Cancer Prevention Trials Open New Era in Medicine : Science: About 16,000 women will participate in a study to see if tamoxifen lowers the rate of breast disease.

Each day for the next five years, 16,000 American and Canadian women are expected to commit themselves to science by opening a plastic vial and swallowing a small, white pill. Each woman is at a greater-than-average risk for developing breast cancer.

As a whole, they represent the hope of the breast cancer research community.

By the end of this $68-million study, researchers expect to know whether the drug tamoxifen, which half of the women will be taking, significantly lowers the risk of getting breast cancer.

The stakes are high, in terms of money, time, professional reputations and the direction in which cancer research should proceed. Ultimately at stake, however, are the lives of thousands of women who develop breast cancer each year.

The tamoxifen trial, known as the Breast Cancer Prevention Trial, is one of the largest cancer prevention studies ever, and the largest study on breast cancer. It opens a new era in medicine by introducing, on a broad scale, the concept of chemo-prevention: giving a drug to healthy people in order to prevent disease.

And that is what has upset a number of critics of the study. They say that for healthy people the risks involved in taking this drug are too high. Tamoxifen has been associated with increased risks of certain cancers and blood-clotting disorders, but the data on side effects is far from conclusive.

“It’s the edge of the envelope. But this is the way to start thinking about stopping disease,” said Dr. Lawrence D. Wagman, director of general oncologic surgery at City of Hope National Medical Center, one of seven Southern California medical centers participating in the study.

Felicia Whittle, 60, of LaVerne is already thinking that way. Her family history puts her at high risk for breast cancer, and she is tired of doing nothing.

“This looks like the only way to go,” she said. “Everything in life is a gamble. But entering the study was not a hard decision for me.”

Apparently, neither has the decision been difficult for many women.

Three months after the recruitment process began, organizers of the study, which is funded by the National Cancer Institute, have been overwhelmed by applications from about 26,000 women. About two-thirds have been deemed eligible, on a preliminary basis, to participate. The response is noteworthy given the publicity about the possible side effects of the drug.

“Clearly, women who perceive themselves to be at high risk for breast cancer want to do anything they can to prevent it,” said Dr. Patricia Ganz, a study investigator at UCLA and a member of the trial’s national steering committee. “I think this is really something women have been waiting for.”

For almost 20 years, tamoxifen has been the weapon of choice to treat breast cancer. Used for advanced and early stage breast cancer, the drug has been shown to increase survival rates and curb the incidence of a second breast cancer by 35%.

Tamoxifen’s glowing record in preventing second cancers has led to the obvious question: Can the drug prevent cancer in healthy but high-risk women?

By the time most breast cancers are discovered, the malignancy has been in place for many years, having begun with minuscule changes in cells. Experts believe that given early enough, tamoxifen might prevent initial cellular changes.

“The breast cancers that are diagnosed today did not begin to develop yesterday,” said Dr. Bernard Fisher, a University of Pittsburgh surgeon and the principal investigator for the study. “A number of women who have what appear to be normal breasts without detectable cancers already have the biological changes that will cause the disease. The goal . . . is to attack these changes so that there will not be a breast cancer.”

The potential success of the effort is breathtaking. An estimated 180,000 U.S. women will receive a diagnosis of breast cancer this year, and 46,000 will die of the disease. If tamoxifen works, those statistics could be lowered by as much as 40%, study planners say.

For reasons that are not understood, breast cancer rates have been rising. And there is little known about preventing the disease. The link between breast cancer and a high-fat diet is unproven. The only recourse for high-risk women is what physicians call “watchful waiting,” including regular mammography and self-examination, or undergoing a preventive mastectomy.

“To me, the most exciting part of the study is that we’re attempting to prevent cancer instead of treating it,” Wagman said. “It’s exciting to identify a population at high risk who will benefit the most. In spite of risks (associated with taking the drug) we can still say that this group will benefit.”

