WEDNESDAY, JUNE 10, 1998
"Integrative Medicine for Breast Cancer: What is the Best Model for Continuing Conventional and Alternative Approaches?"

ASCO UPDATE:

The most interesting finding to be presented were the results of two prevention studies: one was designed to prevent breast cancer using the drug tamoxifen. It has been known for some time that using the drug in adjuvant studies one could lower the risk of recurrence. Women given the drug were also noted to have fewer new breast cancers in the other breast. Tamoxifen almost cut in half these new cancers. This led to the design of a large trial for women at higher risk. In 1992 the trial was open to any woman between the ages of 45 and 70 as long as they met the risk criteria (risk of cancer equal to 60 year old woman, family history of breast cancer, etc.). The women were assigned either to tamoxifen or placebo for 5 years. After 4 years they analyzed the data, and found that the incidence of cancer in the treated half was about half that of the control group. Of the 13,000 women studied, 150 cancers were found in the control group and about 80 in the group receiving therapy. Preinvasive cancers were also reduced in the treatment group, as were the number of fractures found. The negative findings included increased numbers of uterine cancer and increased blood clots in the tamoxifen group. Those women who developed new cancers tended to be ER(-). Because the trial was stopped early, we may never really know whether we have increased survival statistics. This is one criticism of stopping the trial early and is certainly an issue to be considered. Once a treatment is found to be valid do you let the community know or continue with the trial?

Another area of prevention being studied is a drug called roloxafene, a small chemical refinement of tamoxifen makes it stimulate the uterus less, and presumably will not increase the risk of uterine cancer. This drug also reduces the risk of osteoporosis. The study was designed to look at rates of osteoporosis in women over the age of 65 with low BMD (bone mineral density). 10,000 women were enrolled and followed over a 10 year period in a drug vs. placebo trial. Preliminary results indicate a 70% reduction in the odds of getting breast cancer for the treatment group. Those cancers were also a higher proportion of ER(-). Studies must be done with early stage breast cancer in order to see if roloxafene can be substituted for tamoxifen, but these large studies take time. Negative side effects, such as memory loss, hot flashes, etc. still remain the same for both drugs, but a reduction in uterine cancer was seenwith roloxafene. Tamoxifen also cuts metastatic recurrence by 45%, so there would be a reluctance to move to a drug that hasn't yet been tested and may never be tested, due to high costs of testing.

Two seminal papers were presented in the area of adjuvant therapy, treatment following surgery in early stage breast cancer. One group of patients with negative nodes was treated with chemotherapy CMF or CAF with and without tamoxifen. The group with tamoxifen did a few percentage points better, and the CAF group actually did 1% better than CMF. The study was large enough to make this a significant difference. The other study investigated the addition of taxol to adriamycin and cytoxin. It compared patients with positive nodes with AC and then AC plus taxol. Various doses of adriamycin made no difference, but the addition of taxol made a 4% difference in recurrence risk. There was no effect on cardiac toxicity with taxol, but when all patients were checked, 6% of patients in all arms had some cardiac problems. Cardiac toxicity with adriamycin may be underestimated.

Two large HER2/neu studies were big news. In the antibody alone study, 222 women who had received 2 or more chemotherapies for advanced cancer received herceptin: 15% had shrinkage of their tumors, and time to progression was about 9 months. Positive effect is defined as 50% shrinkage of tumor held for at least 4 weeks. The chemo plus antibody study showed a strongly positive effect. Those patients given AC with and without the antibody had a longer time to progression and a better response rate. Herceptin clearly adds some benefits to patients whose tumors overexpress HER2/neu.

There is now a study planned to look at Stage III cancer with AD, then taxol, then cytoxan. After checking the cardiac issue to establish safety, they will go to a large, randomized study. Knowing that herceptin is so effective with taxol, the trial should have a treatment arm: AC then taxol then antibody. The ethical question is: Should there be a control arm knowing that the treatment has such a positive effect? An uncontrolled trial is usually considered more suspect that a trial with a control arm, especially when the benefit is small. It sometimes takes a lot of courage to move forward in a different direction, and valid data is essential. Currently you need to be metastatic to use herceptin.

