Cancer Helper

Federal health officials Tuesday launched the biggest genetic research project since the landmark mapping of the human genome–an ambitious effort to categorize all the hundreds of molecular glitches that turn normal healthy cells into cancers.

The Cancer Genome Atlas, whose total cost could reach $1 billion or more, will for the first time direct the full force of sophisticated genetic technologies to the thorough understanding of a single disease, one that eventually strikes nearly half of all Americans.

Leaders of the National Institutes of Health, which will administer the project through grants and contracts, predicted it would revolutionize the diagnosis, treatment and prevention of cancer, which will kill 564,000 Americans this year.

NIH’s National Human Genome Research Institute and the National Cancer Institute will provide $100 million for a three-year pilot project to test the project’s feasibility.

Dietary fiber doesn’t reduce the risk of colorectal cancer.

That’s the conclusion of researchers here who analyzed data from 13 prospective cohort studies — involving nearly three-quarters of a million people — on the link between fiber and cancer.

“We did not find support for a linear inverse association between dietary fiber intake and risk of colorectal cancer,” Yikyung Park, Sc.D., of the Harvard School of Public Health, and colleagues reported in the Dec. 14 issue of the Journal of the American Medical Association.

On the other hand, the researchers concluded, fiber from whole plants has been shown to be beneficial in other disorders, including heart disease and diabetes, so there’s good reason to keep eating it.

The finding adds to the cloud of uncertainty surrounding dietary fiber, said John A. Baron, M.D., of Dartmouth Medical School in Lebanon, N.H., in an accompanying editorial.

Compared with other disorders and diseases, “colorectal cancer arguably has the most confusing association with fiber,” Dr. Baron wrote, noting that various studies have shown it is beneficial, has no effect, and even increases the risk.

It is even difficult to decide what exactly is meant by the term “dietary fiber,” he said, adding that “dietary fibers often do not conform to their popular image.”

They’re not simply roughage, he said, and most are not even fibrous. Although most share a resistance to breakdown by alimentary enzymes, many dietary fibers are digested by bacteria in the colon.

“The heterogeneity of dietary fibers has been a major contributor to the confusion regarding associations with colorectal cancer,” Dr. Baron wrote.

Dr. Park and colleagues from a range of institutions in the U.S. and elsewhere examined the pooled data from 13 studies, involving 725,628 men and women who were followed for between six and 20 years, depending on the study.

The primary endpoint was incident colorectal cancer.

The analysis found that 8,081 colorectal cancer cases had been identified in the studies. The median energy-adjusted dietary fiber intake ranged from 14 to 28 g/day in men and from 13 to 24 g/day in women. In Europe, the major source of dietary fiber was cereals, while in North America, it was fruits and vegetables.

After adjusting for age alone, the researchers found a significant benefit for fiber: the relative risk was 0.84 (with a 95% confidence interval from 0.77 to 0.92) favoring those with the highest intake of fiber.

But when other dietary factors were included in the analysis - such as folate intake, alcohol use, and red meat consumption - the benefit was attenuated and the association was no longer statistically significant, Dr. Park and colleagues found.

Although its negative result is contradicted by the recent European EPIC study, which found a benefit, the study by Dr. Park and colleagues provides “valuable help” in sorting out the confusion, Dr. Baron said.

“Unfortunately,” he concluded, “there is more to do.”

Primary source: Journal of the American Medical Association
Source reference:
Park Y et al. Dietary Fiber Intake and Risk of Colorectal Cancer: A Pooled Analysis of Prospective Cohort Studies. JAMA. 2005;294:2849-2857.

Additional source: Journal of the American Medical Association
Source reference:
John A. Baron. Dietary Fiber and Colorectal Cancer: An Ongoing Saga. JAMA. 2005;294:2904-2906.

Two new treatments have been described recently. One is the use of an antibody that stops the action of a chemical called interleukin-6 (IL-6), which is made by lymphoid tissue affected by Castleman disease. In a recent study, 7 people with Castleman disease were treated with the antibody and all got better. When the treatment was stopped, the disease returned.

A second new treatment is a drug called all-trans-retinoic acid. In 1 patient treated with this drug, the disease completely disappeared. The treatment was stopped and after a year, the disease had not come back. More patients need to be treated with this drug to determine how effective it is.

Frequent follow-up exams are very important for several years after the treatment for Castleman disease is finished. The doctors will continue to watch you for signs of recurrent disease, as well as for short-term and long-term side effects of treatment. It is important that you report any new symptoms to the doctor right away, so that relapse or side effects can be treated.

Checkups usually include a careful physical exam, x-rays when necessary, and lab tests.

