FDA Approves Gleevec to Treat Leukemia

FDA Approves Gleevec to Treat Leukemia

Published: May, 2001

Chronic myelogenous leukemia (CML), one of four main types of leukemia, strikes about 5,000 people every year. On average, patients live 3-4 years after receiving a diagnosis of CML. Last week, the FDA approved Gleevec (imatinib mesylate, also known as STI 571) as an oral treatment for CML.

Gleevec has been shown to substantially reduce the level of cancerous cells in the bone marrow and blood of treated patients. In clinical trials, 90 percent of patients in the first phase of CML went into remission within the first six months of taking Gleevec. Of patients in the second phase of CML, 63 percent went into remission with Gleevec. The drug produced few side effects.

Additional studies need to be done to determine how long the effects of this drug last, whether patients become resistant to the drug, and, most importantly, whether Gleevec can actually extend a patient's life.

Still, the results are promising. Currently, the only cure for CML is a bone marrow transplant. Even if a patient is lucky enough to find a marrow donor match, the procedure is successful less than 2/3 of the time. Interferon, a widely used treatment for CML, can extend a patient's life for up to two years, but it has several serious side effects and does not cure the disease. Gleevec may be used in patients in the early stage of CML who do not respond to interferon therapy, and in patients in the later stages of CML.

Most people with CML have a chromosomal abnormality, known as the Philadelphia chromosome, in which portions of two different chromosomes are switched. The result is the creation of an abnormal protein that allows the uncontrolled production of white blood cells, which can interfere with the function of other organs in the body. Gleevec blocks a signal sent out by the abnormal protein, thus blocking the rapid growth of white blood cells.

The FDA's approval of the drug came after a surprisingly short 2½ months. Most drugs that, like Gleevec, are granted a priority review, take six months to approve. The approval was based on three separate studies that involved about 1,000 patients with CML. The drug has generated enthusiasm in the medical community because it targets a specific, cancer-causing protein, without damaging other cells.

Scientists at an American Society of Clinical Oncology meeting announced earlier this month that Gleevec had also produced remission in 180 patients with advanced cases of an intestinal cancer known as gastrointestinal stromal tumor (GIST). Until now, GIST cancers have been incurable; GIST patients normally die within one year of receiving their diagnosis.
May 2001 Update

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Good News for Breast-Fed Babies

Breast-feeding has been linked to many advantages, including fewer earaches, colds, and asthma attacks. Now, a large trial involving almost 16,500 mother-infant pairs has shown even more benefits of breast-feeding. The study demonstrated that long-term, exclusive breast-feeding significantly decreases the risk of gastrointestinal tract infections and atopic eczema during a child’s first year of life.

Published in the Journal of the American Medical Association, the study involved mothers from the former Soviet republic of Belarus. To avoid a conflict of interest, given the advantages of breast-feeding that are already established, the program studied mothers who breast fed for a long time compared to mothers who breast fed for a short time then switched to bottle feeding. Some hospitals were randomly chosen to promote breast- feeding, through programs involving counseling from doctors and midwives; other hospitals, which served as a control group, provided the usual obstetric care. After 12 months, nearly 20% of the infants who were part of the breast-feeding program were still nursing, compared to 11.4% of the control group.

In the first year, only 9% of the infants in the breast-feeding program had one or more gastrointestinal infection compared to about 13% of the control group. In addition, 3% of the breast-fed infants developed atopic eczema (a scaly, allergy-associated skin irritation), compared with 6% of the other babies.

The World Health Organization recommends only breast milk for the first four to six months, and recommends that breast-feeding (in combination with formula) continue until 2 years of age. The American Academy of Pediatrics recommends breast milk alone until 6 months, and breast-feeding plus formula until 12 months old. This study suggests that breast-feeding exclusively for the first year could provide greater health benefits to the child.
February 2001 Update

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Manufacturer Voluntarily Withdraws Lotronex

Lotronex (alosetron) is a prescription medication used to treat diarrhea-predominant irritable bowel syndrome in women. Last month, the Food and Drug Administration issued important safety warnings for the use of this drug based upon reports of intestinal damage due to impaired blood flow to the intestine (ischemic colitis) and complications of severe constipation (bowel obstruction and rupture) in patients on Lotronex.

On November 30, the manufacturer (Galaxo Wellcome) informed the FDA that it will voluntarily remove this drug from the market. Any patient currently taking Lotronex should contact her physician to discuss other treatment options. For more information, please visit the Center for Drug Evaluation and Research Web page on Lotronex or call 888-INFO-FDA (888-463-6332).

