An Ounce of Prevention ...
M. D. Anderson GI Researchers Study Chemoprevention

The old adage "An ounce of prevention is worth a pound of cure" is alive, well, and in practice at The University of Texas M. D. Anderson Cancer Center.

Researchers in the center's Department of Gastrointestinal Medicine and Nutrition are studying chemoprevention and its effect on Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colon Cancer, both forms of hereditary colon cancer.

Chemoprevention can be defined as an attempt to use natural and synthetic substances to intervene in early or precancerous stages. Chemoprevention researchers use nutritional, pharmacological, or lifestyle changes to halt cancer, or as a preventive strategy for people with a high risk of cancer.

Dr. Patrick Lynch, an associate professor of gastroenterology and Dr. Frank Sinicrope, interim chairman and associate professor in the department, are leading the charge. Both Drs. Lynch and Sinicrope are principal investigators on several studies researching the technique.

Dr. Lynch said there are two challenges with putting chemoprevention studies together: A) Does it work and how do we measure that? For example: Does it decrease cancer mortality; decrease invasive cancer; decrease precancerous pathologic lesions, such as polyps; or does it just affect a laboratory measure that appears to go along with the precancerous/cancerous entity?, and B) What are the side effects?

"When we're talking about something that is simply preventive, and trying to prevent something that may not happen anyway, the doctor and patient can't be willing to accept as many side effects," said Dr. Lynch.

Dr. Lynch and staff credit Dr. Ernie Hawk, chief medical officer of the National Cancer Institute's GI and Other Reseach Group, Cancer Prevention Division, for spearheading efforts in gastrointestinal chemoprevention.

"In the area of chemoprevention, the NCI has really taken a leadership role. In fact, most of the studies that we're engaged in were actually conceived by the NCI," Dr. Lynch said.

Since the NCI does not have the quantity of patient subjects available for clinical trials, they collaborate with various investigative sites, including M. D. Anderson. Often, there are several institutions involved with the trials, as well as pharmaceutical companies who are developing new drugs.

"New drug development is a fairly hot field in the area of chemoprevention, because there are drugs and substances around that have been shown by epidemiologic investigations to reduce risk of cancer," Dr. Lynch said.

Take, for example, the area of GI cancer. Epidemiologists are the ones who really get things started. They look at scenarios like the fact that colon cancer is virtually unheard of in sub-Saharan Africa, but very common in the United States, and they become detectives, of sorts. They look at factors that are different, such as diet. Then they develop hypotheses they can test around the different factors they observe. They try to find reasonably effective ways whereby a sample population can be taking a substance to reduce the risk of polyps or cancer.

"For example, companies come along trying to develop agents that do the good things that asprin and aspirin-like nonsteroidal anti-inflammatory drugs do, but without the side effects," said Dr. Lynch. "That's where a partnership develops. The NCI wants to foster studies trying to reduce the risk of polyps and cancer. Drug companies have new drugs in the pipeline that are intended to accomplish that, but with a safety profile that makes it reasonable for them to use in prevention, as opposed to treatment trials."

Groups like M. D. Anderson then come on board, because they have, or can find, a patient population that meets the needs of the clinical trial.

Dr. Lynch and colleagues at M. D. Anderson and St. Mark's Hospital in London have recently completed a study on the effects of the drug Celebrex in patients with diagnosed FAP. This was the first NCI contract in GI chemoprevention awarded at M. D. Anderson, and began in 1996. It was a placebo-controlled, double-blind randomized trial. Patients were assigned to either a placebo, or one of two doses of Celebrex for six months, which, interestingly enough, is now on the market for arthritis. The paper on this study was published in the New England Journal of Medicine in 2000, and showed significant polyp reduction in the group on high-dose Celebrex.

Based on the Celebrex trial's findings, several large trials are now being conducted at other sites, both in the United States and internationally, to see if the same drug shown to be effective in FAP, can actually reduce the risk of adenomas in the general population.

Whereas familial polyposis affects approximately only one in 10,000 Americans, current statistics show that adenomas could affect 25 to 50 percent of all Americans at some point in their lives.

So, why not study the more common problem first?

