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Cognitive impairment as a treatment induced toxicity

Katarzyna Broczek MD, PhD

Department of Geriatrics, Medical University of Warsaw

Disclosure

Conflicts of Interests - NONE

Plan of the presentation

• Cognitive impairment in older cancer patients:

–Prevalence

–Possible mechanisms

–Symptoms

–Therapeutic options

–Tips for clinical practice

Cancer Treatment-Induced Neurotoxicity

• CNS– Headache

– Seizures

– Encephalopathy

– Cerebrovascular disease

– Cerebellar dysfunction/ataxia

– Movement disorders

– Stroke-like migraine attacks, SMART

– Secondary malignancies

– Cranial neuropathy, myelopathy

• PNS– Plexopathy

– Peripheral neuropathy

– Inflammatory demyelinating polyneuropathy

– Myasthenic-type syndrome

– Muscle symptoms

– Motor neuron syndrome

Stone JB. Nat Rev Clin Oncol. 2016; 13(2): 92-105

Cognitive impairment due to cancer treatment

Medical and common terms

• Chemo-brain

• Cancer treatment-related cognitive impairment (CRCI)

• Chemotherapy-related cognitive dysfunction

• Cancer-therapy associated cognitive change

• Post-chemotherapy cognitive impairment

• Mental cloudiness

• Mental fogg

• Different thinking

Vulnerable brain

www.naukawpolsce.pap.pl www.fizjoinformator.pl

Brain: 100 billions neurons, each cell may create 10 thousands synapses

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Brain aging

Brain

Brain pathology

Stroke

Dementia

AD, PD

Other diseases

affecting brain Normal aging

Neuroplasticity

How brain is affected by chemotherapy?

• Brain volume, activity and metabolism

• Grey matter

• White matter

• Specific brain regions

– Hippocampus

• Clinical picture

– Subtle/dramatic

– Temporary/permanent

– Stable/progressive

Brain and cancer treatment

Functional and anatomic changes

Hippocampus

• Neuronal loss

• Synaptic dysregulation and loss

• Acumulation of β-amyloid

• Blood vessel damage

• ↑ cell death

• ↓ neurogenesis

• ↓ dendritic complexity

• Impaired activation of brain regions during cognitive tasks

Epidemiology of cognitive decline

related to chemotherapy

short-term

long-term

0

10

20

30

40

50

60

70

80

Cognitive impairment following chemotherapy

short-term

long-term

75%

35%

Janelsins M.C. et al. Semin Oncol. 2011; 38(3): 431-438

Symptoms of chemo-brain

• Cognitive domains

affected by cancer treatment:

– Attention

– Processing speed

– Executive functions

– Learning

– Memory

• Patient’s complaints:

– Memory lapses

– Concentration loss

– Trouble remembering

details: names, dates

– Trouble multi-tasking

– Slower thinking and

processing

– Trouble remembering

common words

Diagnosis of cognitive impairmentCOGNITIVE PERFORMANCE

• Subjective patient’s complaints

• Caregiver’s observations

• Cognitive screening, e.g. MMSE

• Neuropsychological assessment

BRAIN CHANGES

• CT

• MRI, including functional MRI

• High dimensional deformation

mapping - hippocampusApple A.C. et al. NeuroImage: Clinical, 2017

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Patients described in case presentations

• 75-year old patient with stage

III colon cancer

• 85-year old patient with stage

III colon cancer

Determinants of cognitive performance

Related to treatment-toxicity-inflammation

Related to diagnosisBiology of cancerNeurodegenerationAgingCognitive reserve

Patients described in case presentations

The question we need to ask is:

• What was the initial cognitive performance of these patients before cancer treatment?

• The probable answer is:

• Who knows?

• Why the answer is usually not specific?

• Assessment of cognitive performance is not done routinely

• Subtle cognitive impairment is not easily recognizable

• Cognitive disorders are often underdiagnosed without screening

Aging of the brain

10 70 10 10

0 10 20 30 40 50 60 70 80 90 100

successful normal MCI dementia

Memory problems

and cognitive impairment staging

• AAML – Age-associated memory impairment

• SMI – Subjective memory impairment

• MCI – Mild cognitive impairment

• Dementia

– mild

– moderate

– severe

It takes many years for dementia

e.g. Alzheimer’s disease

to develop into clinically relevant syndrome

Trajectories

of treatment related cognitive impairment

0

20

40

60

80

100

120

before during after long-term

Patient A

Patient B

Patient C

Patient D

20-30% of patients demonstrate lower than expected cognitive performance

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Possible interventions for CRCI• No confirmed treatment available

• Use daily planner

• Exercise your brain, try occupational therapy

• Get enough rest and sleep

• Follow routines

• Don’t multi-task

• Ask for help

• Tell others

• Talk to your cancer team

Is talking with cancer patients about their

cognitive impairment common?

• Sister Study and Two Sister Study (USA)

2,296 female breast cancer survivors

↓

60% self-reported cognitive problems

↓ ↓

37% discussed concerns

with a provider

15% treatment

for cognitive symptoms

•Buchanan N.D. at al. Am J Prev Med. 2015; 49(0): S498-S508

Differential diagnosis

• Treatment-related symptoms

–Acute encephalopathy

–Prolonged cognitive impairment (reversible or progressive)

–delirium

• Progression of cancer

• Involvement of the nervous system

Why excluding diagnosis of delirium

is challenging?

Clinical presentation may be „atypical”

• Blurred clinical picture

• Cognitive decline and attention deficit

• Prolonged duration of symptoms

• Irreversible cognitive impairment possible

Interventions for CRCI

Based on experience of a geriatrician

• Reassure the patient and give time for recovery

• Diagnose and treat depression, anxiety and sleep disorders

• Assess functional status, exclude frailty, pain, hearing impairment

• Diagnose nutritional deficiencies

• Revise medication regimen

• Provide follow-up of cognitive problems

• Deficit-oriented cognitive training

• Processing speed training

• Physical exercise

Physical activity and brain functions

ROS

Reactive oxygen species

Regulation of cellularsignaling

Stem cells↓

Neurogenesis?

Lipids, Proteins, DNA

↓neurotransmission

Immunology↓

Plasticity of synapses

Radak Z, 2016

Hormesis

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http://www.alz.org/brain

Conclusions

• Baseline and follow-up cognitive assessment of cancer patients

• Cognitive complaints – do not forget to ask the patient!

• Self-reported memory problem vs. psychological tests

• Neuropsychological assessment may help

• More research needed

• Education

– healthcare providers

– patients

– caregivers

Chemotherapy ↔↔↔↔ Mental status

Winter in the Royal Lazienki Park in Warsaw

kbroczek@gmail.com