Audio and slides for this presentation are available on YouTube: http://youtu.be/49JdPPPRFNw
Cognitive effects of cancer and cancer treatment -- also known as chemobrain -- are widely recognized. Dr. Fremonta Meyer from Dana-Farber Cancer Institute, talks about what chemobrain is, research into its effects, and how to manage and/or treat it.
For more information, watch our YouTube video on chemobrain here:
http://www.youtube.com/watch?v=iK1UqTnD5GI
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How to Manage Chemobrain
1. Cognitive Changes after
Breast Cancer and its
Treatment
Fremonta Meyer, MD
Department of Psychosocial Oncology and Palliative Care
Dana-Farber Cancer Institute
June 6, 2012
2. Outline
Impact
Why focus on breast cancer?
Research findings
Interventions
4. So…
Is it real?
What causes it?
What can be done about it?
5. Patient Experiences
“I have been so lost [while
driving], I just pull over, and
break down and start crying.
Because it’s places I’ve been
before and I know where I
am going…”
“I couldn’t remember if I
looked at a stoplight. I felt
like it was putting myself at
risk.”
“What I have to do
sometimes is have my son
come over and pay my bills.”*
* Boykoff et al, J Cancer Surviv, 2009
6. Impact on Quality of Life
Distress due to lack of acknowledgment by medical
community
Mixed reactions from family and friends
Decline in job performance
Avoidance of social occasions
Depression and anxiety
* Boykoff et al, J Cancer Surviv, 2009
7. Chemobrain can affect many areas of
cognitive function
Memory
Attention/concentration
Information processing speed
Executive function
Initiation
Planning
Organization
Multi-tasking
Response inhibition
8. Research shows that the majority of patients on
chemotherapy experience cognitive side effects
67% of patients reported experiencing memory and
concentration problems during chemotherapy
These problems were still present 6 months after completing
chemotherapy
Memory Concentration
*Kohli et al, J Oncol
Practice, 2007
9. For most people, chemobrain
gradually disappears over time
17-34% of people continue to have problems
after the end of chemotherapy
Some neuroimaging studies show
improvement/resolution of regional brain
volume differences as of 3 years post-
chemotherapy
*Inagaki et al, Cancer, 2007
11. Chemobrain is not the same as dementia
Chemobrain is not a progressive condition
Chemobrain does not increase risk for
Alzheimer’s disease
The cognitive findings in Alzheimer’s disease are
different
In Alzheimer’s, memory cues don’t help
In chemobrain, memory cues help
13. Why do we study breast cancer?
Common cancer with largest population of
survivors (23%; 2.6 million)
Limited direct effects of cancer on brain other
than chemotherapy
Population allows chemotherapy vs non-
chemotherapy study designs
14. Why don’t more oncologists study this?
Oncology research tends to focus on clearly
defined outcomes or “endpoints”
Overall survival (OS)
Progression-free survival (PS)
What’s the “endpoint” for chemobrain?
15. Endpoints for chemobrain are controversial.
Functional neuroimaging findings (fMRI)
Neuropsychological tests
May not reflect “real life”
Self-reported cognitive problems
May have other causes
But, interestingly, seems to be most similar to fMRI
results
16. Empathy for your oncologist
and other physicians…
It’s important to understand where your
oncologist is coming from…
The research on this topic is very confusing
There aren’t yet any FDA approved treatments for
chemobrain
This makes it hard for them to know what to
recommend!
17. Problems with the Older Research
Cross-sectional studies
Looking only at people who already completed cancer treatment
Prospective studies without matched control groups
Looking only at people who had cancer and received chemotherapy
Not enough patients
Multiple chemotherapy regimens
Not controlling for hormonal therapies
Not controlling for patients getting better at neuropsychological tests because they
have practiced them (rather than their chemobrain actually improving)
Excluding people with depression, anxiety, sleep problems
18.
