PROTON THERAPY Better Precision, but What about Accuracy?

When x-rays are fired at a tumor, because they have no charge, they transfer their energy at an evenly decreasing rate to the healthy tissues between the surface of the body and the target, as well as to the tissues beyond the tumor, until they exit the body. Proton beams, on the other hand, have a positive charge and deliver most of their energy at a defined depth, within a region called the Bragg Peak, like a depth charge delivered to its calculated destination. When the target is hit, healthy tissues are largely spared side effects from treatment and there is greater damage to the tumor. This may diminish the chance of it coming back or of new tumors in the surrounding tissue arising later on. Theoretically, proton beams are much more exact than x-rays, said Dr. Norman Coleman, associate director of the Radiation Research Program (RRP) at NCI. On the computer screen, the calculations look great, and the enthusiasm is understandable. But is that whats really happening in the patient? There is no published evidence to indicate that proton therapy is detrimental to patients, Dr. Coleman said, but when you have something that is so precise with such sharp edges, you need to make sure that its also accurate. This requires being certain that the target is hit as planned on the computer, including accounting for the uncertainties in diagnostic imaging, reproducibility in patient setup, and internal organ motion. Dr. Bhadrasain Vikram, who is chief of the Clinical Radiation Oncology Branch in RRP, noted that those who administer proton beams to patients are fairly confident of the width of the beam, but as for the final stopping point, there is some nervousness that what theyre seeing on the computer screen may not be happening in the patient. So for tumors in front of the spinal cord, for example, they will align the proton beam sideways during treatment to minimize the risk of the beam going too far and damaging the neural tissue, he explained. Assessing the Value for Patients Experts at NCI and around the country also point out that there is a lack of published randomized controlled trials (RCT) to show that proton therapy works better than standard radiation therapy at increasing survival or improving quality of life for patients. Dr. Nancy Mendenhall, medical director at the University of Florida Proton Therapy Institute in Jacksonville, explained that while her institution is committed to learning more about the best uses of proton therapy through clinical researchsince the facility opened in 2006, approximately 1,500 patients have been treated there, she said, and 95 percent were enrolled in an observational studythere are numerous practical and ethical barriers to conducting an RCT with proton therapy.

Proton therapy is a rare resource; less than 1 percent of patients in this country have access to it, Dr. Mendenhall said. This is because there are so few centers that provide it, and they can only treat a limited number of patients in a day, she explained. The University of Florida Proton Therapy Institute has three proton therapy rooms where between 110 and 120 patients are treated per day. It would likely take 800 or more patients to complete enrollment for one arm of an RCT, but with the same number of patients and time interval, 4 pilot studies could be completed that would advance our understanding of the potential of proton therapy for dose escalation, dose intensification, andhypofractionation, which are our basic radiation therapy methods of increasing disease control, she said. We believe we have approached these limits with x-ray therapy, but not with proton therapy. We have already completed three pilot studies and feel it is important to continue such studies to learn how to maximize the potential of proton therapy. Furthermore, she explained, most of the people who come to Florida for proton therapy would not accept being randomized to the control group in a clinical trial. These are a very special group of patients who are extraordinarily well informed. Theyve researched the treatment, they understand the technology, and theyve decided that its best for them, she said, adding that in many cases they have also traveled thousands of miles to get it. Dr. Mendenhall believes that for now, comparing the outcomes of proton therapy with previously published studies of x-ray therapy should be sufficient, until the treatment capabilities of proton therapy have been explored more, there are more treatment slots available, and there is more confidence in the technology and tools that are used to assess outcomes for the comparison group. The Ultimate Test: Head-to-Head Comparison The position of those at NCI is that, while this technology is very promising, the gold standard for research is still an RCT. We would encourage patients who are looking into proton therapy for their particular disease to seek out an NCIsponsored clinical trial at one of the facilities that provides the treatment, said Dr. Vikram. At the University of Texas M.D. Anderson Cancer Center and Massachusetts General Hospital, more of these trials will soon be available due to a major P01 Research Project Program grant from NCI to fund their collaborative RCT studies of proton therapy for lung cancer and pediatric cancers, as well as technology development. Studies are also under way through the Childrens Oncology Group, noted Dr. James Deye, program director of medical physics in RRP. To ensure that data can be compared across institutions, he added, RRP recently published guidelines for the clinical trials that it sponsors. In the midst of the national discussion of health care reform, proton therapy may soon start to gather attention for another reason: its suitability for comparative effectiveness research.

