ARE CLINICAL TRIALS FOR YOU?

When Pat Barr was first treated for breast cancer in 1987, a member of a medical research team made a special request: Would she consider participating in a clinical trial on tumor recurrence located at Beth Israel Hospital in Boston? Clinical investigators were conducting the trial in an effort to find a blood marker that would indicate recurrence. Barr would be required to give blood for several years. "I said, 'Thank God people are studying this disease," says Barr, a lawyer and member of the board of the National Breast Cancer Coalition. Since then, Barr has participated in three nondrug-related clinical trials--on stress reduction, genetics and mother-daughter linkages. "I don't want the next generation of women to have only the choices now available, which everyone agrees are inadequate," she says.

Although Barr believes her clinical trial experiences have been positive, not all participation in clinical trials is that way. Valid concerns may arise. If you join a trial, are you advancing the cause of science? Or are you merely a guinea pig caught in a laboratory maze?

For a serious understanding of the benefits and uses of clinical trials in cancer treatment, you may need to answer many more questions: What are the goals of the research? How does it relate to your health and stage of cancer? What are the potential benefits, risks and costs?

THE ABCs OF CLINICAL TRIALS

Clinical trials, sometimes called research protocols or investigational trials, are the means by which new medical drugs, treatments and theories are analyzed scientifically.

Most cancer-related clinical trials test drugs. Others may research surgical techniques, epidemiology, behavioral patterns, environmental influences, clinical outcomes or the effects of nutrition, exercise and other factors on cancer prevention, recovery or recurrence.

Cancer treatments are tested on groups of people before they are recommended for general usage. Through carefully structured and controlled clinical experiments, the research provides evidence to determine whether a new treatment is valuable for patient care. For example, a 1985 clinical trial sponsored by the National Surgical Adjuvant Breast and Bowel Project (NSABP) showed lumpectormy in combination with radiation had the same five-year survival rates for Stage I and Stage II breast cancer patients as mastectomy. Now lumpectomy is an important option for most of these women.

Clinical trials on drugs begin with patients only after laboratory tests on animals have shown benefits. The trials are divided into phases that involve a widening pyramid of participants. As the research successfully passes through one phase, it moves into the next.

Phase I trials of drugs are toxicology studies. Two or three dozen patients in specialized centers receive the new treatment to determine a tolerable dosage level. Risks may be greater than in later phases, and participation generally is appropriate only for those in advanced stages of cancer who are not responding to other treatments. A Phase I participant might experience no benefit from the drug because the dose is so small, or might suffer harm--sometimes severe--because the dose is too high.

Phase II drug trials determine efficacy: They are designed to find out if there is any beneficial effect from the drug. For example, do tumors shrink? These trials expand the patient group to a larger number of individuals at several cancer centers to better establish a well-tolerated and useful dosage.

With proof of effectiveness, the research process moves on to Phase III, or comparison studies, to determine whether the treatment is equal to or better than existing treatments. Phase III trials may include thousands of patients at hundreds of sites. Patients are divided into two groups. One group of patients receives the best available treatment, sometimes called the "gold standard." The other group or "arm" receives the new treatment that is the subject of the clinical test. The two groups are then compared and the efficacy of the new treatment measured.

Clinical investigators screen participants and apply strict eligibility rules, customized to each trial. To remove any possibility that the researchers might skew the results, even unconsciously, the assignment of patients to the two groups or "arms" is done at random. In addition, the majority of Phase III experiments are double blind--neither researchers nor patients know who is receiving which treatment.

Because cancer is often a life-threatening illness, clinical trial participants rarely receive a placebo--a sugar pill, for example, masquerading as a real drug--though placebos are used frequently in other drug trials. "It would be unconscionable to withhold treatment if there were some method that might be of benefit," says Harold Moses, MD, director of the Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center in Nashville, Tennessee.

When the treatment is non-invasive, involving neither drugs or surgery, the research may go directly into Phase III clinical trials. These tests might seek to measure the role of exercise, nutrition or stress on recovery or recurrence.

Many studies are lengthy and track participants for five years or more. In the United States, some 400 cancer-related trials are under way through about a dozen major cooperative groups of researchers primarily funded by the National Cancer Institute (NCI), with another 600 studies organized by other groups, according to an article in the September 1999 Onology Times. As the world's largest sponsor of clinical trials, NCI enrolls about 20,000 people each year. Other trials are funded by biotechnology or pharmaceutical companies, and by private foundations.

REASONS TO PARTICIPATE

IMPROVING FUTURE TREATMENT. Most cancer advocates and medical experts see clinical trials as vital to secure better care in the future. Right now, fewer than 5 percent of breast cancer patients participate in them in the United States, compared to 70 percent enrollment in Scandinavia. Vincent DeVita Jr., MD, former director of NCI, says that if even 10 percent of cancer patients joined in clinical trials, the enrollment process could be completed within one year, instead of three to five years. Thus, the effectiveness of a new therapy could be learned fairly quickly.

