COLORECTAL CANCER: ON THE FRONTIER
By Florence Isaacs
Imagine having your meals at a medical facility twice a day, every day, to benefit medical science. Groups of volunteers will be doing exactly thatand moreat UMDNJ this spring as they participate in innovative research by Steven J. Shiff, MD, on strategies to prevent colorectal cancer, the second leading cause of cancer death in the U.S. (after lung cancer). In a series of short-term controlled studies, Shiff, an associate professor of medicine at UMDNJ-Robert Wood Johnson Medical School (RWJMS), will examine the anti-cancer effects of diet and drugs on the colon. "It's a different way of doing nutritional science that we hope will help cut the toll of this disease," says Shiff, who is also a resident member of The Cancer Institute of New Jersey and Unilever Chair for the study of diet and nutrition in the prevention of chronic disease. His work is particularly significant for New Jersey, which ranks fourth among states in colorectal cancer deaths.
Although earlier diagnosis and treatment advances have reduced the death rate in the last 20 years, colorectal cancer remains a killer. An estimated 56,700 Americans died of the disease in 2001, and preventing it in the first place could make a dramatic difference. While most colon cancers are attributed to dietary factors, research on the nutrition link has been controversial. Shiff's approach aims to expand current knowledge.
"Cancer-related nutrition research usually takes many years, and consists of observational or epidemiological studies of large groups of people. They commonly measure cancer incidence and mortalityrather than experimentally test substances that may prevent cancer. Because research which involves such long-term testing is expensive and difficult, it isn't being done," explains Shiff.
In contrast, short-term research that takes months, not years, is far less costly. It involves small groups of people, and examines critical, yet easier-to-measure factors, such as whether certain foods and plant-based compounds affect the lining of the intestines, where cancer develops.
The Nutrition Connection
An estimated 50 to 70 percent of colon cancers are linked to nutrition. High calorie intake, red meat consumption, and a high fat diet have been associated with increased risk for the disease. Dietary factors are also believed to play a role in preventing colon cancer. Fiber, calcium, folic acid, Vitamins A, C, D and E, and substances found in fruits and vegetables are among the compounds which may contribute to anti-cancer activity. While links have been established in animal studies, they have been difficult to prove in humans. Results of epidemiological studies have been mixed, causing confusion.
Shiff's research will investigate several promising plant-derived compounds. His first study, which begins in March, will look at Quercetin, a yellow substance found in apples, cranberries, and onions, and sulindac, a nonsteroidal anti-inflammatory drug (NSAID). "Some of the best evidence suggests NSAIDs prevent cancer development, especially in the colon," observes Shiff.
For 10 weeks, he will work with three groups of 15 people each, all of whom will eat a carefully designed and controlled diet. One group will also receive Quercetin; a second group will take sulindac; and a control group will receive no treatment.
"I'm pursuing the hypothesis that the total number of cells in the lining of the intestine is tightly regulated, roughly governed by the amount of cell renewal (proliferation) and cell loss (cell death). Cancer involves, in part, disrupted regulation of the number of cells. Increased proliferation (and/or decreased cell loss) tips the balance toward cancer development. If the substances being studied significantly reduce cell proliferation or increase cell death, they may prevent the development of cancer," says Shiff, who began his research at Rockefeller University in New York, and came to UMDNJ in 2001.
A Demanding Regimen
The study process begins with interviews and examinations of volunteers by Shiff's research team. Laboratory tests and evaluations ensure that participants are healthy and free of any hidden conditions (such as polyps, premalignant growths that can develop into cancer, or inflammation in the intestines) which require treatment and/or might interfere with the research. A flexible sigmoidoscopy, which examines the rectum and lower colon for abnormalities, follows. The test is painless and does not require sedation. Next comes a biopsy of the inside lining of the intestine to collect baseline tissue samples, which is also painless. Nerve receptors that feel pain are not located in this area.
