that are grown in a laboratory dish or a test tube. Animal studies: Treatments that look promising in cell studies are next tested on tumors in lab animals. This gives researchers an idea of how safe the new treatment is in a living creature. Although pre-clinical studies provide a lot of useful information, they do not give us all the answers. After all, humans and mice are different. A treatment that works against cancer in a mouse may or may not work in people. And human bodies sometimes process drugs differently. This may result in side effects and other problems that did not 392

show up when the treatment was studied in mice. Clinical trials are needed to answer 2 important questions: * Does the new treatment work? Is it better than what's now available to treat a certain disease? If it's not better, is it at least as good, perhaps while causing fewer side effects? Or does it work in some people who don't benefit from current treatments? In other words, is it a step forward? A treatment that doesn't offer anything new probably isn't worth studying. * Is the new treatment safe? This must be answered while realizing that no treatment or procedure -- even one already in common use -- is entirely without risk. But do the benefits of the new treatment outweigh the possible risks? Answering these questions, while exposing as few people as possible to an unknown treatment, often requires several different clinical trials. These are usually divided into "phases." Each phase of the clinical trial is designed to answer certain questions, while trying to make sure the people taking part are safe. Each new treatment is tested in several phases of clinical trials before being considered reasonably safe and effective. These phases are discussed in the section "What are the phases of clinical trials?" 393

The Investigational New Drug Application (IND) An Investigational New Drug (IND) Application must be filed with the FDA when researchers want to study a drug in humans. The IND application must contain certain information, described below. The FDA reviews this information before human clinical trials start. Animal studies: Pre-clinical study results allow the FDA to decide whether the product is reasonably safe for early testing in humans. This part may include any experience with the drug in humans (if the drug has been used or studied in another country, for example.) Manufacturing information: This explains how the drug is made, who makes it, what is in it, how stable it is, and more about the physical qualities of the drug. The FDA uses this information to decide whether the company can make batches of the drug that will be exactly the same. Clinical protocols and investigator information: Detailed outlines for the planned clinical studies are looked at to see if the study might expose subjects to unnecessary risks (see the section "The study protocol"). Information on the clinical investigators who will 394

supervise the study is reviewed to find out if they are qualified to run clinical trials. Finally, the research sponsor must commit to getting informed consent from the research subjects, having the study reviewed by an institutional review board (IRB), and following all the rules required for studying investigational new drugs (see the section "Safeguards in institutions"). Important points to keep in mind: Correcting some myths about clinical trials Clinical trials are vital in studying all aspects of medicine, not just cancer. The stakes may seem higher when researching medicines to treat cancer, but all new treatments (drugs and medical devices) must go through clinical trials before being approved by the FDA for general use. Not all clinical trials study treatments. Many clinical trials study new ways to detect, diagnose, or learn the extent of disease. Some even look at ways to prevent the disease from happening in the first place. Even among clinical trials that do study treatments, not all of them study drugs. Many clinical trials test other forms of treatment, such as new surgery or radiation therapy techniques, or even complementary or alternative medicines. 395

When clinical trials do look at drugs, not all of them study new ones. Even after a drug has been approved for use against a type of cancer, doctors sometimes find it works better when given a certain way or when combined with other treatments. It may even work on a different kind of cancer. Clinical trials are needed to study these possibilities as well. Very few cancer clinical trials involve a placebo. A placebo is an inactive ingredient or pill used in some types of clinical trials to help make sure results are unbiased. A placebo is sometimes called a "sugar pill." Over the years, doctors have observed that some people begin to feel better even if they just think they're being treated. With the possibility of getting a placebo, people can't tell whether they are getting the treatment being studied or not, which makes the results more likely to be valid. Placebos are rarely used alone in cancer research unless no known effective treatments exist. It's certainly not ethical to have someone take a placebo if an effective standard treatment is already available. When cancer clinical trials compare treatments, they compare the new treatment against the current standard treatment. At times, a study

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may be designed so that patients may not be told which one they are getting, but they know they are at least getting treatment that meets the current standard of care. In some clinical trials, the doctors want to learn whether adding a new drug to the standard therapy improves its effectiveness. In these studies, some patients get the standard drug(s) and a new one, while other patients receive the standard drug(s) and a placebo. But none of the patients would receive a placebo only. Everyone receives standard treatment if there is a standard treatment available. (See the next section for an example of a phase III study involving a placebo.) All clinical trials are voluntary. You always have the right to choose whether or not you will take part in a clinical trial. The level of care you get should not be affected by your decision. And you have the right to leave a clinical trial at any time, for any reason. If you decide to leave, your health care team may ask that you agree to continue to be watched for a certain length of time to look for any long-term effects of treatment. We discuss these issues further in the section "What would taking part in a clinical trial involve?" Return to Top of Page 397

What are the phases of clinical trials? Clinical trials are usually conducted in distinct phases. Each phase is designed to answer specific questions. Knowing the phase of the clinical trial is important because it may give you some idea about how much is known about the treatment being studied. There are pros and cons to taking part in each phase of clinical trial. Although there are clinical trials for other diseases and treatments, drugs for cancer patients are used in the examples of clinical trial phases described below. Phase 0: Exploring if and how a new drug works Even though phase 0 studies are done in humans, this is a newer type of study that is not much like the other phases of clinical trials. It is included here because some cancer patients will likely be asked to take part in these kinds of studies, and it is important to understand how phase 0 studies work. These are exploratory studies that often use only a few small doses of a new drug in each patient. Phase 0 studies test to find out whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells respond to the drug. The patients in these studies must have extra biopsies, scans, and

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blood samples. A big difference between phase 0 and the later phases of clinical trials is that there is no chance of a direct benefit to the patient from a phase 0 trial. Because drug doses are low, there is also less risk to the patient in phase 0 studies compared to phase I. Phase 0 studies help researchers find out early which drugs do not do what they are expected to do. If there are problems with the way the drug is absorbed or acts in the body, this should become clear very quickly in a phase 0 trial. This process may help avoid the delay and expense of finding out years later in phase II or even phase III clinical trials that the drug doesn't act as it was expected to based on lab studies. Phase 0 studies are not yet being used widely, and there are some drugs for which they would not be helpful. They are very small, mostly with fewer than 20 people. They are not a required part of testing a new drug, but are part of an effort to speed up and streamline the process of drug testing. Here's how a phase 0 study might work: Lucia has taken several courses of chemotherapy after her cancer spread. The chemo helped at first, but the cancer came back again. After talking with her doctor, Lucia does 399

not think she wants any of the current options that are offered for standard treatment. She is interested in a clinical trial that might help her. She has found a phase III clinical trial of a new drug, but the study she wants doesn't start enrolling for nearly 4 weeks. While she is waiting, her doctor tells her about a new substance that has been studied and tested in the lab, including animal studies. It looks like it might help her type of cancer. Phase I human studies have not started, but a phase 0 study of the new targeted drug, called "EXP0," is available. This study will only take a few days and is not expected to have many side effects, because she will be getting very small doses of the drug. She learns that extra blood samples and biopsies will be needed to find out how quickly the drug goes into her blood and what it does with the tumor. She decides that, even though this will not help her personally right now, it might help someone else in the future. She knows that other members of her own family have had this type of cancer, and she wants them and others to have as many good options as possible. When she meets with the research coordinator, he explains in detail how the study will

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work. He goes out of his way to make sure that Lucia understands that the study cannot help her at all. Any information gained from the study would help the drug maker know whether they should continue with human studies. Lucia asks more questions about what is known about side effects that happened in animal studies, and what else she might expect. She decides that she is willing to take these risks, so she signs the consent form and finds out which days she needs to be at the study center over the next 2 weeks. She answers some medical questions and signs release forms to get her medical records from her doctor and the hospital where she was treated. The staff draws some blood and they plan to start testing next week. Phase I clinical trials -- Is the treatment safe? These studies are usually the first ones to involve people. Although the treatment has been tested in lab and animal studies, the side effects in people can't always be predicted. For this reason, these studies usually include small numbers of people (15 to 50) and may be reserved for those who do not have other good treatment options. Often, people with different types of cancer are eligible for the same study. These studies are usually done in major cancer centers. 401

The main reasons for doing phase I studies are to find out the highest dose of the new treatment that can be given safely (without serious side effects) and to decide on the best way to give the new treatment. The first few people in the study often receive a low dose of the treatment and are then watched very closely. If there are no or only minor side effects, the next few patients may get a higher dose. This process continues until doctors find the dose that is most likely to work while having an acceptable level of side effects. Safety is the main concern because this is usually the first time the treatment has been used in people. Doctors keep a close eye on how the people in the study are doing. Special tests, such as blood tests to measure levels of the drug in the body at certain time points, are often a part of these trials. Some studies may require time in a hospital. Placebos (sham or inactive treatments) are not part of phase I trials. These studies are not designed to find out if the new treatment works against cancer. Overall, these trials are the ones with the most potential risk. And only phase 0 has a smaller chance of helping you than phase I. But phase I studies do help some patients.

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For those with life-threatening illnesses, weighing the potential risks and benefits carefully is crucial. Here's an example of a typical phase I clinical trial, but keep in mind that each study is slightly different: Bruce was diagnosed with cancer 4 years ago. He was first treated with radiation therapy, but the cancer was later found to have spread to distant parts of his body. His doctor told him two chemotherapy drugs, A and B, might help him. Bruce's cancer shrank for a short time while he was taking drug A, but then it began to grow again. Drug B did not work in his case. Because Bruce is still fairly young, his doctor suggests he might want to consider trying a new form of treatment, "EXP1," which is being studied in a phase I clinical trial at the nearest university hospital. Bruce talks with the university doctor conducting the study. The doctor explains that the drug being studied showed some promise in lab tests, but exactly how well it will work in people is still unknown. What's more, it may have side effects that haven't been seen yet. After getting all of his questions answered and weighing his options, Bruce decides

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to take part in the study. Because 3 people have already enrolled in the study and have had no major side effects, Bruce will be the first person to get a higher dose of the treatment. He will need to stay in the hospital overnight on the first night. This is both to watch for any unexpected reactions and to take blood samples every few hours so that doctors can figure out how long the treatment stays in his body. He will be allowed to go home the next day, but must return regularly over the next few weeks to be watched closely until it is time for the next treatment. Phase II clinical trials -- Does it work? If a new treatment is found to be reasonably safe in phase I clinical trials, the treatment can then be tested in a phase II clinical trial to see if it works the way researchers think it will. Usually, a group of anywhere from 25 to 100 patients with the same type of cancer receives the new treatment in a phase II study. They are treated using the dose and method most likely to be safe and effective in phase I studies. In a typical phase II clinical trial, all participants usually get the same dose, and no placebo is involved.

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But some phase II studies do involve randomizing participants into 1 of 2 treatment groups, much like what is done in phase III trials (see below). These groups may get different doses or get the treatment in different ways to see which provides the best balance of safety and effectiveness. Phase II studies are often done at major cancer centers, but may also be done in community hospitals or even doctors' offices. Doctors look for some evidence that the treatment works. The type of benefit they look for depends on the goals of the clinical trial. This may involve a response (where the tumor shrinks or disappears). Or it may be an extended period of time where the tumor does not get any bigger, or an increase in the length of time before a cancer comes back. In some studies the benefit may be an improved quality of life. Many studies look to see if people getting the new treatment live longer than they would have been expected to without the treatment. If a certain percentage of the patients benefit from the treatment (and the side effects aren't too severe), it is considered to be active enough against that type of cancer to allow it to go on to a phase III clinical trial. Along with watching for responses, the

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research team keeps looking for any side effects. Larger numbers of patients receive the treatment in phase II studies, so there is a better chance that less common side effects may be seen. Here's an example of a phase II clinical trial. Again, some phase II studies may be slightly different: Angela was diagnosed with cancer several months ago. Only one form of treatment, drug C, is known to work for people with her type of cancer, but it only works in about half of the people who try it. After several months of this treatment, Angela's doctor told her that it did not appear to be helping in her case. After doing a little research online, Angela and her doctor decide her best bet may be to enroll in a clinical trial. They find a phase II study being conducted by a doctor nearby, who is testing a new type of medicine, called "EXP2." This medicine was already found to be safe in phase I studies. Although not many people have tried it, a couple of people with Angela's type of cancer were helped by it. Angela, like all of the other people in this study, will receive EXP2 once a week as an outpatient at a local hospital. Before getting the drug each week, she will have physical

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exams and blood tests to see how her body is reacting to the medicine. She will also have scans done after several weeks to see if the drug is affecting the cancer. She had tests like this while receiving drug C, but this time the tests and exams are done more often. Also, her doctor asks more specific questions about side effects. Phase III clinical trials -- Is it better than what's already available? Treatments that have been shown to work in phase II studies usually must go through one more stage of testing before being approved for general use. Phase III clinical trials compare the safety and effectiveness of the new treatment against the current standard treatment. Phase III clinical trials usually have a large number of patients, at least several hundred. These studies are generally conducted in many places across the country (or even around the world) at the same time. Because doctors do not yet know which treatment is better, patients are often randomized (chosen at random, like flipping a coin) to receive either the standard treatment or the new treatment. When possible, the study is doubleblinded. That means neither the doctor nor the patient knows which of the treatments the patient is getting.

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Randomization and blinding are discussed in more detail further on. As with other studies, patients in phase III clinical trials are watched closely for side effects, and treatment is stopped if they are too severe. Placebos may be used in some phase III studies, but they are never used alone if there is already a treatment available that may work. Here's an example of a phase III clinical trial that could possibly involve a placebo: Li has just been diagnosed with cancer. His surgeon was able to remove the tumor, but tells Li that this kind of cancer returns in about one-third of patients. For this reason, doctors usually recommend giving a short course of chemotherapy drug D. Although this is the best drug available for reducing the likelihood of recurrence, some cancers still return. Li's doctor tells him that a new type of therapy, called "EXP3," is now being studied. EXP3 was designed to be given along with drug D. Earlier studies in animals and people have shown that the combination of drug D and EXP3 seems to be safe and effective. But it is not yet known if this combination will be better than the current standard of drug D alone in reducing the risk of recurrence. Therefore, doctors are testing it in a phase III 408

clinical trial. To do this, they've designed a study that assigns people with this cancer to 1 of 2 groups (that is, there are 2 "arms" of the study): one group will get drug D plus EXP3, while the other group will get drug D plus a placebo. The patients will be blinded as to treatment they are on -- that is, they will not know whether they are getting EXP3 or the placebo. But all of the patients will be getting drug D, which is the accepted standard of care. The people who get EXP3 may do better than those who get the placebo. On the other hand, they may do worse because of things like unknown side effects. Or both groups may do equally well, in which case EXP3 would not be any better than the placebo. Li, in deciding whether to take part in the clinical trial, needs to understand that he will be randomized to 1 of the 2 treatment arms, and neither he nor his doctor will have control over this. He also needs to understand that while on this study, he will not know which arm he has been assigned to, so he will not know whether he is getting EXP3 or a placebo. Randomization and blinding are used in many phase III studies because they help make

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the study results more credible. When possible, participants are randomized to ensure that the 2 study groups have the same traits -- for example, to make sure that they both contain people in similar states of health, so the results are not skewed in favor of one group. If people were allowed to choose which treatment they got, the study results might not be as accurate. For example, people who were sicker might tend to choose one treatment over the other. If this treatment was then found not to work as well, doctors couldn't be sure if this was because the treatment wasn't as good or because it was tested in sicker people. Often people have a 50:50 chance of ending up in one group or the other. In some cases, the study may allow for a different ratio, such as 2 out of 3 people receiving the new treatment and only 1 out of 3 getting the standard treatment. Some people find the concept of randomized studies to be distressing, since neither the patient nor the doctor can choose which group the patient is in. This can be especially true if a study is looking at 2 totally different treatments and a person sees one as possibly better than the other. But remember, doctors are doing the study because they

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really don't know which one is better. Unfortunately, taking part in such a study is sometimes the only way a person may have a chance of getting a new form of treatment. But even then, that treatment may or may not be the best one for him or her. Blinding is another area of concern for some people. In a blinded study, the patient doesn't know which treatment he or she is getting. In a double-blinded study, neither the patient nor the doctor knows which treatment is used. Not knowing what you are receiving can be difficult. Your doctor can always find out which group you are in if there is an important medical reason (such as during a possible drug reaction), but it may result in your being removed from the study. The possibility of receiving a placebo can also be upsetting to some people. But this very rarely means you would get no treatment, unless there was no effective standard treatment to compare the new drug to. Again, in the example above, Li will definitely get drug D, but he will also get either EXP3 or a placebo. Submission for FDA approval -- New drug application (NDA) In the United States, when clinical trials show a new treatment is more effective and/or safer than the current standard treatment, a new drug application (NDA) is submitted to 411

the Food and Drug Administration (FDA) for approval. The FDA then reviews the data. If the FDA has questions about the information, it may ask for more information or even that more studies be done. This can extend the approval process to more than 5 years. Based on the results of the clinical trials, the FDA decides if the treatment is appropriate for use in the general public. When this happens, the treatment often becomes the new standard of care, and newer drugs must be tested against it before being approved. Phase IV clinical trials -- What else do we need to know? Even after testing a new medicine on thousands of patients, the full effects of the treatment may not be known, and some questions may still need to be answered. For example, a drug may get FDA approval based on the fact that it was shown to reduce the risk of cancer recurrence. But does this mean that those who get it are more likely to live longer? Are there rare side effects that haven't been seen yet, or side effects that only show up after the drug is used for a long time? These types of questions may take many years to answer fully, and may not be critical for getting a medicine to market. They are often addressed in what are known as phase IV clinical trials.

