Cognitive problems related Cognitive problems related  to chemotherapy for  non CNS disease

Cognitive problems related Cognitive
problems related
to chemotherapy for non CNS disease
non‐CNS disease
Sanne Schagen
Division of Psychosocial Research and Epidemiology
Literature on cognitive effects of cancer and cancer therapy
Pts with CNS disease almost universally experience cognitive
d f ti d i th di
dysfunction during the disease course due to:
d t
• Disease burden
• Surgery, radiotherapy, chemotherapy
• Seizure and seizure therapy
Cognitive function in patients with brain tumor
Cognitive function in patients with brain tumor
• preoperative cognitive function predicts postoperative cognitive outcome
• postoperative cognitive function and changes in cognitive function after postoperative cognitive function and changes in cognitive function after
concurrent chemoradiation is prognostic for survival time
• tumor related epilepsy has an adverse effect on cognitive function
l d il
h
d
ff
ii f
i
• radiation and chemotherapy related toxicities can include cognitive decline
Increasing evidence that chemotherapy for non‐CNS disease can also produce neurobiological changes
disease can also produce neurobiological changes
that are associated with cognitive problems
This will be the focus of the current presentation
Chemotherapy and cognition in non‐CNS adult cancer patients
Self‐perceived cognitive problems often center on memory
p
problems and the notion that an increased mental effort is
needed to achieve results:
“ I paper my house with post
I paper my house with post‐it
it notes reminding me where
notes reminding me where
things are, what time my appointments are, when my
friends’ birthdays are…. ”
“ Automatic processes now require full attention” A patient
A patient
PRO ≠
Cognitive Function
• Not mutually exclusive
• Self‐report more strongly related to mood and fatigue than cognitive problems as assessed with NP tests
assessed with NP tests
PRO
CF
Characteristics of neuropsychological test battery
•
•
•
•
•
•
•
Repeatable (parallel forms, minimal practice effect)
Good psychometric properties (in terms of reliability, validity, norms)
Sensitive to changes in function
Highly standardized, simple administration
Able to be completed by most patients
Able to be completed by most patients
Measurement of relevant cognitive functions
A neuropsychological examination also includes the assessment of anxiety, depression and fatigue symptoms
N
Neuropsychological studies
h l i l t di
Between 1995‐2012:
53 neuropsychological studies on the association between non
53
neuropsychological studies on the association between non‐CNS
CNS directed adjuvant cytotoxic regimens and cognitive functioning in breast cancer patients
Wefel & Schagen, Curr Neurol Neurosci Rep, 2012
Ahles et al. JCO, 2012
Cross‐sectional neuropsychological Cross
sectional neuropsychological
studies: chemotherapy and cognition
py
g
23 studies Sample size n= 17 – 295, total of 1466 pts with CT examined
Most studies assessed pts within 2 years after CT
M
Mean age around 50 (only 2 studies pts >65)
d 50 ( l 2 t di
t 65)
• 78% of studies (18/23) concluded there is evidence of of studies (18/23) concluded there is evidence of
treatment‐related cognitive impairment • Incidence of cognitive decline ranges from 17‐75% • Most common domains affected: learning and memory, processing speed and executive functioning
NKI‐AVL study: BC patients CMF chemotherapy n=196; Reference group n=1509. On average 21 years after completion of treatment
Z-score of the difference (95% CI)
