WEDNESDAY, JANUARY 12, 2000

"Making Decisions in the Face of Uncertainty"

Most people face uncertainty in their lives every day. When this uncertainty involves living with breast cancer, it causes disruption in people's lives. The human body is extremely variable, unpredictable, yet people still want an answer to "What is happening to me, will I die, will I respond to therapy?" In a behavioral sense, because we don't know the cause of breast cancer, we can't know if we are doing the right thing to prevent it. A common sense approach to alternative therapies like yoga, exercise, meditation, etc. is: if it feels right, it usually is right. In research done by Dr. David Spiegel on the role of group therapy on living longer, it was found that the worse outcomes occurred in the socially isolated (especially single men). Although we are not certain as to the reason for this, we can assume that singles don't tend to take as good care of themselves as people living with others. Social interactions are especially good for the cardiovascular system. Psychoneurology and immunology are not well researched. Dr. Spiegel's study was retrospective, so there was no way to study other variables. Prospective studies are underway and should provide more answers.

Don't generalized statistics tend to elevate uncertainty? Generalized statistics do tend to elevate uncertainty. The estimates we can give are only probabilities, that is, a certain percentage of people with specific characteristics will respond to a certain treatment in a certain way. If we start to individualize information we run the risk that the statistical power and error rate of the calculations will start to rise, estimates of risk start to lose precision. The only way to avoid this is to study a large population. The larger the database, the more refined the estimates. Probability data should be seen as providing guidelines. Some patients want to do everything they can, others just want to know all their options. Statistics should be presented with a balance of facts and hope and need because medical survival curves can be harsh.

What about when the statistical population bears no relevance to the patient? Statistics generally control for the treatment variables, that is, the study will compare the treatment option with a control or the standard of care balanced for age, tumor status, etc. It is true that is may be hard to compare studies done in the 1970's with today's clinical trials.

Who will discuss these factors with the patient? An oncologist who sees a fair number of breast cancer patients should be able to convey a reasonable sense of the risks, benefits, and side effect profiles. This information should be communicated to the patient in detail so that the patient can make the best decision based on their own individual profile. To take the example of a 75 year old woman with DCIS and a history of heart problems, although there might be a small benefit from the use of tamoxifen, the risk of cardiovascular problems would probably far outweigh the benefit and should not be recommended. In the case of this same woman with an ER+ tumor and 7 positive nodes (instead of DCIS), tamoxifen would probably have a bigger impact on her mortality than the possibility of an adverse cardiological event. In this case tamoxifen should be used.

Has the death rate from breast cancer remained the same for the last 20 years? The incidence of breast cancer has gone up while the death rate has remained the same. This is due to early detection from mammography and more effective therapy for early stage breast cancer. Treatment for metastatic disease has not undergone dramatic change and very few randomized trials in metastatic cancer have shown a survival benefit. But the odds of survival have gotten better. Early detection is still the best chance to avoid metastatic cancer.

What is a recurrence? A recurrence is the growth of some cells that were left behind when the initial tumor was removed. We know this because genetically analyzed tumors are found to be clones of the original tumor. The mystery is why it takes so long for cells to re-grow in some people. The concept of tumor dormancy and reawakening relates to the fact that even though there are shed cells, they will not all grow at the same time, and in some cases they will never grow at all. Tumor dormancy may relate to the inability of blood vessels to form. Some change in the cell or in the host (body) will activate the cells and cause a recurrence of the cancer.

Should therapies that were effective be used again after a recurrence? In general if a patient shows a sensitivity to a drug, and takes a longer time from diagnosis to metastasis, they will do better in terms of survival.

What about the recently published research regarding number of nodes and risk of recurrence? This study, while intriguing was not a prospective study and did not involve many patients. They did not control for tumor size or grade. It would be more believable if they had looked at the number of nodes taken from each node negative patient.

Why do breast cancers tend to metastasize to bone? Researchers don't really know the reason for this. They postulate that this may have to do with a series of proteins know as addressins which perform somewhat like an address label, telling proteins that are being expressed where to go in a cell. Another possible explanation has to do with the vascularity of the organ. The greater the vascularity of the organ the greater the likelihood of metastasis. Recent research with bisphosphonates which protect the bone (like Clodronate and Zolendronate) has shown some encouraging reduction in metastatic disease to the bone and organs like the liver.

Why are vaccine studies done on metastatic patients first? It is true that there never has been a vaccine compound that was studied in the adjuvant setting without first having some success in the metastatic setting. This is a dilemma because if the treatment doesn't work for metastatic patients, we may never know if it would have worked on patients with early stage disease. A practical reason for this problem is that we are dealing with limited resources and must prioritize funding based on "proof of concept". We need a better predictive model to tell us which strategy is going to work, so we can go right to the adjuvant setting.

Do bone marrow micrometastases tend to be more frequent in people with more aggressive cancers? Yes, while certainly not a guarantee of recurrence, micromets in the bone marrow tends to increase the risk of having a recurrence. More aggressive cancers have an increased proportion of bone marrow activity. With negative nodes and a negative bone marrow biopsy, the risk of recurrence is so low that you may not need any further therapy. UCSF is currently involved in research studying the characteristics of marrow and what makes cancer cells move to the bone.

Is consolidation ever used as a proactive measure? Consolidation usually refers to giving additional chemotherapy after the standard treatment but before recurrence in disease. This concept clearly works in leukemia, one of the first cancers to be cured in the 1950's. So far the consolidation studies in breast cancer have not been positive. Consolidation with biological drugs like protease inhibitors may be more successful.

At what percent reduction in risk should chemotherapy be considered? Generally chemotherapy will be recommended with at least a 3% benefit, but this should be considered in a more individualized light. Factors like whether or not the patient has children should be considered.

When discussing the significance of the results in research studies, what size population is large enough? A more important factor is the heterogeneity of the subject population. The greater the variation within the subject population, the larger the group you need to make a significant statement. Breast cancer patients tend to be rather heterogeneous, hence a study needs to be rather large. Ultimately, everyone must set their own threshold as to what is right for them, especially with toxic therapies.

What are some alternative therapies that should be studied? We need further studies and clinical trials to determine the safety and/or efficacy of macrobiotic diets, iscador (mistletoe), and Chinese herbs. Tibetan herbs to alleviate side effects of chemotherapy are currently in clinical trials at UCSF.