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Phase IV studies look at drugs that have already been approved by the FDA. They are already available for doctors to give to patients, but these studies are still needed to answer important questions. When thinking about taking part in a phase IV trial, you should know that the drug has already been approved for use. You do not need to enroll in the study to get the medicine. At the same time, the care you would receive in these types of studies is often very much like what you could expect if you were to get the treatment outside of a clinical trial. You should be reassured that in taking part you would be getting a form of treatment that has already been studied a lot and that you would be doing a service to future patients. Return to Top of Page Who sponsors clinical trials? Who conducts them? Of the thousands of cancer clinical trials going on at any one time, the National Cancer Institute (NCI), a part of the National Institutes of Health (NIH), sponsors (pays for the costs of) a good portion of them. These studies are often run by NCIsponsored cancer cooperative groups, which are networks of doctors and institutions across the country

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who specialize in a particular aspect of cancer. In the United States, there are currently 10 major cooperative groups conducting cancer studies: American College of Radiology Imaging Network (ACRIN) American College of Surgeons Oncology Group (ACOSOG) Cancer and Leukemia Group B (CALGB) Children's Oncology Group (COG) Eastern Cooperative Oncology Group (ECOG) Gynecologic Oncology Group (GOG) National Surgical Adjuvant Breast and Bowel Project (NSABP) North Central Cancer Treatment Group (NCCTG) Radiation Therapy Oncology Group (RTOG) Southwest Oncology Group (SWOG) Other government agencies, including parts of the Department of Veterans Affairs and the Department of Defense, also sponsor some cancer clinical trials. The other main sponsors of clinical trials are pharmaceutical and biotechnology companies, which must prove their medicines are safe and effective before they can be marketed. Some non-profit organizations also sponsor clinical trials. Researchers conduct clinical trials in many different settings. Major cancer centers are often the focal points of clinical trials research. Because they usually have the most advanced facilities and highly trained staffs, they can conduct all phases of clinical trials. But they are not the only places where these studies take place. Community hospitals across the country also participate in clinical trials, although these

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are usually phase II or III studies. Many of these hospitals are part of the NCI's Community Clinical Oncology Program (CCOP). CCOP members conduct the same clinical trials across the country. Community hospitals may conduct other, privately sponsored, studies as well. Doctors in private practice can also be involved in clinical trials, either as members of cooperative groups or by being actively involved in privately sponsored research. But many doctors decide not to conduct clinical research, for a variety of reasons. What this may mean for you At one time, clinical trials were done only at major medical centers. This often meant that patients had to travel long distances and were treated by doctors they did not know very well. This is sometimes still the case, especially with phase I and some phase II studies. Of course, this is not necessarily a bad thing. Many people prefer to be treated in major cancer centers because of their experience, reputation, and resources. Ultimately, the hassles of traveling must be weighed against the chance of being helped by the treatment. Patients now have more options. This may include staying closer to home during a study 415

or even staying with their own doctors. Your doctor may or may not be involved in clinical trials. If he or she is, you may be eligible for one of them. Whether this is the right study for you is, of course, a question worth asking. Although clinical trials are now done in many different settings, this should not affect the quality of care you receive. No matter where a study is done, the same rules are in place to protect patients. Having so many options can be a burden in and of itself. With the thousands of clinical trials under way across the country, how can you -- or even your doctor -- decide which one is best for you? At this time, there is no complete list of all the cancer clinical trials. But there are several good places to start looking if you're interested. We'll explore these in the section, "What's out there? Finding clinical trials." Return to Top of Page Should I think about taking part in a clinical trial? This is one of the toughest questions many people with cancer will face. The answer won't be the same for everyone. When trying to decide, first ask yourself some basic questions: * Why do I want to take part in a clinical trial? 416

* What are my goals and expectations if I decide to take part? How realistic are these? * How sure are my doctors about what my future holds if: o I decide to participate? o I decide not to participate? * Have I considered: o The chance of benefit versus risk? o Other possible factors, such as time and money? o My other possible options? Some of these questions may not have clear-cut answers, but they should help you start thinking about some important issues. Each person's situation is unique, and each person's reasons for wanting or not wanting to take part in a study may be different. Risk versus benefit Each clinical trial offers its own opportunities and risks, but most have some things in common. Generally, clinical trials (other than phase 0) have some of the same potential benefits: * You may help others who have the same condition in the future by helping to advance cancer research. * You may have access to treatment that is not otherwise available, which might be safer or work better than current treatment options. * You may increase the total number of treatment options available to you, even if you haven't yet received all of the standard treatments.

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* You may feel you have more control over your situation and are taking a more active role in your health care. * You will probably get more attention from your health care team and more careful monitoring of your condition and the possible side effects of treatment. * Some study sponsors may pay for part or all of your medical care and other expenses during the study. This is not true for all clinical trials. Be sure you know who is expected to pay for your care before you enroll in the study. Some of the possible downsides of being in a study can include the following: * The new treatment may have unknown side effects or other risks, which may or may not be more severe than those from existing treatments. This is especially true of early phase trials. * As with other forms of therapy, the new treatment may not work for you, even if it helps others. * There may be inconveniences such as more frequent testing, as well as time and travel commitments. * If you take part in a randomized clinical trial, you may not have a choice about which treatment you get. If the study is blinded, you (and possibly your doctor) will not know which one you are getting (although this information is available if needed for

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your safety). This will be explained to you before you decide to take part. * Insurers may not cover all of the costs of taking part in a clinical trial (although they usually cover the costs for what would normally be standard care). Be sure to talk to your insurance provider and to someone involved with the study before you decide to take part, so you know what you may have to pay for. Answers to some common questions about clinical trials Most people have some concerns about taking part in a clinical trial, often because they're not really sure about what it will mean for them. Taking time to get as much information as you need before you decide is the best way to ensure that you will make the choice that is right for you. Will there be risks? Yes, clinical trials have risks. But, any medical test, drug, or procedure has risks. The risk may be greater in a clinical trial because some aspects of any new treatment are unknown. This is especially true of phase I and II clinical trials, where the treatment has been studied in fewer people. Perhaps a more important question is whether the risks are outweighed by the possible benefits. People with cancer are often willing to accept a certain amount of risk for a 419

chance to be helped, but it is always important to be realistic about what this chance is. Ask your doctor to give you an idea of what the possible benefits are, and exactly what benefit is likely for you. With this in mind, you can make a more informed decision -- one that is right for you. Some people may decide that any chance of being helped is worth the risk, while others may not. Others may be willing to take certain risks to help others. Will I be a "guinea pig?" There's no denying that the ultimate purpose of a clinical trial is to answer a medical question. People who take part in clinical trials may need to do certain things or have certain tests done to stay in the study. But this does not mean that you will not get excellent, compassionate care while in the study. In fact, most people enrolled in clinical trials appreciate the extra attention they receive from their health care team. In 2005, the Coalition of Cancer Cooperative Groups surveyed over 1,700 people with cancer on their awareness and attitudes about clinical trials. Only a few had taken part in clinical trials. But most of those who did were very satisfied: 96% said they were treated with dignity and respect, 92% said they had a 420

positive experience, and 91% would recommend that family or friends take part in a clinical trial if faced with cancer. Will I get a placebo? Most cancer clinical trials do not use placeboes unless they are given along with an active drug. It would be unethical to give someone an inactive medicine if it would deny the person a chance to get a drug that has already been shown to work. Unfortunately with cancer, there are some situations for which no effective treatments are known. In rare cases, testing a new treatment against a placebo might be needed to prove that the treatment is better than nothing at all. The very least you should expect from any clinical trial is to be offered the standard of care already being used. (See the section, "What are the phases of clinical trials?" for an example of a phase III study using a placebo.) Will my information be kept confidential? As much as possible, all of your personal and medical information is kept confidential. Of course, your health care team needs to have access to this information to provide you with the best possible care, just as they would if you were not in a clinical trial.

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Medical information that is important for the study, such as test results, is usually entered onto special forms and into computer databases. This is then given to the people who will analyze the study results. Your information is assigned a specific number or code -your name does not appear on the forms or in the information database. Sometimes, some members from the research team or from the FDA may need to look at your medical records to be sure the information they were given is correct. But your personal information is not given to them and is never used in any published study results. Other questions you should ask your research team Each clinical trial is unique, with its own potential benefits and risks. Before you decide to take part in a clinical trial, make sure you have answers to the following questions: * Why is this study being done? * What is likely to happen if I decide to take part or decide not to take part in the study? * What are my other options (standard treatments, other studies)? What are their pros and cons? * How much experience do you have with this particular treatment? With clinical trials

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in general? * What were the results in previous studies of this treatment? How likely are they to apply to me? * What kinds of treatments and tests would I need to have on this study? How often are they done? * Will this require an extra time or travel commitment on my part? * How could the study affect my daily life? * What side effects might I expect from the study? (Remember that there can also be side effects from standard treatments and from the disease itself.) * Will I have to be in the hospital for any parts of the study? If so, how often and for how long? * Will I still be seeing my regular doctor? * Will I have any costs? Will any of the treatment be free? Will my insurance cover the rest? * If I am harmed as a result of the research, what treatment will I be entitled to? * How long will I remain in the study? * Are there reasons I would be removed from the study? Are there reasons the study might be stopped early?

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* Is long-term follow-up care part of the study? What would it involve? * If the treatment is working for me, can I choose to continue getting it even after the study ends? * Are there others already taking part in the study whom I could speak to? * Will I be able to find out about the results of the study? You might find it helpful to include trusted friends and family members in your decision making process. They may ask questions you hadn't thought of and can help make sure that you're making a decision that's right for you. Also, getting a second opinion from a doctor who is not involved with the study can give you a broader sense of whether this particular study is the best one for you to consider. Who will look out for me as a study participant? Several levels of safeguards are in place to help protect the people who take part in clinical trials. There are still risks involved with any study, but these safeguards try to reduce the risk as much as possible. Three basic principles, as outlined in the Belmont Report from the late 1970s, provide the basis for research involving humans: * Respect for persons: Recognizing that all people should be respected and have the 424

right to choose what treatments they receive * Beneficence: Protecting people from harm by maximizing benefits and minimizing risks * Justice: Trying to ensure that all people share the benefits and burdens of research equally These principles are upheld by individuals and groups at the sites conducting research, and also by government agencies charged with overseeing clinical trials. A very important part of patient protection is the informed consent process, which is described in detail in the section "What would taking part in a clinical trial involve?" Safeguards in institutions Centers conducting clinical trials have committees that review all potential and ongoing clinical trials to protect the safety of those in the study. These are required for all federally funded clinical trials, but even privately sponsored studies typically undergo such reviews. Institutional review boards (IRBs) Institutional review boards (IRBs) are groups of people responsible for protecting the

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welfare of people who take part in the study and making sure that studies comply with federal laws. The boards are often made up of medical experts (such as doctors and nurses), other scientists, and non-medical people. All of the people on the IRB cannot come from only one of these groups. In other words, an IRB couldn't be a group of just doctors. Many institutions have their own IRBs, but some smaller centers may use larger, "central" IRBs. The federal Office of Human Research Protections (OHRP; see below) oversees the activities of IRBs. Researchers who want to start a study must first submit the study protocol (the plan that describes the study in detail) to the IRB for review. The IRB must decide if the study would be acceptable on medical, ethical, and legal grounds. In other words, does the study address a worthwhile question, and is it doing so in a way that ensures the safety of those taking part as much as possible? One of the most important functions of an IRB is to make sure the informed consent form that people entering the study must sign is accurate, complete, and easy to understand. Once a study begins, the IRB also follows its progress regularly to look for potential problems.

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If you take part in a clinical trial, you can contact the study's IRB directly with any questions or concerns regarding safety. Data safety monitoring boards (DSMBs) Data safety monitoring boards (DSMBs) are used for phase III (and some earlier phase) studies. They are committees made up of doctors and other scientists not involved in the study. Their job is to look at study statistics. They monitor the results of the clinical trial at different time points and can stop a study early (before all of the intended participants have been enrolled or completed the study) if: * it becomes clear that the new treatment is much more (or much less) effective, so as to allow all study participants to get the better treatment * safety concerns arise (such as risks of the new treatment clearly outweighing the benefits), so that no more people are exposed to possible harm The clinical investigator The clinical investigator is the person who is in charge of all aspects of a particular study. Most often the clinical investigator is a doctor; in some settings this person is called the principal investigator, or PI. Ultimately, the responsibility for patient safety in a clinical trial lies with the clinical investigator. Part of this responsibility is letting the 427

study sponsor know right away when serious side effects occur. Many clinical investigators have years of experience in running clinical trials. Their credentials are submitted to the FDA along with the investigational new drug application before the study is approved. Government agencies Several government agencies play roles in ensuring that all research is conducted with patient safety in mind. These include: Office of Human Research Protections (OHRP) The Office of Human Research Protections (OHRP) is the government's main guardian of people's safety and welfare in clinical trials. It was established in 2000 to coordinate efforts to protect all people involved in federally funded research. It enforces the rules regarding the informed consent process, institutional review boards (IRBs), and the participation of people with special needs in clinical trials, such as children and those with mental disabilities. The OHRP has suspended research activities at several institutions in the past few years, including those in some major research centers, until system flaws were corrected.