19. Summary of the better-quality research
using neuropsychological testing
8 prospective longitudinal studies with matched control
+/- healthy control group*
Acute declines in motor skills, processing speed,
verbal/visual memory which improved over time
Chemotherapy may have specific negative effect on verbal
fluency
Patients exposed to chemotherapy plus tamoxifen did
worse at later timepoints than pts exposed to chemotherapy
alone
But: 3 studies did not show any cognitive impairment with
standard-dose chemotherapy
*Quesnel 2009, Schagen 2009, Tager 2010, Bender 2006, Collins 2009, Jenkins 2006,
Mehlsen 2009, Ahles 2010
20. How would you design a
study, from your perspective
as a cancer survivor?
21. Added Observations
Some people with breast cancer (11-33%) have
cognitive problems prior to receiving any
chemotherapy at all*
Anxiety
Anesthesia from surgeries
Something that the tumor directly causes –
“paraneoplastic”
*Ahles et al, Breast Cancer Res Treat, 2008
22. The dentate gyrus of the hippocampus is
involved in the formation of new memories
24. What chemotherapy regimens do most
women receive for breast cancer?
“AC” then “T”:
A=adriamycin (doxorubicin)
C=cyclophosphamide (Cytoxan)
T=docetaxel (Taxotere)
25. What is the blood-brain barrier (BBB)?
Microscopic objects (e.g. bacteria) can’t get in. Neither can
hydrophilic molecules. But it doesn’t keep everything out…
26. Cyclophosphamide (cytoxan) and 5-
fluorouracil (often used in treatment for colon
cancer) can cross the BBB.
Doxorubicin and paclitaxel do not directly cross
the BBB.
27. In mice, chemotherapy agents appear to result in reduced
cell growth in the dentate gyrus of the hippocampus
*Janelsins et al, Cancer
Investigation, 2010
28. Take-Home Points
Even chemotherapies that do not cross the BBB (such
as doxorubicin and doxetaxel/paclitaxel) may result in
decreased neurogenesis (growth of neurons)
Growth factors may result in increased survival of
neural cells
IGF-1, BDNF, VEGF, FGF
So, if we can confirm these findings in humans, we
could speculate that growth factors may help future
patients…. BUT…
What could be the problem with giving growth factors?
*Joshi et al, Neuroscience, 2010
30. Cancer and Chemotherapy…
Leads to increased production of inflammatory chemicals called
cytokines
e.g. TNF (tumor necrosis factor)
Higher levels may predict worse cognitive function after
chemotherapy for breast cancer*
Some women had genetic differences in the TNF gene that
made them less likely to develop problems
What are these differences?
*Ganz, et al, abstract at ASCO, 2011
31. Single Nucleotide Polymorphisms (SNPs)
Variations in sequences of DNA
A single allele is different
Make us differentially susceptible
to (or protected from!) all kinds of
diseases
Examples:
TNF
BDNF (brain-derived neurotropic
factor)
Apolipoprotein (ApoE4=more
prone to Alzheimer’s disease)
These SNPs may make some
people unable to repair the DNA
damage that causes cognitive
problems
32. Hormonal therapy for breast cancer may
also have a negative effect on cognition
High levels of estrogen increase verbal memory, verbal fluency
and fine motor skills
Surgically induced or abrupt menopause
Acute decline in verbal memory
It’s unclear that hormone replacement therapy truly protects
against dementia
Tamoxifen and aromatase inhibitors (eg Aromasin, Arimidex,
Femara) may have an anti-estrogen role in some brain areas
related to cognitive function
Effects are not widespread or severe
Primarily seen in verbal memory and processing speed
33. Chemobrain is associated with several
common, treatable problems
Sleep disturbance
Fatigue
Depression
Anxiety
35. Medications-1
Stimulants
methylphenidate (Ritalin, Concerta, Focalin),
dextroamphetamine (Adderall)
Despite negative study*, they are sometimes effective in
clinical practice
Modafinil (Provigil)*
Improved attention and memory in a group of breast cancer
survivors with fatigue
*Mar Fan et al, Support Care Cancer, 2008
*Kohli et al, Cancer, 2009
37. SSRIs (e.g. citalopram, fluoxetine, sertraline)
increase levels of BDNF, increase neurogenesis,
and increase branching of dendritic connections.