Specific populations are generally underrepresented in clinical trials, especially older women and people of color. Research reported in 1999 by Kathy Albain, MD, chair of the Committee on Women and Special Populations at the Southwest Oncology Group (SWOG), one of the cooperative research groups that works with NCI, found only 25 percent of clinical trial patients in the mid-1990s were over 65, despite the fact that 63 percent of people with cancer were then in that age category. Analyses conflict on the participation of people of color. A recent trial on the use of tamoxifen for risk reduction had too few African American participants to provide sufficient information on benefits to that population group, according to Lisa Newman, M.D, assistant professor of surgery in the department of surgical oncology at the University of Texas MD Anderson Cancer Center. But Dr. Albain's research for SWOG did not find significant underrepresentation of African Americans or women in clinical trials.

SECURING HIGHER QUALITY CARE Doctors involved in clinical trials often work at top medical centers. Participating patients are monitored carefully and frequently. "Women in clinical trials--even if they don't get the new treatment--receive better care than other women,"' says Cindy Pearson, executive director of the National Women's Health Network (NWHN).

For breast cancer survivor Sandra Zook-Fischler, enrolling in a trial brought an immediate benefit. In 1998, Zook-Fischler participated in one that tested nine women with three different vaccines designed to prevent recurrence. "During careful pretrial screening, a recurrence was found," says Zook-Fischler, an education specialist. "It might not have been found without the clinical trial." She was treated with radiation and was then included in the study.

DETERMINING THAT THE RISKS ARE MINIMAL When the trials are non-invasive, such as the ones in which Barr participated, there may be no attendant health risks.

The vaccine trial in which Zook-Fischler took part "had no downside risk, just some minor tolerable side effects," she says. Measured against the possibility of helping other women, she was willing to take the chance.

In some cases, women who have cancer in an advanced stage believe their participation in clinical trials will be useful to researchers. For patients diagnosed as terminal, clinical trials may offer a chance to do something meaningful at the end of their lives.

PAYING TRIBUTE TO THOSE WHO HAVE HELPED IN THE PAST. NWHN's Pearson says that the lumpectomy trial which has saved many women from mastectomy involved "unbelievably brave women" who volunteered in a clinical trial that called for their surgery decisions to be made by random assignment.

"If you are interested in participating in a clinical trial, start by asking your oncologist about trials that might be appropriate for you. Check nearby medical centers, contact breast and ovarian advocacy groups. Visit MAMM's website at www.mamm.com.

Likewise, Barr knows that breast cancer patients now have treatments, no matter how imperfect, only because other women have participated in clinical trials. "The protocols we choose are available to us because thousands of individuals have taken part in clinical trials," she says.

SUFFERING FROM SIDE EFFECTS Clinical trials may involve serious side effects, and although participants can drop out at any time, they need to carefully weigh information provided by the researchers. A consent form advises participants of the risks, but some advocates complain that the documents are excessively long, written in technical language, and downplay side effects. Even for the same trial, the forms can vary from hospital to hospital.

Sherri Margalit, a New York City resident, says although she was advised that participating in a high-dose chemotherapy trial might leave her ill, she didn't think she'd suffer permanent damage. Margalit, mother of a 12-year-old daughter, decided to participate in the trial after her breast cancer recurred; she says one doctor told her she had Stage IV cancer. "I thought I'd be aggressive," she says. But the trial left Margalit unable to eat for a few days, and her arms and legs atrophied. She withdrew from the study, but a year and a half later, still has difficulty walking.

MAKING A LONG-TERM COMMITMENT Participation in clinical trials involves follow-up tests, sometimes for five or more years, according to NWHN's Pearson. In some cases, long-term participation is made easier when the studies are conducted by the NCI, which has a nationwide network of cooperative cancer centers.

DETERMINING THAT THE TRIAL IS NOT VITAL Some critics suggest that not all trials are of equal value to patients. They argue that some clinical trials may primarily benefit drug companies bringing their products to the market, including new versions of older drugs. "The drug companies have built-in incentives to do controlled trials on medications that will cost a lot more," says Sharon Batt, author of Patient No More: The Politics of Breast Cancer (Gynergy Books, 1994). "Meanwhile, the inexpensive remedies are not studied much."

Pharmaceutical companies disagree. Steven Benner, MD, executive director of clinical oncology at the Pharmaceutical Research Institute of Bristol Myers Squibb, the manufacturer of Taxol (paclitaxel), claims that profit motives do not drive clinical testing. "Our focus is on finding new treatment," he says. Bristol Myers Squibb conducted 1,000 clinical trials on Taxol, including many after its initial approval, in order to refine its effectiveness, according to Benner. "Patients' participation in clinical trials is critical for establishing that a drug is effective, and learning its patient profile," he says.