The magnitude of the effects is comparable to approximately six yyears of age‐related decline in cognitive function
g
g
Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB
JCO, 2012
Prospective neuropsychological studies: P
ti
h l i l t di
chemotherapy and cognition I
26 studies 23 with a pre‐chemotherapy
23 with a pre
chemotherapy assessment
assessment
Sample size n=16 –136, total of 1462 pts with CT examined
Most studies assessed pts within a year after completion of CT
Pts on average in their forties (only 4 studies pts >60)
• 17 studies reported on pre‐chemotherapy cognitive functioning
• 8 studies found lower than expected cognitive performance 8 studies found lower than expected cognitive performance
in cancer pts compared to controls
Prospective neuropsychological studies: chemotherapy and cognition II
No causal explanation at present for pre‐CT cognitive problems:
l
l
f
bl
Not due to anxiety depression surgical factors
Not due to anxiety, depression, surgical factors
Postulated mechanisms include: • shared biological mechanisms contributing to both cancer and cognitive decline decline
• inflammatory cascades associated with cancer Unclear whether pre‐treatment cognitive impairment is related to increased
risk for cognitive dysfunction post chemotherapy Prospective neuropsychological studies: chemotherapy and cognition III
69% of studies (16/23) concluded that there was evidence of
of studies (16/23) concluded that there was evidence of
chemotherapy related cognitive decline
• Incidence of cognitive decline ranges from 19%‐78%
• Most common domains affected: learning and memory, processing speed and executive functioning consistent with a frontal‐
speed and executive functioning ‐
consistent with a frontal
subcortical profile
• Follow‐up assessments indicate both partial recovery but also progressive or new emerging cognitive decline
MDACC study in breast cancer patients FAC‐Paclitaxel
• Acute interval: 65% cognitive decline
• long‐term evaluation: 61% cognitive decline long term evaluation: 61% cognitive decline
• Within this group of patients, 71% evidenced continuous decline from the acute interval and 29% evidenced new delayed cognitive decline
Wefel JS, Saleeba AK, Buzdar AU, Meyers CA. Cancer 2010 Risk factors for neurotoxicity
Risk factors for neurotoxicity
Treatment‐related:
Treatment
related:
• High dose exposure
• Multi‐agent therapy with additive/synergistic effects (ET?)
g
py
y g
( )
Patient‐related:
• None consistently identified
(age, cognitive reserve, education, depression, anxiety, fatigue, treatment induced menopause)
treatment induced menopause)
But given the small sample sizes, exploration of risk factors is likely
underpowered
Summary neuropsychological studies
in pts with non‐CNS disease after CT
•
•
>50 neuropsychological studies in BC – 70% show relation CT and
cognitive impairment
Subgroup of patients exhibit cognitive problems following
chemotherapy (17%-70%). Limited knowledge on treatment and patientrelated risk factors for chemotherapy-induced cognitive decline
•
•
Core impairments:
p
learning
g new information,, forgetting
g
g of
information, executive functions, psychomotor speed
Arise during treatment and persist well into survivorship period.
Limited knowledge on trajectory of cognitive problems
Mechanisms
stem cell
progenitor
•
•
•
•
•
Myelin damage
Myelin
damage
Vascular injury
Inflammation
Decreased neurogenesis Neurochemical changes
Not mutually exclusive, many factors involved
• regimen, dosimetry, sequence & timing
• Individual differences
Individual differences
lineage restricted progenitor cells
Oligodendrocyte
Astrocyte
Neuron
Neural substrate?