38. Other Activities
Regular aerobic exercise
May improve neural proliferation
in the dentate gyrus!
In a review of many studies, this
was the only factor associated
with lowering your risk of
dementia
Social connections
Good nutrition
e.g. fish w/omega 3’s,
antioxidants, flavanols
39. First Step: Get Help!
If you’re more than 6 months out from chemotherapy and you are having difficulty
functioning in your daily life (with work, school, relationships) due to chemobrain…
Ask your oncologist for a referral to a neuropsychologist.
A neurologist can be helpful if you have a family history of dementia, or if you have
other neurological symptoms such as persistent neuropathy, headaches,
weakness/numbness in a body part, etc.
If you have any sleep problems, fatigue, depression, or anxiety:
Consider seeing a psychiatrist
Also consider seeing a sleep medicine physician (who can decide if a sleep study is needed).
Finally, make sure your PCP is in the loop.
40. Sleep Apnea…
Weight gain after breast
cancer treatment puts
people at higher risk
Masks are more
comfortable than they
used to be
Don’t give up!!
Start with a few hours a
night and work up
gradually
41. Cognitive Behavioral Therapy
Usually delivered by a psychologist, psychiatrist, or
social worker
Research shows it’s very effective for depression and
anxiety
Doesn’t necessarily change your chemobrain, but
changes your relationship with your chemobrain
Corrects negative “automatic thoughts” and distortions
43. Filtering: We take the negative details and magnify them while filtering out all positive
aspects of a situation. For instance, a person may pick out a single, unpleasant detail
and dwell on it exclusively so that their vision of reality becomes darkened or
distorted.
“Black and White” Thinking: In polarized thinking, things are either “black-or-white.”
We have to be perfect or we’re a failure — there is no middle ground. You place
people or situations in “either/or” categories, with no shades of gray or allowing
for the complexity of most people and situations. If your performance falls short of
perfect, you see yourself as a total failure.
Overgeneralization: In this cognitive distortion, we come to a general conclusion based
on a single incident or a single piece of evidence. If something bad happens only
once, we expect it to happen over and over again. A person may see a single,
unpleasant event as part of a never-ending pattern of defeat.
Jumping to Conclusions: Without individuals saying so, we know what they are feeling
and why they act the way they do. In particular, we are able to determine how
people are feeling toward us.
For example, a person may conclude that someone is reacting negatively toward
them but doesn’t actually bother to find out if they are correct. Another example is
a person may anticipate that things will turn out badly, and will feel convinced that
their prediction is already an established fact.
http://psychcentral.com/lib/2009/15-common-cognitive-distortions/
44. Catastrophizing: We expect disaster to strike, no matter what. This is also referred to as
“magnifying or minimizing.” We hear about a problem and use what if questions (e.g.,
“What if tragedy strikes?” “What if it happens to me?”).
For example, a person might exaggerate the importance of insignificant events (such as
their mistake, or someone else’s achievement). Or they may inappropriately shrink the
magnitude of significant events until they appear tiny (for example, a person’s own
desirable qualities or someone else’s imperfections)
Personalization: Personalization is a distortion where a person believes that everything
others do or say is some kind of direct, personal reaction to the person. We also compare
ourselves to others trying to determine who is smarter, better looking, etc.
A person engaging in personalization may also see themselves as the cause of some
unhealthy external event that they were not responsible for. For example, “We were late
to the dinner party and caused the hostess to overcook the meal. If I had only pushed my
husband to leave on time, this wouldn’t have happened.”
Control Fallacies: If we feel externally controlled, we see ourselves as helpless a victim of fate.
