1. What are cyclooxygenase (COX) inhibitors?
   

   Cyclooxygenase (COX) inhibitors are compounds that block the action of cyclooxygenase enzymes, which are produced in response to inflammation and by precancerous and cancerous tissues. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation from many medical conditions by inhibiting both of these enzymes (COX-1 and COX-2). NSAIDs that inhibit only COX-2 enzymes were created to allow people to have relief from pain and inflammation while reducing the chances of certain medical problems, such as stomach bleeding, that can occur when NSAIDs are taken regularly for long periods of time.

2. Why is the National Cancer Institute (NCI) studying COX inhibitors in cancer prevention and treatment?
   

   More than a decade of epidemiologic research suggests that people who regularly take drugs that block COX enzymes have lower rates of certain precancers, cancers, and cancer-related deaths. The data are most consistent for colorectal cancer, but this reduction in risk is also seen for other cancers. Laboratory and animal studies using a variety of NSAIDs and COX-2 specific inhibitors show a decrease in cancer incidence with the use of these compounds. On a molecular level, studies have shown that the inhibition of the COX pathway changes the characteristics of cancer cells by reducing cell proliferation, increasing programmed cell death, reducing formation of blood vessels to feed cancer cells, and changing the body's immune response.

   In addition, a laboratory study of colorectal cancer cells that do not produce COX-2, showed that treating these cells with celecoxib resulted in wide-ranging changes in protein production independent of COX-2. Following celecoxib treatment of these cells, researchers observed global changes in proteins involved in a variety of cellular functions, including metabolism, DNA and protein synthesis, protein folding, and the pattern of chemical decorations added to proteins. These results, published in the September 2006 issue of Cancer Epidemiology Biomarkers and Prevention, help explain the ability of celecoxib to prevent colorectal adenoma formation in the absence of COX-2 and could also potentially provide an explanation for the harmful effects of celecoxib observed when the drug is given at high doses.

3. What is celecoxib (Celebrex™)?
   

   Celecoxib (Celebrex^TM) is a COX-2 inhibiting drug manufactured by Pfizer, Inc., New York. Celecoxib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of both osteoarthritis and adult rheumatoid arthritis (diseases in which the joints are inflamed) in December 1998. Because scientific work suggested the potential for COX-2 inhibitors to prevent and treat cancer, the NCI, part of the National Institutes of Health (NIH), formed agreements with Pfizer to study this drug for the prevention and treatment of a variety of cancers.

4. What is the Adenoma Prevention with Celecoxib (APC) Trial?
   

   The APC Trial was a clinical trial to determine if the arthritis drug celecoxib, which inhibits the enzyme COX-2, reduces the occurrence of new adenomas (precancerous polyps) in the colon and rectum of people who have already had such a polyp removed. More than 2,000 men and women age 30 and older were randomly assigned to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo twice a day for three years. Participants taking celecoxib were found to have 33 percent to 45 percent fewer new adenomas than those taking a placebo. More than 90 centers, located mainly in the United States, but also in the United Kingdom, Australia, and Canada, took part in the trial. The trial enrolled participants from late 1999 through February 2002.

5. Why did NCI suspend the use of celecoxib in the Adenoma Prevention with Celecoxib (APC) Trial?
   

   The use of celecoxib in the APC Trial was suspended on Dec. 17, 2004, because an initial analysis by an independent Data Safety and Monitoring Board (DSMB) showed that the risk of major fatal and non-fatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) was 2.5 times higher for participants taking the drug compared to those on a placebo. Investigators in the APC Trial immediately suspended study drug use, although the participants were observed for the planned remainder of the trial.

6. What did analysis of the cardiovascular events on the APC Trial show?
   

   After the suspension of the trial in December 2004, an independent safety committee was established by NCI and the DSMBs of APC and another celecoxib study, Prevention of Spontaneous Adenomatous Polyps (PreSAP), to assess the cardiovascular risks caused by celecoxib in these two trials. In the APC Trial, the committee found that for patients taking 200 mg of celecoxib twice a day, the risk of cardiovascular death, heart attack, stroke, or heart failure increased 2.6 fold. The risk of these serious cardiovascular events increased 3.4 fold for patients taking 400 mg twice daily. PreSAP Trial participants took 400 mg of celecoxib once daily and experienced a slight (1.3 fold) but non-statistically significant increased risk of these adverse cardiovascular outcomes. The results were published in the August 31, 2006, issue of Circulation: Journal of the American Heart Association.