Multicentric Castleman disease may come back as early as the first year after treatment. Eventually some people with multicentric Castleman disease develop non-Hodgkin lymphoma or Kaposi sarcoma. It helps to diagnose and treat these conditions as early as possible.

Another benefit of follow-up care is that it gives you a chance to discuss questions and concerns that can arise during and after your recovery.

As you cope with Castleman disease and its treatment, we encourage you to have honest, open discussions with your doctor. Feel free to ask any question that’s on your mind, no matter how small it might seem. Here are some questions you might want to ask. Be sure to add your own questions as you think of them. Nurses, social workers, and other members of the treatment team may also be able to answer many of your questions.

• Do you know what caused my disease?
• Is my Castleman disease localized or multicentric?
• Do I also have HIV infection and AIDS? If so, how does it influence the prognosis and treatment of Castleman disease?
• What treatment choices do I have?
• Which treatment do you recommend, and why?
• What side effects are there to the treatments that you recommend?
• What is my outlook for survival?
• What can I do to help reduce the side effects I may have from the treatment?
• What are the chances that the disease will come back once I am in remission?
• Am I eligible to participate in clinical trials of any new treatments?

Once localized Castleman disease is removed, the outlook is very good. But sometimes the surgeon cannot safely remove all the disease. This doesn’t necessarily mean it will come back. Even partial removal may help and the disease may not grow back.

The outlook (prognosis) for multicentric disease is not as good. Although treatment helps, cures are rare and the disease often comes back. In one study, by the end of 2?years, 50% of people with multicentric Castleman disease had died. The outlook is better if the Castleman disease is not associated with HIV infection and AIDS. Another problem is that about 20% of people with the multicentric form of the disease develop lymphomas, which also affects treatment and outlook. Kaposi sarcoma is another cancer that is associated with HIV infection and AIDS. Some people with Castleman disease and AIDS also have Kaposi sarcoma, which complicates their medical situation.

Treatment of this form of Castleman disease is much more difficult. Surgery does not usually cure the disease because it is too widespread. Occasionally people are helped by surgical removal of some of the diseased tissue. No single treatment has proven effective for most patients. Several types of treatment, however, have been successful in some patients. Doctors will try 1 or a combination of them to put the disease in remission. The most favored treatments are corticosteroid drugs, chemotherapy, and radiation therapy. Sometimes 2 or more of these treatments are combined. In about half of patients the disease completely disappears. This is less likely to happen in patients with AIDS or HIV infection. Even if the HIV infection is successfully treated with drugs, the Castleman disease likely will not go away.

Corticosteroids and chemotherapy have produced long remissions for some patients. In other cases, the benefit does not last long and the symptoms worsen after the course of therapy is done. Some patients do not respond to these drugs at all.

Another drug that might be used is the monoclonal antibody rituximab. This can be successful, but some patients have gotten worse after receiving the drug. Antiviral drugs in addition to anti-HIV treatment may also help.

Surgery is the recommended treatment for people with localized Castleman disease. Removing the abnormal lymph node(s) appears to cure the disease. Symptoms such as fever and fatigue that are caused by the Castleman disease go away. Relapses are rare. Although not used as often, radiation is also effective in treating localized disease. Either of these treatments is usually curative.

Some patients with localized Castleman disease develop secondary amyloidosis, a condition in which abnormal proteins build up in the kidneys, skin, and some other organs. This accumulation does not progress once the lymph node affected by Castleman disease is removed.

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.

Phase II clinical trials: These studies are designed to see if the drug works. Patients are given the highest dose that doesn??掳 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 patients & ndash; 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 and nurses 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 cancer care team. 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?
• 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?

The American Cancer Society (ACS) offers a clinical trials matching service for patients, their family, and friends. You can reach this service at 1-800-303-5691 or on our Web site at http://clinicaltrials.cancer.org. Based on the information you provide about your cancer type, stage, and previous treatments, this service can compile a list of clinical trials that match your medical needs. In finding a center most convenient for you, the service can also take into account where you live and whether you are willing to travel.

You can also get a list of current clinical trials by calling the National Cancer Institute’s Cancer Information Service toll free at 1-800-4-CANCER or by visiting the NCI clinical trials Web site at http://www.cancer.gov/clinicaltrials.

Because Castleman disease is so rare, clinical trials to test new treatments for this condition may not be available. However, patients with Castleman disease should consider a clinical trial as one of the options for their care. Those who are interested in looking into this option should talk to their doctor and check with the ACS, the National Institutes of Health, and the National Cancer Institute to see if there are any clinical trials that might be right for them.

Surgery

Surgery is often used to obtain a tissue sample to diagnose Castleman disease. It is usually a minor procedure to biopsy a lymph node.