For example, “I can’t help it if the quality of the work is poor, my boss demanded I work
overtime on it.” The fallacy of internal control has us assuming responsibility for the pain
and happiness of everyone around us. For example, “Why aren’t you happy? Is it because
of something I did?”
Fallacy of Fairness: We feel resentful because we think we know what is fair, but other
people won’t agree with us. As our parents tell us, “Life is always fair,” and people who go
through life applying a measuring ruler against every situation judging its “fairness” will
often feel badly and negative because of it.
45. Shoulds: We have a list of ironclad rules about how others and we
should behave. People who break the rules make us angry, and
we feel guilty when we violate these rules. A person may often
believe they are trying to motivate themselves with shoulds and
shouldn’ts, as if they have to be punished before they can do
anything.
For example, “I really should exercise. I shouldn’t be so lazy.”
Musts and oughts are also offenders. The emotional consequence
is guilt. When a person directs should statements toward others,
they often feel anger, frustration and resentment.
Emotional Reasoning: We believe that what we feel must be true
automatically. If we feel stupid and boring, then we must be
stupid and boring. You assume that your unhealthy emotions
reflect he way things really are — “I feel it, therefore it must be
true.”
46. Naming Emotions
Anxiety= signal of an emotion that lies underneath
Primary emotions (like primary colors!)
Sadness
Fear
Anger
Guilt
Shame
Envy
Jealousy
Naming the emotion can reduce the anxiety
47. Behavioral Approaches
Behavioral activation
Systematic desensitization
Gradually exposing yourself to feared situations over
time
48. Cognitive rehabilitation helps many patients
It’s done by a speech-language pathologist
This is often covered by insurance – specifically, your physical/occupational
therapy benefit
Exercises to retrain your brain
Tracking and understanding what causes cognitive worsening
e.g. fatigue
Coping strategies
PDAs; 1 notebook w/3 sections; Note taking
Stress relief strategies
Diaphragmatic breathing; muscle relaxation; guided imagery
49. The idea behind cognitive rehabilitation is to
compensate for the deficits by learning to
work around them
“But… I want my backhand to
come back!!”
50. Newest developments are trying
to take advantage of brain plasticity
to restore function
POSIT brain science program
(http://www.positscience.com)
40-hour training program
Effective for age-related cognitive decline and mild
cognitive impairment
It’s being studied in chemobrain by Janelle Vardy at
the University of Sydney
Study results not yet available
52. Preliminary Study of EEG
Biofeedback
Preliminary data from Alvarez et al (we are submitting
to journals presently): 23 breast cancer survivors
showed marked improvements in self-reported
cognitive function, sleep, and fatigue after 20 sessions
of neurofeedback over 10 weeks
More study with neuropsychological tests is needed.
53. In order to have chemobrain, you have to be alive
Notes de l'éditeur
Lost wages, credit card late fees, higher car insurance premiums. “My condition is as real as the cost has been.”
This was a study done in 2007 in about 600 patients who were being treated with chemotherapy and radiation for solid tumors. Patients self-reported any problems with memory and concentration. Women had more symptoms than men during treatment. About ½ of patients had problems at baseline, before any treatment. This went up to 67% during treatment, and remained at 50-60% 6 months after treatment. The graphs show that chemo was significantly more likely to cause problems than radiation. They also show that for most patients, the problems were fairly mild (0=no problem; 10=worst problem you could imagine). But they suggest that people are still having some trouble 6 months after chemotherapy ends.
Basal ganglia- control the decision of which of several possible behaviors to execute at a given time
This was a study of 60 y/o twins who were raised together. Twin A had breast cancer and was 2 years out from chemotherapy; twin B did not have cancer. They put both twins in a functional MRI scanner. They tested working memory by asking the twins to listen to a string of letters presented once every 3 seconds. The twins had to press a button if the letter was a match with a designated target (e.g. “F”) or if it was the same as the letter presented 3 back in the sequence (e.g. “C”). The results were that both twins were equally accurate at the task. But twin A (top) had to activate a much larger area of the brain than twin B did. So, this may translate into twin A experiencing the task as more difficult.
