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

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

3. What symptoms are you experiencing?

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

10. Chemobrain leads to dysfunction of
frontal-subcortical brain networks

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

12. *Ferguson et al, JCO, 2007

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

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

23. A Close-Up of the Dentate Gyrus

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

29. “Seed”
“Soil”
“Pesticide”

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

34. What can be done?

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

36. Medications-2
 Antidepressants
 Celexa (citalopram), Zoloft (sertraline), Lexapro (escitalopram), Prozac
(fluoxetine), Paxil (paroxetine)
 Effexor (venlafaxine), Cymbalta (duloxetine)
 Wellbutrin (bupropion)
 Remeron (mirtazapine)
 Anxiolytics
 lorazepam (Ativan), clonazepam (Klonopin), alprazolam (Xanax), diazepam
(Valium)
 Use with caution
 Sleep medications
 zolpidem (Ambien), eszopiclone (Lunesta), trazodone (desyrel)
 Use with caution

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

42. Cognitive Behavioral Therapy
Triad/Quartet

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

51. EEG Biofeedback

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