Saturday, June 22, 2013

After Chemo | The Scientist Magazine

When my mother was treated for inflammatory breast cancer 20 years ago, I watched as she forgot appointments, where she had put her keys, and whether or not she had taken her medications. Once she even put a chicken still in its wrapping into the oven and didn't realize the mistake until the plastic began to smoke. As a psychologist and a pharmacologist, I suspected what many patients complain of to their oncologists: that the chemotherapy was affecting her ability to remember and to reason.

The American Cancer Society estimates that more than 1.65 million new cancer cases will be diagnosed in 2013. For many cancers, the prognosis will be very good. For example, 90 percent of breast cancer patients will survive their cancers for at least 5 years. But while cancer chemotherapy is lifesaving, it also has a number of post-treatment adverse effects. Despite the fact that most chemotherapeutic agents do not enter the brain in significant amounts, recent research has shown they can directly and indirectly produce a number of acute and delayed changes to the central nervous system, such as headaches, vision or hearing loss, and cognitive dysfunction, colloquially called "chemo fog" or "chemo brain." These effects can last for years, then dissipate, or, when they occur in young children, can ripple into adulthood.

In part because of my own experience and in part because my colleague Robert Raffa at Temple University suggested I collaborate with him, I began to research the phenomenon of chemo fog. What I learned at the start was that little preclinical or animal research definitively linked chemotherapy to cognitive effects, and some researchers didn't believe that chemotherapy was really responsible for the observed decline. In recent years, however, more clinical and preclinical researchers have begun to tease out the contribution of chemo, and have created models that are a useful first step in developing interventions that could mitigate the cognitive decline.

From the clinic

It is challenging to pinpoint whether the drugs used to kill cancer cells are really causing cognitive deficits, because there are so many confounding factors that cloud the observations. Patients are often administered multiple cancer chemotherapeutic agents in different phases of treatment, as well as additional drugs to mitigate the accompanying nausea, fatigue, suppressed immune function, and anemia. Aside from this battery of drugs, surgery can also affect cognition.

In addition to factors that can affect the brain directly, chemotherapy has been known to induce menopause in premenopausal women and bring on depression and anxiety, both of which can affect cognition.1,2 What makes it even more difficult to pinpoint the effects specifically caused by chemotherapy is that not all cancer patients will exhibit cognitive deficits—the prevalence ranges from 17 to 75 percent in breast cancer patients, for instance, depending on the drugs used and the cognitive tests employed by the study. And patients can experience the effects years or even a decade after treatment has ended. Thus, controversy remains over the existence, extent, and underlying mechanisms of chemotherapy-induced cognitive dysfunction.

A number of clinical trials and animal studies have tried to address some of the confounding factors and reveal the precise contribution of chemotherapy treatments. Part of the difficulty in identifying cognitive changes in humans can be attributed to how and when baseline measures of cognitive function are taken. Chemotherapy-induced cognitive deficits are best measured with a full battery of neuropsychological tests administered by a psychologist trained in performing such surveys. However, these tests can be expensive and time-consuming, so about half the clinical studies in this area have used simpler, but less-informative, screening measures. In longitudinal studies, the baseline control tests can be administered before diagnosis to rule out the emotional impact of the news on cognition, before surgery to remove tumors, and after surgery but before chemotherapy, which together provide results that aren't easily comparable. These methodological differences add to the variability in the field, and researchers have begun to call for consensus in the timing and quality of testing.

Despite these difficulties, neuroscientists have been making progress in identifying some of the underlying brain structures that chemo may be impacting—information that will be helpful in categorizing the deficits and knowing what to test for in cognitive experiments. Imaging studies have revealed volume decreases in areas of the brain that correlated with poor attention and impaired memory. Functionally, even years after chemo, patients showed lower levels of responsiveness in both the prefrontal cortex—which is involved in executive functions such as decision-making and social behavior—and the parahippocampal gyrus, which feeds into the hippocampus and is involved in memory formation and retrieval. Using magnetic resonance diffusion tensor imaging, which produces a structural picture of the functionality of the neural tracts, researchers have also found decreased structural integrity of white matter in a number of brain regions, including frontal cortex, as well as white-matter microstructure damage in breast cancer survivors.3 

The majority of clinical studies examining chemotherapy-induced cognitive deficits have been performed in women with breast cancer because of how long they tend to survive after treatment and because the chemo regimens are somewhat more standardized than for other cancers. However, the Childhood Cancer Survivor Study has also been following patients treated as children with chemotherapy for acute lymphoblastic leukemia (ALL) and measuring the prevalence of chemotherapy-related cognitive deficits later in life, known as late effects. These effects, which include impairments in attention, working memory, IQ score, and processing speed, manifest in adolescence and young adulthood in 40–70 percent of ALL survivors. Evidence from neuropsychological and physiological testing has indicated involvement of the hippocampus, prefrontal cortex, and white matter, but few imaging studies have been done in children to confirm the areas implicated by cognitive tests.

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