ALTERNATE AND COMPLEMENTARY MEDICINE

At the Breast Care Center, we have developed a two pronged approach to studying alternative medicine with a research focus. First we want to determine practice patterns: who is seeking alternative medicine, what are their reasons, what kinds of Western medicines are they using, are they experiencing any side effects or benefits. Then we are planning a cohort study: develop a registry and then simply follow people. This type of study does not require FDA approval, and so is much easier to set up. We have decided to focus on Traditional Chinese Medicine (TCM) because it is widely used here in the Bay area, there are many texts available, and licensure is required in California, so there is some standardization among practitioners. The plan is to enroll patients with any stage breast cancer, who are using TCM. They can be using any other modality as well. Histories (epidemiologic, environmental, family, medical, etc.) will be obtained, and then we will follow their outcomes over time. We will be working collaboratively with TCM practitioners, who will be responsible for filling out case reports which will detail herbs prescribed, acupuncture points used, etc. We will then analyze the relationships between Eastern and Western diagnoses. For example does a patient diagnosed with stagnant liver function have a more aggressive cancer? Are there obvious benefits or side effects to taking certain herbs?

The next approach will be to see if there are some areas in which we can do a controlled randomized study. This will begin this month. We have decided to use an herbal regimen which is designed to alleviate side effects of chemotherapy. In China, we found a remarkable consistency in the prescription of herbs for certain conditions. For our study we have created a powdered herbal compound. The study will recruit women who are taking AC and are willing to be randomized to herb vs. placebo. We also want women who have not used herbal therapy previously. This is basically a feasibility/toxicity study. With our plan for 60 patients we don't expect major changes, but would like to track for better white counts, less nausea and vomiting, less fatigue, and other quality of life changes. We then plan to look at women with menopausal symptoms taking herbs, women with fibrocystic breast disease who have no cancer, but pain, and after applying to the FDA, studying certain herbs in the laboratory. There are some cautions: herbs from India are proving difficult to use due to chemicals in them. Also some herbs contain estrogenic compounds, so they could be potentially dangerous to some patients. There are potentially large risks and benefits in alternate therapy, probably best worked in conjunction with Western medicine.

Based on studies of fatty tissue, people that modify their diets can affect their relationship to the clinical course of cancer. Fats, soy, fish oil are all being studied in ongoing pilot studies, but there needs to be a change toward individualization of programs, to see what cancer benefits from what modification of diet. This will not be the same for all people. There is also an ethical question about doing nutrition studies on women with metastatic breast cancer. Is is reasonable to ask to withhold other treatment if their cancer is not immediately life threatening? How else can you develop a control group? Dr. Al Mulley from Boston proposes a patient choice model to help patients make better choices. People who have strong feelings in either direction regarding randomization or being deprived of treatment options could make their choices, while those people who do not feel strongly could be part of the randomization process. This is not a perfect solution, but might work in some cases.

How effective are herbs on cancer patients in China? In two studies, over 1000 patients with either lung or gastric cancer were studied. Patients either received standard chemotherapy or chemotherapy with herbs. Both studies showed improvement in survival in patients who had chemotherapy plus herbs. While these studies have some problems from a Western point of view, the arms weren't balanced so that the modes cannot be compared, they are still significant. Although breast cancer is on the rise in Chinese cities, no such studies are being done for breast cancer.

The Office of Alternative Medicine, part of the National Institutes of Health put out requests for studies on acupuncture. Andy Avins,M.D., Ph.D., a member of the Board of Directors of UCSF's Center on Integrative Medicine is a clinical trials design expert. He designed the acupuncture study here. It will look at nausea and vomiting after chemotherapy for breast cancer. It was hard to take the conventional method of therapy using standard doses and giving them to patients regardless of their condition, and fit this with the alternative model, as acupuncturists don't work that way. They check pulses, look under tongues, all treatments are individualized. This study will take two cohorts of people: one will use specific acupuncture points, another will use sham points, and another will use none at all. We will hope to find out if there are differences between the points stimulated. One possibility is that acupuncture works as a non-specific irritation, and that any stimulation has an effect. Or there may be no differences between the arms of the study. This is a feasibility study, the hope is to lend credibility to the research in this area. There has just been a large endowment by the Osher Foundation into research into alternative and complementary medicine. Everyone is reminded that the Symposium on Integrative Medicine will be on October 24, 1998. More information will be forthcoming on this important event.