• Progress on Prevention
• Interviews with Prevention Experts
• Thoughts on Conveying Prevention News

Progress on Prevention

The field of cancer prevention has passionate champions. Chief among them is Michael B. Sporn, M.D., professor of pharmacology and medicine at Dartmouth Medical School in Hanover, N.H. He articulated the importance of the field during a recent speech in Boston as the winner of the American Association of Cancer Research-Cancer Research Foundation Award for Excellence in Cancer Prevention Research.

"Chemotherapy has been highly successful for the treatment of relatively rare cancers such as childhood leukemias, Hodgkin's disease, and testicular cancer. But the prognosis for patients with advanced cancers of the lung, breast, prostate, colon, pancreas, and ovary remains poor," he said. The fact that after 25 years of research these common epithelial cancers still account for more than half of the cancer deaths in men and women is a sign, he thinks, that our treatment strategies for these cancers have failed.

"Rather than trying to cure end-stage disease, we need to redirect our focus to preventing the disease. This means controlling the carcinogenic process before the complex series of events that result in metastatic malignancy have occurred," said Sporn. " We have to get rid of the common misconception that people are healthy until they are told they have an invasive cancer. The process leading to cancer takes many, many years."

"Our common sense tells us that it is easier to fix anything when the smallest numbers of its components are broken," he continued. "Unfortunately, this intuition has been ignored in our allocation of resources to deal with the cancer problem."

The word chemoprevention, coined in the 1970s by Sporn, refers to the use of agents to impede, arrest, or reverse carcinogenesis at its earliest state. Both preventing progression to cancer and reversing precancer are goals for prevention agents.

Pathologists have long recognized the series of cellular changes that transform a normal epithelial cell to cancer. Distinct structural patterns are apparent as normal cells progress through the stages leading to cancer: the first is early dysplasia where a few cells become irregular in size and shape, to increasingly severe intraepithelial neoplasia (IEN), superficial cancer, and finally to invasive disease where the normal cell pattern is totally disrupted. According to prevention scientists, the long latency period associated with these changes -- as long as 20 years for some cancers -- represents a period of missed opportunities for intervention.

Even though the logic of chemoprevention seems irrefutable -- treating precancer before it reaches the more lethal cancer stage -- the prevention field hasn't had an easy time gaining acceptance in major research institutions. That appears to be changing.

"There has been a growing interest in cancer prevention," said Peter Greenwald, M.D., Dr.P.H., director of National Cancer Institute's (NCI) Division of Cancer Prevention and the recipient of the 2002 American Society of Clinical Oncology - American Cancer Society Award. "The commitment to basic biology and etiology has led to important opportunities to intervene early in carcinogenesis to lower risk. We now need to build up the field of cancer prevention."

Many Drugs Under Investigation

For the first time in its 96-year history, the American Association for Cancer Research (AACR) sponsored an international prevention meeting, "Frontiers in Cancer Prevention Research," in Boston last month. Greenwald, a leader in the prevention field for many years, was pleased to see a lot of names on the list of attendees he didn't recognize, most of whom were young. "The heavy turnout for the Boston meeting was a good sign," he commented. "I really see an excitement in prevention now."

One of the big boosts to the field was the Food and Drug Administration (FDA) approval in 1998 of the first cancer risk-reduction drug, tamoxifen, followed shortly by the approval in 2000 of celecoxib for reducing precancerous polyps in people with FAP (familial adenomatous polyposis), a precursor of colorectal cancer. And currently, there are a number of promising agents in the pipeline in preclinical and clinical development. Greenwald estimates that there are about 60 NCI-sponsored phase I, II, and III clinical prevention trials. (These trials are described in more detail on (http://www.cancer.gov/search/clinical_trials; http://crisp.cit.nih.gov/ and http://www3.cancer.gov/prevention/)

Some of the agents under investigation include:

• Those that block the activation or facilitate the elimination of carcinogens (e.g., benzyl isothiocyanates in cruciferous vegetables such as broccoli, cauliflower, cabbage, and watercress; flavonoids in fruits and vegetables; sulforaphane and dithiolthione compounds in broccoli; and indoles)

• Antioxidants that scavenge free radicals, preventing damage to DNA (e.g., selenium, a-tocopherol, Vitamins C and E, soy isoflavones and tea polyphenolics)

• Those that inhibit the carcinogenic process (retinoids, a-tocopherol, many antioxidants in fruits and vegetables, tamoxifen, raloxifene, inhibitors of cyclo-oxygenase [COX] and lipoxygenase [LOX], tyrosine kinase inhibitors, PPAR [peroxisome proliferator-activated receptor] modulators, farnesyl transferase inhibitors, and analogues of Vitamin D)

• Dietary substances such as organosulfur compounds in garlic and onions, curcumin in turmeric/curry, polyphenols in green tea, soy isoflavones, and resveratrol in red grapes.