And the potential benefits of tamoxifen do not stop at breast cancer. Researchers believe that the drug might lower blood cholesterol to reduce a woman’s risk of heart disease by 40%. Moreover, the drug may slow bone loss--a natural part of the aging process that can lead to osteoporosis--by 30%.

The tamoxifen study is also different from many medical research trials in which the outcome is far from certain. In this case, researchers expect positive results, Ganz said.

“I don’t think the trial would have been funded and launched if that were not the case,” she said.

But tamoxifen is not without its risks. And in this, the first sweeping chemo-prevention trial ever, the fundamental question of how much risk is too much is far from settled.

Critics of the Breast Cancer Prevention Trial are worried that the potential for adverse effects has been underplayed by study organizers. They say tamoxifen will convey unnecessarily high risks of uterine cancer, liver cancer, liver failure, blood clots and severe menopausal symptoms on healthy women in order to prevent a disease that statistics show only 20% of the study participants will get.

Studies show that women on tamoxifen to prevent a recurrence of breast cancer have a 0.3% risk of developing uterine cancer, or double the risk of a woman not taking the drug.

A woman on tamoxifen has a 1.3% risk of developing phlebitis (an inflammation of the veins) or blood clots, which, although low, is much higher than normal. Women with a history of blood-clotting disorders will not be allowed into the trial.

Study officials also acknowledge that the drug may increase the risk of liver cancer, a rare but often fatal disease. An increased rate of liver cancer has been observed in rats given tamoxifen. And a Swedish study found two cases of liver cancer among 4,028 women taking the drug--about four times the normal rate. These women were taking a dose double (40 milligrams) that which women in the prevention trial will receive.

However, other studies in the United States and elsewhere have found no cases of liver cancer among women taking tamoxifen to prevent a second cancer. And scientists generally agree that lab studies on rats are difficult to extrapolate to humans.

“We all know these hormones can have an effect on the liver, but we know that the 20-milligram dose appears safe,” Ganz said. “I personally don’t have any major concerns about that.”

But the ambiguous findings on liver cancer have caused health officials in Great Britain to temporarily halt their 13,000-woman breast cancer prevention study using tamoxifen. And some researchers believe that U.S. health officials should do the same.

“We have concerns about the efficacy of the trial and the safety of it,” said Leslie Bernstein, an associate professor in the USC School of Medicine’s department of preventive medicine. “My major concern is that no pilot study has been done. You usually don’t start out with a large, randomized study without the safety and efficacy established in a small trial.

“While it’s always a big leap to take animal data and extrapolate it to women, the animal data suggests that there can be problems with the liver. I think it’s something people needed to evaluate beforehand.”

Bernstein was one of two dozen medical professionals, few of whom are cancer specialists, who signed a letter directed to the Food and Drug Administration late last year detailing their concerns over the tamoxifen prevention study. (Virtually no one objects to tamoxifen therapy for women who have cancer.)

The letter, spearheaded by the National Women’s Health Network, a Washington advocacy group, argued that preventive studies should be well defined and low risk. And, the authors stated, there is no evidence that reduction of second tumors in women with breast cancer will translate into primary prevention of breast cancer in all healthy women.

“I think it’s very important if we’re going to prevent some condition that we don’t do any harm along the way,” said Dr. Joyce Lashoff, former dean and professor of public health at UC Berkeley. “We want to use preventive measures that have been shown to be safe for a broad-based population.”

Lashoff says the study will involve too many women who have only a minimal risk of breast cancer. Women are eligible to enter the study if they are between 35 and 59 and have certain risk factors, such as a family history of breast cancer or a personal history of benign breast tumors. Women 60 or older with no risk factors for breast cancer can also be admitted to the study on the theory that the likelihood of developing breast cancer increases with age.

Statistically, all women have about a 10% chance of developing breast cancer. But Lashoff and others argue that at age 60 a healthy woman who has no other risk factors for breast cancer has only a 1.8% chance of developing the disease within the next 10 years. She says the study should be limited to women at higher risk. For example, a 40-year-old woman who has a history of benign breast tumors--sometimes a precursor to breast cancer--and whose mother and a sister or sisters have battled with the disease has a 13.4% chance of developing the disease in the next 10 years.

