From OncoLog, October 2007, Vol. 52, No. 10

Cancer Chemoprevention: A Prescription for Health?

by Dianne C. Witter

It’s an intuitive concept and, on the face of it, a simple one: Wouldn’t it be better to prevent cancer than to wait for a tumor to form and then launch an attack? That’s the philosophy behind the relatively new and quickly growing field of cancer chemoprevention—using medications or natural substances to initiate a pre-emptive strike that will prevent or delay cancer, rather than taking action only after a malignancy has developed.

The idea has found a receptive audience in the medical and scientific communities and among the public. Significant research successes have been achieved, and there is strong federal support for developing chemopreventive agents: more than 100 such drugs have been or are in early clinical trials supported by the U.S. National Cancer Institute, and just as many are in preclinical studies. In fact, the National Cancer Institute has established six consortia for phase I and II clinical trials of cancer chemopreventive agents; each consortium consists of international cancer research centers led by a U.S. center. A handful of agents have earned U.S. Food and Drug Administration approval for use as chemopreventives or are showing efficacy in phase III trials.

“Chemoprevention represents a very different way for physicians to think about cancer treatment, but one that is playing an increasingly important role in medicine,” said Waun Ki Hong, M.D., professor and head of the Division of Cancer Medicine at The University of Texas M. D. Anderson Cancer Center. “Cancer doesn’t begin with the appearance of a tumor; by the time a tumor has formed, the processes that lead to cancer have been developing for years, often for decades. The idea behind chemoprevention is to interrupt the process before it is too firmly entrenched.”

Early successes

In the early 1990s, Dr. Hong and colleagues demonstrated for the first time that cancer chemoprevention is possible in humans; they demonstrated that high-dose retinoids could stop or reverse the progression of oral precancerous growths and prevent new cancers in patients with a history of head and neck malignancies. These vitamin A analogs appear to suppress carcinogenesis through several routes, including inhibiting the growth and differentiation of premalignant and malignant cells.

The concept of chemoprevention is not new—a similar approach has been used for years to ward off heart disease. People at risk for heart attack are prescribed medications that treat hypertension and/or elevated cholesterol, significantly lowering their heart attack risk. The solutions are more complex for cancer, given its heterogeneity, but some important clinical strides have been made since Dr. Hong’s vitamin A findings less than two decades ago.

The first chemopreventive agent to reach the clinic—and possibly the best known—was tamoxifen, which has been shown to cut breast cancer incidence in high-risk women by 50%. It was followed by finasteride, found to reduce prostate cancer incidence by 25% in men at high risk for the disease. However, the large-scale trials that confirmed these benefits brought to light a troublesome issue: the drugs caused serious side effects in some patients. This is an issue of particular concern when considering long-term administration of a drug to healthy people who may or may not develop cancer.

Balancing act: risks vs. benefits

“This trade-off between agent risks and benefits has led to a new focus in cancer prevention—interventions for specific groups of people who will be most likely to benefit,” said Scott M. Lippman, M.D., professor in and chair of the Department of Thoracic/Head and Neck Medical Oncology and principal investigator of the phase I and II clinical trials of the cancer chemopreventive agents consortium headed by M. D. Anderson. “Subgroups of people who most likely will benefit from cancer prevention include people who are at a very high risk of developing cancer and/or at-risk individuals who have the highest potential sensitivity to an agent’s beneficial effect. Efforts to identify these target subpopulations will be crucial to the future of cancer prevention.”

Experience with celecoxib (Celebrex) and other COX-2 inhibitors illustrates the importance of the risk/benefit ratio in patient selection, according to Bernard Levin, M.D., professor emeritus and former vice president and head of the Division of Cancer Prevention and Population Sciences. “COX-2 inhibitors have shown impressive efficacy in the prevention of colon cancer and several other forms of cancer, but they also increase the risk of serious cardiovascular side effects,” Dr. Levin said. “We have to strike a very careful balance between the risks and the benefits, based on a number of factors.” Celecoxib is an anti-inflammatory drug that blocks the cyclooxygenase-2 enzyme, which is overproduced when cells are inflamed. An M. D. Anderson study showed a 36% reduction in the cumulative rate of colon adenoma development and a 50% reduction in larger, more dangerous adenomas with celecoxib. This study did not show an increase in cardiovascular harm, but other studies found celecoxib to double the incidence of cardiovascular harm. A parallel study led by Robert S. Bresalier, M.D., professor in the Department of Gastroenterology, Hepatology and Nutrition, using the COX-2 inhibitor rofecoxib, demonstrated a 25% reduction in new adenoma formation but a doubling of cardiovascular risk.