Treatment and Prevention Fields Share Agents and Approaches

Scott M. Lippman, M.D., professor of medicine and cancer prevention in the department of clinical cancer prevention, University of Texas M. D. Anderson Cancer Center in Houston, who has been active in the prevention field for many years, thinks the distinction between prevention and treatment agents is becoming blurred. That is certainly true for tamoxifen and celecoxib. Tamoxifen has been approved for both treatment and prevention of breast cancer, and celecoxib, already shown to reduce precancerous colon polyps in people with FAP, is now being tested for the treatment of several cancers.

Most of the agents tested in early prevention trials were vitamins and minerals (J Natl Cancer Inst 1998;90:1514). In contrast, many of the drugs used in treatment trials involved cytotoxic agents that kill cancer cells as well as normal cells, resulting in a substantial number of side effects.

"Now cancer prevention and cancer therapy are merging together," Lippman said. "For treatment, the trend is now going toward oral, molecular-targeted drugs with relatively low toxicity. That makes them more attractive for prevention as well. In some phase I trials, such as those for Iressa, (which targets the epidermal growth factor receptor), you can now determine the optimal biologic dose for both prevention and treatment."

The commonality between the two fields is no accident. "We look for opportunities from treatment studies," said Greenwald. "There's an advantage in that we already know about safety, and we can bring the drugs into human testing early. It can save us years." Some leads for today's prevention drugs came from observations made in other trials. Raloxifene was first tested for prevention of osteoporosis; celecoxib for arthritis relief; and selenium for skin cancer prevention.

There are also efforts in both fields to evaluate molecular markers that will result in more targeted therapies or prevention drugs. Scientists are trying to identify molecular markers either from precancerous lesions, malignant tumors, blood, or urine that will predict who is likely to respond to a particular agent.

Rachel Ballard-Barbash, M.D., M.P.H., from NCI's Division of Cancer Control and Population Sciences, said most investigators for prevention trials are collecting tumor and blood samples so they can test biological markers at an appropriate date. The hope is that this information will allow researchers to conduct trials in more targeted risk groups with higher rates of success.

A recent observational study (Lancet 2000;356:724), looking at the effect of isothiocyanates, a class of nutrients found in cruciferous vegetables, on lung cancer rates, illustrates the usefulness of molecular information. The researchers found that in a population in Shanghai whose diet included large amounts of cruciferous vegetables, the participants who were genetically deficient in an enzyme (GSTM1) that eliminates isothiocynanates from the body had a lower risk of lung cancer than those without the enzyme deficiency. The report suggests that prevention efforts with isothiocyanates and lung cancer may be more successful with people carrying this particular gene alteration than with noncarriers.

Along with these commonalities, Greenwald points out that "there also can be major differences between treatment and prevention. Prevention requires agents of low or no toxicity, is focused on different groups of people (generally not cancer patients), may be done in different settings, and has different endpoints (cancer occurrence rather than survival)."

Difficulty in Approval of Prevention Drugs

Despite these encouraging efforts, drug approvals for prevention agents have been slow to emerge. So far, tamoxifen is the only drug approved to lower the risk of cancer. Much of the problem is that reduced cancer incidence or mortality has traditionally been the endpoint in prevention trials. This makes prevention studies too long, large, and costly for most academic research centers and drug companies to undertake alone. The result is that large prevention trials tend to be done through cooperative networks, such as NCI's Community Clinical Oncology Program.

Some scientists believe the best alternative endpoint is the prevention and regression of the precancerous lesion, IEN, a stage on the pathway leading from normal tissue to cancer when cells viewed under a microscope appear irregular in shape and densely packed. A drug that prevents or halts the regression of IEN would be presumed to lower the risk of developing cancer in the same way that lowering cholesterol or blood pressure reduces the risk of heart disease (Clinical Cancer Research 2002:8;314).

But Greenwald says that at this point it is important that we not jump ahead and assume that if you prevent IEN, you prevent clinical cancer. "It's a very important question, but we're going to have to demonstrate that if we're preventing IEN, we are preventing cancer," he said. We should not push for this as the final endpoint at this point."