But study organizers say that the potential benefits of tamoxifen outweigh the risks. And the decision to enter the trial is left up to the individual.

“Obviously someone who doesn’t think they are at high risk won’t want to take a pill for something,” Ganz said. “But a woman living with the fact that every woman in her family has had breast cancer before the age of 50 has a terrible weight on her. The medication may give her security and hope that she won’t get the disease.”

Further, study planners say, participants will be so closely monitored that all adverse side effects should be spotted early enough to be treated effectively.

Once a woman qualifies for the study, she is assigned to receive either the tamoxifen or a placebo, a harmless sugar pill. Neither the woman nor her doctor will know what she is receiving.

The woman then undergoes physical examinations and blood work after three, six and 12 months. During the second through fifth years of the study, physical exams and blood work are performed every six months and a mammogram and pelvic exam every year. Women entered at Harbor-UCLA Medical Center will also undergo occasional tests to monitor uterine tissue, Ganz said. Participants will be followed for another two years after the five-year medication phase of the study is completed.

“A prevention trial is very different from a disease trial,” Ganz says. “We’ve got healthy women (participating). We’re giving tamoxifen earlier and earlier, so we’re worried about the long-term risks. It’s very exciting, but it’s a new era in clinical trials research.”

One woman who is more worried than excited is Mary Joan Hiller, 59, of Van Nuys. She applied to enter the study but dropped out after hearing some of the criticisms. She says she became nervous about the risks of liver cancer and because tamoxifen can cause changes to the retina. Hiller said she has an eye condition that she fears the drug could aggravate.

Her mother and maternal grandmother died of breast cancer. And Hiller has never had children, which increases the risk of breast cancer. According to risk-assessment charts, Hiller has an 11% chance of developing the disease in the next 10 years.

“I still feel it’s too dangerous a drug,” she said. “If I got uterine cancer, I could have a hysterectomy. But what about liver cancer? There isn’t much that can be done for that. And what about the side effects? I might feel so terrible my quality of life would be diminished. Yes, I’m terrified of breast cancer. But I don’t feel I’ve made the wrong decision.”

Despite the potential for serious side effects, many women who have considered entering the study say they are most concerned with the more likely potential for less serious side effects. These include hot flashes, vaginal discharge, menstrual irregularities, depression, loss of appetite, nausea or vomiting, dizziness, headaches and fatigue--conditions that will not kill or injure but can dramatically affect the quality of life. Moreover, post-menopausal women who are taking estrogen replacement therapy are required to go off that therapy for the duration of the study. Menopausal symptoms, such as hot flashes, will be treated by other methods, researchers say.

Participants will be counseled about dealing with these situations, and study leaders say that the majority of side effects can be treated with non-hormonal methods.

Given the controversy among experts, the potential for side effects and the lack of guarantee that they will receive tamoxifen, it seems surprising to some researchers that so many women are entering the trial.

Many who have chosen to enter have few reservations.

Carol, 62, a Rosamond woman who asked not to be further identified, descends from a family with a four-generation history of breast cancer. “Years ago I told my children that this is what I’ll die of. It seems preordained.”

Carol has no health insurance and has not seen a doctor in 16 years. Like all participants, her care on the tamoxifen trial will be free.

Sally Markowitz, who lives in Los Angeles, has seen a mother and aunt suffer with breast cancer. She is over 50 and has cysts in her breasts.

“It’s something that keeps you on the edge of your seat,” she said. “I want to do this for myself and also for all the other women who are sitting on the edge of their seats.”

Breast Cancer on Rise

The breast cancer rate has soared in the last 50 years. Today, one in nine women will develop the disease. Experts attribute some of the increase to better detection methods, such as mammography. But it is still unclear why the rate has climbed so dramatically. Meanwhile, improvements in early detection and treatment have helped keep the death rate almost unchanged.

Source: American Cancer Society