   In the APC Trial placebo group, 7 of 679 people (1.0 percent) experienced a serious cardiovascular event, including one cardiovascular death. In the group of people taking 200 mg of celecoxib twice a day, 18 of 685 people (2.6 percent) had a serious cardiovascular event, including five cardiovascular deaths. In participants taking 400 mg of celecoxib twice a day, 23 of 671 people (3.4 percent) had a serious cardiovascular event, including six cardiovascular deaths. In the PreSAP Trial, 12 of 628 participants (1.9 percent) in the placebo group had a serious cardiovascular event, including four cardiovascular deaths. In PreSAP participants taking 400 mg once a day, 23 of 933 people (2.5 percent) experienced a serious cardiovascular event, including four cardiovascular deaths.

   Participants in the APC Trial and the PreSAP Trial were allowed to take low-dose aspirin for cardiac protection (81 mg daily). Those who took low-dose aspirin had no different risk of serious cardiovascular events than those who did not take aspirin. However, the risk of a serious cardiovascular event was clearly higher in patients with a history of prior cardiovascular disease. In a combined analysis of the two trials, risk increased 1.8 fold for participants without cardiovascular event history and raised 2.3 fold for participants with a history of cardiovascular events.

7. Why did celecoxib increase the risk of these serious cardiovascular events?
   

   The reason for the increased risk is not clear. An analysis of the cardiovascular events from the APC Trial published in Circulation: Journal of the American Heart Association showed that study participants taking celecoxib had a significant increase in their blood pressure, which may have affected their heart disease risk. Researchers are working to understand the possible mechanisms so they may one day be able to determine who is at risk for these serious cardiovascular events and who might be able to take the drug safely. Researchers may investigate giving lower doses of celecoxib or different dose regimens (giving once instead of twice a day) to determine if this causes less cardiovascular risk while still providing pain relief or polyp prevention.

8. What did NCI do to notify patients on COX-2 inhibitor clinical trials about this risk for serious cardiovascular events?
   

   NCI notified all of the principal investigators of its sponsored trials involving COX-2 inhibitors about the increased cardiovascular risk seen in the APC Trial. The principal investigators were instructed to notify their institutional review boards (IRBs), data safety monitoring boards (DSMBs), and trial participants about this new information. NCI also required that the informed consent for these trials be revised to reflect this new information and that participants in the trials be re-consented (that is, asked to sign new consent forms with updated information about the risks and benefits of the trials).

9. What language was added to the informed consent for these trials?
   

   As recommended by NCI, the following language was added to revised informed consent forms: "Recently, an increased risk of heart attacks, strokes, and/or deaths resulting from heart or blood vessel disease has been reported among people taking celecoxib in clinical studies. Although the increased risk is two to three times greater than the risk of patients who did not take celecoxib, these serious adverse events are rare. Taking celecoxib may increase your risk of one of these events."

10. How many clinical trials were affected by this information? Were any trials closed?
    

    As of December 2004, NCI had about 50 prevention and treatment clinical trials with celecoxib of varying sizes, either open or in planning stages. The 26 prevention trials ranged in size from under 10 participants to more than 2,000 participants and were for the prevention of bladder, breast, cervical, colorectal, esophageal, head and neck, skin, lung, oral, and prostate cancers, as well as multiple myeloma. NCI collaborated with Pfizer on the majority of the large prevention trials. The 23 treatment trials were mostly small phase I or II clinical trials in cancers including pancreatic, breast, ovarian, non-small cell lung, and other solid tumors. The treatment trials included two randomized, phase III clinical trials in women with breast cancer.

    NCI did not close any trials, but required that the PIs notify their IRBs, DSMBs, and participants of the new information. In response to the new information, the PIs, IRBs, and DSMBs had to consider the risks and benefits of continuing each trial, including both ethical and practical issues. For instance, some trials were close to completion and the PIs chose not to continue the intervention and to move to analyze the data at that point. For many treatment trials, celecoxib was not the primary treatment being used, nor was its effectiveness the primary objective of the trial; for these studies, celecoxib was discontinued. Other trials, in which the duration or dosage of celecoxib was short or low, and the cohort was at increased risk for cancer, continued as they were designed.

    NCI continues to test celecoxib in 18 clinical trials for prevention and one clinical trial for treatment, as well as in numerous laboratory studies.

11. What other NCI-supported analyses are under way to better understand the potential risks of taking celecoxib?
    

    A panel of NCI-sponsored investigators is assessing the cardiovascular and cerebrovascular safety of celecoxib using data from six randomized, placebo-controlled trials testing celecoxib. Use of celecoxib was nearly complete, suspended, or dropped in all of these trials. By analyzing the cardiovascular and cerebrovascular safety data from these studies (and using consistent definitions of these events), a clearer picture of the risk profile of celecoxib may emerge. Analysis is ongoing and completion is expected in late 2006.

