WEDNESDAY, DECEMBER 9, 1998
"A Panel and Community Forum: Beating the Odds of Breast Cancer: The Role of Research"

This month's Forum was videotaped for distribution to medical investigators who are interested in identifying barriers to clinical trial enrollment, and to the general public, in order to give a general flavor of what we are trying to accomplish in our research.

The Panel:

Debu Tripathy, M.D. served as moderator for tonight's panel. He is Associate Clinical Professor of Medicine, Clinical Co-Director of the Cancer Center Breast Program at UCSF, and heads clinical research at the Carol Franc Buck Breast Care Center at UCSF. He is principal investigator on several clinical trials currently, and has worked closely with the advocacy community in the development and implementation of trials.

Jennifer Stoll-Hadayia, M.P.A. is the Program Manager for the National Asian Women's Health Center's Breast and Cervical Cancer Program. Ms. Stoll-Hadayia oversees the development of NAWHO's cultural competency training curriculum, toll-free breast and cervical cancer information hotline, and partnership-building efforts with cancer control programs across the country.

Bonnie Wheatley, MPH is Project Director of the Breast Cancer Early Detection Program at Highland Hospital. Holder of a Master's degree in Public Health, she is also the Northern California coordinator of the African National Black Initiative on Cancer, funded by the National Cancer Institute. She is Co-Principal Investigator on "Shared Decision Making on Rescreening Among African American Women" at Stanford University.

H.L.Ittner is a breast cancer survivor and advocate. She became interested in breast cancer when her mother was diagnosed in 1958. Her interest in the subject grew when she was introduced to Helene Smith, an early pioneer in breast cancer research, in the early 1980's and toured her lab. Then, her only sister was diagnosed with breast cancer in 1986. Her mother died from breast cancer at the age of 56, and her sister died at the age of 45. Neither were involved in clinical trials. In 1995, H.L. herself was diagnosed with breast cancer. After a double mastectomy and reconstruction, she learned that she had two tumors in one breast and six positive lymph nodes. She joined one of Dr. Tripathy's clinical trials in which she received a standard dose of adriamycin and cytoxan and was randomized to receive taxol.

Mildred Cho, Ph.D. is Senior Research Scholar at the Stanford University Center for Biomedical Ethics. Her post-doctoral training was in Health Policy as a Pew Fellow at the Institute for Health Policy Studies at the University of California, San Francisco and at the Palo Alto VA Center for Health Care Evaluation. Dr. Cho's major areas of interest are the ethical and social impacts of genetic testing and gene therapy, and how conflicts of interest affect the conduct of clinical research.

Questions and Answers:

DT: Jennifer, recently you have been working with members of the federal government to increase Asian American women's participation in research. Do you see the Asian family as having specific cultural issues which preclude their involvement with clinical trials?

JS-H: I would like to begin my answer on a level of public policy and education. The first major barrier to Asian women's participation in clinical trials is a fairly widely held misperception that Asian women don't get cancer. The research data would indicate that Asian women have the lowest cancer incidence and mortality rate in the country. The designation "Asian" actually relates to more than 50 national and ethnic origins. But when the data is broken down, we see that Hawaiian women, for example, are second only to white women in their incidence of breast cancer. Incidence rates of breast cancer in Japanese women are second only to African American women. So the first barrier that my agency must overcome is that there is simply no need for clinical trial research in the Asian community. The perception is that they don't need to be concerned because they are not at risk. This has created a false sense of security in Asian communities. Secondly, language is a barrier. More than half of Asians report that they do not speak English well, but I have yet to see clinical trials information in Asian languages. Another barrier within the family is that Asian women tend to prioritize the health of other family members over their own health. They also don't feel comfortable talking about cancer diagnoses within their communities. NAWHO has tried to profile Asian American cancer survivors in their initiatives so that role models will be available within the community. Finally, there is distrust or lack of familiarity with the western medical system. Many Asian Americans have no history of clinical investigation. Submitting to an "experiment" does not feel comfortable to them.

DT: I would like to clarify a point and that is the difference between generations. As time goes on we will have larger groups of second generation Asians. How will these perceptions change?

JS-H: Many studies have shown that as Asian women acculturate, their risk of breast cancer increases up to sixfold. This could be a serious health risk in the future. Increased exposure to a western medical system, as well as younger family members serving as negotiators for their older family members may be helpful.

DT: We are all aware of the underrepresentation of women of color in clinical trials. The National Institutes of Health mandated that federal funded research include women of color in its design. What are your views on this mandate and what do you think are the specific barriers to participation that need to be overcome to achieve compliance?