The answer lies in the way the trials have to be conducted. To evaluate sporadic adenomas, 1,500 to 2,000 subjects may need to be enrolled and followed for five years or more.

"The enormity of such effort requires that some homework be done first. That's where our work comes in," said Dr. Lynch.

Sherri Patterson, program director of GI chemoprevention at M. D. Anderson, and a graduate student at The University of Texas School of Public Health at Houston, said the objective of these studies is to find a surrogate endpoint biomarker. She said they look for a sign that is not necessarily a polyp or prepolyp, and monitor it.

"You can shorten the duration of the study and follow the biomarker to see if or when you can prevent or cause a change with your intervention," Patterson said.

Unlike more traditional cancer treatments, such as chemotherapy or radiation therapy, Dr. Lynch said chemoprevention prevents cancer, rather than curing it.

"Cancer prevention, whether due to a lifestyle change such as stopping smoking or a change in diet, or through chemoprevention, prevents a lot more cancers than ever get cured with chemotherapy," Dr. Lynch said. "Chemotherapy tends to be ineffective for a lot of cancers, anyway."

He said cure rates for advanced colon cancer are maybe in the range of 5 to 10 percent at best. "If you can only cure 5 percent with an advanced stage of the disease, making even a small impact from the prevention standpoint is going to save a lot of lives."

In another study nearing completion, subjects with HNPCC were enrolled. Nancy Viscofsky, a senior reseach assistant and study coordinator, has worked closely with Dr. Lynch on the trial.

"I can count a dozen or so people, that if they hadn't enrolled in a study, they would have been dead," said Viscofsky. "They just didn't know anything was wrong."

In order to become a trial participant, a genetic counselor must first predetermine if a patient has a very high probability of developing hereditary cancer.

"The genetic counselors are an integral part of our study team," said Patterson. "The patients who are seen for these trials must have a genetic diagnosis. Genetic testing is a very complicated issue, so the genetic counselor explains the process of genetic testing and the test results to the patient."

Most patients who come to M. D. Anderson have cancer, but the usual institutional population isn't always the population that these studies are looking for. Some chemoprevention studies actually exclude those who have already had cancer.

In many of the chemoprevention clinical trials, a number of services are provided for the patients, and the team believes in providing comprehensive care, Patterson said.

"We rarely bill an insurance company, we provide for endoscopic surveillance and study medication, and usually provide allowance for travel and accommodations."

In most of these trials, participants undergo either a colonoscopy or a flexible sigmoidoscopy to look at all or a portion of their colorectum. They may also have an esophagogastroduodenoscopy, or EGD, to look at their esophagus, stomach and the first part of the small intestine, called the duodenum. Another procedure sometimes used is a magnifying chromoendoscopy, where a washable dye spray is applied to the colon and viewed with a magnifying colonoscope. It enables the doctor to see precursors to polyps that the naked eye would otherwise miss.

"Dr. Lynch was the earliest pioneer at M. D. Anderson to do a magnifying chromoendoscopy," said Patterson. "He has clearly mastered this technique, and has mentored others on this procedure."

Patterson said she finds enormous satisfaction in her work, both with the studies and with what the team is able to achieve.

"I am very enthusiastic about these studies - we have a wonderful team, well-designed trials and generous support from the National Cancer Institute, Division of Cancer Prevention. Dr. Ernie Hawk is a wonderful advocate of chemoprevention," said Patterson. "If the NCI didn't provide funding, we wouldn't be able to do these kinds of studies."

For more information on chemoprevention studies, a free quarterly newsletter, Generation to Generation, is available. With a circulation of nearly 5,000, it publicizes colorectal news from around the globe. Web sites that provide valuable information on chemoprevention and colon cancer include:

National Cancer Institute - Designated Cancer Centers Clinical Trials http://cancertrials.nci.nih.gov/finding/centers/index.html

The Division of Cancer Prevention, National Cancer Institute http://dcp.nci.nih.gov/

The Collaborative Group of the Americas on Inherited Colorectal Cancer http://www.fascrs.org/ascrs-cancer-reg.html

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©2006 Texas Medical Center

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