He cited the studies on postmenopausal hormone therapy. "We presumed that hormone therapy would have a beneficial effect on the heart because it had a beneficial effect on the lipid profile," he said. However, when heart disease and stroke were the endpoints, users had a 41 percent increase in stroke and 29 percent increase in heart disease compared with the non-users.

"We have to take it on a case by case basis," Greenwald explained. "Many organ sites have IEN -- cervix has dysplasia of the cervix, prostate has HGPIN (high-grade prostate intraepithelial neoplasia), breast has DCIS (ductal carcinoma in situ), colon has adenomous polyps, there is dysplasia of the bronchi, and the mouth has leukoplakia. All of these are IEN, but we have to characterize each one at a molecular level. Say, for example, that you prevent some portion of IEN. You don't know if you have prevented the milder form that will never progress or the more aggressive form. Likewise, we know that HGPIN appears to predispose to prostate cancer, but I can't say if we prevent HGPIN we have prevented prostate cancer. I want to see proof that preventing IEN leads to a lower rate of clinical prostate cancer."

To get at that question, as a first step, NCI is conducting Phase II trials of nearly every organ site with IEN as an endpoint. "These are important trials," explained Greenwald. "We're going to have to choose agents where we have clear evidence of favorable biological effect, and then test them in large, randomized Phase III trials to show reduced cancer incidence along with biological endpoints. We can only do a limited number of large-scale trials, so the Phase II trials are very, very, important." NCI is also working with FDA to reach agreement on what is a reasonable amount of evidence for approving drugs.

Many people believe that the drug approval process needs rethinking. "There needs to be an ongoing dialogue between FDA, NCI, academia, and the pharmaceutical industry about how to develop drugs to treat precancer. The incentive needs to be there if the pharmaceutical industry is to invest in the discovery process," said Andrew Dannenberg, M.D., director of cancer prevention at New York Presbyterian Hospital-Cornell. He believes that all of these voices are needed to rethink the paradigm that success in cancer treatment is prolonging life by a few months.

In addition to continuing to develop drugs to treat cancer, prevention researchers believe the focus needs to shift to treating the underlying disease process and thereby preventing the development of life- threatening cancer. "We're losing 15 years of missed opportunities while cancer is developing. The challenge is to be able to identify the precancer and stabilize, reverse, or remove it," Dannenberg continued. "There will be rewards in the prevention field, but they will only come with dialogue, sacrifice, and investment."

Interviews with Prevention Experts

While the cancer prevention field continues to evolve and move forward, tamoxifen is the only drug approved to lower the risk of cancer. Given what we know today, what do you think is the best strategy for lowering the risk of cancer?

John Milner, Ph.D., chief of the nutrition science research group at NCI's Division of Cancer Prevention: The best strategy for reducing the risk of cancer is to increase fruit and vegetable consumption and decrease total caloric intake. It's not terribly sexy, but that's reality. We have a very high incidence of obesity in this country, so people are not hearing even that simple message.

There are likely going to be cases in which certain foods or food components ought to be consumed in higher quantities. We are probably going to find out that individual needs vary and that certain kinds of food may be needed in higher quantities to reduce risk. That's where we're headed. But we don't know what foods these are, so I think at this point it's wise to eat a variety of foods and enjoy it. Foods should be a pleasure in life.

Rachel Ballard-Barbash, M.D., M.P.H., at NCI's Division of Cancer Control and Population Sciences: I suggest that people look at the overall pattern of diseases in their extended family, and not simply focus on cancer prevention. For example, if you have a strong family history of heart disease, high blood pressure, or diabetes, become educated about those conditions. In fact, most of us are concerned about remaining healthy and enjoying a long and productive life that is not limited by any disease or health concern. Fortunately, there are a number of lifestyle behaviors that should reduce risk and improve quality of life for most major diseases. They include: Don't gain a lot of weight as you get older. Be physically active. Pay attention to what you eat and drink. Don't smoke. Wear seat belts. Get immunized. Know which screening tests are recommended, and how often you should get them. These are our big prevention messages.

Also, understand that our knowledge is evolving. If you want to know what's best, you can't assume that what you knew five years ago necessarily still holds today. Committing to a healthy lifestyle means committing to lifelong learning.