Surgery is also a very effective treatment for localized disease. The type of surgery depends on where the disease is located. It may be in a place that is hard to get to, like the center of the chest or abdomen. The surgeon would then have to cut into the chest or abdomen. These are common procedures, but they can cause pain and people will need to be in the hospital for a few days after the operation. If the involved lymph nodes are easy to get to, such as in the armpit, then surgery is simpler, there is less pain after the operation, and hospitalization may not be needed.

Radiation Therapy

Radiation therapy uses high-energy radiation to kill cells. Radiation focused from a source outside the body is called external beam radiation. Radiation therapy has sometimes been used instead of surgery to effectively treat localized disease.

Side effects of radiation therapy may include mild skin problems or fatigue. Radiation of the abdomen may cause nausea and diarrhea. Often these go away after a short while. Chest radiation therapy may cause lung damage and lead to breathing problems and shortness of breath. Radiation may also make the side effects of chemotherapy worse.

Corticosteroids

Corticosteroids are a group of drugs related to hormones produced by the adrenal glands. These drugs are useful in treating people with certain immune system diseases and cancers that develop from immune system cells, such as lymphomas. Some patients with multicentric Castleman disease benefit from treatment with these drugs.

Corticosteroids are taken as pills. Prednisone is the corticosteroid drug most commonly used in these conditions.

Side effects of corticosteroids can include increased blood sugar that may lead to diabetes, depression, reduced resistance to infections, weakened bones, fatigue, muscle weakness, weight gain, fluid retention, and high blood pressure.

Chemotherapy

Chemotherapy is the use of anticancer drugs that are injected into a vein or a muscle or are taken by mouth. These drugs enter the bloodstream and reach all areas of the body, making this treatment very useful for multicentric disease. Chemotherapy may be used alone, in combination with corticosteroids, or in combination with radiation therapy (chemoradiation).

Many drugs may be used to treat patients with Castleman disease. Those used most often include cyclophosphamide, chlorambucil, melphalan, doxorubicin, vincristine, vinblastine, carmustine, and etoposide. Often several drugs are combined. Depending on the drugs, the treatments are given on different schedules but are usually repeated several times in cycles 3 or 4 weeks apart. Recently, a study reported a good response to the drug 2-chloro-deoxyadenosine (2CdA) in 2 of 3 patients.

Many chemotherapy treatments are given on an outpatient basis (in the doctor’s office or clinic), but some require hospital admission. Sometimes a patient may take one chemotherapy combination for several cycles and later be switched to a different one. Because multicentric Castleman disease is so rare, there is not a lot of information about the effectiveness of chemotherapy.

Because chemotherapy drugs can damage normal cells, some side effects may occur. These depend on the type and dose of drugs given and the length of time they are taken. Drugs used in chemotherapy attack cells that are rapidly dividing. This means they will also attack some normal tissues such as the bone marrow, the lining of the mouth and intestines, and the hair follicles, which also grow rapidly to replace cells that wear out. As a result, a patient may have:

• hair loss
• mouth sores
• loss of appetite
• nausea and vomiting
• lowered resistance to infection (due to low white blood cell counts)
• easy bruising and bleeding (due to low platelet counts)

These side effects are usually temporary and go away after treatment is finished. Still, doctors try to avoid or minimize them as much as possible. There are ways to lessen these side effects. For example, drugs can be given before or along with the chemotherapy to prevent or reduce nausea and vomiting.

Because a low white blood cell count is an important risk factor for serious infections, some patients find it helpful to keep track of their counts. If you are interested in this information ask your doctor or nurse about your blood cell counts and what these numbers mean. You may want to keep a diary of your treatment and blood counts to help you follow the effects of your treatment.

Organs that could be damaged by chemotherapy drugs include the kidneys, liver, testes, ovaries, brain, heart, and lungs. With careful monitoring, such side effects are rare. If serious side effects occur, the chemotherapy may have to be reduced or stopped, at least temporarily. Careful monitoring and adjustment of drug doses is important because some side effects to organs can be permanent.

Monoclonal Antibodies

Monoclonal antibodies are special immune proteins made in the lab. They are directed toward specific molecules on the surface of cells. One particular monoclonal antibody called rituximab (Rituxan) has been effective in treating many types of lymphomas and has also helped a few patients with Castleman disease. Rituximab is given by IV injection, usually once a week for 4 weeks. Some people may have an allergic reaction with fever and need treatment with drugs such as acetaminophen (Tylenol) and diphenhydramine (Benadryl).

Antiviral Drugs

Because Castleman disease is associated with the HHV-8, doctors have had some success in treating a few patients with multicentric Castleman with drugs that kill this virus. One drug that was used is called ganciclovir.