Grey matter
Grey matter Neuronal cell bodies
White matter
M li t d
Myelinated axons
Grey matter volume
Grey matter volume
1 month after anthracycline
1
month after anthracycline‐based
based chemotherapy (n=17)
Yoshikawa et al., Breast Cancer Res Treat, 2005
Inagaki et al., Cancer, 2007
McDonald et al.,
al Breast Cancer Res Treat,
Treat 2010
Koppelmans et al., Breast Cancer Res Treat, 2012
Grey matter volume
Grey matter volume
On average 21 years after CMF CT
CT n=184
Mean sd
Mean
ml
Gray matter
Koppelmans et al., BCRT 2012
Smaller grey matter volumes; smaller with increasing time since CT
617 16
Ref n=368
Mean sd
Mean
ml
620
21
β β
ml
p
‐3
.003
Comparable to decline in gray matter volumes of ~4 years l
f ~4
of age
White matter integrity (diffusion tensor imaging [DTI])
3 months after FEC or FEC + paclitaxel (n=34)
Abraham et al., Clinical Breast Cancer, 2008
Deprez et al., Human Brain Mapping, epub 2011
Deprez et al., JCO, 2012
De Ruiter et al Human Brain Mapping 2011
De Ruiter et al., Human Brain Mapping, 2011
Koppelmans et al., HBM, in 2012
Study Deprez et al. JCO, 2012
y p
,
White matter integrity (diffusion tensor imaging [DTI])
On average 10 years after CT
De Ruiter et al., Human Brain Mapping, 2011:
Differences in white matter integrity, HD>SD>RT=Healthy controls
Koppelmans et al., HBM, 2013
Koppelmans et al., HBM, 2013
Decreasing white matter integrity with increasing time since treatment with pts treated with CMF CT
Summary structural imaging studies
• VBM
VBM studies show volume reductions of white and grey matter one year studies show volume reductions of white and grey matter one year
to 20 years post HD and SD CT
• The cerebral white matter seems particularly vulnerable to the effects of chemotherapy: DTI studies show affected cerebral white matter integrity
chemotherapy: DTI studies show affected cerebral white matter integrity post HD and SD CT
• Link between the abnormal microstructural properties in WM regions and g
p
g
cognitive impairments on testing
• Observed changes in DTI parameters may be related to demyelination of white matter axons or axonal injury after CT
•
Long‐term (or even delayed) damage?
•
Protection or recovery possible?
Protection or recovery possible?
• No “baseline" differences observed on structural MRI
Functional imaging studies I
Functional imaging studies I
As of February 2013
As of February 2013
• 6 cross‐sectional studies
• 2 prospective studies
• 3 baseline studies
• In general task performance does not differ between groups
Functional imaging studies II
Functional imaging studies II
• Executive functioning and BOLD activation (n=79), 1 month to 10 years f
d
(
)
h
after CT: Hypoactivation of task relevant brain areas in CT+ pts vs CT‐
yp
f
p
or HC at 5‐10 yrs after treatment. Closer to treatment also hyperactivation occurs.
• Episodic memory (encoding and subsequent recognition) and BOLD i di
(
di
d b
ii ) d O
activation (n=51), 1 month to 10 years after CT: Hypoactivation during memory encoding, with sometimes hyperactivation yp
g
y
g,
yp
during retrieval
A
Associations with task performance are observed.
i i
ih k
f
b
d
Functional imaging studies III
Functional imaging studies III
• Patterns of BOLD activation before the start of chemotherapy or in f
b f
h
f h
h
patients not treated with chemotherapy (n=73):
Both hypoactivation and hyperactivation is observed in BC not treated with yp
yp
CT.
At baseline, predominanty hyperactivation was observed.
Associations with task performance limited.
Future: Are the regional brain areas revealing functional alterations at baseline also more sensitive to the effects of CT?
Preclinical studies
l
l d
• Preclinical studies support neuropsychological and imaging findings
• Studies teach us that many different mechanisms are involved in cognitive and brain changes following chemotherapy
• Studies have implications for the design of intervention studies
Pre‐clinical/animal studies /
Abundant evidence:
• Many common chemotherapeutic agents are associated with adverse gy
effect on neurobiology and behavior • Damage of mature post‐mitotic oligodendrocytes and immature p g
progenitor cell populations required for ongoing neurogenesis, p p
q
g g
g
gliogenesis, and maintenance of white matter integrity are etiologic factors