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The OHRP also educates research centers and individuals to help them comply with current clinical trials standards. Food and Drug Administration (FDA) The FDA has the final say about whether or not a new treatment can be prescribed to patients. Once all phases of clinical trials on a new treatment are completed, the FDA reviews the information and decides if it is safe and effective enough to be approved. But the FDA's role in many clinical trials begins long before this. Any sponsor seeking approval for a new treatment must submit all study protocols to the FDA before the clinical trials are allowed to begin. Researchers who will be involved in the study must submit their credentials for review as well. The FDA also inspects (audits) sites conducting clinical trials, especially if there is reason to think they are not following proper procedures. If serious problems are found, the FDA can forbid a particular site or doctor from doing any further research. But the authority of the FDA is not absolute. Clinical trials that study treatments that are already on the market are not subject to the same FDA regulations (although many are still done in much the same way). And substances considered to be "dietary

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supplements" do not need FDA approval to be sold in the first place. Dietary supplement makers aren't required to prove that their products are safe or effective. So they usually do not bother to conduct clinical trials. A relatively small number of clinical trials are done to study the effects of dietary supplements. Most of these are funded by the National Institutes of Health (NIH). National Cancer Institute The National Cancer Institute (NCI), part of the NIH, sponsors many of the cancer clinical trials going on at any one time, including those being conducted by cooperative groups. Proposals for such studies must be approved by the NCI before funding is granted. The NCI also inspects (audits) each site involved in NCI-sponsored research at least once every 3 years. Return to Top of Page What's out there? Finding clinical trials People find out about clinical trials in different ways. Most people who enter clinical trials do so after hearing about them from their doctor. Many cancer patients actively look for clinical trials on the Internet or in other places, hoping to find more options for treatment. Some clinical trials are advertised directly to patients. 430

If you already have a particular clinical trial in mind, you may want to go to the section ("How do I figure out which study is for me?") to learn what you should know about the study. Types of clinical trial information At this time there is no single place to get information on all of the cancer clinical trials now enrolling patients. But you should be aware of several resources. These resources can be divided into 2 main types -- clinical trials lists and clinical trials matching services. Clinical trials lists These sources can give you the names and descriptions of clinical trials of new treatments. If there is a study you are interested in, you will probably be able to find it in a list. It will often include a description of the study, the criteria for patient eligibility, and whom to contact. If you (or your health care providers) are willing and able to read through descriptions of all the studies listed for your cancer type, then a list may be all you need. Some organizations that provide lists can help you narrow the list a little, according to the kind of treatment you are looking for (chemotherapy, immunotherapy, 431

radiation therapy, etc.) and the stage of your cancer. Clinical trials matching services Over the past few years, several organizations have developed computer-based systems to match patients with studies they may be eligible for. These organizations generally offer their services online. Each may differ somewhat in how it works. Some of the services allow you to search for clinical trials without registering at the site. Even if you have to register, they usually assure you that the information will be kept confidential. Either way, you will probably have to enter certain details, such as the type of cancer, the stage of the disease, and any previous treatments you may have had. When given this information, these systems can find clinical trials for which you are probably eligible, and save you the time and effort of reading descriptions of studies that are not relevant to you. Some groups also allow you to subscribe to mailing lists so that you are informed as new studies open up. Although they are usually free to users, most clinical trial matching services receive a fee for listing studies or get a "finder's fee" from those running the studies when

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someone enrolls. Because of this, there may be some differences in the way they "rank" or present the studies to you. How to choose a clinical trials matching service Because different services work differently, be sure you understand how the service you are looking at operates. Ask the following questions. Note that the answers do not necessarily mean that the service is not worth using: * Is there a fee for using the service? * Do I have to register to use the service? * Does the service keep my information confidential? * Where does the service get its list of clinical trials? * Does the service rank the studies in any particular order? Is this based on fees they get? * Can I contact the service through the Internet or by telephone? The American Cancer Society Clinical Trials Matching Service After reviewing the available matching services, the American Cancer Society chose to work with the Coalition of Cancer Cooperative Groups to provide a free, confidential, and reliable matching and referral service for patients looking for clinical trials. The Coalition of Cancer Cooperative Groups is a non-profit service organization formed in

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1997 with the goal of assuring access to cancer clinical trials. The American Cancer Society helps patients find high quality care in clinical trials that best match their medical needs and personal preferences, while helping researchers study more effective treatments for future patients The TrialCheck database, developed and maintained by the Coalition of Cancer Cooperative Groups, is a comprehensive database that includes the Coalition, National Cancer Institute, and industry trials. To our knowledge, this is the most complete matching database of cancer clinical trials available. A unique feature of TrialCheck, called TrialTracker, will let the Coalition see which patients actually enrolled in a clinical trial and track their experiences in the study. The clinical trials information provided by the American Cancer Society is not biased in any way. It is updated every day, as is the contact information that allows patients to get in touch with the doctors and nurses at cancer centers running each of the studies. You can access the TrialCheck system through our Web site, www.cancer.org (click on "Find a Clinical Trial") and through a toll-free number, 1-800-303-5691. For information about the Coalition of Cancer Cooperative Groups and TrialCheck products used by the 434

American Cancer Society Clinical Trials Matching Service, visit http://www.cancertrialshelp.org/patientsCaregivers/patientsCaregivers.j sp. Other clinical trials lists and matching services The National Cancer Institute (NCI) sponsors most government-funded cancer clinical trials. The NCI has a list of active studies (those currently enrolling patients), as well as some privately funded studies. You can find the list on their Web site at www.cancer.gov/clinicaltrials or by calling 1-800-4-CANCER. You can search the list by the type and stage of cancer, by the type of study (for example, treatment or prevention), or by geographic location. The National Institutes of Health (NIH) has an even larger database of clinical trials at www.clinicaltrials.gov, but not all of these are cancer specific. EmergingMed provides a free and confidential matching and referral service for patients looking for clinical trials at www.emergingmed.com. CenterWatch (www.centerwatch.com) is a publishing and information services company that keeps a list of both industry-sponsored and government-funded clinical trials for cancer and other diseases. Major cancer centers (and even some community hospitals and doctors' offices) usually 435

offer lists of the clinical trials being conducted there. Look on their Web sites. You can find the major cancer centers closest to you on the American Cancer Society Web site at www.cancer.org/docroot/FTC/ftc_0.asp. Private companies, such as pharmaceutical or biotechnology firms, may list the studies they are sponsoring on their Web sites or offer toll-free numbers so you can call and ask about them. Some of these firms also offer matching systems for the studies they sponsor. This can be helpful if you are interested in research on a particular experimental treatment and know the company developing it. How do I figure out which study is for me? Whether your doctor suggests a certain clinical trial or you use the available lists or matching services on the Web, how do you know which study makes the most sense for you? You could be eligible for several studies at the same time. There may be obvious reasons for not choosing some, such as those that are being done too far away from where you live, but with others the choice may not be so clear. Understanding what each study involves can help you make your decision.

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The study protocol The study protocol is the written plan for how a clinical trial is to be conducted. It is what is submitted to the FDA and to an institutional review board (IRB) before a new treatment can be studied. A protocol contains the following information: * Why the study is being done (including the goals of the study) * Information about the treatment being tested, often including results of studies done before * The phase of the study and how many people will be enrolled * Who is eligible for the study * How the treatment is to be given * What tests will be done during the study and how often * Other information that will be collected on participants Actual study protocols can be as long as100 pages or more, and they can be very technical. Because they are not written with patients in mind, making sense of their language is not always easy. The clinical trial lists available on the Web often include summaries of these protocols, just highlighting some key points. Research team members may also have protocol summaries or other information about the study they can share with you. Often, the most

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important information for patients looking for studies is the eligibility criteria and any information available about the new treatment. Eligibility (inclusion) criteria Each clinical trial has certain conditions, or criteria, that must match the patients' conditions before they can enter the study. These are necessary to ensure that the study can answer the specific questions it was designed to answer. For cancer clinical trials, these criteria usually have to do with: * * * * * * * * * the type of cancer a person has the stage (extent) of the cancer previous treatments a person must or must not have had the length of time since a person last received treatment results of certain lab tests the medicines a person is taking other medical conditions the person has any previous history of another cancer a person's activity level (also known as performance status)

Other factors, such as a person's age and sex, may also be part of the criteria. There may be other criteria for each study, as well. Advertisements and clinical trial lists may not contain all of a study's eligibility criteria. If you've found a study you think you might qualify for, you can usually contact someone involved with the study to get a full list of the eligibility criteria. I think I'm eligible. Now what?

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Once you've found a study that you think you're eligible for, deciding if it's the right one for you can still be hard. There may even be more than one that looks promising. Again, it is important to learn as much as you can. Talk with someone connected to the study. This could be the principal investigator (PI) -the person in charge of the study -- or a research coordinator. Research coordinators are usually nurses. One of their jobs is to check to see if people meet eligibility criteria before they get into a study. They also make sure that the study protocol is followed for each patient. Often they serve as a link between study patients and their doctors. Both PIs and research coordinators should be able to answer your questions about the study. See the section "Should I think about taking part in a clinical trial?" for a list of questions you should ask. Although they can give you answers about their particular clinical trial, they are not likely to be helpful in discussing other studies you may be considering. What's more, they may be biased (even if they don't mean to be) toward their own study. If you haven't already, talk to your doctor about studies you are looking at. Bring in

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whatever information you can, so that your doctor can help you judge what might be right for you. While no doctor knows about every clinical trial being done, your doctor knows your medical situation best and can probably tell you if the study is worth considering. This discussion can take some time, so you may need to make a special appointment to allow your doctor enough time to look over the information you provide. You may also want to get a second opinion from a doctor not connected to the studies you are looking at. Doctors who are well known in their fields are usually up on the latest experimental treatments, and they may be able to point to those that look more promising. If you have access to the Internet, you can do some research on your own. Try to find out if the new treatment has been studied before or if it is being studied now in other diseases, as well as if any results are available. If this is hard for you, have someone close to you help or do it for you. People with a medical background may have an easier time sorting through such information. Finally, talk to friends and family members you trust. Although the decision is ultimately

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yours, their opinions may give you insight into things you had not thought about. Return to Top of Page What about cost? Will my insurance cover it? It is important to get these questions answered before deciding to take part in a clinical trial. Recent studies have shown that the overall costs of taking part in a clinical trial are not much more than the costs of treatment outside of a study. Still, insurance coverage can vary widely. When insurers do cover costs related to clinical trials, it is usually only for tests, treatments, or doctor's visits that would have been part of your treatment plan if you were not taking part in a study. In other words, they are not likely to pay for special tests or treatments you are getting just because you're in the study. The study sponsor (whether it is the government or a pharmaceutical or biotechnology company) usually provides the new treatment at no cost and pays for special testing or extra doctor visits. Some sponsors may pay for more than this; for example, some may offer to pay you back for travel time and mileage. It is important to find out what they will pay for before entering the study. Private insurers 441

In the past, insurers were sometimes reluctant to pay for any of the costs related to a clinical trial. Their concern was that they would be paying for treatments that had not been proven to be effective. In recent years, many (but not all) major insurance providers have volunteered to cover some of the costs of clinical trials. Still, they may limit which types of trials they will cover. They are more likely to pay for costs from phase II or phase III clinical trials, but they generally look at each request on a case-by-case basis. Medicare Medicare normally covers any cancer care when it is part of either: * a clinical trial for the diagnosis and treatment of cancer; or * a clinical trial funded by the National Cancer Institute (NCI), NCIDesignated Cancer Centers, NCI-Sponsored Clinical Trials Cooperative Groups, or another federal agency that funds cancer research. This care may include the following: * Routine tests, procedures, and doctor visits * Services or items that are part of the experimental treatment, such as costs to give the investigational drugs

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* Health care needs linked to being in a clinical trial, such as a test or hospitalization because of a side effect or complication What costs are not covered? * Investigational drugs, items, or services that are being tested as part of the clinical trial * Items or services used only to collect data for the clinical trial * Anything being provided free by the sponsor of the clinical trial * Any co-insurance and deductibles Cancer prevention trials currently are not covered by Medicare. If you are not sure whether your trial meets all of the requirements, discuss these concerns with your doctor or call the Medicare information number (1-800-633-4227). Other trials may be covered, so be sure to ask about any clinical trial before you begin taking part in one that may not be covered. Laws about insurance coverage of clinical trials Recognizing the importance of clinical trials, many states have passed laws about insurance coverage for research studies. Several more states are now considering legislation. A few states have worked out voluntary agreements with insurance companies to provide coverage of clinical trials. 443

The types of studies and exact coverage required by these laws vary from state to state -some cover all clinical trials, while others may cover only certain phases of clinical trials. For a list of state clinical trials insurance laws, see our document Clinical Trials: State Laws Regarding Insurance Coverage. The federal government may become involved as well. Bills have been introduced in both houses of Congress that, if passed, would make insurers cover certain clinical trials. This would allow more people to take part in them. What you can do If possible, find out what your insurer will cover before you get involved in a clinical trial. Find out if your state has laws that require coverage of routine costs of clinical trials. Then gather as much information as you can about the study and contact your insurance provider to find out about coverage. Many providers may not be able to give you a simple yes or no answer, because they may review claims on a case-bycase basis. But you may be able to find out if they've covered costs for clinical trials similar to yours (or ones that studied the same treatment) in the past.

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Have a summary of your study available, and, if possible, any results of previous studies of the treatment. You may need to ask your doctor or the study's research coordinator to help you get this information. If needed, your doctor may be able to give your insurer the reasons this study is a good match for you. Study sponsors are often eager to recruit eligible patients for their clinical trials, and they may be willing to cover costs if your insurance does not. If needed, ask your doctor or the research coordinator to contact the study sponsor on your behalf. Return to Top of Page What would taking part in a clinical trial involve? Having an idea of what you can expect from taking part in a study can help relieve some of your concerns and make things go more smoothly. The first thing you will need to do is give your informed consent to take part in the study. Informed consent The people running the study are required to get your written, informed consent before you take part in any way (often even before you have any needed tests to see if you are eligible for the study). In the informed consent process, the researchers (doctors or nurses) will explain the details of the study to you and answer all of your questions and 445

concerns. You will then be given a written consent form to sign. Consent forms are not all the same, but they should include the following: * the reason for the study (what the researchers hope to find out) * who is eligible to take part in the study * what is known about the new type of treatment * the possible risks and benefits of the new treatment (based on what is known so far) * other treatments that may be an option for you * the design of the study (whether it is randomized, double blinded, etc.) * how many and what types of tests and doctor's visits are involved * who must pay for the costs of the clinical trial (tests, doctor's visits, etc.) and for the costs if you need additional care as a result of the clinical trial * a statement about how your identity will be protected * a statement about the voluntary nature of the study and your right to leave the study at any time without fear of affecting the care that you would normally get outside the study * contact information if you have further questions Before you sign the consent form, ask questions. Be sure someone from the research

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team goes over the form with you in detail. Efforts are made for consent forms to be easy to understand , but there still may be words or ideas that are confusing to you. You may want to bring someone along with you to the meeting to make sure all your concerns are addressed. Be sure you understand what is involved and what is expected of you. Try to explain what you heard to your doctor or nurse to make sure you got it right. Recent surveys have shown that while most people are satisfied with the informed consent process, more than half do not understand some of the main points on the consent form. Finally, don't be rushed into making a decision. Take the consent form home with you if you need to. Ask trusted family members and friends what they think. If possible, you may want to get a second opinion from another doctor, too. Taking part in the study Once you've signed the consent form, you will be ready to take part in the study. You will probably need to have blood tests or imaging tests done before you start treatment (if you haven't had them recently). A full medical history and physical exam are also usually done. The results are needed before you start the actual study to be sure that 447

you meet the eligibility criteria and to help ensure your safety. As mentioned earlier, some studies may require you to stay in a hospital for a day or 2 to get treatment. In other studies the participants are treated much the same way as other patients getting treatment outside of a clinical trial. You may have tests done more often, to find out how well the treatment is going and to look out for your welfare. It is likely that you will get more attention as a study participant than you would otherwise. The doctors and nurses may examine you more often and will want to know if you are having any side effects (called adverse events) while being treated. Because the possible complications may not fully be known, it is very important to let the research team know about anything out of the ordinary. They can then decide if symptoms you are having are related to the study, and if they need to be treated or your therapy needs to be changed. Your participation in the study may end for any number of reasons: * You complete treatment on the study * The treatment does not appear to be working for you * You have serious side effects while in the study

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* The study itself is stopped early because the treatment either has proven to be effective or has proven to be too harmful in others * You decide to leave the study Once out of the study, you may still be watched for a time so that researchers can continue to get an idea of how you are doing. Some studies allow you to continue to receive the new treatment even after the study ends. This is known as "open label," because you and your doctor know which treatment you are getting. This option varies among clinical trials, so be sure to ask about it before you begin. What if I want to leave the study early? You will be told many times before you enter the study that taking part in the study is always voluntary. This is an important point. You have the right to leave the study at any time, for any reason. Your doctor will still take care of you to the best of his or her ability. Regardless of when or why you leave the study, you may be asked if the researchers can follow up with you from time to time to see how you are doing. This may provide them with important information and can also help ensure your safety, even after you leave 449

the study. Return to Top of Page What if I'm not eligible for a clinical trial? Although some people may be too ill or have other problems that do not allow them to take part in clinical trials, most people will probably be eligible for some type of study, even if they've had several treatments already. Of course, not all studies you are eligible for are a good fit for you. It's always important to understand the purpose of the study and to have a realistic idea of the possible risks and benefits for you. Clinical trials offer the best access to experimental treatments. Study protocols, which are written based on the results of studies done before, are strictly followed and patients are watched carefully. Some people may be interested in a certain treatment that is only available in clinical trials, but may not meet the eligibility criteria outlined for the studies. In some of these cases, a person's doctor may ask the study sponsor if they can get an eligibility waiver or special exception to allow the person into the study, even though he or she does not strictly meet all of the criteria. This decision is usually made by the study's clinical

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investigator, who sometimes consults with others involved in the study about your request. If entered in the study, the person is treated according to the study protocol (the same tests, doctor's visits, follow-up, etc.), but the results from that person are not included in the final study results. In other cases, the studies may have already enrolled enough people and aren't accepting more participants. At times, there may be ways to get access to treatments that are in late phase clinical trials but not yet approved by the FDA. These are usually referred to as "expanded access" or "compassionate use" programs. In recent years the FDA has broadened these programs to allow some patients who urgently need these treatments to be able to get them. For more information, see the American Cancer Society document, Compassionate Drug Use. But it is not always easy to get access to these treatments. The programs are voluntary on the part of the company making the treatment. The company is not required to provide the treatment in these settings, and some companies may decide not to for various reasons (manufacturing issues, excess demand, etc.). Because of the amount of 451

effort and paperwork involved, the process can at times be slow (weeks to months). Some of these programs are described below. All require your informed consent, much the same as for any clinical trial. Treatment use of an investigational new drug (Treatment IND) In some cases, if a treatment is showing promise in late phase clinical trials, the maker may apply to the FDA for a "treatment IND" (investigational new drug) status. This is much like setting up a new study, but it is meant mainly as a way for patients with no other options to be able to get the treatment before it is approved. This is sometimes done when a person would not have met the eligibility criteria for the clinical trials or when the studies are already closed to further enrollment. The patient must have a life-threatening or severely debilitating condition for which there are no other treatment options. Your doctor would need to get in touch with the treatment manufacturer to see if such a program exists and what would be needed for you to enter it. As with clinical trials, these programs have to have a protocol (written guideline or plan) that meets FDA approval, as well as approval by an institutional review board (IRB) in many cases. 452

