WEDNESDAY, April 10, 2002

"Where Are My Keys?: Cognitive Dysfunction After Chemotherapy for Breast Cancer"

While the topic of neurocognitive change--or how our bodies react to the drugs, hormones and toxins that we use--is an important one, it is one we know little about. While the chemotherapy that is used for breast cancer is not as intense as that which is used for many other cancers, it clearly has side effects that can be measured and quantified. We know how many patients lose hair or develop infections, but it is very difficult to quantitatively measure the expected changes in cognition, even though this is a very important element in a patient’s decision-making.

Dr. Hope Rugo is putting together a nationwide network of clinicians who are studying the theories behind cognitive changes.

HR: The big questions are when should we test and how to test. All the studies to date have looked at the women who are getting chemotherapy, or who were tested a long time afterward. The question is, "To whom do you compare them?" Any other group of women who have not had chemotherapy, even those matched for age, socioeconomic status, and education, can have a testing bias. You don’t know if it is a difference between groups or a testing phenomenon, or something else. And you really don’t care how you compare to the woman sitting next to you. You want to know how you compare to yourself—how has chemotherapy affected you. None of the studies to date have tested the women from diagnosis, all the way through treatment, and for some time afterwards. We did a small study with women with high I.Q. and high socioeconomic background. Right at the time of diagnosis, they had high anxiety, and scored low on the tests. As they became more familiar with the testing situation, they began to score higher, even though they were now receiving chemotherapy. This suggests that much of the cognitive dysfunction was a result of the stress of diagnosis and decision-making, although women who didn’t receive chemotherapy recovered sooner and better. Another big issue is how to do the testing. Most of the tests are quite complicated; they take at least 2 hours of time and involve tasks such as pegboard, computer, paper and pencil, etc. But do we really want to know how patients perform on these tasks or do we want to know how patients perform on tests of executive function? Development of this type of test takes expertise. They are quite expensive to produce and administer.

What is the effect of estrogen? Is there a cognitive decline associated with taking Tamoxifen or going into menopause due to chemotherapy? There is a lot of controversy over this issue and we don’t yet have an answer. It appears that in women with normal cognitive function, the effect of estrogen is quite minor. In women who are impaired, say with schizophrenia, the effect of estrogen is more marked.

Is there a way to identify the populations of women who might be at risk? There is an area of research. A group at Dartmouth is looking at a genetic marker to see if there are people at particular high risk for cognitive effects of treatment.

Is there a treatment? The NCI is funding a prospective trial to test women at the time of diagnosis, at the time of their surgery, as they go through their treatment and then 1-1/2 years after their chemotherapy to see what and when the effect is on cognitive function. Some studies are looking at the red cell growth hormone erythropoetin to see if making more red blood cells and more oxygenation to the brain might actually reduce the cognitive effects of adjuvant chemotherapy.

Has anybody looked at the side effects of benadryl which is given to breast cancer patients along with chemotherapy? Benadryl is given with taxol for a number of different cancers, and cognitive dysfunction has been seen in cancers other than breast. A study at Dartmouth looked at women diagnosed with breast cancer and with men and women diagnosed with lymphoma who might have received drugs like adriamycin. The results between the control and treatment groups with the two cancers were similar at 10 years. Looking at small cell lung cancer, where patients received prophylactic whole brain radiation, predictably saw tremendous cognitive dysfunction. The challenge in this field is the number of variables that need controls.

What are the side effects of Nuprogen? There was some concern that hyperstimulation of the bone marrow might cause leukemia, but not a lot of Nuprogen crosses the blood/brain barrier, and the most recent large studies have disproven it. There is a lot of interesting data on Procrit. The glial cells in the brain have receptors for erythropoetin. If you give mice erythropoetin and put them through mazes they will learn faster in less time. Rats that have had brain damage induced by cutting off blood vessels took twice as long to develop it when on erythropoetin. This has lead to research on stroke and CNS trauma.

Does erythropoetin impact the DNA? It stimulates the red blood cell recursors, but there is not direct effect on DNA.

What is the effect of chemotherapy on blood vessels and could it be related to cognitive changes? Cognitive changes are real, but we don’t yet know the underlying physiology. There are two general kinds of side effects that seem to be very irritating to the blood vessels. Vessicants are drugs that have enough toxicity to injure cells on contact (adriamycin, Navelbine are examples). Non-vessicant drugs like 5-FU, taken orally, can cause scarring of the vessels or inflammation of the veins. These effects usually go away over time. There are theories that chemotherapy can inhibit the development of new blood vessels at low doses. This is known as anti-angiogenesis. Angiogenesis is the process of blood vessels forming normally in embryonic growth or in wound repair. Tumors need a blood supply to grow. This is abnormal angiogenesis and could be related to cognitive changes. Thickening of the blood vessels can lead to small strokes and early dementia, but 5-FU has only rarely shown this side effect. It is probably multifactorial involving menopause and stress. PET scans and MRI are useful in patients taking Tamoxifen to highlight redistribution of blood flow in the brain.