Activists raise two important questions about research priorities. Some would like to see more trials of treatment options other than drugs; others are concerned about how outcomes are measured.

Trials on alternatives to drugs, such as diet or exercise for risk reduction, are far less common than drug trials. Advocates would like to see these kinds of largely nontoxic trials pursued.

They would also like researchers to rethink the way outcomes are measured in clinical trials. The results are usually described in increased survival time or time-to-progression--the amount of time that elapses before the continued progression of the cancer. When the survival time increases or the time-to-progression is extended, the treatment is considered successful.

But these measures do not take into account the patient's quality of life during the extended period of treatment--comfort, pain, mobility or ability to eat, read, work. Activists want to know whether drugs improve survival rates and how drugs make people feel. Says Maryann Napoli, associate director of the Center for Medical Consumers, "In some cases, a drug would make your life miserable, although you may gain a couple of weeks on it."

POTENTIAL BENEFITS OUTWEIGHED BY COSTS. Even Phase III clinical drug trials cannot guarantee that the drug will be better than, or even as good as, the conventional treatments.

Bette Crigger, an editor at The Hastings Center, a bioethics think tank in Garrison, New York, cautions that women must realize the experimental nature of clinical trials. "Researchers hope their work will benefit people someday, but being in a clinical trial is research, not treatment."

In addition, clinical trials may involve costs for participants. NCI pays travel expenses for trials held at its Bethesda, Maryland headquarters, but in other situations, participants may be required to pay for travel. Usually the funder of the trial pays for any drugs used. Participants should have their doctors consult the insurance companies about costs related to clinical trials, including treatment for side effects. Older women who rely upon Medicare are not currently covered for experimental techniques (which is how clinical trials are categorized).

But getting coverage may be easier than you think: A survey of American Society of Clinical Oncologists members found that insurance companies denied fewer than 10 percent of the claims for clinical trials (other than bone marrow transplants). And two bills pending in Congress at press time aim to expand clinical trial coverage for Medicare patients and for those enrolled in HMOs.

Unfortunately, some physicians never even broach the idea of clinical trials with their patients. Another ASCO survey found that only half of the eligible patients are advised about potential participation in clinical trials. Ann E. Fonfa, founder of the Annie Appleseed Project, which educates cancer patients about treatment options, says that some doctors don't think to contact patients when they receive news of available clinical trials. Othters, she feels, are loathe to see a patient go elsewhere by enrolling in a clinical trial at another facility.

That's why patient advocates are increasingly active in the world of clinical research. In 1994, Deborah Collyar, founder and president of the California-based national organization PAIR: Patient Advocates In Research, made a presentation on why so few patients enrolled in clinical trials before a committee on breast cancer of Cancer and Leukemia Group B (CALGB), one of the large cooperative research groups. "They focus on the science questions. I said, 'No one thinks about the patients until after the trials are designed.' " Collyar was asked to be the group's first patient representative; now CALBG has 15. Patient representatives have been able to raise questions about the number of trips required to get to the trial site and about onerous testing requirements. Patients, she says, want exact information, feedback and access to care. Two trials planned with patient input showed substantially faster enrollment rates, Collyar says.

Breast cancer activist Sharon Batt had concerns about consent documents provided to patients and became the first patient advocate to join an Institutional Review Board (IRB), at McGill University in Montreal. (Institutional Review Boards are designed to protect patients from harm, interpret regulations, and review the protocol and consent forms for a clinical trial. Facilities conducting clinical trials they hope to present to the Food & Drug Administration must have them.) "Some of them were queasy [about including me]," she says. "Six months later, one doctor told me he'd opposed my joining but now felt I made an important contribution."

The best current source of information on clinical trials is on the NCI website. However, many pharmaceutical manufacturers fail to list their clinical trials there, and activists are working to establish a complete, centralized listing. (MAMM publishes a column each month listing clinical trials seeking participants.)

Organizations are also building stronger networks to support those who are considering clinical trial participation. New York City's SHARE provides information about clinical trials when women call with questions. A recent online chat sponsored by the medical website WebMD featured a session with an expert sharing information on ovarian cancer clinical trials.

One researcher is even studying a buddy program for participants in breast cancer trials. Allison C. Morrill, PhD, at the New England Research Institutes in Watertown, Massachusetts, will evaluate the effectiveness of a program that enlists women who have participated in clinical trials to act as trained talk-buddies for women considering clinical trial participation.

Barr, who is continuing her breast cancer advocacy, has a simple reason for involvement. "It would be really nice if we had a cure for this disease," she says. "But scientists can't work alone. Clinical trials are essential."

Many of these articles appear on the publication's website, which are often password-protected or members-only. For your convenience, I've gathered them on my own website.