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Benefits of COX-2 Inhibitors for Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a condition in which an inherited mutation in the APC (adenomatous polyposis coli) gene results in the formation of multiple polyps in the mucous membrane of the large intestine. As early as puberty, hundreds of polyps may be evident in people with FAP and the presence of these growths practically ensures that these individuals will develop colon cancer. The risk is so close to 100% that many FAP patients have their large intestines removed (colectomy) to protect them from this very serious diagnosis.

The enzyme cyclooxygenase-2 appears to play a role in the growth of polyps. It makes sense then, that researchers would be interested in seeing whether COX-2 inhibitors — a new class of nonsteroidal antiiflammatory medication that suppresses cyclooxygenase-2 — might provide some protection against colon cancer. In fact, data from a study conducted at the M.D. Anderson Cancer Center (Houston, TX) and St. Mark's Hospital (London) suggest that 400 mg of the COX-2 inhibitor celecoxib (Celebrex), taken twice daily can suppress colorectal adenomas in people with familial adenomatous polyposis.

Researchers studied 77 FAP patients between the ages of 18 and 65 years old. At the start of the trial, these volunteers were tested for the APC gene mutation and also underwent endoscopy. During the procedure, physicians identified areas of the rectum and/or colon with a high density of polyps so they could compare the degree of polyposis before and after treatment with celecoxib. Investigators then randomly assigned the study subjects to one of three protocols: 1) 400 mg of celecoxib twice daily, 2) 100 mg of celecoxib twice daily, or 3) placebo. The three groups were followed for six months. Fifty-three percent of the individuals taking 400 mg of celecoxib experienced a 25% or more reduction of the average number of colorectal polyps. Only 31% of patients taking the 100 mg dose (and a mere 7% of the placebo group) showed a comparable benefit. In addition, the 400 mg group experienced significant improvement in polyposis throughout the large intestine (including the rectum, ascending colon, and cecum, and in the transverse descending, and sigmoid colon). The patients in the 100 mg group and placebo group did not show similar improvement.

Right now it is unclear whether prolonged treatment with celecoxib, or a medication like it, could limit the extent of polyps, replace or delay the need for colectomy, or perhaps keep polyps from becoming cancerous. However, this data suggest that celecoxib could be used along with current treatments to suppress the formation of polyps in patients who are waiting to undergo surgical removal of the intestine and in cases where the rectum is not removed along with the colon.

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High-Fiber Diet Doesn't Lower Colon Cancer Risk

Observational studies have suggested a link between diet and the risk of developing colon cancer. Consuming lots of red meat and fatty foods has been associated with a higher risk of this disease, while a diet high in fiber and fruits and vegetables seemed to lower that risk. Two recent studies in the New England Journal of Medicine suggest otherwise. In these clinical trials, researchers examined the role diet might play in the development of adenomatous polyps in the colon. (These growths are the precursors of most colon cancers.)

The first study followed 2,079 men and women who had had such polyps removed within the previous six months. These volunteers were assigned to one of two groups. The first group ate a diet that was low in fat (20% of total calories), high in fiber (18 grams of fiber per 1,000 calories of food consumed), and included 3.5 servings of fruits and vegetables per 1,000 calories of food eaten. Researchers provided the second group with a pamphlet on healthy eating and told these patients to follow their normal diets. Both groups were followed for roughly four years and had a colonoscopy (examination of the colon) once a year during this period. Surprisingly, the rate of recurrence of large polyps did not differ significantly between the two groups, leading study investigators to conclude that a low-fat, high-fiber diet rich in fruits and vegetables did not help prevent recurrence of these precancerous polyps.

The second study focused on cereal fiber, specifically wheat bran. Again, study participants included only patients who had had adenomatous polyps removed within three months of the trial's start. Of the 1,303 people who completed the study, investigators assigned 719 to a high-fiber diet (13.5 grams per day) and 584 to a low-fiber diet (2 grams per day). At the end of three years, the polyp recurrence rate was 47% in the high-fiber group and 51.2% in the low-fiber group. Again, not a significant difference.

Does this discouraging news about fiber mean people should abandon whole grains and fruits and vegetables? No. First, it is important to remember that these studies looked at whether or not the polyps returned within four years, but couldn't really assess whether diet may or may not play a role in preventing those polyps from turning into cancer. Observational studies do show that people who eat diets higher in fiber and fruits and vegetables have a lower risk of colon cancer and that when their diets change, so does their level of risk. But researchers are not yet sure why. Second, these dietary elements are important for general health and have been shown to reduce the risk of heart disease and diabetes. So make sure you eat enough fruits and vegetables and whole grains.

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Cox-2 Inhibitors: The Latest Generation of Antiinflammatory Drugs

Pain relief has come a long way. Aspirin has been used for over one hundred years to quell aches and pains and relieve fever. Its ability to interfere with the blood-clotting cells called platelets, makes it an important preventive measure in reducing heart disease risk and some studies suggest aspirin's anti-inflammatory properties might help lower colon-cancer risk. You can find this wonder drug in virtually every home medicine cabinet.