Is there any evidence that short term memory and concentration are affected? There are three studies. One looked at people at 10 years and showed relatively small deficits when compared to a control group. Another study looked at women who were getting CMF and women 3 years out from their chemotherapy. It showed that women getting chemotherapy had lower cognitive function. A third study looked at women getting high dose chemo, standard dose and none. The findings show that high dose chemotherapy is associated with higher levels of cognitive defect. The problem is that they have not broken down cognitive defect into areas like short and long term memory, attention deficit, eye-hand coordination. To test all these areas requires a test at least two hours long and is exhausting. We are aiming for shorter tests, screening for what people think is important. We are not looking for short term effects, rather the goal is to test at the beginning and end of therapy and then a year and a half later.

What drugs are effective antiangiogenics? About 50 antiangiogenic drugs are in clinical development, none seem to be dramatically effective. Of the drugs which have been tested, the one garnering the most attention is the antibody to a growth factor, VEG-F. A Phase I trial was done in which a small number of patients had transient responses. Some people got hypertension, blood clots and kidney side effects. As a single agent it is not effective enough. A large study just completed compared chemotherapy (Xeloda) alone to chemotherapy plus the antibody (VEGF). It will be interesting to see if the patients that got the antibody had a better response to therapy. Thalidomide has no effect in breast cancer but seems to be effective in multiple myeloma. Oral drugs that block new blood vessel growth from the inside of the cell are called tyrosine kinase inhibitors. Gleevec has been proven effective in chronic myologenous leukemia.

Is there an association between Taxol toxicity of the peripheral nerves and cognition dysfunction? Peripheral neuropathy is the damage to the small blood vessels that causes numbness and tingling to the fingers and toes. Currently there has been no association made to cognitive dysfunction. Taxol toxicity to the nerves is a direct toxicity.

What is the difference between Tamoxifen and the aromatase inhibitors? Tamoxifen is a drug that blocks the estrogen receptor in the cancer cell. Aromatase inhibitors block an enzyme which converts testosterone to estrogen in menopause. These drugs completely block the growth factor rather than the receptor. Preliminary results show that there may be some benefit to an aromatase inhibitor, Arimidex, over Tamoxifen.

Any research on the effect of exercise? Endorphins seem to help mental acuity on Tamoxifen. There are some medications which produce this effect, like Ritalin, but they have side effects. There is data that suggests that women who exercise a lot tend to do better with their treatment.

When is a study of sufficient size? It depends on the effect of the drug you are looking at. If the drug has a big effect, the size of the study can be smaller. The study that looked at the effect of Tamoxifen on node negative breast cancer had to be quite large. In order to pick up a 2% difference, you need several thousand. Generally, in metastatic cancer where patients have a greater likelihood of progressing, trials tend to be smaller: hundreds of patients rather than the thousands of patients seen in trials for early stage breast cancer. Drugs tested to improve cognitive function would need to be quite large, at least 600-800 patients. There are statistical formulas which tell you the number of patients needed to achieve certain levels of statistical confidence. Not all treatment options are data driven—we also use common sense.

Are there trials on looking at different ways of giving Taxol in relation to neuropathy? There is still a problem in gauging neuropathy and measuring it. The older literature is based on what patients report rather than detailed questionnaires looking at the effects of Taxol.Taxol weekly versus every three weeks show different side effects, but neuropathy is not very schedule-dependent. In a large ongoing study, the neuropathy rate was higher than expected, but when there was a small drop in dose, the neuropathy rate went down in the weekly arm. One of the problems with population-based studies is they do not answer what will be right for a given individual.

Does neuropathy become worse as treatment progresses? 3 to 6 weeks after finishing the chemo we still see some, but there have been no reports of very delayed neuropathy. Radiation can make it worse. As nerves regenerate, the pain might be worse than when there is numbness, but this is actually improvement.

Does glutamine help? There are some anecdotal reports that it does. You have to take a lot, 10 grams three times a day. It may be beneficial and is worth studying.

What are your impressions of the treatments currently available for cognitive dysfunction? We have definitely determined that there is a problem, but for now have no definitive treatments. Erythropoetin may help by reducing fatigue, and possibly a Ritalin-like drug, but the research is just not definitive. Much depends on where you are in your treatment. It is useful to treat anemia even if it is mild. We emphasize the impact of exercise, and not doing too much during chemotherapy so that fatigue is minimized.

Any other strategies? Rehabilitation seems to have a small effect. Time away from work or vacations haven’t been studied. As with Alzheimer’s, more stimulation may be good. Everyone seems to believe that chemotherapy has a real impact on cognitive function, but the evidence is just not there yet in terms of scientific studies. We can’t even say that it is a measurable phenomenon. Feasibility is important in designing a clinical trial, so although it is important to hear what patients have to say, we also need to know what the intervention might be and how to have good compliance.

What would a patient be willing to do? About half the women would be willing to participate in a 1-1/2 hour questionnaire at the beginning of their chemo, about halfway through, at the end, and then again in 6 months time. Most people thought that two hours was too long.

Why is "chemo"brain so prominent with breast cancer? It is not confined to breast cancer patients, lung cancer patients with brain radiation display the same symptoms. The numbers are large because breast cancer is common and many people get chemotherapy. It affects women at an age when they are very productive and aware. Fortunately many women will enjoy long-term survival and be well, so some cognitive dysfunction is very evident with these patients.