Source: www.cancer.gov
Author: Carmen Phillips

Numerous studies suggest that avoiding excess weight, exercising regularly, and eating a diet heavy on fruits and vegetables decreases the risk of many diseases, including cancer. But as the expanding obesity epidemic has shown, there are major obstacles to getting broad swaths of people to adopt such a healthful lifestyle. So, for many years, cancer researchers have investigated whether specific nutrients—those that epidemiologic and animal model studies have suggested could sway cancer’s course—could decrease cancer risk.

Much has been learned from this work, researchers in the field say, but, as is the case with treatment, each new discovery points to new areas of focus and other potential avenues of progress.

With promising bioactive compounds in the pipeline, many prevention researchers are focused on figuring out not just whether something like sulforaphane, a natural compound found in broccoli and broccoli sprouts, can kill cancer cells in a test tube or animal model—which it does, quite well—but how, at the molecular level, it accomplishes this task, whether there are some cancer cells that are more likely to respond to it, and whether there are ways of discerning early on that the intervention is having its intended effect.

Prevention: A Complex Matter

A number of supplements have been tested in large prevention trials, including vitamins A, C, and E; selenium; beta-carotene; and folic acid. At least one trial has demonstrated a reduction in cancer deaths with a combination of supplements, while several others found no reduction or even a small increased risk.

“There was suggestive evidence in humans” to support the large clinical trials conducted to date, said Dr. Peter Greenwald, director of NCI’s Division of Cancer Prevention (DCP). Millions of people are taking supplements in the belief that they can improve their health, including preventing cancer, he continued, so getting data from randomized clinical trials—the gold standard of biomedical research—is critical.

But given the complexity of cancer, acknowledged Dr. Alan Kristal, a long-time cancer prevention researcher at the Fred Hutchinson Cancer Research Center, it raises questions about whether “high doses of micronutrients are going to have an impact on cancer risk.”

And Dr. John Milner, chief of DCP’s Nutritional Science Research Group, says that, in the pursuit of nutrition-based cancer prevention, it’s more than just the complexity of cancer that has been underestimated. “In many ways, the lesson is that food and what we need to live is a lot more complex than we’ve ever thought,” Dr. Milner said.

It’s that complexity that researchers are increasingly tackling more directly.

Small Steps

At Ohio State University, Dr. Gary Stoner and his colleagues have been studying the cancer prevention potential of black raspberries for the last decade. Much of their work has focused on a powdered form of the entire berry, which eliminates the water that makes up 85 to 90 percent of the berry’s weight.

The researchers began with laboratory and animal model studies, and when these studies demonstrated that the berry powder had prevention potential, they transitioned to small human trials. Some promising results have been seen in early stage human trials for esophageal, oral, and colorectal cancer prevention. A small skin cancer prevention trial is on the immediate horizon.

In the case of oral cancer, the Ohio State team worked with collaborators from the University of Kentucky to produce a berry powder-infused gel that is applied to precancerous oral lesions. Treatment for 6 weeks shrunk the lesions by as much as 50 percent and decreased the activity of genes related to cell growth and proliferation. Based on the results, NCI is funding a phase II, placebo-controlled trial of the gel.

“You can establish that something might work in a much smaller trial with a lot less money,” Dr. Stoner said. “You can get a good idea if it will inhibit proliferation in a trial of 20 patients.”

Small human trials, explained Dr. Kristal, can “integrate what’s known about the carcinogenesis process and see whether we can manipulate that process with micronutrients or bioactive compounds.” Even then, he stressed, they have to be carefully designed to ensure that they produce meaningful results that can potentially inform further studies and larger trials.

At UCLA’s Jonsson Comprehensive Cancer Center, for instance, Dr. William Aronson is leading a phase II clinical trial of fish oil supplements, which are a plentiful source of omega-3 polyunsaturated fatty acids. The trial is randomly assigning men with prostate cancer who are scheduled to have their prostates removed to a low-fat diet with fish oil supplements or a standard Western diet for 4 to 8 weeks.

By analyzing tissue and blood samples taken before and after surgery, the researchers aim to determine whether the low-fat diet and fish oil combination alters the levels of certain serum and tissue proteins that may be associated with prostate cancer progression. “Such biomarkers may indicate that the intervention is working and will be an essential component of long-term human dietary intervention trials,” Dr. Aronson explained.

Even here there are challenges, noted Dr. Kristal, because once potential biomarkers are discovered, it then has to be demonstrated that a change in a biomarker alters the course of the disease.

Both short-term trials and analyses of tissue samples from the large trials that have already been conducted may also help to address another critical issue: variability in response. “Any time you do a study, even with drugs, you don’t get 100 percent effectiveness. You only get some people who respond,” said Dr. Milner. “That’s what happens with many nutrients as well.”

All of this work, stressed Dr. Greenwald, is moving in the right direction to get these nutritional interventions into phase II and III trials. “If you have studies that clearly show an effect on biological endpoints that we think are related to cancer risk, a mechanism, and human data, that’s very useful information,” he said.

Moving Forward to Phase III Trials

While more early stage trials are on the horizon, those in the field agree that there will probably be somewhat fewer large phase III trials. One such trial, the VITamin D and omegA-3 triaL, dubbed VITAL, is set to begin enrolling the first of 20,000 planned participants in January 2010. The NCI-supported trial will test whether regular use of vitamin D and fish oil supplements, taken either alone or in combination, reduces overall cancer risk (as well as the risk of heart disease and stroke) in women aged 65 and older and men aged 60 and older.

“There is a narrow window of opportunity for doing a trial of this nature,” said the study’s principal investigator, Dr. JoAnn Manson, from Brigham and Women’s Hospital and Harvard Medical School. Only in the last 2 years, Dr. Manson believes, “has the strength of the evidence for vitamin D and fish oil reached that threshold” to support launching a trial of this size. In addition, she argued, if researchers wait too long, “so many people could be taking [these supplements] that the trial will no longer be feasible.”

Sales data on supplements support her concern. According to The Nielsen Company, sales of vitamins and supplements for June 2008 to June 2009 were up 5 percent over the previous year, totaling $1.5 billion. Vitamin D and fish oil are two of the biggest sellers.

VITAL researchers will analyze blood samples from a subset of participants to see if baseline levels of markers like 25-hydroxy vitamin D, the primary form of vitamin D circulating in the blood, and omega-3s correlate with reduced disease risk. And because the trial has a specific focus on recruiting a large number of minority participants, the researchers can analyze whether factors like participants’ race or ethnic background influenced the response to the supplements and whether supplement consumption can reduce health disparities by race.

Advances may not come as fast as some might like, but they are happening, said Dr. Aronson. “I think we’re going to make very significant progress over the next 5 years and we’re going to gain important information that we can incorporate into larger trials.”