A younger class of antiinflammatory medications is nonsteroidal antiinflammatory drugs (NSAIDs). Early NSAIDs such as ibuprofen (Motrin) and naproxen (Naprosyn, Aleve) were once available only by prescription. Today you can get them over-the-counter and they are widely used for headaches, muscle aches, and menstrual cramps. These NSAIDs inhibit two enzymes. One of those enzymes, Cox-2, is related to inflammation, and naturally, that action is what gives NSAIDs their antiinflammatory properties. The other enzyme, Cox-1 protects the lining of the stomach and intestines. The inhibition of this enzyme is what contributes to the gastrointestinal side effects of these drugs. Now entering the arena is a new, more selective, class of antiinflammatory drugs called Cox-2 inhibitors. These drugs inhibit only the Cox-2 enzyme, and interestingly do not affect blood clotting, as does aspirin.

The premier Cox-2 inhibitors are Celebrex (celecoxib) and Vioxx (rofecoxib), which have become two of the best-selling prescription drugs of all time. To date, most of the evidence suggests that Cox-2 inhibitors are easier on the lining of the stomach and intestine than other nonsteroidal antiinflammatory drugs like ibuprofen and naproxen.

Clinical trial results recently reported support the claim that Cox-2 inhibitors are indeed gentler drugs. The Journal of the American Medical Association (JAMA) published two of these studies. The first compared the use of Celebrex and naproxen in patients with symptomatic rheumatoid arthritis. Study volunteers took 100 mg, 200 mg, or 400 mg of Celebrex twice a day; or 500 mg of naproxen twice a day; or a placebo twice a day. At the end of the 12-week treatment period, the researchers used an endoscope, a fiber-optic viewing tube to look for ulcers (small sores) in the stomach and the duodenum, the first few inches of the small intestine. The fraction of patients who had "endoscopically determined" ulcers was roughly the same, 4%-6%, in both the placebo and the Celebrex groups, regardless of the dosage. The researchers saw ulcers in 26% of the naproxen patients. The second study, an analysis of eight Vioxx clinical trials, found that users of the once-a-day Cox-2 inhibitor had fewer ulcers than NSAID users.

Gastroenterology published results of a trial similar to the rheumatoid arthritis study in JAMA: Patients with osteoarthritis were treated with Vioxx for 12 weeks and then had their stomachs and duodenums endoscopically searched for ulcers. Again, the ulcer rates in the Vioxx and placebo groups were comparable, ranging from 4-10%, whereas the ulcer rate among the patients who took ibuprofen was 28%.

Do these data mean everyone should toss out the Motrin and head to the doctor's office for a prescription? Not yet. Cox-2 inhibitors have fewer side effects, but they are really no more effective than aspirin and the other NSAIDs at reducing inflammation and the pain it causes. And the risk of ulcers from occasional NSAID use, while real, is small. Even among rheumatoid arthritis sufferers, the likelihood of developing an NSAID-related ulcer is only about 0.4%. What's more, it is unclear just how medically significant the small ulcers found by endoscope in these clinical trials really are. It wouldn't make any sense to take a Cox-2 inhibitor for the occasional headache, trick knee, or menstrual cramps.

Right now, most experts suggest Cox-2 inhibitors might be reserved for patients most at risk for developing ulcers: people over age 75 with a prior history of ulcer or gastrointestinal bleeding. These drugs are very expensive and, despite their good track record with ulcers, they are not completely free of side effects. For example, in the Vioxx study in JAMA, 23.5% of people taking the drug on a daily basis reported dyspepsia compared with 25.5% of people taking a daily NSAID.

Just as aspirin has evolved from analgesic to preventive, it appears its sister drug, Celebrex might also help prevent colon cancer. In December 1999, the U.S. Food and Drug Administration approved Celebrex as a first-line drug to reduce the number of intestinal polyps in patients with familial adenomatous polyposis (FAP). Patients with this rare genetic disorder develop large numbers of intestinal polyps and as a result are at very high risk for colon and rectal cancers at an early age.

The National Cancer Institute's Division of Cancer Prevention conducted a small study involving 83 patients. Researchers found that in patients taking 400 mg of Celebrex, the number of intestinal polyps fell by 28%. Study volunteers taking a placebo experienced only a 5% reduction in the number of polyps. It is not certain whether polyps will stay away after a person stops taking Celebrex nor has it been proven that reducing the number of polyps will eliminate the risk of cancer. Celebrex does not supplant standard care for this condition, which may involve surgical removal of much of the lower intestine and careful monitoring of any existing polyps.

