BETHESDA, MdEvidence of a relationship between diet
and the origins of colorectal cancer is tantalizing but shadowy, two longtime
researchers said at the Colorectal Cancer Prevention and Treatment conference,
co-sponsored by the Cancer Research Foundation of America and the American
Digestive Health Foundation.
"Nutritional factors associated with adenoma formation are
likely important in the development of cancer, but there is much
uncertainty," said Arthur Schatzkin, MD, DrPH, chief of the Nutritional
Epidemiology Branch of the National Cancer Institute.
It is unreasonable to expect one single factor to explain the
relationship between diet and colon cancer, warned Edward Giovannucci, MD, ScD,
of the Harvard School of Public Health. "The old high-fat, low-fiber
hypothesis for colorectal carcinogenesis is too simplistic," he said.
That long-standing hypothesis, Dr. Schatzkin said, focuses on
dietary elements that are presumed to increase riskfat, meat (especially red
and processed meats), high-temperature cooking, sugar, and alcoholand those
that are thought to decrease riskvitamins (especially A, D, and folic acid),
minerals (calcium and selenium), fiber, and fruits and vegetables.
Trials with APC knockout mice, which are genetically engineered
to produce intestinal adenomas, have shown that a low-fat, high-fiber diet
produces a 36% reduction in small, intestinal polyps, Dr. Schatzkin said.
Comparisons with humans are not simple, but this dietary intervention study
does demonstrate that dietary manipulation can interfere with the carcinogenic
Observational studies in humans, he said, have shown increased
relative risk for total fat (2.3) and for red meat vs chicken and fish (1.8),
and protection by fiber (0.4) and vegetables (0.5), for highest vs lowest
quintiles. But findings diminish with time, and prospective studies show less
effect, especially for fiber. The problem with observational studies is that
multiple other factorsnot just dietmay confound the effect.
As an example, he cited the Polyp Prevention Trial he carried
out with Elaine Lanza, PhD, a decade ago. They hypothesized that a low-fat
diet, high in fiber and fruits and vegetables, would decrease the recurrence of
colorectal adenomas. Their targets were fat as 20% of total energy intake; 18
g/1,000 kcal of fiber daily; and 5 to 8 servings of fruits and vegetables
Drs. Schatzkin and Lanza randomized 2,000 patients who had had
at least one polyp removed into two groups, one with the usual diet and one
with the intervention diet and intensive nutritional counseling. The latter
included recipe development, newsletters, social events, and a "fruit- and
veg-a-thon." Colonoscopy was performed at entry and again after 1 year and
The intervention group did lower their fat intake by one third
and increased fiber by three fourths and fruit and vegetables by two thirds, he
said, and 90% completed the 4-year trial. The result? "After 10 years of
work and the expenditure of much money," Dr. Schatzkin said, "there
was no difference in the recurrence rate, and only a hint of reduction in the
These results are open to varying interpretations, he said.
They may mean that dietary change, in fact, has no effect. But it could be that
a longer intervention time might result in a greater observable effect. Or
perhaps diet has its effects on colorectal cancer earlier or later in the
process. Or possibly a more radical diet is called for, one that more
explicitly cuts down on red meat, for instance.
Dr. Giovannucci pointed out that many of the risk factors for
colon cancerreduced physical activity, increased simple carbohydrate, fat,
and saturated fat intake, and higher polyunsaturated-to-saturated fat ratioare
also important in diabetes. "I suspect the factors we are looking for are
not luminal but systemic, such as insulin or an insulin-like growth
factor," he said.
Insulin and insulin-like growth factor (IGF) enhance cell
proliferation and inhibit apoptosis, he said. In animal models, direct
injection of insulin increases tumor growth, as do hypercaloric diets. However,
insulin resistance also increases tumor promotion. "No matter how you affect insulin resistance, it
affects the tumors," he said.
Similar trials cannot be carried out on humans, Dr. Giovannucci
said, but one can look at clinical conditions like diabetes or at plasma
markers like post-meal insulin, fasting insulin, C-reactive peptide, IGF
binding protein-2 (IGFBP-2), and triglycerides. IGF binding proteins reduce the
activity of IGF-1, so high levels of IGFBP-1, which is determined by insulin
levels, may reduce the risk of colon cancer, he said.
Three published studies, he said, show that higher insulin
levels predict colorectal cancer risk. However, this correlation is not
simple. "Insulin levels are tied to lifestyle issues. Diet is important
but is not the only issue. Someone who is overweight and inactive will have
increased post-meal insulin levels," he said.
More than 50 studies have shown an inverse risk of colon cancer
with physical activity, both leisure and occupational, in both men and women,
across a variety of populations. "Walking 3 hours a week appears to have a
major impact on development of the disease," he said.
Red meat may have a direct, deleterious effect on insulin
resistance or may be a marker for other dietary patterns. The
polyunsaturated-to-saturated fat ratio is also an important determinant of
insulin resistance. "Fiber may be important, but the question is, how
important?" Dr. Giovannucci asked. "We have to look at a
constellation of factors."
So what does the conscientious physician say about this welter
of factors to an inquiring population? "Risk reduction is a matter of
total lifestyle," Dr. Giovannucci said. "Start with increased
physical activity. Cut down on red meats, and increase your intake of fruits
and vegetables. There may be a lifetime impact on risk that is hard to discern
in the short term."