    This safety analysis includes data from:

    • Three trials sponsored by NCI

      • The Adenoma Prevention with Celecoxib Trial, a study of men and women with a prior colorectal adenoma.
      • The SelCel trial, a study of men and women with a prior colorectal adenoma.
      • The MA27 Breast Adjuvant Trial, a study of postmenopausal women with estrogen receptor-positive breast cancer.

    • Two trials sponsored by other institutes at the NIH
      • The National Institute on Aging's ADAPT trial, which includes men and women at risk for Alzheimer's disease.
      • The National Eye Institute's Diabetic Retinopathy Trial of people with diabetes and diabetic macular edema.

    • Pfizer-sponsored Pre-SAP trial of men and women with a prior colorectal adenoma.
    
    
12. Should people continue to use celecoxib for pain relief?
    

    The average dose of celecoxib used for pain relief in osteoarthritis and adult rheumatoid arthritis patients, 200 mg once a day, is less than all doses studied in the APC and PreSAP trials. Therefore, it is unknown if the cardiovascular risks seen in these trials of higher doses apply to the use of celecoxib at lower doses in these patients. The FDA has advice for consumers and physicians regarding pain relievers and celecoxib on its Web site at http://www.fda.gov on the Internet.

# # #

• National Cancer Institute Fact Sheet 2.11, Clinical Trials ¹
  (http://www.cancer.gov/cancertopics/factsheet/Information/clinical-trials)
• Colon and Rectal Cancer Home Page ²
  (http://www.cancer.gov/cancertopics/types/colon-and-rectal)

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Glossary Terms

A tumor that is not cancer. It starts in gland-like cells of the epithelial tissue (thin layer of tissue that covers organs, glands, and other structures within the body).

A process in which anything complex is separated into simple or less complex parts.

A laboratory experiment using animals to study the development and progression of diseases. Animal studies also test how safe and effective new treatments are before they are tested in people.

Having to do with reducing inflammation.

A disease that causes inflammation and pain in the joints.

A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention.

A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule.

The organ that stores urine.

The force of circulating blood on the walls of the arteries. Blood pressure is taken using two measurements: systolic (measured when the heart beats, when blood pressure is at its highest) and diastolic (measured between heart beats, when blood pressure is at its lowest). Blood pressure is written with the systolic blood pressure first, followed by the diastolic blood pressure (for example 120/80).

A tube through which the blood circulates in the body. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins.

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Having to do with the heart.

Having to do with the heart and blood vessels.

A drug that reduces pain. Celecoxib belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is being studied in the prevention of cancer.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

An increase in the number of cells as a result of cell growth and cell division.

Cancer that forms in tissues of the cervix (the organ connecting the uterus and vagina). It is usually a slow-growing cancer that may not have symptoms but can be found with regular Pap tests (a procedure in which cells are scraped from the cervix and looked at under a microscope). Cervical cancer is almost always caused by human papillomavirus (HPV) infection.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical trial.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

The longest part of the large intestine, which is a tube-like organ connected to the small intestine at one end and the anus at the other. The colon removes water and some nutrients and electrolytes from partially digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus.

Cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus).

In science, a substance that is made up of more than one ingredient.

An enzyme that speeds up the formation of substances that cause inflammation and pain. It may also cause tumor cells to grow. Some tumors have high levels of COX-2 and blocking its activity may reduce tumor growth. Also called cyclooxygenase-2 and prostaglandin-endoperoxide synthase 2.

Any of several diseases in which the kidneys make a large amount of urine. Diabetes usually refers to diabetes mellitus in which there is also a high level of glucose (a type of sugar) in the blood because the body does not make enough insulin or use it the way it should.

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

The amount of medicine taken, or radiation given, at one time.

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Data and Safety Monitoring Board. An impartial group that oversees a clinical trial and reviews the results to see if they are acceptable. This group determines if the trial should be changed or closed. Also called Data and Safety Monitoring Board.

Swelling caused by excess fluid in body tissues.

A protein that speeds up chemical reactions in the body.

The study of the patterns, causes, and control of disease in groups of people.

Having to do with the esophagus, the muscular tube through which food passes from the throat to the stomach.

A protein found inside the cells of the female reproductive tissue, some other types of tissue, and some cancer cells. The hormone estrogen will bind to the receptors inside the cells and may cause the cells to grow. Also called ER.

Having to do with beliefs about what is right and wrong in terms of how people behave. Also called moral.

An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The FDA also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called Food and Drug Administration.

An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The Food and Drug Administration also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called FDA.

The activity of the immune system against foreign substances (antigens).

The number of new cases of a disease diagnosed each year.