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The Role of Colonoscopy in Colon Cancer Screening

Colon cancer is the second leading cause of cancer deaths in the United States. Despite its prevalence, researchers are uncertain how best to screen people for the disease. Typically, physicians perform sigmoidoscopy on their patients who have no symptoms of colon cancer. This procedure, however, allows doctors to view only the lower third of the colon, so cancer can go undetected. Colonoscopies, which allow the physician to view the entire large intestine, are usually reserved for patients with positive screening results in the lower colon or those with a higher-than-average risk for colon cancer.

The thought of a colonoscopy may leave some people squeamish, but two recent studies suggest the procedure deserves more attention. Both studies investigated the risk of tumors in the upper portion of the colon in patients with and without abnormal growths in their lower colons. The first study, which involved colonoscopies performed on over 3,000 participants, found that patients with growths in the lower portion of the colon were more likely to have tumors in the upper portion of the colon than patients without growths in the lower colon. However, over half of the patients with growths in the upper colon did not have any abnormal growth in the lower colon. This suggests that the majority of tumors in the upper colon would not be detected if colonoscopies were reserved only for those patients with positive results from sigmoidoscopies.

The second study, involving nearly 2,000 participants, echoed the above results that stressed the role of colonoscopies in detecting colon cancer. In addition, this study found that older age and male sex, as well as growths in the lower colon, were risk factors for cancer in the upper portion of the colon.

Keep in mind that colonoscopies involve more bowel preparation (which includes a clear diet and laxatives) and intravenous sedation. Colonscopy also carries a slightly higher risk of complications than does flexible simoidoscopy. For these reasons, colonoscopy is not necessarily always the first choice for screening for every patient.

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Young Men and Women with Anorexia Nervosa or Inflammatory Bowel Disease at Greater Risk for Osteoporosis

We usually think of osteoporosis as a condition that primarily strikes older women as a result of the aging process. However, certain disorders and medications can also lead to bone loss in younger people, both male and female. Two recent studies from the Annals of Internal Medicine show that bone loss is significantly more likely to occur in young men and women suffering from anorexia nervosa or inflammatory bowel disease than in the general population.

Researchers evaluated the loss of bone tissue in women with the eating disorder anorexia nervosa by measuring bone mineral density at different regions of the skeleton. More than 90% of the women had significant bone loss at one or more skeletal regions. Depending on the region measured, this bone loss put 13–24% of the women at risk for fractures. Physicians commonly prescribe estrogen to slow bone loss in postmenopausal women. Estrogen is also given to women who do not menstruate regularly, which is the case for many women with anorexia. Interestingly, in this study, women who used estrogen experienced the same levels of bone loss as women who did not. The researchers theorized that poor nutrition might decrease the effectiveness of estrogen in preserving bone. The results also showed that current weight, independent of other factors, is the best predictor of bone density in anorectic women.

In a separate study, researchers sought to determine the risk of bone fractures associated with osteoporosis in patients with inflammatory bowel disease. Results of the study showed that patients with the disease had a 40% greater risk of hip, spine, wrist, or rib fractures than healthy people. Researchers are still uncertain what factors contribute to bone loss in these patients. They speculate that corticosteroids, which are used to treat inflammatory bowel disease, may play a role, and that cigarette smoking, lower levels of sex hormones, and low dietary intake of calcium and vitamin D may also contribute to bone loss.

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Study Links Smoking to Colorectal Cancer

Lung, mouth, and bladder cancers, among others, are well established as cancers caused by cigarette smoking. A recent study from the American Cancer Society, published in the Journal of the National Cancer Institute shows that cigarette smoking also raises the risk of dying from colorectal cancer, which is cancer of the colon or rectum. Indeed, the study notes that as many as 12% of colorectal cancer deaths in the United States may be associated with smoking.

Researchers analyzed data from 312,332 men and 469,019 women enrolled in the Cancer Prevention Study II. They found that for both men and women, risk of colorectal cancer increased after 20 or more years of smoking. Among men, current smokers were 31% more likely to die from colorectal cancer than nonsmokers; female smokers were 41% more likely than nonsmokers to die from the disease. The risk of death from colorectal cancer rose with the number of years cigarettes were smoked, the number of cigarettes smoked per day, and the number of packs smoked over the years. In addition, the risk of death was higher the younger a person was when he or she started smoking. The association was not confined to cigarette smoke. Those who smoked pipes or cigars also faced a significantly increased risk of death from colorectal cancer.

The bright spot of the study was that it showed a benefit from quitting. Twenty years after quitting, men's risk of colorectal cancer death returned to normal. And women who had stopped smoking 10 or more years earlier had the same risk as nonsmokers. The take-home message: If you smoke, stop. If you don't smoke, don't start.

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