Radiologists and radiation oncologists accumulate electronic data easily; its just part of the way that we go about our daily business, said Dr. Coleman, who explained how the field is particularly ripe for doing comparative effectiveness research with proton therapy, as well as other emerging radiation therapies, such as carbon ion therapy. We have the images and the data right in front of us, he said. If we add outcomes to that, then we have a lot of good information about whether something new actually works better in the long run than what we were already using. INTERNAL RDIATION THERAPY About the treatment: Brachytherapy uses radiation to destroy cancer cells and shrink tumors. The radiation source, which looks like seeds, ribbons, or wires, is put into your body. Before treatment starts: Here is what happens at most meetings. You will: Talk about your health and medical history. Get a checkup (physical exam). You may also have tests to take pictures of the cancer. Learn how brachytherapy can help you. Learn about any side effects you may have. These differ depending on where the radiation is placed. Ask and get answers to all your questions before starting treatment. During treatment: Your doctor will place a small holder, such as a thin tube called a catheter, into your body. It is placed in or near the cancer cells. Sometimes an applicator or a balloon attached to a thin tube is used. Then the seeds, ribbons, or wires are put inside the small holder so that the radiation can reach and destroy cancer cells. Depending on the type of implant you receive, the radiation source may stay in place for minutes, hours, or days. Or if you receive a permanent implant, it will not be taken out. See below to learn more about the type of brachytherapy that you will be getting. Types of brachytherapy: Low-dose rate High-dose rate (LDR) implants (HDR) implants These implants stay in for hours or days. Often they stay in for 1 to 7 days and then are taken out. These implants stay in place for a few minutes at a time and are then taken out. Your entire visit will be longer, though, since it also takes time to prepare for

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Permanent implants These implants stay in your body and are not removed. Over time the radiation gets

You are likely to stay in a special room in the hospital. You may need to limit time with visitors in the hospital, while your implant is in place. Once the implant is removed, you are not radioactive and can be around people.

the treatment. The holder or catheter may stay in place or it may be put in place before each treatment. You are likely to make daily trips to the hospital for your treatment. Or you may stay in the hospital. Talk with your doctor or nurse to learn how often you will get treatment and how long it will last. This is different for different types of cancers. You can be around people after the implant is removed. You are not radioactive.

weaker, but the implants stay in place. Your doctor or nurse will talk with you about what safety measures to take.

Be sure to follow all special instructions from your doctor or nurse after these treatments EXTERNAL RADIATION THERAPY About the treatment: What is external beam radiation therapy? It is a common cancer treatment that uses high doses of radiation to destroy cancer cells and shrink tumors. A large machine aims radiation at the cancer. The machine moves around you without touching you. It doesn't hurt. It doesn't make you radioactive. It can't be seen, felt, or smelled. How does treatment work? At low doses, radiation is used as an x-ray to take pictures inside your body. In cancer treatment, higher doses of radiation are used to destroy cancer cells. The radiation that destroys cancer cells also injures nearby healthy cells. This is why you may have some side effects. How long does treatment take? The length of your treatment depends on your type and stage of cancer. Most treatments take 2 to 10 weeks. Most people get treatment once a day for 5 days in a row. Treatment usually happens on Monday through Friday. Sometimes, people get treatment twice in 1 day. Most treatment visits last for 30 minutes to 1 hour. You will get radiation for only 1 to 5 minutes, but you may be in the treatment room for 15 to 30 minutes. Your visit may be longer if you have other tests done.

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Before treatment starts: You will meet with a doctor or nurse before your first treatment. He or she will tell you how the treatment works and how it can help you. You will also learn about any side effects to expect. Be sure to ask any questions you have. Your first meeting: You will get a checkup (physical exam). You and your doctor will talk about your health and medical history. You might get tests, such as x-rays or CT scans. Follow-up meeting: Your radiation therapist will put small marks (tattoos or dots of colored ink) on your skin. These marks show where to aim the radiation. A body mold or mask might be made at this meeting. It will help you stay still during your treatment sessions. During your treatment: You will probably lie down on a treatment table. Your radiation therapist will be in the next room to control the machine. He or she will be able to see, hear, and talk with you through a speaker at all times. You will need to stay very still, but you won't have to hold your breath. You may see lights pointed at you. They are safe and show the therapist where to aim the radiation. When you go for treatment: Don't have powder, deodorant, Band-Aids, or jewelry near your treatment area. Wear loose-fitting, comfortable clothes.