During the study, volunteers will eat two meals a day at the clinical research center at RWJMS. They can also take a third, prepackaged meal (usually lunch) off site to eat at the office or elsewhere. "The hospital will prepare the foods for us and we'll dole out everything that goes in their mouths," notes Shiff. "We want to control what they eat, since foods and other compounds affect the digestive system in different ways. We need to be able to measure what we need to in the intestines with precision." No dinner with friends unless participants abstain from food and simply socialize. They can ingest only water or decaffeinated diet soda outside of prescribed meals. (Caffeine, which may influence cancer development, could affect measurements.)
After a few weeks on the diet, volunteers undergo a second sigmoidoscopy and biopsy, which is compared to the baseline to see whether the diet affects the lining of the intestine. Then people are randomly assigned to the three groups. Those taking Quercetin or sulindac receive their first pills; those in the control group take nothing. Two more sigmoidoscopies and biopsies will be re- peated at four week intervals to check the effects of the compounds and compare them to the control group and to the baseline.
Isn't a few weeks a short period of time in which to measure such effects? "You would think so, but the kinds of things we're measuring are changing all the time," says Shiff. "The lining of the intestine is one of the most highly proliferate organs of the body, completely replacing itself every 7 to 14 days. It's very feasible that anything we take into our bodies may increase or decrease this rate of proliferation."
The physician will follow this research with a four-month study of other compounds, involving four groups of volunteers. One group will take curcumin, the substance which causes the yellow color in mustard and curry. "Curcumin has been shown to prevent colon cancer in animal models and also acts as an anti-inflammatory," explains Shiff. "We want to see if it affects the colon in the same way in humans."
A second group will take orange peel extract, which has chemical structures similar to curcumin. A third group will take sulindac; a control group will receive no treatment. This and other studies will also explore dosage issues. Although NSAIDs are known anti-cancer agents, they can produce serious side effects if taken regularly on a long term basis. The risk of side effects of any agent would be reduced, if doses can be lowered to a minimum, yet remain effective.
The Volunteer Response
Considering the inconvenience, why do people agree to participate in the research? At Rockefeller University, volunteers (who actually lived at the facility), were primarily single people who didn't have family obligations. They included actors, freelance writers, retirees, and the unemployed, ages 18 to 80, who answered Shiff's newspaper ads and were attracted by the free room and board and the money: about $30 per day. At UMDNJ, the hope is that students and personnel will form a large part of the volunteer pool. They will receive the same payments as previous participants, which adds up to $2100 to $3500, depending on the length of the study.
"People will not sleep overnight here except after the biopsies, for safety purposes. Since there are four biopsies, they will stay four nights in a 12 week period," says Shiff, who seeks volunteers for these and future studies. Those interested can contact his research study office at 732-235-6265 for further information. Participants must be generally healthy, at least 18 years of age, and live or work nearby, since they must come in for meals twice a day.
Shiff's studies have already accomplished a great deal. "Part of the work of research is to develop the system and improve it, and I think we're doing that," he comments. "We've proved that short-term studies are safe and practical. A big question was: Can you repeatedly biopsy the colon without endangering the health of participants, and subjecting them to the potential risk of bleeding, infection, a perforated colon, or other complications? The answer is yes, you can; we've had no such cases."
Shiff and his team will do similar studies with black tea and green tea, which have been shown to have significant anti-cancer effects in animal models. They are also developing ways to improve data analysis, use automation to speed sample analysis, and refine the overall approach to make it more definitive.
"We're convinced that diet does play a role in colorectal cancer, and we think short-term studies
will help advance our knowledge. Future research will examine whether these compounds reduce the number of very early colon lesions, which cannot be seen by the eye, but eventually grow into polyps. If the substances we're studying prove to be statistically significant anti-cancer agents, the data can spearhead long term multi-center studies to see if they can stop polyp recurrence in patients prone to them," says Shiff. The ultimate goal is saving lives.
The magazine of the University of Medicine and Dentistry of New Jersey