BW: First let me say that I support the mandate but wish there were no need for one. Tax dollars are paid by all people. African American men and women are sceptical about clinical trials because of the Tuskegee study. This is a study where the government watched 100 poor black men with syphilis deteriorate without any treatment. African Americans are fearful that this will happen again when they hear about clinical trials. They are concerned that there are people who are not as ethical as other people. It is up to us to inform patients about informed consent, and about risks which they may encounter. A prime example is the recent tamoxifen trial in which less that two percent of participants were African American women. Before trials begin, women of color must be at the policy table, be a part of the research. We should not wait until the research design is set, and try to fit the community into the design. If a program is to be successful, it first must be acceptable, available, accessible, and ultimately accountable.

DT: H.L. as a breast cancer patient, what were your concerns as you moved through the process, and how were they addressed over time?

HL: After I was diagnosed, it was recommended that I take adriamycin and cytoxan, and possibly taxol, which was only available through a clinical trial. The clinical trial was clearly described to me, I had plenty of time to think about it and ask questions. I took the trial to a community physician, to get outside of academia, to see if there was something I might not be understanding. I also went to a university in the Midwest. I was approaching this very cautiously. The trial was about dosage. I would get standard treatment, or more. I was also randomized for taxol. It turned out I got standard treatment and taxol. I am doing extremely well, and not sorry at all that I went on the trial. I took all the treatment very well, and subsequently I have joined other clinical trials.

DT: In your encounters with other people, have they experienced problems with trials, or barriers to treatment?

H.L.: Most of the people who I have met, have experienced problems in that they have not qualified for clinical trials. One is metastatic and is very frustrated because she has not qualifed for any trial, so there are barriers in that respect, too.

Q#1: How might you have felt if you had not been randomized to the treatment arm of the trial, would this have affected your enthusiasm for staying in the trial?

H.L.: I may have been concerned had I not been randomized to the treatment arm of my trial.

DT: In order to test any new agent in the treatment of breast cancer, unless the outcome is shown to have a dramatic benefit, you must do a randomized trial. There has to be a control (placebo or inactive drug), or whatever the standard of therapy might be. Often there is a bias that the new drug is better. The general principle in designing a successful randomized trial is called equipoise, the need to design arms of equal weight. This also relates to what physicians and patients perceive as equal weight. The perception in H.L.'s case is that the taxol arm was better.

Q#2: What are the statistics about how many offerings are made to women on clinical trials, and what are the decline rates?

DT: In a small pilot study in our practice here at UCSF, we found that about 8% enrolled in clinical trials. This is significantly higher that the national average of 3%. Many patients are just not eligible for many trials based on the timing of their diagnosis, or certain clinical characteristics. Many trials are written with a very narrow scope of eligibility.

DT: I would now like to move on to Mildred Cho. In what ways can patients voice or have their concerns addressed regarding the uncertainties and ethics of clinical trials, especially in life threatening situations? What about loss of privacy? Loss of regular physician/healthcare links?

MC: The first place that people should go to get information is local or national advocacy groups who are savvy about clinical trials. They will tell you what questions to ask before enrolling. Secondly, you can go to the lead investigator who should have an informed consent which will have a lot of information about the specific trial or the Institutional Revew Board which will have information on many clinical trials. Any institution which does federally funded research is required to have a board like this. At the federal level, the funding source such as the American Cancer Society, NIH, or the FDA is a good place to get ethical information on a trial.

DT: Do you think that these agencies would have a more critical view of clinical trials than the university investigator? Are there any agencies that might be more grassroots oriented?

MC: The advocacy organizations that are very focused on patients might be a place to go for information that you think you can trust, although the offices within the government agencies do exist solely for monitoring.

DT: Jennifer, I would like to get you ideas on design aspects of an outreach program that might address some of the problems we have outlined as barriers to participation in the Asian community.

JS-H: The key step is to include the community from the very beginning. An example is a program called "Health is Strength" which offered a collarboration between an academic research institution and a community based clinic in Alameda to increase the use of mammography in the Korean community. From the very beginning members of the community were recruited to advisory boards to design the outreach and needs assessment. Their input was solicited as to recruitment of patients, who will interview and what the questions will be. A priority was that the education and those that educate be bilingual.

DT: Is there a trust barrier between patients in the black community and the medical community and research establishment? If so, what mechanisms might overcome this?

BW: One of the biggest barriers we have at BCEDP were provider barriers. Patients did not feel comfortable talking to them. Providers need to be representative of the culture they are serving. I developed an ethnic council consisting of women from various ethnic groups. A questionaire was developed for the patient to present to the provider. We met with the provider to discuss the responses so that they could understand the concerns of their patients. People tend to go to providers for whom they feel a sense of cultural or ethnic identity‹it's as simple as that. We have solved this problem in Alameda county where we have 102 providers of all ethnicities.

DT: H.L. in your experience as a patient, what issues should women consider when deciding whether or not to join a study, be they medical, practical or psychological?

H.L.: Probably the first thing that needs to be discussed is the language. When you are first diagnosed there tends to be a lot of terminology that you do not understand. I recommend writing your questions down and do not leave the office until those questions are answered in terms that you can understand. If a treatment is recommended which is only available in a clinical trial, what treatment is available to me otherwise? What are the side effects of treatment? All of this can be taped and listened to at home. You should not take any treatment that you do not feel comfortable with.

