NCI Cancer Bulletin Publication Break Next week's special issue on the 35th anniversary of the National Cancer Act, which Cancer.gov currently commemorates, will be our final issue of 2006. Since today's edition is the last regular issue of the year, the editors and writers of the NCI Cancer Bulletin would like to wish all of our readers a happy and healthy holiday season. We will resume publication on our usual schedule with the January 2, 2007, issue.

The field of prevention is public health's first line of defense against cancer. A key strategy has become short-term clinical nutrition trials linked to rigorous basic nutritional science, says Dr. Peter Greenwald, director of NCI's Division of Cancer Prevention (DCP).

The presence or absence of certain bioactive food components - along with other lifestyle factors such as exercising throughout life - are now thought to significantly affect one's risk for cancer. Identifying these lifestyle factors "has been one of the most important medical contributions for improving the public health in the past half century," says Dr. Greenwald.

In 1981, the idea became concrete after Drs. Richard Doll and Richard Peto from Oxford University used meta-analysis and epidemiologic studies to show that 30 percent of deaths worldwide were attributable to tobacco. Dietary risk factors were roughly estimated to account for even more - as much as 35 percent of cancer deaths. "However," explains Dr. Greenwald, "although obesity is known to increase risk and physical activity to be beneficial, much more basic nutritional research is needed to better understand the role of bioactive food components."

The epidemiologic lens on nutrition confirms the impact of lifestyle. A recent study led by Dr. Eugenia Calle of the American Cancer Society estimated that "the proportion of all deaths from cancer that is attributable to overweight and obesity in U.S. adults 50 years of age or older may be as high as 14 percent in men and 20 percent in women."

The challenge for cancer prevention is to transform the insights from nutritional science and risk numbers from observational epidemiology into cancers averted and lives saved. Producing scientific evidence is only the first step, notes Dr. Greenwald, because cancer prevention requires changing human behavior in a fundamental way. "Working with city planners, school systems, employers, markets, restaurants, and others in our communities would make this much easier for many people," he explains.

A magic molecule in a pill?
As a society, observes Dr. Greenwald, "We are far more inclined to prescribe than proscribe." Scientists are forever "seeking out simplicity in scientific thinking - in modern times preferably a magic molecule in a pill." Reductionism is a powerful approach to science, but the complex interactions involved in nutrition need the addition of a systems approach.

Multivitamins and mineral supplements (MVMs) are being used by half of American adults, but may produce different effects than the same ingredients that occur naturally in foods. Adverse effects have been linked to megadoses of these ingredients, although most commonly consumed MVMs don't exceed the U.S. Department of Agriculture's Recommended Dietary Allowance (RDA).

In May, NCI and the NIH Office of Dietary Supplements (ODS) were two of the sponsors of the "NIH State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention," which looked closely at the randomized controlled trials evidence. The expert panel concluded that, although dietary supplements and MVMs "are now used by more than half the population…the present evidence is insufficient to recommend either for or against [their use] by the American public to prevent chronic disease."

"It is also important to remember," points out Dr. Paul M. Coates, director of ODS, "that people who take MVMs tend to be more health conscious than nonusers. For example, they're more likely to eat healthier diets and exercise regularly, which makes it harder to determine if the MVMs themselves are actually responsible for any improvements in health."

Back to the drawing board?
Large-scale randomized controlled trials can also swing the other way, not only failing to confirm protective effects from observational epidemiology, but also uncovering harmful effects. "Everyone was surprised when the Alpha-Tocopherol, Beta-Carotene (ATBC) Study and the Beta-Carotene and Retinol Efficacy Trial (CARET) found that beta-carotene supplementation actually increased lung cancer risk in heavy smokers," says Dr. Greenwald.

ATBC and CARET were 2 of the 9 large phase III trials that composed the first generation of nutritional interventions in cancer prevention, which together enrolled nearly 150,000 participants.

Lessons learned from these first-generation trials will help to evolve the model, notes Dr. Greenwald, because "there are already more exciting leads of how bioactive food components may reduce cancer risk than there are practical possibilities for phase III trials." Thus, newer trials need to reflect what has been learned so far.

The NCI-sponsored 30,000-participant General Nutrition Trial in China tested a number of different pill formulation and packaging complexities, using a design that allows researchers to look at biological interactions between agents and incorporates multiple primary endpoints, assessing other major conditions such as diabetes and cardiovascular disease. Such multifactorial approaches should become a design of choice, Dr. Greenwald and others believe.

A second promising strategy is the use of biomarkers, which could help to establish eligibility criteria for participants and may be a good way to validate how much of the substances being tested actually arrive in the target tissues.

Other technical issues also are critical for more efficient and productive nutrition trials. Certain interventions take longer to manifest their effects; the duration of the intervention should not be set but instead depend on a number of factors.

"It will be important to carefully consider the doses of each dietary supplement ingredient given to study participants," says Dr. Coates. "Rather than megadoses, they should be in line with RDA levels."

"The beta-carotene/lung cancer link established a new paradigm for how to think about potential side effects," says Dr. Greenwald, which requires careful consideration beyond effects on cancer alone to monitor other major causes of morbidity and mortality.

Careful thinking about how to prepare for and mount such trials was a primary goal of a 2003 workshop at the Fred Hutchison Cancer Center entitled "Research Strategies for the Study of Nutrition, Physical Activity and Chronic Disease."

"We came away with a very cogent, though admittedly ambitious, set of recommendations," says Dr. John Milner, chief of DCP's Nutritional Sciences Research Group. "When an intervention appears biologically plausible and promises substantial potential benefits for the public health, funding should be found to mount a full-scale clinical trial."

By Addison Greenwood