The supplier may or may not charge for the treatment in question. It is important to find out beforehand whether you or your insurance company would pay for the treatment. Single patient and emergency use of an investigational new drug A single patient IND is used to get access to an unapproved treatment for one person with a serious condition who is not eligible for a clinical trial. It is much like a treatment IND in some ways. It does not require that the clinical trial protocol be followed, but it would probably require that your doctor spell out in detail the proposed treatment plan. To get a single patient IND, your doctor would need to contact the manufacturer of the treatment to see if they would supply it. He or she would then need to have the proposed treatment protocol approved by the IRB and the FDA before treatment would be allowed to begin. An emergency IND can be used when there isn't time to get approval from the IRB. Your doctor would need to contact the manufacturer to see if the treatment is available and then file the needed paperwork with the FDA. While IRB approval is not needed before starting treatment, the IRB would have to be notified of the situation and would have to

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approve future uses. Conclusions Clinical trials can offer benefits for many people during their cancer experience. These may include access to newer or more treatment options, getting more involved medical care, and having a greater sense of control over one's situation. But by their nature, clinical trials involve some possible risks and downsides, too, and they may not be right for everyone. Your decision on whether to look into or enter a clinical trial should be based on a realistic understanding of these possible risks and benefits. If you are thinking about entering a clinical trial, there are many groups, including the American Cancer Society, who can help guide you through the information needed to make your decision. Can I Take Other Medicines While I Am Getting Chemo? Some medicines may interfere with the effects of your chemo. To be sure that your treatment is as effective as it can be, tell your doctor or nurse about any and all prescription and non-prescription medicines, herbs, and supplements you are taking. * Make a list of the name of each drug, the dose, how often you take it, who

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prescribed it, and the reason you take it. * Be sure to include the things you may not think of as medicines. This includes aspirin, herbal and dietary supplements, vitamins, minerals, and overthe-counter medicines. Your doctor will tell you if you should stop taking any of these medicines before you start chemo. After your treatments start, check with your doctor before taking any new medicines or supplements and before stopping the ones you already take. Can I Be Around My Family and Friends While I Am Getting Chemotherapy? Only a few treatments will require you to avoid close contact with loved ones for a short amount of time. If this is something you will have to do, your doctor will tell you about it when going over treatment options. Most chemo drugs do make you less able to fight infection. It is very important that you stay away from anyone who is sick. The best way to prevent infection is by washing your hands often and having your family and friends do the same when they are with you. For more information, see the section How will chemo affect my blood cell count?" For more information on being at home with family and friends during treatment, please 455

see our booklets, Helping Children When A Family Member Has Cancer: Dealing with Treatment and Caring for the Patient with Cancer at Home: A Guide for Patients and Families. How Will Chemotherapy Affect My Blood Cell Count? The bone marrow produces 3 important parts of your blood: * red blood cells, which carry oxygen to cells throughout the body * white blood cells, which fight infection * platelets, which help blood to clot and stop bleeding Chemo destroys some of the bone marrow cells so fewer blood cells are produced. A drop in the levels of any of these cells leads to specific side effects. Your doctor will check your blood cell count by doing a test called a complete blood count or CBC. This will be done often during your treatment. Anemia When you have too few red blood cells, your body tissues don't get enough oxygen to do their work. This condition is called anemia. You may have these symptoms: * * * * * * * fatigue dizziness paleness a tendency to feel cold shortness of breath weakness a racing heart rate

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Try the suggestions listed in the previous section if your anemia is causing fatigue. Report any symptoms to your doctor or nurse. Your doctor will check your blood cell count (also called a complete blood count) often during your treatment. If your red blood cell count falls too low, you may need a blood transfusion or treatment with a growth factor to boost the number of red blood cells your bone marrow makes. Infection Having a low white blood cell count decreases your body's ability to fight infections. One type of white blood cell, the neutrophil, is especially important in fighting infections. A shortage of neutrophils is called neutropenia. Infections can begin in almost any part of your body and most often start in your mouth, skin, lungs, urinary tract, and rectum. If your white blood cell count drops too much, your doctor may put off treatment, give you a lower dose of chemo, or give you a growth factor shot that makes your bone marrow put out more white blood cells. Things that may help you prevent infections: * Wash your hands often during the day, especially before you eat and after you use the bathroom.

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* Avoid crowds. * Stay away from people who have diseases you can catch, such as colds, flu, measles, or chickenpox. * Do not get any immunization shots (vaccines) without first checking with your oncologist (cancer doctor). * Stay away from people who have recently had an immunization, such as a vaccine for chicken pox, small pox, or the flu. Check with your doctor about which vaccines are important and how long you should stay away from people who have had them. * Clean your rectal area very well but gently after each bowel movement. Ask your doctor or nurse for advice if the area becomes sore or if you have hemorrhoids. Also, check with your doctor before using enemas or suppositories. * Don't cut, bite, or tear the cuticles of your nails. * Be careful not to cut or nick yourself when using scissors, needles, or knives. * Use an electric shaver instead of a razor to prevent breaks or cuts in your skin. * Use an extra soft toothbrush that wont hurt your gums and talk to your doctor before using dental floss. * Don't squeeze or scratch pimples.

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* Take a warm (not hot) bath, shower, or sponge bath every day. Pat your skin dry using a light touch. Don't rub. * Use lotion or oil to soften and heal your skin if it becomes dry and cracked. * Clean cuts and scrapes right away with warm water and soap. Use an antibiotic cream and cover with a bandage. * Wear waterproof gloves when gardening or cleaning up after animals and others, especially small children. Even if you are being extra careful, your body may not be able to fight infections when your white blood cell count is low. Look out for and check your body regularly for signs and symptoms that you might have an infection. Pay special attention to your eyes, nose, mouth, and genital and rectal areas. The symptoms of infection could be: * fever of 100.5F or greater when your temperature is taken by mouth * chills * sweating * loose stools (This can also be a side effect of chemo.) * a burning feeling when you urinate * a severe cough or sore throat * unusual vaginal discharge or itching * redness, swelling, or tenderness, especially around a wound, sore, pimple, IV site, or vascular access device * abdominal (belly) pain

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Report any signs of infection to your doctor right away. If you have a fever, don't use aspirin, acetaminophen (Tylenol), or any other medicine to bring your temperature down without first checking with your doctor. Bleeding or clotting problems Chemo drugs can affect the bone marrow's ability to make platelets. These are the blood cells that help stop bleeding by plugging up damaged blood vessels and by helping your blood to clot. If your blood does not have enough platelets, you may bleed or bruise more easily than usual, even from a minor injury. A shortage of platelets is called thrombocytopenia. Report these signs of thrombocytopenia to your doctor: * * * * * * * * * unexpected bruising small red spots under the skin red or pink urine black or bloody bowel movements any bleeding from your gums or nose bad headaches dizziness an increase in weakness pain in joints and muscles

Your doctor will check your platelet count often during your treatment. If it falls too low, you may need a platelet transfusion. Things that may help you avoid problems if your platelet count is low:

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* Don't take any medicine without first checking with your doctor or nurse. This includes aspirin and aspirin-free pain relievers, like acetaminophen (Tylenol), ibuprofen, and any other medicines you can buy without a prescription. Some of these medicines can weaken the platelets and make bleeding problems worse. * Don't drink any alcohol (beer, wine, or liquor) unless your doctor says it's all right. * Use an extra soft toothbrush to clean your teeth and talk to your doctor before using dental floss. * If you have a runny nose, blow gently into a soft tissue. * Take care not to cut or nick yourself when using scissors, needles, knives, or tools. * Be careful not to burn yourself when ironing or cooking. Use a padded glove when you reach into the oven. * Avoid contact sports and other activities that might cause an injury. * Avoid becoming constipated. * Use an electric shaver instead of a razor. * When bending over, keep your head above your heart. Caring for the Patient with Cancer at Home: A Guide for Patients and Families Advances in cancer treatment and changing health care systems have led to shorter

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hospital stays and sicker people being cared for at home. Non-medical caregivers find themselves taking on roles that, just a short time ago, were carried out by trained health professionals. This guide gives you general information about caring for the person with cancer at home. It lists the more common problems people with cancer experience, what signs of problems you can look for, and some ideas for things you can do if problems come up. It also lists some of the more common treatments and possible side effects that go with them. The information given here is not meant to replace talking with your doctor or nurse. Those who know your situation well can give you the information that you will need the most. There are many other materials on cancer and cancer treatment that may be helpful to you. They are available from the local office of your American Cancer Society, on our Web site at www.cancer.org, or by calling 1-800-ACS-2345. Trade names are used in this guide because they are well-known. Their use does not represent any previous testing or backing by the American Cancer Society. Generic and other brands may be recommended by your doctor or cancer care team. Anxiety and Fear Appetite, Poor Blood Counts 462

Blood in Stool Blood in Urine Bone Marrow or Stem Cell Transplant Chemotherapy Clinical Trials Confusion Constipation Depression Diarrhea Difficulty in Moving Exercise Falls Fatigue Fever Fluids and Dehydration Gene Therapy Genetic Testing and Counseling Grooming and Appearance Hair Loss Health Insurance Hiccups Hospice Care Immunotherapy Learn More Additional Resources References Itching Leg Cramps Mouth Dryness Mouth Sores Mouth, Bleeding in Nausea and Vomiting Pain Protheses Radiation Therapy Scars and Wounds Seizures Sexuality Shortness of Breath Skin (Pressure) Sores Skin Color Changes 463

Skin Dryness Sleep Problems Steroids and Hormones Stomas (or Ostomies) Swallowing Problems Sweating Swelling Treatment at Home Tubes and IV Lines Weight Changes When Death Is Approaching

Anxiety and Fear Anxiety (a feeling of worry or unease) and fear are common feelings that patients and families sometimes have when coping with cancer. These feelings are normal responses to the stress of cancer, and may be more noticeable around the time the cancer is first diagnosed. Feelings of fear or anxiety may be due to changes in the ability to continue family duties, loss of control over events in life, changes in appearance or body image, or simply the shock of a cancer diagnosis. They may involve uncertainty about the future and concerns about suffering, pain, and the unknown. Fears around loss of independence, changes in relationships with loved ones, and becoming a burden to others may overwhelm the patient and complicate family life. Family members may have these feelings because they, too, are uncertain about the 464

future or angry that their loved one has cancer. They may feel guilt and frustration at not being able to "do enough." Or they may feel overwhelmed by everything they now have to do. Many caregivers feel stressed because of problems balancing work, child care, self care, and other tasks, along with more responsibility at home. All of this is on top of having to worry about and take care of the person with cancer. Sometimes a person with cancer may become overly anxious, fearful, or depressed and may no longer cope well with his or her day-to-day life. If this happens, it often helps the patient and family to get help from a professional therapist or counselor. What to look for * * * * * * * * * * * Feeling anxious Trouble thinking or solving problems Being nervous, agitated, irritable, or restless Feeling or looking tense Concern about "losing control" Uneasy sense that something bad is going to happen Trembling and shaking Headaches Being cranky or angry with others Tiredness or fatigue Trouble sleeping or restless sleep

What the patient can do * Talk about feelings and fears that you or family members may have -- its OK to feel sad and frustrated.

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* Decide together with your family or caregiver what things you can do to support each other. * Do not blame yourself and others when you feel anxious and afraid. Instead, look at your emotions, concerns, and beliefs about what has been going on in your life, and talk about those things. * Get help through counseling and support groups. * Use prayer, meditation, or other types of spiritual support. * Try deep breathing and relaxation exercises several times a day. (With closed eyes, breathe deeply, focus on one body part and relax it, starting with toes and working up to head. When relaxed, imagine being in a pleasant place, such as a warm beach at sunset or peaceful mountain meadow.) * Cut down on caffeine. It can worsen anxiety symptoms. * Think about asking your doctor or nurse for a referral to a counselor to work with you and your family. * Talk with your doctor about the possible use of medicine for anxiety. What caregivers can do * Gently invite the patient to talk about his or her fears and concerns. * Do not try to force the patient to talk before he or she is ready. * Listen carefully without judging the patients feelings, or your own. * Decide together with the patient what you can do to support each other.For severe anxiety, it is usually not helpful to try to reason with the patient. Instead, talk with the doctor about the symptoms and problems you notice. 466

* To reduce your own stress, try suggestions from the above list, and any others that have worked for you in the past. * Consider getting support for yourself, through groups or individual counseling. Call the doctor if the patient: * has trouble breathing * is sweating, with a fast or pounding heartbeat * is feeling very restless Note that some medicines or supplements can cause or worsen anxiety symptoms. If anxiety gets worse after a new medicine is started, talk with your doctor about it. Appetite, Poor A person with a poor or no appetite may eat much less than he or she normally does, or may not eat at all. A poor appetite can be caused by many things, such as trouble swallowing (see section on difficulty swallowing), depression (see section on depression), pain (see section on pain), nausea, or vomiting (see section on nausea and vomiting). A poor appetite can also be due to a changed sense of taste or smell, feeling full, tumor growth, dehydration (see section on fluids and dehydration), or side effects of chemotherapy or radiation. A poor appetite is most often a short-term problem. What to look for 467

* Lack of interest in food * Refusing to eat favorite foods * Weight loss What the patient can do * Talk with your doctor about what may be causing your poor appetite. * Eat as much as you want to, but dont force yourself to eat. * Think of food as a necessary part of treatment. * Start the day with breakfast. * Eat small, frequent meals of favorite foods. * Try foods high in calories that are easy to eat (pudding, gelatin, ice cream, sherbet, yogurt, milk shakes). * Add sauces and gravies to meats, and cut meats into small pieces to make them easy to swallow. * Use butter, oils, syrups, and milk in foods to increase calories. Avoid low-fat foods unless fats cause heartburn or other problems. * Try strong flavorings or spices. * Plan meals with favorite foods. * Create pleasant settings for meals. Soft music, conversation, and other distractions may help you eat better. * Eat with other family members. * Drink liquids between meals instead of with meals. (Liquids at mealtime can lead to early fullness.) * Try light exercise an hour before meals. * Hard candies, mint tea, or ginger ale may help get rid of strange tastes in the mouth. * With your doctors OK, enjoy a glass of beer or wine before eating. * Eat a snack at bedtime. * When you don't feel like eating, try liquid meals, such as flavored supplements

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(Ensure, Sustacal, Boost, Carnation Instant Breakfast, and others). Using a straw may help. What caregivers can do * Try giving the patient 6 to 8 small meals and snacks each day. * Offer starchy foods (bread, pasta, potatoes) with high-protein foods, such as fish, chicken, meats, turkey, eggs, cheeses, milk, tofu, nuts, peanut butter, yogurt, peas, and beans. * Keep cool drinks and juices within the patients reach. * If the smell of food bothers the patient, offer bland foods cold or at room temperature. * Create pleasant settings for meals, and eat with the patient. * Offer fruit smoothies, milkshakes, or liquid meals when the patient doesn't want to eat. * Try plastic forks and knives instead of metal if the patient is bothered by bitter or metallic tastes. * Dont "beat yourself up" when the patient refuses food or cant eat. * If the patient cannot eat, you may want to offer just your company, reading, or massage. Call the doctor if the patient: * feels nauseated and cannot eat for a day or more * loses 5 lbs or more * feels pain when he or she eats * does not urinate for an entire day or does not move bowels for 2 days or more * does not urinate often, and when he or she does, the urine comes out in small 469

amounts, smells strong, or is dark colored * has vomiting for more than 24 hours * is unable to drink or keep down liquids * has pain that is not controlled Blood Counts Blood counts measure 3 important parts of blood: The hemoglobin percentage measures the ability of the red blood cells to carry oxygen. A normal hemoglobin range is about 14.5 to18 for men and 12 to 16 for women. Most people still feel well with a hemoglobin as low as 10. A low hemoglobin level is called anemia. The white blood cell count measures your bodys ability to fight infection. A normal white blood cell count is about 5,000 to 10,000. A low white blood cell count may put you at higher risk of infection. You will want to watch for signs of infection so that you can go to your doctor for treatment right away. A high white blood cell count may be a sign of an infection, or it may be due to certain types of disease. The platelet count looks at the cells that help your blood to clot. A normal platelet count is about 150,000 to 450,000. Normal clotting is still possible with a platelet count of 100,000. Dangerous bleeding may occur when the platelet count goes below 20,000.