And anecdotally, breast cancer survivors complain about this a lot.
Don ’t have OS or PS like oncologists!!
Most objective to least objective ; most expensive to least expensive
Unlikely to be stress of dx, given findings in stage 0 patients vs stage I-III pts. RF: higher levels of proinflammatory cytokines may be correlated with both cancer and MCI/AlzD, or polymorphisms in DNA repair genes
In this study (published in early 2011) researchers wanted to see if the chemo drugs that cross the BBB were more likely to interfere with growth of neurons than the chemo drugs that don ’t cross the BBB. They took mice and gave 1 group saline and the other group chemotherapy. On the 2 nd day, they injected all the mice with a tracer chemical that binds to neurons. On the 3 rd day, they sacrificed the mice and isolated their brains. Then after 5 days of incubation they examined the dentate gyrus. What they found was that all of the 4 chemotherapy drugs, even the 2 that don’t cross the BBB, caused reduced growth of neurons. The reductions ranged from 15% to 36%. There was no cell death – only a slowing in growth.
Growth factors are proteins that stimulate cells to grow and mature. Some of you probably took Neupogen during chemotherapy (G-CSF). This is a growth factor that stimulates white blood cells to grow. They are many others which make other cells (including neurons) grow.
b/c Self-reported cognitive dysfunction correlates with these sx – NOT objective cognitive findings
In a study published on Jan. 31, 2011, in The Proceedings of the National Academy of Sciences, researchers randomly assigned 120 healthy but sedentary men and women (average age mid-60s) to one of two exercise groups. One group walked around a track three times a week, building up to 40 minutes at a stretch; the other did a variety of less aerobic exercises, including yoga and resistance training with bands. After a year, brain scans showed that among the walkers, the hippocampus had increased in volume by about 2 percent on average; in the others, it had declined by about 1.4 percent. Since such a decline is normal in older adults, “a 2 percent increase is fairly significant,” said the lead author, Kirk Erickson, a psychologist at the University of Pittsburgh. Both groups also improved on a test of spatial memory, but the walkers improved more.
I think it ’s important to mention here that there is a stigma associated with seeking help for emotional problems. Many of you may never have done this before cancer. But I think at the same time when you’re in this situation it’s even more important to challenge yourself on that stigma and take advantage of any resources that may be able to help you.
I ’m a psychiatrist, so I can’t get through a talk without focusing on some of the areas
Here, physical reactions can be replaced with “cognitive side effects/chemobrain”
Brain plasticity refers to the brain ’s ability to change at any age (not just in childhood). Gray matter can grow or shrink. Neural connections can be forged, or severed. Forgetting a name reflects weakened wiring. Learning a new dance step strengthens a set of wiring.
Growing out of the emerging recognition that brain function is far more distributed than localized, with each neuron broadly connected in networks, it uses a single sensor for each hemisphere (placed midway between the top of the ear and the crown of the head), and simultaneously analyzes the activity at eight clusters of frequencies ( “time-frequency envelopes”) in each hemisphere. The software does not reward the brain for movement toward a “normal” or “desired” pattern, but simply provides information to the brain—in the form of very brief subliminal interruptions in music the subject is hearing—whenever the brain shows signs of turbulence (indicated by phase state changes) in one or more of the 16 time-frequency envelopes. These brief interruptions trigger the orienting response in the brain, which—as a complex adaptive system—is able to self-organize in a way that avoids continued turbulence and moves to a more optimal dynamical pattern of flexibility and resilience. Interestingly, the concept of “turbulence,” as used in this software, is a mathematical concept, not an experiential one, so the client undergoing this form of neurofeedback is generally unaware of the brain activity triggering the feedback and the brain’s response.