On day 3 of the Experimental Biology conference, I listened to a fascinating talk on cognitive dysfunction following chemotherapy, how we can study it, and how we might go about treating it. Check it out.
When we think about cancer, what we usually think about is a cure. Science has made great strides in treatments for cancer, such as chemotherapy, radiation, and surgery. Some cancers, such as breast cancer and childhood leukemia, have 90% survival rates, and survival is always a cause for celebration.
But with the success cancer treatments, questions arise after the celebration. What are the long-term effects of chemotherapy? How will someone’s quality of life be impacted after the cancer? These are important questions to ask. Chemotherapy has many side effects immediately after delivery; everyone knows about the nausea, vomiting, and headaches. But there are also consequences of chemotherapy in the long term, including cognitive dysfunction. Patients who have been treated with chemotherapy for leukemia as children suffer from increased medical complications, poor academic outcomes, and impairments in executive brain function such as working memory and attention. Adult women who have been treated with chemotherapy for breast cancer show problems with memory performance, which correlates with brain changes included decreased volume in areas like superior frontal gyrus and parahippocampal gyrus, important areas for learning and memory.
How do we go about trying to help people with this cognitive dysfunction? The usual “cognitive enhancers” like Ritalin may work, though they might have a larger side effect profile in some people who have undergone chemo, and Modafanil also shows promise. Erithropoetin works during chemotherapy, but what about later? But the real issue is not treatment, it's know why people who undergo chemotherapy have long-term cognitive dysfunction. How does it occur? What does it mean?
If we are going to help the cognitive dysfunction that occurs after chemotherapy, we need to find ways to study it. There are many potential confounds. First, there are the confounds associated with cancer itself: fatigue, the effects of surgery, elevated cytokines and other inflammatory markers. Chemotherapy drugs are often given in batches, and the combinations are often changed. There are many things that could confound how much cognitive impairment cancer patients experience. In order to try and get around the many confounds associated with studying the cognitive effects of chemotherapy in humans, Ellen Walker and her group at Temple University are looking at the effects of chemotherapy drugs in mice, looking in particular at adults, and at juvenile mice treated with chemotherapy.
First, the group looked at adult female mice doing an operant task, putting their noses into a nosepoke hole to receive food. The animals learn the task on the first day, and are back into the test the second day, to see how well they recall what they learned.
Walker and her group found that chemotherapy drugs like paclitaxel, carboplatin, and 5-Fluorouracil disrupted the performance of the mice, and the effects were not dose dependent. In a dose-dependent response, the learning deficits would get worse as the dose increased, but in this case, the effects of learning were actually worse at lower doses of carboplatin, meaning that we can’t just lower the dose to try and prevent the effects of cognitive impairment.
Walker et al also wanted to look at the effects of chemotherapy in a childhood model. So they looked a young mice treated with the chemotherapy drugs mexthotrexate or cytarabine individually and in combination during development, carefully mimicking the doses used in humans. Then they tested the mice in a cognitive test called ‘novel object recognition’ when they were adults. Novel object is fairly simple, you give a mouse a single object on the first day, which it explores and gets to know. On the second day, you give it the first object, and a second, unknown object. This makes the mouse discriminate between an object it has seen before and one it hasn’t. Mice treated with methotrexate or cytarabine showed deficits in novel object discrimination, suggesting that being treated with chemotherapy drugs during development resulted in cognitive deficits, similar to those seen in humans.
And the changes went further than cognitive deficits. The mice treated with chemotherapy during development also showed more sensitivity to the rewarding properties of amphetamine (spending more time in drug paired environments).
By developing models of chemotherapy treatment in mice, Walker et al hope to understand the mechanisms that might underlie the cognitive dysfunctions seen in humans. Then, they hope to find ways to help, and help cancer survivors experience their new lease on life without some of the problems that might go with it.