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After cancer treatment it may take a few weeks for your counts to get back to normal. If you see any other doctors or dentists during this time, be sure they know your counts are low. Some very common treatments may cause problems for you. Call the American Cancer Society at 1-800-ACS-2345 and ask for a copy of Understanding Your Lab Results if you would like to know more about what your lab values mean. Low hemoglobin What to look for * New or worsening tiredness making it harder to do your regular activities * Chest pain or shortness of breath * Pale skin, nail beds, or gums * Dizziness * Weakness * Blood in stool (bright red, dark red, or black stools) * Vomiting dark brown or bright red material (The last 2 are signs of bleeding, which can cause anemia.) What the patient can do * Balance rest and activities. * Tell the doctor if you're not able to get around as well as usual. * Plan your important activities when you have the most energy. * Eat a balanced diet that includes protein (meat, eggs, cheese, and legumes such as peas and beans) and drink 8-10 glasses of water a day, unless your care team gives you other instructions. What caregivers can do

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* Help schedule friends and family members to prepare meals, clean house, do yard work, or run errands for the patient. * Watch for confusion, faintness, or dizziness, as noted below. Call the doctor if the patient: * * * * * * * has chest pains has shortness of breath when resting feels dizzy or faint becomes confused or cannot concentrate has not been able to get out of bed for more than 24 hours has blood in his or her stool vomits dark brown or bright red material

Low white blood cell count What to look for * * * * * * * * * Temperature taken by mouth more than 100.5F Any new area of redness or swelling Pus or yellowish discharge from an injury or other location New cough or shortness of breath New abdominal pain Shaking chills, which may be followed by sweating Burning or pain when urinating Sore throat Sores or white patches in the mouth

What the patient can do * Check temperature by mouth or under armpit if you can't keep a thermometer in your mouth. * Take acetaminophen (Tylenol) for a fever after calling your doctor. * Keep warm. * Take antibiotics or other medicine as prescribed. * Drink fluids, but do not force more than you can tolerate. * Avoid anything that can cause cuts in the skin.

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* Wash cuts and scrapes with soap and water every day, apply antibiotic ointment, and keep covered until healed. * Keep your body clean by bathing daily and washing hands after using the bathroom. * Avoid crowds and don't visit with people who have infections, coughs, or fevers. * Talk with your doctor or nurse about eating raw fruits and vegetables. Some suggest eating only cooked fruits and vegetables until the white blood cell counts come up again. If you eat raw foods, wash them carefully and peel them to avoid germs. * Keep your mouth clean by brushing your teeth twice a day and flossing once a day (unless you were told not to floss). * Use a stool softener to avoid constipation and straining to have a bowel movement. Do not use enemas or suppositories of any kind (see section on constipation). * If constipated, see section on constipation. Check with your doctor before using laxatives. * Drink 2 to 3 quarts of liquid each day, if your doctor approves. What caregivers can do * Watch for shaking chills, and check the patient's temperature after the shaking stops. * Check temperature by placing the thermometer in the patient's mouth or under armpit. (Do not take a rectal temperature.) * Encourage visitors who have fevers or the flu to visit the patient only by phone until they are well. * Offer extra fluids. 473

* Help the patient take medicines on schedule. Call the doctor if the patient: * * * * has a temperature of more than 100.5F taken by mouth has shaking chills feels or seems "different" to others cannot take fluids

Low platelet count What to look for * Bleeding from anywhere (such as mouth, nose, or rectum) * New bruises on the skin * Red rash that looks like pinpoint dots, usually starting on feet and legs * Bad headaches, dizziness, or blurred vision * Weakness that gets worse * Pain in joints or muscles * Vomiting blood or dark material that looks like coffee grounds * Blood in stool (bright red, dark red, or black stools) * More than the usual amount of vaginal bleeding during monthly periods What the patient can do * Use only an electric razor (not blade) for shaving. * Avoid contact sports (such as wrestling, boxing, or football) and any other activities that might result in injury. * Protect skin from cuts, scrapes, and sharp objects. * Use a soft toothbrush. * If your mouth is bleeding, rinse mouth with cold water. * Talk to your doctor or nurse about whether you should put off flossing your teeth until platelet counts improve. * Do not blow your nose or cough with great force. * Stay upright; keep your head level with or above your heart. * Avoid placing anything in the rectum, including suppositories, enemas,

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thermometers, etc. * Stay away from anti-inflammatory pain medicines, such as naproxen or ibuprofen, or medicines that contain aspirin unless your doctor tells you to use them. * If bleeding starts, stay calm. Sit or lie down and get help. What caregivers can do * For nosebleeds, have the patient sit up with head tilted forward, to keep blood from dripping down the back of the throat. Put ice on the nose and pinch the nostrils shut for 5 minutes before releasing them. Ice on the back of the neck may also help. * For bleeding from other areas, press on the bleeding area with a clean, dry washcloth until bleeding stops. Call the doctor if the patient: * has bleeding or any of the symptoms listed above in "What to Look for" * has trouble speaking or moving

Blood in Stool Blood in the stool may be caused by irritation of the bowel during a bowel movement. It can also be caused by straining very hard, by an ulcer or a tumor in the bowel, by hemorrhoids (enlarged blood vessels in or around the anus), a pressure sore or ulcer in the anal area, or a low platelet count (see the section on blood counts). 475

What to look for * Blood on toilet tissue * Blood on underwear, sheets, or underpads * Streaks of blood in stool * Bright red blood from rectum * Dark red or black bowel movements (But remember that eating beets can cause red stools, and iron tablets or bismuth medicines such as Pepto-Bismol and Kaopectate can temporarily cause black stools. This is normal.) What the patient can do * Check how much blood is being passed. * Avoid placing anything in the rectum, including suppositories, enemas, thermometers, etc. * Keep stool soft by taking in plenty of fluids and fiber. * Use stool softeners, and avoid enemas or laxatives. * Wash anal area very carefully with warm, soapy water, rinse well, and pat dry. * A sitz bath (sitting in warm water) may be helpful for hemorrhoids. What caregivers can do * Help the patient watch for bleeding. * Offer extra fluids, fruits, and vegetables to keep stool soft. Call the doctor if the patient: * has blood on toilet tissue 2 or more times * has blood streaks in stool * has bright red blood from rectum * has dark red or black stools Blood in Urine Blood can be seen in the urine when a patient is bleeding in some part of his or her

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urinary system and the blood is being flushed out along with the urine. Common causes include urinary tract infections (UTIs), injury to the urinary tract, kidney or bladder stones, tumor growing in the urinary tract, or a low platelet count (see section on blood counts). What to look for * Red, pink, or tea-colored urine * Blood or clots in urine * Pain with urination What the patient can do * Drink about 1 quart of water (or other fluids) during each 8-hour period (3 quarts each day), unless your doctor has limited the amount you can drink. * Take medicines as prescribed. What caregivers can do * Offer extra fluids. * Help the patient watch his or her urine, if needed. Call the doctor if the patient: * * * * * * * * * sees blood in the urine or discolored urine has pain in lower back, or on lower sides of back when urinating has pink, cloudy, or foul-smelling urine has symptoms that do not improve after treatment has a sudden, urgent need to urinate urinates more often than usual is unable to urinate has a fever of more than 100.5F taken by mouth, or shaking chills is confused or feels or seems "different" to others

Bone Marrow or Stem Cell Transplant

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Stem cells are cells in the bone marrow (the spongy, liquid center of certain bones) that constantly make blood cells for the body. Stem cell transplants are used to restock the bone marrow when it has been destroyed by chemotherapy, radiation, or disease. Stem cells can be taken from bone marrow or blood. Stem cells may be the patients own (autologous), or may come from someone else (allogeneic). Bone marrow transplants (BMTs) were the first method for replacing stem cells, but are used less often today. Donors are usually given medicine to make them sleep before bone marrow can be taken to use in a transplant. Peripheral blood stem cell donation means that stem cells are taken from circulating blood. This allows the donor to stay awake while the cells are taken. Before collection, the donor must take special medicines to cause stem cells to grow and enter the bloodstream. This is the stem cell transplant (SCT) method most commonly used today. Your doctor or cancer care team will be able to tell you more about treatment or clinical trials using stem cell transplants. If you have had a BMT/SCT What to look for * Skin rashes, especially on palms of hands or soles of feet 478

* Poor appetite, weight loss * Shortness of breath or cough * Tiredness or fatigue * Pain or aching * Stomach cramps * Nausea or vomiting * Mouth sores or dryness * Diarrhea * Skin or whites of eyes begin to look yellow * Dizziness, paleness, or other signs of low hemoglobin (see section on blood counts) * Fever, shaking chills or other signs of infection (see section on blood counts, low white blood cells) * Blood in stool or urine, bleeding from anywhere (see section on blood counts, low platelets) What patients can do * Go to every scheduled appointment. * Ask questions. Your cancer care team will help you. * Ask about side effects and what to do if you have them. * Take medicines exactly as prescribed. * Ask about when you should notify your doctor of any changes. * If you are having other symptoms, such as nausea or vomiting, please see that section in this booklet, and call your doctor. What caregivers can do * Go with the patient to appointments and ask the cancer team about any concerns you have. * Help watch for side effects and symptoms, and see those sections in this booklet. Call the doctor if the patient:

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* has any of the problems above, or other symptoms that cause concern * has a question or hears things about stem cell or bone marrow transplants that concern him or her For more in-depth information on bone marrow or peripheral blood stem cell transplants, see Bone Marrow and Peripheral Blood Stem Cell Transplants. This document is also available by calling your American Cancer Society at 1800-ACS-2345. Bone Marrow and Peripheral Blood Stem Cell Transplants This document will give you an overview of bone marrow transplants and other types of stem cell transplants that are used to treat cancer. If you would like more details about donating stem cells or having a stem cell transplant, please contact the organizations listed in the "Additional resources" section. Stem cells are cells in the bone marrow that make all of the body's blood cells. Stem cell transplants are used to restore the stem cells when the bone marrow has been destroyed by disease, chemotherapy, or radiation. Depending on the source of the stem cells, this procedure may be called a bone marrow transplant, a peripheral blood stem cell transplant, or a cord blood transplant.

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The first successful bone marrow transplant was done in 1968. It was not until nearly 20 years later that stem cells taken from circulating (peripheral) blood were transplanted with success. More recently, doctors have begun using cord blood from the placenta and umbilical cords of newborn babies as another source of stem cells. Today tens of thousands of patients have had stem cell transplants. This has lead to better care for transplant patients and helped doctors know more about which patients are likely to have better results after transplant. What Are Stem Cells? All of the blood cells in our bodies start out as young (immature) cells called hematopoietic (blood-forming) stem cells. Learn about the different types of stem cells and where they are found in the body. Reasons for Stem Cell Transplants Stem cell transplants can be an important part of cancer treatment. Learn how stem cell transplants can be used to treat cancer or to replace bone marrow that has been destroyed. Types of Stem Cell Transplants The type of transplant depends on where the stem cells come from. Learn the differences between the three types of stem cell transplants. Sources of Stem Cells for Transplants There are 3 possible sources of stem cells to use for transplants. Learn how stem cells

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can be extracted from bone marrow, circulating blood and umbilical cord blood. Which Stem Cell Source Is Best? All 3 sources of stem cells can be used for the same goal. Learn about the advantages and drawbacks to each of the sources. Allogeneic Transplant: Importance of a Matched Donor A working immune system recognizes cells coming from other people as foreign. Learn how doctors try to find the best match possible to avoid possible complications with allogeneic stem cell transplants. The Donor Experience People usually volunteer to become stem cell donors either because they have a family member in need of a match or because they want to help people they don't know. Learn what to expect from the donor experience. The Transplant Process There are several steps in the transplant process, no matter what type of transplant you are going to have. Learn what to expect from the transplant process. Problems in the Post-Transplant Period Stem cell transplants have certain risks. Learn about possible problems and what to look out for after a transplant. What Questions Should I Ask My Doctor? Good communication with your doctor is important. Learn some questions you may want to ask before agreeing to a transplant. Issues Related to Stem Cell Transplants There are a number of issues related to stem cell transplantation. Learn what issues you should take into account as you make your treatment decisions. 482

Additional Resources Find additional resources for Bone Marrow & Peripheral Blood Stem Cell Transplants. Reasons for Stem Cell Transplants Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References Stem cell transplants are used to replace bone marrow that has been destroyed by disease, chemotherapy, or radiation. A stem cell transplant can also be used to treat cancer by using another person's stem cells to help fight the cancer. In some diseases, such as leukemia, aplastic anemia, certain inherited blood diseases,

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and diseases of the immune system, the stem cells in the bone marrow don't work the way they should. They either make too few blood cells, too few immune cells, or too many abnormal cells. Any of these problems can cause the body to not have enough normal red blood cells, white blood cells, platelets, or immune cells. An allogeneic (from another donor) stem cell transplant may help correct these problems. In some cancers, such as lymphomas and multiple myeloma, an autologous stem cell transplant can sometimes be used as part of treatment. To do this, a person's own stem cells are collected, saved, and stored before the actual cancer treatment is done. Very high doses of chemotherapy are then given. The chemotherapy kills normal cells along with the cancer cells, which destroys the bone marrow. The stem cells are then returned to the patient after the treatment to supply the bone marrow with normal, healthy stem cells. Types of Stem Cell Transplants Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants 484

Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References In a typical stem cell transplant high doses of chemotherapy are used, sometimes along with radiation therapy, to treat the cancer. This treatment also kills the stem cells in the bone marrow. In some diseases, like aplastic anemia, treatment is meant to kill the existing bone marrow to make room for new stem cells. Very soon after treatment, a stem cell transplant is done to provide new stem cells that will grow into healthy blood cells. These normal stem cells are given into a vein, much like a blood transfusion. Over time they will settle in the bone marrow and begin to grow and make blood cells. This process is called engraftment.

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There are 3 basic types of stem cell transplants: autologous, allogeneic, and syngeneic. The type of transplant depends on where the stem cells come from. Autologous stem cell transplant In this type of transplant, you are your own donor, using stem cells from either your bone marrow or circulating blood. Your stem cells are removed or harvested before treatment and then frozen. After you get high doses of chemo and/or radiation the stem cells are thawed and given back to you. An advantage of autologous stem cell transplant is that you are getting your own cells back. This means there is no risk that your immune system will reject the transplant or that the transplanted cells will attack your own body. A possible disadvantage is that cancer cells may be harvested along with the stem cells and then put back into your body. To prevent this, doctors may treat your stem cells with anti-cancer drugs or other therapies to reduce the number of cancerous cells that may be present. This is called purging. Purging may damage some healthy stem cells, so extra cells are taken from the patient before the transplant to be sure that enough healthy stem cells will be left after purging.

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This kind of transplant is mainly used to treat leukemias, lymphomas, and multiple myeloma, but it is sometimes used for other cancers. Tandem transplants A tandem transplant is a "double autologous transplant." In a tandem transplant, a patient gets 2 courses of high-dose chemo, each followed by a stem cell transplant. All of the stem cells needed are collected before the first high-dose chemo treatment and half of them are used for each procedure. Most often both courses are given within 6-months, with the second one done after the patient recovers from the first one. Researchers hope that this method can keep the cancer from coming back and are still studying how this method can best be used. This type is being used for the treatment of certain types of cancer, including multiple myeloma, Hodgkin disease, and non-Hodgkin's lymphoma. Allogeneic stem cell transplant Here, the stem cells do not come from the patient, but from a donor whose tissue type (described below under "HLA matching") best matches the patient. The donor is most often a family member, usually a brother or sister. If you do not have a good match in

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the family, a donor may be found from the general public through a national registry. Blood taken from the placenta and umbilical cord of newborns is a newer source of stem cells. This small amount of blood has a high number of stem cells. Still, the numbers are often too low for large adults, so this source of stem cells is used mostly in small adults and children. An advantage of allogeneic stem cell transplant is that the donor stem cells produce their own immune cells, which may help destroy any cancer cells that remain after high-dose treatment. Another possible advantage is that the donor can often be asked to donate more stem cells if needed. Stem cells from healthy donors are also free of cancer cells. Still, there are many possible drawbacks to allogeneic stem cell transplant. The transplant, also known as a graft, may not "take" -- that is, the donor cells may be more likely to die or be destroyed by the patient's immune system before settling in the bone marrow. Another possibility is that the donor cells will make new immune cells that attack the recipient's body -- a condition known as graft-versus-host disease (described in

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the "Problems in the post-transplant period" section). There is also a very small risk of certain infections from the donor cells, although donors are always tested beforehand to minimize this risk. This type of transplant is most often used to treat leukemias, lymphomas, and other bone marrow disorders. Non-myeloablative or mini-transplants Another type of allogeneic transplant is called a reduced-intensity transplant, non-myeloablative transplant, or mini-transplant. This transplant uses less intense chemo and/or radiation to get the patient ready for the transplant compared with a standard allogeneic transplant. The idea here is to kill some of the cancer cells, some of the bone marrow, and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow. The new immune cells then begin to destroy the remaining cancer cells, in what is known as a "graft-versus-tumor" effect. In this procedure, the patient is given low doses of chemo -- not enough to destroy all the cancer or all of the bone marrow, but enough to suppress the patient's immune system. After the chemo the donor stem cells are infused. Unlike the standard allogeneic

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transplant, cells from both the donor and the patient may exist together in the patient's body for some time after a mini-transplant. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patient's own bone marrow cells. These new cells then develop an immune reaction to the cancer and kill off the patient's cancer cells. The advantage of a mini-transplant is that you don't need high doses of chemo and/or radiation. This makes it especially useful in older patients, those with other health problems who aren't strong enough for a normal stem cell transplant, or patients who have already had a transplant. Mini-transplants have been found to treat some diseases better than others. They may not work well for patients with a lot of disease in their body at the time of transplant or those with fast-growing disease. Also, the lowered immune response could still lead to graft-versus-host disease. Although it is actively being studied, this procedure has only been in use since the late 1990's and long-term patient outcomes are not yet available. Ways to improve the procedure are still being studied.