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What is biological therapy?

Biological therapy (BYE-o-loj-ee-cal THER-ah-py) is a type of treatment that works with your immune system. It can help fight cancer or help control side effects (how your body reacts to the drugs you are taking) from other cancer treatments like chemotherapy.

What is the difference between biological therapy and chemotherapy?

Biological therapy and chemotherapy are both treatments that fight cancer. While they may seem alike, they work in different ways. Biological therapy helps your immune system fight cancer. Chemotherapy attacks the cancer cells directly.

How does biological therapy fight cancer?

Doctors are not sure how biological therapy helps your immune system fight cancer. But they think it may: Stop or slow the growth of cancer cells. Make it easier for your immune system to destroy, or get rid of, cancer cells. Keep cancer from spreading to other parts of your body.

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What is my immune system and how does it work?

Your immune system includes your spleen, lymph nodes, tonsils, bone marrow, and white blood cells. These all help protect you from getting infections and diseases. When your immune system works the way it should, it can tell the difference between "good" cells that keep you healthy and "bad" cells that make you sick. But sometimes this doesn't happen. Doctors are doing research to learn why some immune systems don't fight off diseases like cancer. White blood cells are an important part of your immune system. When your doctor or nurse talks about your white blood cells, he or she may use words like: Monocytes (MON-o-cites) are types of white blood cells. Lymphocytes (LYM-fo-cites) are types of white blood cells. B cells are kinds of lymphocytes. T cells are kinds of lymphocytes. Natural killer cells are kinds of lymphocytes.

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Parts of the immune system

What are some questions to ask my doctor or nurse about biological therapy?
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Why do you recommend biological therapy for me? Your treatment choices depend on the type of cancer you have, how far your cancer has spread, and the treatments you have already tried. For some people, biological therapy is the best treatment choice. Will biological therapy be my only treatment? Some people only need biological therapy. Others also get chemotherapy and radiation treatment. Talk with your doctor about the kind of treatment you will be on and how it can help. Where do I go to get my treatment? Some biological therapy are pills or shots that you can take at home. Others are given through an IV, and you must go to the hospital or clinic to get them. If this is the case, find out how long you will need to stay at the hospital or clinic. How often will I get my treatment? Treatment schedules vary. Biological therapy may be given once a day or a couple of times a day. Others are given less often--sometimes once a week, or perhaps just once every month or two. Your doctor will tell you how often you will get your treatment and how long you will need to be on it. How much will my treatment cost? Talk with your nurse, social worker, or doctor about the cost of your treatment. Make sure to ask if your insurance company pays for biological therapy. What side effects can I expect? Just like other forms of cancer treatment, biological therapy sometimes causes side effects. Side effects can include: Rashes or swelling where the treatment is injected. Flu-like symptoms such as fever, chills, nausea, vomiting, loss of appetite, fatigue, bone pain, and muscle aches. Lowered blood pressure (blood pressure goes down).

What are cancer vaccines?

Cancer vaccines are a form of biological therapy. While other vaccines (like ones for measles or mumps) are given before you get sick, cancer vaccines are given after you have cancer. Cancer vaccines may help your body fight the cancer and keep it from coming back. Doctors are learning more all the time about cancer vaccines. They are now doing research about how cancer vaccines can help people diagnosed with melanoma, lymphoma, and kidney, breast, ovarian, prostate, colon, and rectal cancers.

What are the names of some biological therapy?