Animal studies II
Studies have explored interventions or identified neuroprotective strategies
•
Konat 2009: N‐acetyl cysteine, an anti‐oxidant, ameliorated cognitive impairment following cyclophosphamide and doxorubicin
•
Vijayanathan 2011: treatment with a glutamate receptor antagonist improved cognition after intrathecal administration of MTX
•
Lyons 2012: fluoxetine prevents cognitive impairment after 5‐FU
Next steps:
Next steps:
•
•
•
Animal studies to explore basis of individual differences in vulnerability
g
Interventions tested in tumor bearing models
Novel targeted agents? Licht et al. 2011. VEGF‐blockade disrupt memory function
Common agents impair neurogenesis and/or gliogenesis
i preclinical
in
li i l in
i vivo
i studies
di
Chemotherapy regimen
Reference
Year
Carmustine
Cisplatin
Cytosine arabinoside
Dietrich
Hyrien
2006
2010
Thiotepa
Mignone
Mondie
2006
2010
5-FU
FU
Han
H
Mustafa
2008
2008
Methotrexate
Seigers
Yang
2008
2009
2010
2012
Cyclophosphamide
Yang
Briones
Christie
2010
2011
2012
Doxorubicin
Christie
2012
Temozolomide
Nokia
2012
Chemotherapy in adult CNS cancers
py
Improvement due to disease control vs neurotoxicity of CT
• Temozolomide (SD or DD) in new GBM, 30% cognitive decline
(Hilverda 2010, Wefel 2011)
• PCV in anaplastic glioma and GBM, 35‐50% cognitive decline
(Levin 2002, Gorves, 1999: did not distinguish between chemoradiation and adj CT)
• PCNSL pts improvement in cognitive functioning after rituximab, mtx, p
procarbazine and vincristine followed by reduced‐dose brain radiation y
and high‐dose cytarabine (Correa 2007, 2009)
• GBM pts treated with standard chemoradiation, maintenance p
,
temozolomide and bevacizumab showed higher level of cognitive decline than those receiving a placebo (RTOG 0825 Wefel 2013)
Interventions
Cognitive and Neurobehavioral interventions
• Cognitive rehabilitation (based on compensation)
• Work Accommodations
• Sleep Hygiene, Exercise Psychosocial Interventions
• Identification and management of distress
Identification and management of distress
(Psychotherapy, support groups)
Pharmacotherapy
• EPO, methylphenidate, Modafinil, Donepezil, Fluoxetine, Antioxidant
Cognitive function as an clinical trial endpoint in survivorship research
Growing number of survivors possible confronted with cognitive problems
Cognitive impairment is predictive of problems in daily life functioning
Interventions are possible
p
There is rationale for cognitive endpoints in large clinical trials:
•
•
•
•
•
Actual incidence (currently studied n=3000) Differential toxicity profiles
T j t
Trajectory of decline f d li
Risk factors
Prophylaxis
With the aim to: • maximize ability to function TMT
Word fluency
TOL
Digit span
Corsi block-tapping
15 words
Visual reaction time
Grooved pegboard
U
Unmonitored setting
i
d
i
Ongoing and future initiatives in patients with CNS disease and in pts with non‐CNS disease
Detect: incidence of cognitive decline, differential toxicity profiles,
trajectory of decline, risk factors O
Ongoing: prospective studies
i
i
di
Future: online neuropsychological testing/screening; collaborate with
Cooperative groups, cognitive endpoints in phase II studies
p
g p, g
p
p
Explain: mechanisms responsible for CT, ET, RT damage to the brain
Ongoing: detailed experimental animal and human imaging studies, in‐depth neuropsychological work‐up
Future: genetics
Ongoing and future initiatives in patients with CNS disease and in pts with non‐CNS disease
Prevention & rehabilitation: develop strategies to prevent and/or
Prevention
& rehabilitation: develop strategies to prevent and/or
improve cognitive function Ongoing: cognitive and behavioral rehabilitation programs,
RT avoiding hippocampal damage Future: pharmacological interventions, restoration training,
guidance of treatment choices
guidance of treatment choices
Cognition and Cancer Conference
Cognition and Cancer Conference
ICCTF Seattle February 9‐10, 2014
www.icctf.com
Acknowledgements
Michiel de Ruiter
h ld
Vincent Koppelmans
Riejanne Seigers
Riejanne Seigers
Sanne Menning
Myrle Kemperman
Heleen Feenstra
Wendy Jacobs
M i
Marianne Kuenen
K
[email protected]
Willem Boogerd
ll
d
Liesbeth Reneman
Monique Breteler
Monique Breteler
Olaf van Tellingen
Guus Smit
Gabe Sonke
Sabine Linn