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Another possibility that is being studied is autologous transplant followed by non-myeloablative allogeneic transplant. This decreases the amount of cancer present so that a non-myeloablative conditioning regimen with an allogeneic transplant can be more effective. Syngeneic stem cell transplant This is a special kind of allogeneic transplant because the donor is an identical twin with identical tissue types. Since few people are identical twins, this type of transplant is very rare. An advantage of syngeneic stem cell transplant is that graftversus-host disease will not be a problem. A disadvantage is that this type of transplant won't help destroy any remaining cancer cells. So every effort must be made to destroy all the cancer cells before the transplant is done. Sources of Stem Cells for Transplants Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best?

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Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References There are 3 possible sources of stem cells to use for transplants: bone marrow, circulating blood (from the bloodstream), and umbilical cord blood. Bone marrow Bone marrow is the spongy tissue in the center of bones. Its main function is to make blood cells that circulate in your body and immune cells that fight infection. Bone marrow was the first source used for stem cell transplants because it has a rich supply of stem cells. The bones of the pelvis contain the most marrow and thus have large numbers of stem cells. For this reason, cells from the pelvic (hip) bone are used most often for a bone marrow transplant. Enough marrow must be removed to collect a large number of healthy stem cells.

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For a bone marrow transplant, the donor gets general anesthesia (is put into a deep sleep). Several large needle punctures are made through the skin into the back of his or her pelvic bone (an area called the iliac crest) to remove marrow. The marrow is pulled out through the needle into a large syringe. Aside from the risks of general anesthesia, the main side effect is that the donor is sore for a few days afterward. The harvested marrow is filtered, stored in a special solution in bags, and then frozen in liquid nitrogen. When the marrow is to be used, it is thawed and then given just like a blood transfusion. The stem cells travel to the recipient's bone marrow, where they engraft and begin to grow and make blood cells. Signs of the new blood cells usually can be measured in the patient's blood tests in about 2 to 4 weeks. Peripheral blood Normally, very few stem cells are found in the blood. But giving hormone-like substances called growth factors to stem cell donors a few days before the harvest causes their stem cells to grow faster and move from the bone marrow into the blood. For a peripheral blood stem cell transplant, the stem cells are removed or harvested from the circulating blood through a process called apheresis. This procedure takes 493

several hours. A catheter (a very thin flexible tube) is put into a vein in the donor's arm and attached to tubing connected to a special machine. The donor's blood is run through this machine which separates and keeps only the stem cells. The rest of the blood is returned to the donor. This process is sometimes repeated for a few days until enough stem cells have been collected. The harvested stem cells are filtered, stored in a special solution in bags, and frozen until the patient is ready for them. After the patient gets his or her treatment, the stem cells are given in an infusion much like a blood transfusion. The stem cells travel to the bone marrow, engraft, and then grow and make new, normal blood cells. The new cells are usually found in the patient's blood a few days sooner than when bone marrow stem cells are used. Umbilical cord blood Not everyone who needs an allogeneic stem cell transplant can find a well-matched donor among the people who have signed up to donate. For these patients, umbilical cord blood may be another potential source of stem cells. A large number of stem cells are normally present in the blood of newborn babies. After birth, the blood that is left behind in the placenta and umbilical cord (known as cord 494

blood) can be collected and stored for later use in a stem cell transplant. After the umbilical cord is clamped and cut, the placenta and umbilical cord are cleaned and cord blood is collected in a sterile container. The cord blood is mixed with a preservative solution and frozen until needed. Cord blood transplant uses blood that would otherwise be discarded. It is fairly easy to collect and does not pose a risk to the donor. The first cord blood transplant was done in 1988, but it is still a fairly new technique. A possible drawback is the smaller number of stem cells present. But this may be balanced by the fact that each cord blood stem cell can form more blood cells than a stem cell from adult bone marrow. To be safe, most cord blood transplants done so far have been in children and smaller adults. Researchers are now looking for ways to increase the numbers of these cells in the lab prior to transplant so that this source can be used in larger adults, too. Which Stem Cell Source Is Best? Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells?

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Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References All 3 sources of stem cells can be used for the same goal: to give the patient healthy stem cells that will mature into healthy blood cells. There may be some minor advantages and drawbacks to each of the sources, but all are usually capable of providing the needed number of stem cells. At first, all stem cell transplants done were bone marrow transplants. Today peripheral blood stem cell transplants are more common. Often, doctors are able to harvest more stem cells from peripheral blood than from bone marrow. The donation procedure for

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peripheral blood stem cells is also easier on the donor than donating bone marrow. Another plus for peripheral blood stem cell transplant is that the recipient's blood count often recovers faster than with a bone marrow transplant. Cord blood transplant is usually considered an alternative source of stem cells if a good match can't be found among volunteer donors. Even though wellmatched cord blood is best, studies suggest that cord blood may not have to be as closely matched as marrow or peripheral blood. This may be an advantage for patients with rare tissue types. This type of transplant does not require a separate donation procedure and may also reduce the severity of graft-versus-host disease (described in the "Problems in the post-transplant period" section). But it is still a new technique, and it is not known if cord blood has enough stem cells for larger adults. Cord blood cells also usually take longer to engraft, leaving the patient at a high risk for infection longer than transplanted marrow or peripheral blood stem cells. Another drawback is that unlike bone marrow transplant or peripheral blood stem cell transplant, once the donated stem cells from the cord blood are used, the donor cannot be called back to give more if needed.

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Allogeneic Transplant: Importance of a Matched Donor Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References The immune system plays an important role in the success of any allogeneic stem cell transplant. The immune system normally keeps us healthy by destroying anything in the body it sees as "foreign," such as bacteria or viruses. A working immune system recognizes cells coming from other people as foreign, too. If the tissue type match between donor and recipient is not close, the immune system

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may see the new stem cells as foreign and destroy them. This is called graft rejection. Usually this doesn't happen because the pre-transplant treatment (chemo and/or radiation therapy) damages the immune system. What can happen is the donor stem cells may see the patient's cells as foreign and turn against their new home. This type of attack is called graft-versus-host disease (GVHD). The grafted stem cells attack the host recipient. To avoid this, every effort is made to find the best match possible. HLA matching Many factors determine how the immune system knows the difference between "self" and "non-self," but the most important for transplants is the human leukocyte antigen (HLA) system. Human leukocyte antigens are proteins found on the surface of most cells. They determine a person's tissue type. (This is different from a person's blood type.) Each person has 3 pairs of major HLA antigens (known as A, B, and DR), for a total of 6 antigens. We inherit 1 set of A, B, and DR antigens from each of our parents (and pass 1 of our 2 sets on to each of our children). How well the donor's and recipient's HLA tissue types match plays a large part in

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determining whether the transplant will be successful. The best matches are where all of the HLA antigens are the same -- a 6 out of 6 match. These have a lower chance of rejection or GVHD. For bone marrow and peripheral blood stem cell transplants, often a 5 out of 6 match is acceptable, too. For cord blood transplants a perfect HLA match doesn't seem to be as crucial for success, and even a 4 out of 6 match may be acceptable. Finding a match There are literally thousands of different combinations of possible HLA tissue types. This can make it hard to find an exact match. Because HLA antigens are inherited, the search for a donor usually starts with the patient's brothers and sisters (siblings), if possible. The chance that any sibling would be a perfect match (that is, that you both received the same set of HLA antigens from each of your parents) is 1 out of 4. If a good match is not found in a sibling, the search may then move on to relatives who are less likely to be a good match -- parents and extended family such as aunts, uncles, or cousins. (Spouses are no more likely to be good matches than people in the general population.) If no relatives are found to be a close match, the search widens to the 500

general public. As unlikely as it seems, it is possible to find a good match with a stranger. To help with this process, bone marrow transplant registries are used (see the "Additional resources" section). Registries serve as matchmakers between patients and volunteer donors. The largest registry in the United States is the National Marrow Donor Program. It lists the tissue types of more than 5 million volunteer donors and about 30,000 cord blood units. Another agency, the Caitlin Raymond International Registry, has access to millions of international records. These agencies have successfully matched thousands of donors and recipients. Depending on a person's tissue typing, several other international registries also are available. The Donor Experience Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best?

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Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References People usually volunteer to become stem cell donors either because they have a family member in need of a match or because they want to help people they don't know. Becoming a donor People wanting to donate stem cells or join a volunteer registry can speak with their doctors or contact the National Marrow Donor Program to find the nearest donor center. Potential donors are asked some questions to make sure they are healthy enough to donate and don't pose an unacceptable risk of infection to the recipient. For more information about donor eligibility guidelines, contact the National Marrow Donor Program or the donor center in your area (see the "Additional resources" section). The potential donor's HLA type is then determined by a simple blood test. There is 502

usually a one-time, tax-deductible fee of about $50 to $100 for this test. Those joining a volunteer donor registry will most likely have their tissue type kept on file until they reach age 60. Expectant mothers wishing to donate their baby's umbilical cord blood can contact the National Marrow Donor Program to find the nearest cord blood donation center. Donation is safe, free, and does not affect the birth process. As with donors of other sources of stem cells, the mother must meet certain eligibility guidelines. (Privately storing a baby's cord blood for future use is a separate issue, described in the section, "Issues related to stem cell transplants.") Informed consent and further testing If a potential stem cell donor is found to be a good match for a recipient, steps are taken to educate that person about the transplant process and to make sure he or she is making an informed decision. No pressure is placed on the donor to take part. It is that individual's choice. If a person decides to donate, a medical exam and blood tests are done to make sure the donor is in good health. A donor might also have a couple of

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pints of blood removed and stored in a blood bank to use after the donation. The blood is then given back on the day the stem cells are removed. The techniques for autologous stem cell donation are basically the same as those for allogeneic donation. Collecting bone marrow stem cells When a person donates stem cells during a bone marrow harvest, the donor is put under general anesthesia (given medicine to put them into a deep sleep) in an operating room. The marrow cells are removed from the back of the pelvic (hip) bone. Enough cells must be collected for a transplant, but the amount taken depends on the donor's weight. Often, about 10% of the donor's marrow, or about 2 pints, are collected during the procedure, which takes about 1 to 2 hours. The body will replace these cells within 4 to 6 weeks. After the procedure is done, the donor is taken to the recovery room while the anesthesia wears off. Once back in the hospital room, the donor is watched until he or she is fully alert and able to eat and drink. In most cases, the donor is free to leave the hospital within a few hours or by the next morning.

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The donor may have soreness, bruising, and achiness at the back of his or her hips and lower back for a few days. Over-the-counter acetaminophen (Tylenol) or non-steroidal anti-inflammatory drugs (aspirin, ibuprofen) are usually helpful. Some people may feel tired, weak, and have trouble walking for a few days. The donor might be told to take iron supplements until the number of red blood cells returns to normal. Most donors are back to their usual activities in 2 to 3 days. But it may take 2 or 3 weeks before they feel completely back to normal. Risks for donors are minimal and serious complications are unusual. But bone marrow donation is a surgical procedure. Rare complications could include anesthesia reactions, infection, transfusion reactions, or injury at the needle insertion sites. Problems such as sore throat or nausea may be caused by anesthesia. Allogeneic stem cell donors do not have to pay for the harvesting because the recipient's insurance company usually covers the cost. Once the cells are collected, they are filtered through fine mesh screens. This prevents bone or fat particles from being given back to the recipient. For an allogeneic or syngeneic transplant, the cells may be given to the recipient through a vein within 505

several hours of removal from the donor. Sometimes they are frozen, particularly if the donor lives far away from the recipient. Collecting peripheral blood stem cells For several days before starting the donation process, the donor is given a daily injection of filgrastim, a growth-factor drug that causes the bone marrow to make and release stem cells into the blood. This can cause some side effects, the most common being bone pain and headaches. Nausea, sleeping problems, and tiredness are other possible effects. These all go away once the injections are finished and collection is completed. Peripheral blood stem cells are collected through a catheter placed in a large vein in the arm. The blood is cycled through a special machine that separates the stem cells from the other blood cells. The stem cells are kept while the rest of the blood is returned to the donor. This process, called apheresis, takes about 2 to 4 hours and is done on an outpatient basis. Sometimes the process needs to be repeated daily for a few days Possible side effects of the procedure can include trouble placing the catheter, infection

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in the catheter, and blockage of the catheter. Blood clots are another possible side effect. During the apheresis procedure donors may feel lightheaded or a tingling and/or chills from the anticoagulant used to keep the blood from clotting in the machine. These effects go away after the donation is complete. Purging techniques Some centers cleanse or "purge" the stem cells used for autologous transplants. This is done before the stem cells are given back to the patient to remove any cancer cells that might be mixed in with them. This process remains controversial, as it has not yet been shown to reduce the risk of cancer recurrence (coming back). A possible downside is that some stem cells can be lost during the purging process. This may cause the patient to need more time to recover normal blood cell production and leave the patient without white blood cells or platelets for a longer period of time. This may cause an increased risk of infection or bleeding problems. Research is being done to look at the need for purging stem cells and the best way to do it. The Transplant Process Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? 507

Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References There are several steps in the transplant process, no matter what type of transplant you are going to have. Patient evaluation and preparation You will first be evaluated to find out if you are eligible for a transplant. A transplant is hard on your body. It can be hard emotionally too. Depending on the situation, many different medical tests may be done to try to find out how well you can handle the transplant process. These might include: * HLA tissue typing 508

* a complete history and physical exam * evaluation of your psychological and emotional strengths * identifying who will be your primary caregiver through the transplant process * bone marrow biopsy * CT (computed tomography) scan or MRI (magnetic resonance imaging) * heart tests such as an electrocardiogram (EKG) or echocardiogram * lung studies such as a chest x-ray and pulmonary function tests * consults with other members of the transplant team, such as a dentist, dietitian, or social worker * blood tests such as a complete blood count, blood chemistries, and screening for viruses (for example, hepatitis B, CMV, and HIV) * discussion of health insurance coverage and related costs that you might have to pay You may have a central venous catheter surgically placed into a large vein in the chest so that blood can be drawn and medicines can be given. This is minor surgery and usually only local anesthesia is needed (the area where the catheter is to be put in is made numb). This catheter will stay in place during your treatment and for some time afterward (usually until your transplanted stem cells have engrafted and your blood counts are steadily returning to normal levels). Eligibility Younger people, those who are in the early stages of disease, or those who have not

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already had a lot of treatment, are often better able to tolerate transplants. Some transplant centers set age limits and do not allow allogeneic transplants for people over 50 or autologous transplants for people over 60 or 65. Some people also may not be eligible for transplants if they have other major health problems, such as serious heart, lung, liver, or kidney disease. A "mini-transplant" (described in the section, "Issues related to stem cell transplants") may be an option for some of these patients. Hospital admission The hospital's transplant program will decide if you need to be admitted to the hospital to have your transplant or if it will be done in an outpatient center. Usually, if admitted, you will come in the day before the transplant is scheduled. During this time, the transplant team makes sure you and your family understand the process and want to go forward with it. This is important because once the process begins, there is no going back--serious problems can occur if treatment is stopped during the process. To reduce the chance of infection during treatment, patients who are in the hospital are put in rooms that have special air filters. The room may also have a protective barrier to