Redness, swelling, pain, and/or a feeling of heat in an area of the body. This is a protective reaction to injury, disease, or irritation of the tissues.

A process in which a person is given important facts about a medical procedure or treatment, a clinical trial, or genetic testing before deciding whether or not to participate. It also includes informing the patient when there is new information that may affect his or her decision to continue. Informed consent includes information about the possible risks, benefits, and limits of the procedure, treatment, trial, or genetic testing.

In medicine, a treatment or action taken to prevent or treat disease, or improve health in other ways.

Research done in a laboratory. These studies may use test tubes or animals to find out if a drug, procedure, or treatment is likely to be useful. Laboratory studies take place before any testing is done in humans.

One of a pair of organs in the chest that supplies the body with oxygen, and removes carbon dioxide from the body.

The total of all chemical changes that take place in a cell or an organism. These changes make energy and the materials needed for growth, reproduction, and maintaining health. They also help get rid of toxic substances.

A type of cancer that begins in plasma cells (white blood cells that produce antibodies). Also called Kahler disease, myelomatosis, and plasma cell myeloma.

The National Cancer Institute, part of the National Institutes of Health of the United States Department of Health and Human Services, is the Federal Government's principal agency for cancer research. The National Cancer Institute conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the National Cancer Institute Web site at http://www.cancer.gov. Also called NCI.

A federal agency in the U.S. that conducts biomedical research in its own laboratories; supports the research of non-Federal scientists in universities, medical schools, hospitals, and research institutions throughout the country and abroad; helps in the training of research investigators; and fosters communication of medical information. Access the National Institutes of Health Web site at http://www.nih.gov. Also called NIH.

NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the Federal Government's principal agency for cancer research. It conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://www.cancer.gov. Also called National Cancer Institute.

A federal agency in the U.S. that conducts biomedical research in its own laboratories; supports the research of non-Federal scientists in universities, medical schools, hospitals, and research institutions throughout the country and abroad; helps in the training of research investigators; and fosters communication of medical information. Access the NIH Web site at http://www.nih.gov. Also called National Institutes of Health.

A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

A drug that decreases fever, swelling, pain, and redness. Also called nonsteroidal anti-inflammatory drug.

By or having to do with the mouth.

Having to do with the ovaries, the female reproductive glands in which the ova (eggs) are formed. The ovaries are located in the pelvis, one on each side of the uterus.

Having to do with the pancreas.

The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

Medical doctor.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

A growth that protrudes from a mucous membrane.

Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.

A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant.

Growths that may become cancer that protrude from a mucous membrane.

In medicine, action taken to decrease the chance of getting a disease or condition. For example, cancer prevention includes avoiding risk factors (such as smoking, obesity, lack of exercise, and radiation exposure) and increasing protective factors (such as getting regular physical activity, staying at a healthy weight, and having a healthy diet).

Initial treatment used to reduce a cancer. Primary treatment is followed by other treatments, such as chemotherapy, radiation therapy, and hormone therapy to get rid of cancer that remains. Also called first-line therapy, induction therapy, and primary therapy.

A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal cells. The process of programmed cell death may be blocked in cancer cells. Also called apoptosis.

A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

The last several inches of the large intestine closest to the anus.

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.

An autoimmune disease that causes pain, swelling, and stiffness in the joints, and may cause severe joint damage, loss of function, and disability. The disease may last from months to a lifetime, and symptoms may improve and worsen over time.

A person who has studied science, especially one who is active in a particular field of investigation.

Cancer that forms in tissues of the skin. There are several types of skin cancer. Skin cancer that forms in melanocytes (skin cells that make pigment) is called melanoma. Skin cancer that forms in basal cells (small, round cells in the base of the outer layer of skin) is called basal cell carcinoma. Skin cancer that forms in squamous cells (flat cells that form the surface of the skin) is called squamous cell carcinoma. Skin cancer that forms in neuroendocrine cells (cells that release hormones in response to signals from the nervous system) is called neuroendocrine carcinoma of the skin. Most skin cancers form in older people on parts of the body exposed to the sun or in people who have weakened immune systems.

An abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.

An organ that is part of the digestive system. The stomach helps digest food by mixing it with digestive juices and churning it into a thin liquid.

In medicine, a loss of blood flow to part of the brain, which damages brain tissue. Strokes are caused by blood clots and broken blood vessels in the brain. Symptoms include dizziness, numbness, weakness on one side of the body, and problems with talking, writing, or understanding language. The risk of stroke is increased by high blood pressure, older age, smoking, diabetes, high cholesterol, heart disease, atherosclerosis (a build-up of fatty material and plaque inside the coronary arteries), and a family history of stroke.

A group or layer of cells that work together to perform a specific function.