For now, celecoxib’s potential role in chemoprevention for people at high risk of colon cancer is still being studied—alone and in combination with other agents—and the drug has yet to be recommended for widespread use. However, it has been approved by the Food and Drug Administration for use as a chemopreventive agent in people who have the condition familial adenomatous polyposis (FAP), in which hundreds of precancerous polyps form in the colon and rectum. Untreated, the inherited condition almost invariably leads to colon cancer, so the benefits of celecoxib for this high-risk population easily outweigh the risks. A clinical trial at M. D. Anderson is evaluating the safety and efficacy of using celecoxib to delay or prevent the need for a colectomy in children with FAP. Another trial at the institution is testing whether celecoxib can repair precancerous lung damage in current and former smokers.

Careful patient selection to minimize side effects is key in breast cancer chemoprevention as well, said Therese Bevers, M.D., associate professor and medical director of M. D. Anderson’s Cancer Prevention Center. A large multicenter study last year showed the osteoporosis drug raloxifene to be as effective as tamoxifen in preventing estrogen-receptor– positive, invasive breast cancer—both agents reduced the incidence of breast cancer by 50% in high-risk women—but raloxifene had fewer side effects. Both drugs are selective estrogen receptor modulators, which block the effects of estrogen, an important contributor to 80% of breast cancers.

“Assessing a woman’s risk of developing breast cancer and understanding how tamoxifen and raloxifene’s side effect profiles compare is key in determining which to prescribe for a given woman—there isn’t one right answer for everyone,” explained Dr. Bevers. With tamoxifen, there is an increased risk of serious side effects such as uterine cancer, blood clots, and stroke—however, tamoxifen also decreases the risk of non-invasive breast cancer, which raloxifene does not do. A woman’s menopausal status, her bone health, and other issues are also factors that should be weighed in the decision of whether to prescribe tamoxifen or raloxifene.

On the horizon

Now under investigation for their potential as breast cancer chemopreventive agents are anastrozole and exemestane. These are aromatase inhibitors, another class of estrogen blockers, which are approved to treat metastatic breast cancer in post-menopausal women.

“There is now some very solid evidence that aromatase inhibitors may inhibit or prevent breast cancer more effectively than tamoxifen or raloxifene, and a number of studies looking at this are ongoing,” said Dr. Bevers.

M. D. Anderson researchers have also been involved in studies of other promising chemoprevention agents, including:

Erlotinib, which inhibits tumor growth by targeting the human epidermal growth factor receptor. A major study of erlotinib to prevent oral cancer in people at a high risk of developing this disease is under way at M. D. Anderson and other U.S. cancer centers. A molecular marker, loss of heterozygosity at certain critical chromosomal regions, signals increased risk. (Please see related story at right.)

Low-dose baby aspirin, which was shown to be modestly effective as a colon cancer chemopreventive. Dr. Bresalier was a leader of this national trial, in which baby aspirin reduced the number of new precancerous colon polyps by 19% in individuals with a history of these lesions. Baby aspirin has been shown to have cardiovascular benefits as well, although it has also been associated with an increased risk of upper gastrointestinal bleeding and stroke.

Curcumin (found in the curry spice turmeric), which has shown dramatic anticancer results in preclinical studies owing to its significant anti-inflammatory properties. Curcumin has been used for thousands of years in the diets of people in the Middle and Far East and therefore is believed to have a low probability of serious side effects.

Calcium compounds, which may inhibit tumorigenesis in the colon through their effect on dietary lipids, according to laboratory studies. A study in humans showed a 19% reduction in adenoma formation in individuals taking calcium supplements. M. D. Anderson researchers are looking at the possibility of combining calcium with vitamin D in new clinical trials.

As encouraging as some of the research has been, M. D. Anderson’s chemoprevention experts stress that most current chemoprevention studies test promising agents in people who are at higher risk of developing cancer, such as former smokers, as a first step in predicting whether these agents will help those who are at average risk.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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