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separate it from the outside and/or a positive air pressure system to make sure outside air does not enter the room. The transplant experience can be overwhelming. Your transplant team will be there to help you physically and emotionally prepare for the process and discuss your needs. Every effort will be made to answer questions so you and your family fully understand what will be happening to you as you go through transplant. Conditioning treatment Conditioning, also known as bone marrow preparation or myeloablation, is treatment with high-dose chemotherapy and/or radiation therapy. It is done for one or more of the following reasons: * to make room in the bone marrow for transplanted cells * to suppress the patient's immune system to lessen the chance of graft rejection * to destroy all of the cancer cells anywhere in the patient's body No single conditioning treatment is used for every transplant. Your treatment will be planned just for you based on the type of disease you have, the type of transplant, and any chemo or radiation therapy you have had in the past. If chemo is part of your treatment plan, it will be given through an intravenous (IV) catheter or as pills. If radiation therapy is planned, it is given to the entire body (called 511

total body irradiation or TBI). The TBI may be given all at once in a single treatment session or in divided doses over a few days. Because of the high doses being used, this phase of the transplant can be very uncomfortable. Chemo and radiation side effects can make you sick, and it may take months to fully recover. A very common problem is mouth sores that will need to be treated with strong pain medicines. You may also have nausea, vomiting, be unable to eat, lose your hair, and have lung or breathing problems. Conditioning may also cause premature menopause in women and will likely make both men and women unable to have children. (See "Stem cell transplants and having children" in the section "Issues related to stem cell transplants.") Before having this procedure, you need to discuss the transplant process and all the consequences with your doctors. It also helps to talk to others who have already had transplants. Infusion of cells After the conditioning treatment, you are given a couple of days rest before getting the new, healthy cells. If the stem cells were frozen, they are thawed in warm water then infused right away. 512

For allogeneic or syngeneic transplants, the donor cells may be harvested in an operating room, then processed in the lab. Once they are ready, the cells are brought to the recipient's room and infused much like a fast blood transfusion. The length of time the infusion takes depends on the volume of fluid that the stem cells are in. You will be awake for this process and it doesn't hurt. This is an important step and has great meaning for recipients and their families. Many people consider this their rebirth or chance at a second life. They may celebrate this day as they would their actual birthday. Infusion side effects are rare and usually mild. For one, the preserving agent dimethylsulfoxide (DMSO), used when freezing cells, can cause you to have a strong taste of garlic or creamed corn in your mouth. Sucking on candy or sipping flavored drinks after the infusion can help this. Your body will also smell like this, which can be unpleasant to those around you, but you won't usually notice it. The smell, along with the taste, may last for a few days. Often having cut oranges in the room will offset the odor and make the experience more pleasant. Patients who have transplants from cells 513

that were not frozen do not experience this problem because the cells were not mixed with the preserving agent. Other short-term side effects of the stem cell infusion may include: * * * * * * * * * fever or chills shortness of breath hives tightness in the chest low blood pressure coughing chest pain less urine output feeling weak

Again, side effects are rare and usually mild. If they do happen, they are treated as needed and the stem cell infusion is always completed. Recovery The recovery stage begins after the cell infusion. During this time, you and your family wait for the infused cells to engraft, or "take," after which they begin to multiply and make new blood cells. The time it takes to start seeing a steady return to normal blood count levels varies depending on the patient and the transplant type, but is usually about 2 to 6 weeks. During the first couple of weeks you will have low numbers of red and white blood cells and platelets. Right after transplant, when your counts are the lowest, you may be given 514

antibiotics to keep you from getting infections (prophylactic antibiotics). You may get anti-bacterial, anti-fungal, and anti-viral drugs. These antibiotics are usually given until your white blood cell count reaches a certain level. Still, complications such as infection due to low white blood cell counts (neutropenia), or bleeding problems due to low platelet levels (thrombocytopenia), may develop. Many patients develop high fevers and need IV antibiotics. Transfusions of red blood cells and platelets are given until the bone marrow function returns and blood cells are made. Except for graft-versus-host disease, which only happens with allogeneic transplants, the side effects from autologous, allogeneic, and syngeneic stem cell transplants are much the same. Problems may include gastrointestinal (GI) or stomach problems, and heart, lung, liver or kidney problems. You might also go through times of distress, anxiety, depression, joy, or anger. Adjusting emotionally after the infusion can be difficult because of the length of time you feel ill and may be isolated from others. Having a transplant is a big decision. Your life and family relationships will be disrupted. Your future becomes uncertain, the process makes you feel bad, and financially it can 515

be overwhelming. Emotions can feel like being on a roller coaster during this time. Support and encouragement from family, friends, and the transplant team are very important to get you through the challenges of transplant. Discharge The discharge process actually begins weeks before your transplant. It starts with teaching done by the transplant team that will include: * what precautions to take * how to prepare your home * how to care for your central venous catheter * how to take good care of your mouth and teeth * what type of diet and activity to maintain * when to call the transplant team or other health care professionals * who will take the role of primary caregiver and what the job will involve For the most part, transplant centers don't discharge patients until they meet the following criteria: * they have no fever for 48 hours * they are able to take and keep down oral medicines for 48 hours * their nausea, vomiting, and diarrhea are controlled with medicine * their neutrophil count (absolute neutrophil count or ANC) is at least 500 to 1,000/mm3 * they have a hematocrit of at least 25% to 30% * they have a platelet count of at least 15,000 to 20,000/mm3 * they have someone to help them at home and an adequate and supportive home environment If patients do not meet discharge criteria, but do not need the intensive care of the 516

transplant unit, they may stay in another hospital unit. Rehabilitation The roller coaster ride may continue in the post-discharge phase. Plus, you will be feeling pretty tired after going through the transplant process. After discharge, some people have physical or psychological problems. These ongoing needs must now be managed at home. Transplant patients are still followed closely during the rehabilitation period. You may need daily or weekly exams along with such things as blood tests, chest x-rays, bone marrow tests, or spinal taps (lumbar punctures). During the early rehab stage, you also may need blood and platelet transfusions, or treatment with antibiotics and/or blood-stimulating growth factors. These visits are frequent at first, but will decrease if things are going well.. It can take 6 to 12 months or even longer for blood counts to get close to normal and the immune system to work well. Some problems may show up even a year or more after healthy cells are infused. Physical complications are usually from the chemo and/or radiation treatment, but other issues may pop up too. Problems can include: * GVHD (in allogeneic transplants) 517

* * * * * * * * * * * * * * *

infections lung problems, such as pneumonia kidney, liver, or heart problems cataracts low thyroid function slowed growth and development in children reproductive/sexual dysfunction (infertility, early menopause) secondary cancers overwhelming fatigue memory loss, trouble concentrating emotional distress, depression, body image changes, anxiety job and insurance discrimination changes in relationships changes in how you view the meaning of life feeling indebted to others

Problems in the Post-Transplant Period Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants

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Additional Resources References Infection During the first 6 weeks after transplant, until the new bone marrow starts making white blood cells (engraftment), you can easily get infections. (During this time of having low white blood cell counts you are said to be neutropenic.) Bacterial infections are the most common during this time. The use of growth factor drugs may shorten this period of danger. After engraftment, the risk of infection is lower, but it still can happen. It takes 6 months to a year after a transplant for the immune system of most patients to work as well as it should. It can take longer for patients with GVHD. Because of the increased risk, you will be watched closely for signs of infection, such as a fever, and extra precautions will be taken. Anyone who enters your hospital room must wash their hands thoroughly. They must also wear gowns, shoe coverings, gloves, and masks. Since flowers and plants can harbor bacteria and fungi, they are not allowed in your room. For the same reason, you cannot eat fresh fruits and vegetables. All food must be well cooked. You might need other dietary restrictions as well. 519

Despite all these precautions, patients often develop fevers, one of the first signs of infection. If this happens, tests will be done to look for the cause of the infection (chest x-rays, urine tests, and blood cultures) and antibiotics will be started right away. Bleeding and transfusions After a transplant, you are at risk for bleeding because the conditioning treatment destroys most of your body's platelets. Platelets are the blood cells that help blood to clot. Your low platelet count usually lasts at least 3 weeks after the transplant. In the meantime, you might have bruising and bleeding, such as nosebleeds and bleeding gums.. If your platelet count drops below 20,000/mm3 (called thrombocytopenia), a platelet transfusion may be needed. It also takes time for the bone marrow to begin making red blood cells, and you might need transfusions from time to time as you recover. Interstitial pneumonia This type of pneumonia is most common in the first 100 days after a stem cell transplant. It may be caused by a virus or by radiation or chemo. It is a nonbacterial, non-fungal form of pneumonia that is caused by damage to the interstitial spaces (areas between 520

the cells) of the lungs. It can be severe, especially if TBI (total body irradiation) was given with chemo as part of the conditioning treatment. You should report any shortness of breath or changes in your breathing to your doctor right away. Chest x-rays will be taken in the hospital to watch for signs of pneumonia. Graft-versus-host disease Graft-versus-host disease (GVHD) occurs in allogeneic transplants when the donor immune cells view the recipient's body as foreign. (The recipient's immune system has mostly been destroyed by conditioning treatment and cannot fight back.) The donor immune cells may attack certain organs, most often the skin, gastrointestinal (GI) tract, and liver. This can impair the organs' functions and increase the chances of infection. GVHD reactions are very common and can vary from barely noticeable to life-threatening. Acute GVHD may happen 10 to 70 days after a transplant, though the average time is around 25 days. About one third to one half of allogeneic transplant recipients develop acute GVHD. It is less common in younger patients and in those with closer HLA matches between donor

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and recipient. The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms include nausea, vomiting, stomach cramps, diarrhea, loss of appetite, yellowing of the skin and eyes (jaundice), and belly pain. Most cases are mild, and those who develop it usually have no long-term effects. In some cases, though, it can be serious or even life threatening. Doctors try to prevent acute GVHD by giving drugs to lessen the immune response, such as steroids, monoclonal antibodies, methotrexate, cyclosporine, and tacrolimus. Although these help prevent serious GVHD, mild GVHD will almost always happen. GVHD usually does not happen in syngeneic or autologous transplant patients. Chronic (ongoing) GVHD can occur anywhere from about 70 to 400 days after the stem cell transplant. A rash on the palms of the hands or the soles of the feet is often the earliest sign. The rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like after a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include: * decreased appetite * diarrhea * abdominal cramps 522

* * * * * * * * * * *

weight loss jaundice (yellow color of the skin and eyes) enlarged liver bloated abdomen pain in the upper right part of the abdomen increased levels of liver enzymes in the blood a tight feeling to the skin dry, burning eyes dryness or sores in the mouth burning sensations when eating acidic foods bacterial infections

Chronic GVHD is treated with medicines that suppress the immune system, much like those used for acute GVHD. The risk of GVHD can be decreased by removing some immune cells (known as T-cells) from the donor stem cells before the transplant. But this can also increase the risk of graft failure (see next section). Researchers are looking at newer techniques to deplete only certain cells, called alloactivated Tcells, from donor grafts. This would reduce the severity of GVHD and allow the donor Tcells to destroy any cancer cells that may have been left. Graft failure Graft failure happens when the body does not accept the new stem cells (the graft). Graft failure is more common in patients whose donor marrow is not well matched and in patients who get bone marrow that has had T-cells removed. In general, it very rarely happens. 523

What Questions Should I Ask My Doctor? Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References Before agreeing to a transplant, you may want to ask your doctor the following questions: * Is a transplant the best option for me? Why? Are there other options I should consider? * What type of stem cell transplant will I have? Why? 524

* What is the chance of finding a good match? * What are the chances of the transplant being successful? * Is stem cell transplant considered experimental for my disease? Why? * What are the risks? * What type of conditioning treatment will I need? * What is the estimated cost? * What costs, if any, will be covered by my insurance? * What side effects might I expect? How bad will they be? How long will they last? * Will I be able to have children after the transplant? What options do I have if I do want to have children later? * What types of medicine or self-care will be used to control the side effects? * Will I be able to have visitors? * When will I be able to return to work? * What type of follow-up will be needed after I am discharged? How often? * What are the chances that my cancer will come back after treatment?

Issues Related to Stem Cell Transplants Bone Marrow & Peripheral Blood Stem Cell Transplants What Are Stem Cells? 525

Reasons for Stem Cell Transplants Types of Stem Cell Transplants Sources of Stem Cells for Transplants Which Stem Cell Source Is Best? Allogeneic Transplant: Importance of a Matched Donor The Donor Experience The Transplant Process Problems in the Post-Transplant Period What Questions Should I Ask My Doctor? Issues Related to Stem Cell Transplants Additional Resources References Costs of stem cell transplants Stem cell transplants can be very expensive. Although it may vary, the total cost for the procedure can easily reach $100,000 or more. Because a transplant is still considered experimental for many types of cancer, especially solid tumors, insurers may not cover the costs of the procedure. No matter what condition you have, it is important to find out what your insurer will cover before deciding on a transplant and to have an idea of what you might have to pay.

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Long-term problems after transplant The type of problems that can happen after transplant depend on many factors, such as the type of transplant done, the conditioning treatment used, the patient's overall health, the patient's age at the time of transplant, the length and degree of immune system suppression, whether chronic GVHD is present and how severe it is. The problems can be caused by the conditioning treatment (the pre-transplant chemotherapy and radiation therapy), especially TBI, or by other drugs used during transplant (such as the immunosuppressant drugs that may be needed after transplant). Potential long-term risks of transplant include: * infertility (the inability to produce children) This is discussed in the next section, "Stem cell transplant and having children." * hormone changes, such as changes in the thyroid or pituitary gland * damage to the liver, kidneys, lungs, heart and/or bones and joints * cataracts (clouding of the lens of the eye, which causes loss of vision) * secondary (new) cancers * post-transplant lymphoproliferative disorders (abnormal growth of lymph tissues) Organ problems You may need careful follow-up with close monitoring and treatment of the long-term organ problems that the transplant process can cause. Some of these, such as infertility, 527

will be discussed early in the transplant process, so you can be prepared for them. It is important that any long-term problems are found and treated quickly. Physical exams by your doctor, blood work, imaging studies, and telling your doctor about any changes or problems you've noticed will help with this. As transplant methods have improved, more people are living longer and doctors are learning more about the long-term results of stem cell transplant. Researchers continue to look for better ways to care for these survivors to ensure the best possible quality of life. Secondary (new) cancers Along with the possibility of the original cancer coming back after it was treated with a stem cell transplant, there is also the chance of having a second cancer after transplant. This is especially true for those who have had an allogeneic transplant. Studies have shown that people who have had allogeneic transplants have a higher risk than other people of getting a second cancer. The most common secondary cancers are solid tumors, often of the skin, mouth, and lung. Risk factors for developing a second cancer are being studied and may include: * radiation (such as TBI) as part of the conditioning treatment 528

* previous radiation treatment that was not part of the transplant process * immune system problems (such as GVHD, HLA-mismatched allogeneic transplant, and immunosuppressant therapy) * having a female donor * being over age 40 at the time of transplant Because it can take many years for second cancers to develop, they have been studied best in those who have lived a long time after treatment. Successfully treating a first cancer gives a second cancer time (and the chance) to develop. No matter what type of cancer is treated, treatments such as radiation and chemotherapy can lead to a second cancer in the long run. For more information on this, please see the American Cancer Society document Second Cancers Caused by Cancer Treatment. Post-transplant lymphoproliferative disorders Post-transplant lymphoproliferative disorders (PTLD) is an out-of-control growth of lymph cells that can be seen after an allogeneic stem cell transplant. It is linked to a malfunction of T cells (a type of immune cell) and the presence of Epstein-Barr virus (EBV). T cells normally help rid the body of cells that are infected with a virus. When the T cells aren't working well, EBV-infected B-lymphocytes can grow and multiply. Most

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people are infected with EBV at some time during their lives. In the United States, as many as 95% of adults between 35 and 40 years of age have been infected, but the infection is controlled by a healthy immune system. The conditioning treatment given before transplant weakens the immune system, allowing the EBV infection to get out of control which can lead to a PTLD. PTLD after allogeneic stem cell transplant is rare. It most often happens in recipients of T-cell-depleted stem cells, recipients of non-T-cell depleted stem cells that came from a mismatched or unrelated donor. It also happens in people who need antithymocyte globulin (ATG) or anti-CD3 monoclonal antibody for treatment of acute graft vs host disease (AGVHD). Recipients who got stem cells from older donors and recipients who had severe immune problems before transplant may also have a higher risk of developing a PTLD. PTLDs after allogeneic stem cell transplant most often happen within 1 to 6 months after transplant, when the immune system is still very weak. They are often linked to the effects of Epstein-Barr virus (EBV) on donor B lymphocytes. PTLD is lifethreatening. It