There are many kinds of biological therapy. Here are the names of some common ones with ways to say them and brief statements about how they are used in cancer care. Treatments for cancer: BCG or Bacillus Calmette-Gurin (ba-SIL-us KAL-met gay-RAIN) treats bladder tumors or bladder cancer. IL-2 or Interleukin-2 (in-ter-LOO-kin 2) treats certain types of cancer. Interferon alpha (in-ter-FEER-on AL-fa) treats certain types of cancer. Rituxan or Rituximab (ri-TUX-i-mab) treats non-Hodgkin's lymphoma. Herceptin (her-SEP-tin) or Trastuzumab treats breast cancer. Treatments for controlling side effects: Neupogen (NU-po-jen) or G-CSF increases white blood cell counts and helps prevent infection in people who are getting chemotherapy. Procrit, Epogen, or Erythropoietin (e-RITH-ro-po-i-tin) helps make red blood cells in people who have anemia. IL-11, Interleukin-11, Oprelvekin (oh-PREL-ve-kin), or Neumega helps make platelets (a type of blood cell).

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How can I learn more about biological therapy research?

Doctors are studying biological therapy in clinical trials--research studies that test new cancer treatments.

Angiogenesis Inhibitors Therapy

1. What is angiogenesis? Angiogenesis is the formation of new blood vessels. Angiogenesis is a process controlled by certain chemicals produced in the body. Some of these chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, called angiogenesis inhibitors, signal the process to stop. 2. Why is angiogenesis important in cancer? Angiogenesis plays an important role in the growth and spread of cancer. New blood vessels feed the cancer cells with oxygen and nutrients,

allowing these cells to grow, invade nearbytissue, spread to other parts of the body, and form new colonies of cancer cells. 3. How can angiogenesis be stopped in tumors? Because tumors cannot grow or spread without the formation of new blood vessels, scientists are trying to find ways to stop angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called antiangiogenic agents, in the hope that these chemicals will prevent or slow down the growth of cancer by blocking the formation of new blood vessels. 4. Are any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab (Avastin) for use with other drugs to treat colorectal cancer that has spread to other parts of the body, some non-small cell lung cancers, and some breast cancers that have spread to other parts of the body. Bevacizumab was the first angiogenesis inhibitor proven to delay tumor growth and, more importantly, extend the lives of patients. The FDA has also approved other drugs with antiangiogenic activity as cancer therapies for multiple myeloma, mantle cell lymphoma, gastrointestinal stromal tumors (GIST), and kidney cancer. Researchers are also exploring the use of these drugs to treat other cancers (see Question 8). 5. What are the advantages of angiogenesis inhibitors? Angiogenesis inhibitors usually have only mild side effects and are not toxic to most healthy cells. Tumors do not seem to develop a resistance to angiogenesis inhibitors, even when given over a long period of time, unlike the resistance seen when chemotherapy drugs are used. Angiogenesis inhibitors seem to help some chemotherapy drugs and radiation therapy work more effectively when given in combination. 6. What are the limitations of angiogenesis inhibitors? Angiogenesis inhibitor therapy may not necessarily kill tumors, but instead may keep tumors stable. Therefore, this type of therapy may need to be administered over a long period. Because angiogenesis is important in wound healing and in reproduction, long-term treatment with antiangiogenic agents could cause problems with bleeding, blood clotting, heart function, theimmune system, and the reproductive system (1). 7. Does angiogenesis inhibitor therapy have any complications or side effects? A patients immune system may be compromised, making the patient more susceptible toinfection and causing wounds to heal poorly, if at all. Patients may experience reproductive problems, and damage to the fetus is likely if

a patient becomes pregnant while taking the antiangiogenic drug. Heart problems and high blood pressure could be made worse, and bleeding or blood clots could increase (1). Since angiogenesis inhibitor therapy is still under investigation, all of the possible complications and side effects are still unknown. 8. What does the future hold for angiogenesis inhibitor therapy? Other angiogenesis inhibitors are currently being tested in clinical trials (research studies) but have not yet been shown to be effective against cancer in humans. If these angiogenesis inhibitors are proven to be both safe and effective in treating human cancer, they may be approved by the FDA and made available for widespread use.

A sarcoma (from the Greek sarx meaning "flesh") is a cancer that arises from transformedcells in one of a number of tissues that develop from embryonic mesoderm.[1] Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues. (This is in contrast to carcinomas, which originate from epithelial cells and thus give rise to more common malignancies, such as breast, colon, and lung cancer.) Sarcomas are given a number of different names, based on the type of tissue from which they arise. For example, osteosarcoma arises from bone, chondrosarcoma arises from cartilage,liposarcoma arises from fat, and leiomyosarcoma arises from smooth muscle.