DT: Mildred, do you feel that physicians, based on certain trial designs might feel ethically compromised, and are there driving forces that might put them in an ethical dilemma when enrolling and conducting clinical trials?

MC: Any physician who takes care of patients and also conducts a clinical trial has a built-in conflict of interest. This may not be nefarious, but there is a dilemma. A physican's primary duty is to keep the individual patient's interest at heart. A researcher's primary interest is to maintain the integrity of the study, make sure the information in the study will be in the long range interests of patients in the future. These interests may not coincide. I would take H.L.'s advice and get all the information you can on the study. Be very proactive. Read and listen to everything that is told to you. Take responsibility for yourself. Take advantage of the IRB and the informed consent.

Q#3: What happens after several years on a clinical trial, and the evidence begins to form that one arm of a trial is looking better than another?

MC: A design element that is incorporated into many clinical trials is the concept of stopping points. Data analysis is done at intermediate time points before the end of the trial. If certain effect sizes are measured before the end of the trial is reached, the study will be stopped. There is a danger in looking at results before they are "fully cooked". You can get trends that could be misleading. Trials are set up to give answers that will give confidence in results. If they are stopped early that confidence level may not be reached.

DT: The tamoxifen prevention trial is an example. The trial was set up so that in interim analysis if women were getting more breast cancers in one arm, the trial would be stopped. After 4 years, that rule was met, and so the trial was stopped in May, 1998. However, it is not known whether being on tamoxifen saves your life or not. Maybe the cancers in women on the drug are more aggressive. Survival may not be affected. European investigators who continued the trial have not found these same differences. So although we know that in the short term, using tamoxifen can lower the change of getting breast cancer, we don't know what the long term effects are.

Q#4: I would like to pose a question about the parameters that researchers use to determine who to admit into the trial. Because I am considered "statistically terminal", I am eliminated from virtually all trials. Are there ways around those narrow eligibility criteria?

DT: Yes, the eligibility criteria for most studies are quite restrictive by virtue of the question that is being asked. We usually must have a very defined study and very discreet group of people on each trial. There is a revisionist trend developing which would simplify all these rules. Eligibility criteria will be made easy, baseline tests will be minimized, and all the rules for follow up studies will be simplified. Our hope is that we can make clinical trials easier for patients, broader in scope, quicker and less expensive. An example of this is the trial on Herceptin, the antibody to HER2/neu. It was really the grassroots advocacy community that got the sponsor of the trial to open a parallel trial that was much less restrictive.There is a cost attached to this. As you simplify the procedures, you may obscure the question you are trying to answer.

Q#5: What might be the best way to get the message regarding clinical trials in breast cancer out to women?

JT: The method most likely to be trusted by women is informal networks, word of mouth. Some atypical points of entry to healthcare are: churches, community and senior centers, peers, alternatives to traditional medical places.

H.L.: Truly education is the way. Anywhere that women gather and share information.

BW: It is not easy to go into churches to do health education. You must have an entre to that church or a relationship with someone there. There are however a good place to get the word out regarding basic health education for the population you are trying to reach.

Q#6: Do we need to design special interventions to get the word out to our ethnically diverse populations?

BW: There must be a mechanism for providing clients with access to state of the art treatment in cancer. I do not think that one exists now. We need to have someone advocating for these populations, providing them with the information in a language they understand.

DT: One important factor is where clinical trials are open and where they are not. One trend that might alleviate this problem is to get trials out into the community cancer centers, to move away from having trials exclusively at the university.

Q#7: What can we do to advocate for adequate nutrition in the underserved communities?

BW: What we are doing at Highland Hospital is look at the total women, nutrition being one component. What do you tell women who cannot afford 5 fruits and vegetables a day? We raise money to give women baskets of food, and vitamins. We also contact vendors who have contracts with the hospital and request that they contribute to this program. The patients then knows who has contributed to this program, pharmaceutical companies, etc. Another option is to go to where the produce is and request donations.

Q#8: Are institutions or physicians ever economically compromised by the enrollment of patients in clinical trials particularly in a managed care environment?

DT: We have recently developed a survey of breast care providers and found that one of the biggest barriers to patient enrollment in clinical trials is staff time and inconvenience. It takes time, infrastructure and expense. This is something that many practices are unable to do. Some ways to overcome this: grant money from the federal government as well as large insurance companies is available. Industry provides a large amount of resources to physicians and organization for enrollment of patients.

The way to make headway in research is with a true partnership of community, patients, physicians, and government. Although there are barriers and incentives on both sides, it is in everyone's interest to move forward. Our program is looking at outreach and improved information about access to clinical trials. What we need now is to make the trials more accessible. These are extraordinary tasks which will require a joint effort.