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may show up as lymph node swelling, fever, and chills. There is no single standard treatment, but it is often treated by reducing immunosuppressant drugs to strengthen the patient's immune system. Other treatments include lymphocyte infusions to boost the immune response, using drugs like rituximab to kill the B cells, and giving anti-viral drugs to treat the EBV. Even though PTLD doesn't happen a lot after transplant, it is likely to happen more as the use of less-matched donors and the need for greater immunosuppression goes up. Studies are being done to identify risk factors for PTLD and look for ways to watch out for it in at risk transplant patients. Despite these possible long-term problems, stem cell transplant has been used to cure thousands of people with otherwise deadly cancers. Research today is being done to not only to cure a patient's cancer, but also improve transplant methods and reduce the chance of problems after stem cell transplant. Stem cell transplant and having children Most people who have transplants become infertile or unable to have children. This is not caused by the transplant itself, but rather by the high doses of chemo or radiation

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therapy used in treatment. These treatments affect both normal and abnormal cells and may damage reproductive organs. But not all stem cell transplant recipients become infertile. If having children is important to you, talk to your doctor before treatment about ways to save your fertility. Your doctor may be able to tell you if a particular treatment will be likely to cause infertility. After chemo or radiation, women may find their menstrual periods become irregular or stop altogether. This doesn't necessarily mean they cannot get pregnant, so birth control is recommended before and after a transplant. Men might consider storing their sperm before having a transplant. Sperm samples are collected, then frozen and stored in a sperm bank. This process can take several days. The stored sperm can later be thawed and used to fertilize a partner's egg using artificial insemination. Other kinds of reproductive techniques, including cryogenic preservation (freezing) of embryos, sperm, and eggs are available for future donation. Adoption is another of the many possibilities open to couples who want to have families after the transplant. For more information see the American Cancer Society document, Fertility and Cancer: 532

What Are My Options? This document is also available by calling 1-800ACS-2345. "Banking" umbilical cord blood for later use Volunteer or public cord blood banks have been set up to increase both the availability of stem cells and the chances for good HLA matches for those in need. Parents can donate their newborn's cord blood to these banks at no cost. Another option is that parents can store their newborn's cord blood in private cord blood banks for possible future use by the child or a close relative. Several private companies offer this service as a form of "biological insurance," should the child need a stem cell transplant at some point later in life. The collection fee can be $1,000 to $2,000 and the fee to store the cord blood is around $150 per year. Parents may want to think about banking their child's cord blood, especially in families that have a history of, or close relatives with, diseases that may benefit from stem cell transplant. But there are some important points to consider: * Most medical specialists feel that the chance that the average child or close relative will benefit from storing his or her own cord blood is extremely low (estimates have ranged from 1 out of 1,000 to 1 out of 200,000), and that most privately collected cord 533

blood is likely to be wasted. * Some diseases are currently treatable by transplant, but these require allogeneic stem cells (from another donor). Infusing autologous cord blood stem cells that contained the same defect would not cure the disease. * The "shelf life" of cord blood is not known. Because cord blood storage is a recent development, scientists do not know whether blood collected at the time of birth will be useful if the individual develops a disease treatable by stem cell transplant 50 years later. Some scientists suspect that advances in immunology and genetics may make use of stored cord blood unnecessary by that time. Remember that if you do want to donate or bank your child's cord blood, it is best if the arrangements are made before the baby is born. More information on private family cord blood banking can be found at The Parent's Guide to Cord Blood Foundation. You can visit their Web site at http://parentsguidecordblood.org/ Chemotherapy Chemotherapy is the use of drugs to kill cancer cells. It is often just called "chemo." The drugs are given in the form of injections or pills. They enter the bloodstream and reach

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all areas of the body. Chemo may be used along with surgery and other types of treatment in hopes of a cure, a remission, or as a way to relieve symptoms in advanced cancer. Another way to use these drugs is to inject them directly into the affected area of the body. This is called "regional chemo," and is only used for certain types of cancer. It allows a higher dose of medicine to go right to the cancer site. Side effects from chemo depend on the type of drug, how much is used, how often it is given and for how long. They can include short-term hair loss, fatigue, nausea, and vomiting, to name a few. There are drugs and other treatments to help with chemo side effects. It is important to know that many patients have few or no side effects. No one can predict who will and who will not. You may be among those who have few problems. What the patient can do * Find out what chemo drugs you will be taking, how they will be given, how often and how long you will get them. * Ask your doctor or nurse about side effects that might happen with the drugs you are taking and what you can do to prevent or reduce them. * Ask about things you should or should not do during chemo. 535

* Talk with your doctor about how chemo will affect plans to have children (see section on sexuality in this booklet). * Do not get pregnant while you are getting chemo. Ask your doctor how long you should wait after chemo to try to get pregnant. * Learn how to contact your doctor or nurse during non-office hours. * Find out whether you should take vitamins or supplements during your chemo. * Before chemo starts, get all prescriptions filled and be sure you understand how to use each one. * Go to every scheduled appointment. * Report all side effects to your doctor. * If you have nausea and vomiting, see section on nausea and vomiting, and talk to your doctor. * If fatigued or tired, see section on fatigue. * If suffering from diarrhea or constipation, see those sections. * See section on blood counts if hemoglobin, platelet, or white blood cell counts are low. * For hair loss you can wear hats, cotton scarves, or a wig. In cold weather cover your head and ears (see section on hair loss). * Eat as much as you can (if not hungry, see section on appetite). * If you have a fever, see section on fever. What caregivers can do * Go with the patient to appointments, especially on chemo days. * If you are unable to drive or go for appointments, talk with the social worker or nurse at the doctors office to get help. * Know how to get in touch with the patient's doctor, even when the office is closed.

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* If the patient is unable to get to an appointment, talk with the doctor or nurse as soon as possible, and plan what to do next. * Be sure that someone is with the patient during the first couple of days after each chemo treatment, since more help may be needed at those times. * Help watch for side effects and symptoms, and see those sections in this guide. Call the doctor if the patient: * * * * * has any side effect that lasts more than 1 day has a fever of 100.5F taken by mouth has any bleeding has pain or redness at the IV site where the chemo was given becomes unable to swallow or keep down chemo pills or liquids

How Can I Protect Myself and Those I Live With While I Am Getting Chemo? There are many things you can do during and after chemo to keep yourself and your loved ones from being affected by the drugs while your body is getting rid of them. It takes about 48 hours for your body to break down and/or get rid of most chemo drugs. Most of the waste comes out in your body fluids--urine, stool, tears, and vomit. The drugs are also found in your blood. When these drugs get outside your body, they can harm or irritate skin--even other people's. Keep in mind that for this reason, toilets can be a hazard for children and pets and it is important to be careful. Talk to your doctor about these and any other precautions you should follow. 537

During and for 48 hours after you get chemo: * Flush the toilet twice after you use it. Put the lid down before flushing to avoid splashing. If possible, you may want to use a separate toilet during this time. * Both men and women should sit on the toilet to use it. This cuts down on splashing. * Always wash your hands with warm water and soap after using the toilet. Use paper towels to dry your hands and throw them away. * If you vomit into the toilet, clean off all splashes and flush twice. If you vomit into a bucket or basin, carefully empty it into the toilet without splashing the contents and flush twice. Wash out the bucket with hot soapy water and rinse it, emptying the wash and rinse water into the toilet, then flushing it. Dry the bucket with paper towels and throw them away. * Caregivers should wear throw-away gloves if they need to touch any of your body fluids. (These can be bought in most drug stores.) They should always wash their hands with warm water and soap afterward--even if they had gloves on. * If a caregiver does come in contact with any of your body fluids they should wash the area very well with warm soap and water. Although this is not likely to cause any 538

harm, try to take extra care to avoid this. At your next visit, let your doctor know this happened. Being exposed frequently may lead to problems and extra care should be taken to avoid this. * Any clothes or sheets that have body fluids on them should be washed in your washing machine--not by hand. Wash them twice in hot water with regular laundry detergent. Do not wash them with other clothes. If they cannot be washed right away seal them in a plastic bag. * If using throw-away adult diapers, underwear, or sanitary pads, seal them in plastic and throw them away with your regular trash. Will I Be Able to Work During Treatment? Whether you can continue work, school, and other activities depends on your treatment and how it affects you. For some treatments, you may need to stay in a hospital for a week or more, but most people are able to keep working during treatment. You might be able to schedule your treatments late in the day or right before the weekend so that they interfere with work as little as possible. If chemo makes you tired, try to adjust your work schedule for a while. You may be able 539

to arrange a part-time schedule or work from home. Federal and state laws may require some employers to allow you to work a flexible schedule during your treatment. To find out more about your rights as an employee, call your local American Cancer Society office or our toll-free number, or email us. You may also find out about employment-related rights by contacting your congressional or state representatives. How Will I Know If My Chemotherapy Is Working? Your cancer care team will measure how well your treatments are working by doing certain tests. This will include physical exams, blood tests, bone marrow biopsies, scans, and x-rays. Ask your doctor about the test results and what they show about your progress. Although you may have side effects, these side effects do not tell you whether or not treatment is working. How Do I Give My Permission for this Treatment? You will be asked to give your written permission to get chemo based on your understanding of the drugs your doctor recommends. Know the answers to all of these questions before you sign the consent form.

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* Which chemo drugs will I be given for my cancer? * How will the drugs be given to me? * How often will I need to get chemo? * How long will my treatments last? * What side effects could I have from these drugs? * How likely is this treatment to be successful? Although the specifics of the consent form may vary from state to state, the form usually states that your doctor has explained your condition to you, how the chemo will benefit you, the risks, and the other options available to you. Your signature on the form means that you have gotten this information and that you are willing to be treated with chemo. This process is called giving informed consent. Glossary These are some words that you may hear your health care team use. Adjuvant therapy: Treatment used in addition to main treatment. It usually refers to hormone therapy, chemotherapy, radiation therapy, or immunotherapy given after surgery to increase the chances of curing the disease or keeping it in check. Alopecia: Hair loss. It is usually short term and is caused by the use of chemo drugs.

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Anemia: Having too few red blood cells. Symptoms of anemia include feeling tired, weak, and short of breath. Anti-emetic: A medicine to prevent or control nausea and vomiting. Benign: Non-cancerous, or not cancer. Blood cell count: The number of red blood cells, white blood cells, and platelets in a sample of blood. This is also called complete blood count (CBC). Bone marrow: The inner, spongy tissue of bones where blood cells are made. Cancer: A general term for more than 100 diseases in which abnormal cells grow out of control. Also used to refer to a malignant tumor or cancerous tumor. Catheter: A thin, flexible tube. Doctors use these to place fluids in your body or as a way for fluids to leave your body. Central venous catheter (CVC): A special thin, flexible tube placed in a large vein, usually in the chest, neck, or upper arm. It can remain there for as long as it is needed to deliver and withdraw fluids. Chemotherapy: The use of drugs to treat disease. The term most often refers to drugs used to treat cancer. Often called chemo. Chromosomes: Threadlike bodies that carry genetic information. They are found in the nucleus, or center part, of a cell. 542

Clinical trials: Medical research studies done in patient volunteers. Each study is designed to answer scientific questions and to find better ways to detect, prevent, or treat cancer or its side effects. Combination chemotherapy: The use of more than one chemo drug to treat cancer. Complementary and alternative medicine (CAM): Non-conventional ways of dealing with disease. This term covers a broad range, such as herbs/vitamins/minerals, mind/body/spirit, diet and nutrition, physical touch, and biological methods. Fatigue: The feeling of being tired physically, mentally, and emotionally. Cancer-related fatigue persists over time and can interfere with usual activities. This fatigue is different from the fatigue of everyday life, which is usually short term and relieved by rest. Growth factors: Also known as colony-stimulating factors, growth factors are substances that stimulate the production of blood cells in the bone marrow. They can help the blood-forming tissue recover from the effects of chemotherapy and radiation therapy. Hormones: Natural substances released by an organ that can influence the function of other organs in the body and the growth of some types of cancer.

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Infusion: Slow and/or prolonged intravenous (IV) delivery of a drug or fluids. Injection: Using a syringe and needle to push fluids or drugs into the body; often called a shot. Intra-arterial: Into an artery. Intracavitary: Into a cavity or space; most often the abdomen, pelvis, or the chest. Intralesional: Into a tumor. Intramuscular (IM): Into a muscle. Intrathecal (IT): Into the spinal fluid (also called cerebrospinal fluid or CSF). Intravenous (IV): Into a vein. Malignant: Cancerous. Metastasis/Metastasized: The spread of cancer cells to other areas of the body through the lymph system or bloodstream. Neoadjuvant therapy: Systemic therapy, such as chemotherapy, hormone therapy, or radiation therapy, given to shrink a tumor before surgery is done. Orally (PO): taken by mouth Peripheral neuropathy: A condition of the nervous system that usually begins in the hands and/or feet with symptoms of numbness, tingling, burning, and/or weakness. It can be caused by some chemo drugs.

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Platelets (Plts): Special blood cells that plug up damaged blood vessels and help blood clot to stop bleeding. Radiation therapy: The use of high-energy rays or subatomic particles to treat disease. Types of radiation include x-ray, electron beam, alpha and beta particles, and gamma ray. Red blood cells (RBCs): Cells that carry oxygen from the lungs to tissues throughout the body. Remission: The partial or complete disappearance of signs and symptoms of disease. Stomatitis: Sores on the lining of the mouth. Topical: Put directly to the skin. Tumor: An abnormal growth of cells or tissues. Tumors are either benign (non-cancerous) or malignant (cancerous). White blood cells (WBCs): The blood cells that fight infection. Detailed Guide: Cancer (General Information) Biologic Therapies There is a lot of evidence that suggests that the immune system, the body's natural defense mechanism, plays a major role in the body's response to cancer. At least some forms of cancer occur when the immune system fails to destroy cancer cells or to

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prevent their growth. Biologic therapy is an effective treatment for certain cancers. It is sometimes called immunotherapy, biotherapy, or biological response modifier therapy. Biologic therapies use the body's immune system to fight cancer or to lessen the side effects of some cancer treatments. Biologic therapies can act in several ways in cancer treatment. These include interfering with cancer cell growth, acting indirectly to help healthy immune cells control cancer, and helping to repair normal cells damaged by other forms of cancer treatment. There are several kinds of biologic therapy now in use. More than one kind of biologic therapy may be used, or biologic therapy may be combined with chemotherapy or radiation therapy to treat cancer. For more information, please see Immunotherapy. Immunotherapy Immunotherapy uses your immune system (either boosting your own or using parts of another) to fight cancer. Many future advances against cancer will probably come from this field. This document explains: the different cells of the immune system and how they normally

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work to protect you from disease; the different types of immunotherapy (monoclonal antibodies,cancer vaccines, non-specific immunotherapies and adjuvants [immune stimulants]); and the forms of immunotherapy used for specific cancers. What Is Immunotherapy? Immunotherapy is also called biologic therapy or biotherapy. Learn how immunotherapy uses certain parts of the immune system to fight disease, including cancer. What the Immune System Does The immune system is your body's defense force. Learn how immune system cells and the substances they make circulate through your body to protect it from germs that cause infections, and to some extent from cancer. The Immune System: Key Players The response to antigens is a highly coordinated process that uses the many types of cells of the immune system. Learn about the key types of cells that make up your immune system. Types of Immunotherapy Researchers have designed ways to help the immune system recognize cancer cells and strengthen its response so that it will destroy the cancer. Learn about the 2 main types of immunotherapy. Monoclonal Antibodies Monoclonal antibodies are the most widely used form of cancer immunotherapy at this 547

time. Learn about this type of passive immunotherapy. Cancer Vaccines Cancer vaccines are active specific immunotherapies. Learn about several types of cancer vaccines now being studied. Other Active Specific Immunotherapies Some forms of active immunotherapy are not considered "vaccines." Learn about other active specific immunotherapies. Nonspecific Immunotherapies and Adjuvants Non-specific immunotherapies stimulate the immune system in a very general way, but this may still result in more activity against cancer cells. Learn how nonspecific immunotherapies can be used as treatments or as adjuvants. Clinical Trials Because they are still fairly new, different forms of immunotherapy must be studied thoroughly to be sure they work and are safe to use. Learn how this is done through the use of carefully controlled research studies that are done with patients. Immunotherapy for Specific Cancers The FDA has approved several cancer immunotherapies, while many other immunotherapies have shown promising results and are moving through the testing process in clinical trials. Learn about which immunotherapies are being studied for

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specific cancers Additional Resources Find sources of patient information and support for immunotherapy.

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