Peter Greenwald, M.D., Dr. P.H., director of NCI's Division of Cancer Prevention: We know that there are several things that people can do to reduce their chances of getting cancer. One is to keep trim, avoid obesity and get some exercise. We know that weight gain as an adult is associated with postmenopausal breast cancer. We know that obesity is associated with cancer of uterus, gall bladder, probably colon cancer and prostate cancer. That's quite solid. We also know that people who eat plenty of vegetables and fruits and whole grains have lower cancer rates. The key message is to keep trim and eat plenty of vegetables and fruits. The specific nutrients, vitamins and minerals are still a subject of research. We don't have completely solid, irrefutable evidence.

Thoughts on Conveying Prevention News

How can science writers help the public understand the conflicting reports about what to eat and what not to eat? What do you think are the most important facts that the public should know?

Peter Greenwald, M.D., Dr. P.H., director of NCI's Division of Cancer Prevention: I don't think the main problem is communication. I think reporters report what scientists cite. But they often report the last study rather than the whole body of evidence, so that's a problem. The best strategy for interpretation is to have expert groups review the evidence, and sum it up. The problem is that there have been changes in what the research results have shown over the years, and there's not a consistency. We need to do a better job of communicating when the information is uncertain.

Andrew Dannenberg, M.D., director of cancer prevention at New York Presbyterian Hospital-Cornell: If you could communicate one message to professionals and the public it would be: You don't just wake up one day with life-threatening cancer. Ordinarily, it takes many years to develop. The underlying disease process leading to cancer is called carcinogenesis. It's quite analogous to the atherosclerotic process leading to heart disease. Therefore, people need to become much more sensitive about the need to undergo screening so that precancerous lesions can be detected and removed. If there is a disease, then treatments need to be developed for the underlying disease process (carcinogenesis) not simply for its endproduct (cancer).

Prevention really needs to be thought of as treatment of precancer. That can be achieved through a combination of early detection and appropriate interventions, whether dietary or medicinal. There's a huge mismatch between what cancer researchers already know and what the consumer believes. The consumer thinks he wakes up with cancer. What we really need to be concerned about is the 10 to 15 years of missed opportunity when cancer was developing. Drugs need to be developed to stabilize or reverse the disease process that leads to invasive cancer. We've learned that medications that reduce cholesterol protect against heart disease. By analogy, there already is evidence that drugs can be developed to prevent cancer.

Rachel Ballard-Barbash, M.D., M.P.H., from NCI's Division of Cancer Control and Population Sciences: The role of diet in disease prevention is complex with information derived from many fields of research. We are continually evolving our understanding. We try to give the best suggestions at any one time based on that evolving evidence. Given the complexity, this summary may often appear contradictory to previous statements. The other factor that increases the sense of contradiction in this field is the reality that controversy is newsworthy. Therefore, if reporting a complex statement, it is expected that the media will tend to focus on those issues that are most controversial and not report on the evolution of the evidence that is consistent with prior reports. These conflicting data reflect, in part, an evolution of the science, but it is also a reflection of what we and all other people in the world consider newsworthy. Because conflict is a critical trump card in media reporting, it is reported, and what the public hears is conflict.

In terms of what the public should know: There are basic elements that will stand the test of time. But it won't be true for all people. Some people may be at relatively at low or high risk irrespective of what they do. We don't know how many people are in those categories, and right now, that's confusing.

Scott Lippman, M.D., professor of medicine and cancer prevention in the department of clinical cancer prevention, the University of Texas M. D. Anderson Cancer Center in Houston: It is very difficult to know how to handle conflicting information on diet and cancer prevention. It obviously takes a long time and a lot of resources to do a definitive randomized trial to measure the effect of dietary or natural compounds on cancer prevention. When the results of a large, randomized controlled trial are published, they're fairly definitive -- the b-carotene story, for example. I think that the difficulty for science writers, and therefore for the public, is that there are a lot more observational studies than definitive randomized trials. Typically, the results of an important cohort study are published with large numbers of people followed for many years. The data are analyzed, and the conclusion is one compound may be protective. There is a lot of interest because this is not an animal study -- it's in people. So, the stories come out in newspapers with headlines that say Vitamin X prevents cancer, rather than putting it in context of observational vs. randomized trial.

It seems to me that there's such a temptation for the public to over-interpret that. Science writers could convey the concept of levels of scientific evidence early in the story -- explain in lay language the difference between an observational study and a randomized trial, so the public can put the study in perspective.

Another problem is that the public certainly doesn't understand the concept of secondary analysis, such as the osteoporosis trial with raloxifene, which first suggested that this drug might be used a prevention agent for breast cancer. Secondary analyses are great for hypothesis generation and should be tested in future studies. Writers need to help the public separate out what's a promising finding from a definitive finding.