As only a subgroup of breast cancer patients experience long-term cognitive decline after adjuvant chemotherapy, it is critical to identify risk factors for this decline. Some risk factor like higher age, lower cognitive reserve (either defined as…
ID
Source
Brief title
Condition
- Cognitive and attention disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) Cognitive decline 3 years after chemotherapy (dependent variable)
Cognitive decline 3 years after chemotherapy completion is evaluated with
standardised neurocognitive tests. These are well-known tests that are often
used at the department of Psychosocial Research and Epidemiology of the
Netherlands Cancer Institute.
Overall cognitive decline can range from 0 to 18 based on cognitive decline on
the number of individual outcome measures (for details see Statistical Analysis
section).
The following tests are administered: Flanker test, Digit Span and Digit Symbol
of the Wechsler Adult Intelligence Scale III, Behavioural Assessment of the
Dysexecutive Syndrome (BADS) Zoo map test, Controlled oral word association
test (COWAT), Hopkins Verbal Learning Test Revised (HVLT-R,Trail making test,
Visual Reproduction of the Wechsler Memory Scale, Fepsy Finger Tapping Task,
Fepsy Visual Reaction Time Task. The official Dutch versions of the tests are
used.
For each of the 18 outcome measures cognitive decline is calculated with the
reliable change index corrected for practice effects. When a patients score
drops below a 90% confidence interval of the baseline score (assessed at
baseline before chemotherapy exposure in the PROSPECT study) this is considered
significant cognitive decline. When a patients declines on all outcome measures
she scores 18, when she doesn*t decline on any outcomes measure she scores 0.
2) White matter reserve (independent variable)
White matter reserve (premorbid microstructural white matter integrity before
chemotherapy exposure) is measured with diffusion MRI scans. These scans are
collected in an ongoing study (PROSPECT, NL32148.031.10).
Secondary outcome
(*) Cognitive decline 2 years after chemotherapy (dependent variable)
Cognitive decline 2 years after chemotherapy is measured in the same way as the
3 year measurement (see above).
(*)Early decline of white matter integrity
Early decline of white matter integrity (6 months after chemotherapy) is
measured with diffusion MRI scans (difference baseline measurement and
measurement 6 months after chemotherapy). These scans have been acquired in an
ongoing study (PROSPECT, NL32148.031.10).
(*) Late decline of white matter integrity as measured with diffusion MRI and
other MRI markers for late decline of the brain
MRI scans are acquired on a Philips 3 Tesla scanner with an 8 channel SENSE
head coil. MRI scan sequences: 1. Diffusion tensor imaging (DTI) is used to
measure late decline of white matter integrity (3 years after chemotherapy). 2.
3-dimsional inversion recovery T1 weighted sequence for (automated) volumetrics
as a global marker for tissue injury. 3. FLAIR sequence for rating of white
matter lesions. 4. Proton MR spectroscopy for evaluation of brain chemistry.
Metabolites that can be measured are N-acetyl aspartate (NAA), choline (Cho)
and myo-inositol (MI). NAA is a marker for neuronal function. Choline is a
marker for demyelination. MI is a glia marker. 5. Functional MRI (fMRI): 3 fMRI
scans will be acquired that are sensitive to the BOLD signal (blood oxygenation
level dependent) and are a proxy for local brain activation. One scan is
acquired while participants perform an fMRI version of the Tower of London, an
executive functioning test to measure activation of the prefrontal lobe, 1 scan
during performance of a paired associates test, a memory test (encoding and
retrieval) to measure activation of (para)hippocampal structures, 1 resting
state scan to measure activity of neural network during rest.
The following data will be collected for all participants 2 and 3 years after
chemotherapy (or matched intervals for cancer patients who did not receive
chemotherapy and healthy controls): age, educational status, smoking habits,
alcohol intake, body mass index, age at menopause (if applicable), type of
menopause (natural or artificial), psychological distress (Hopkins Symptom
Checklist), health related quality of life (EORTC QLQ-C30), self-reported
cognitive problems (MOS questionnaire), self-reported medical history and
medication use. For all cancer patients the following additional information
will be obtained through the medical records: kind of cytotoxic treatment,
radiotherapy yes/no, endocrine therapy yes/no. For the breast cancer patients
not treated with chemotherapy, the following information will be obtained
through the medical records: radiotherapy yes/no, endocrine therapy yes/no,
type and dose of chemotherapy (if applicable). To study potential effects of
stress on brain and cognition, cortisol levels will be measured in hair samples
(only at 3 year measurement). Blood samples will be collected in all
participants to allow for analyses of hormonal levels and cytokines (only at 3
year measurement). Previous studies have shown that fluctuations and changes of
sex hormones, such as LH, FSH, estradiol and progesterone, correlate with
decreased cognitive performance. Deregulation of cytokines, such as IL1, IL6,
TNFα, has been associated with cognitive dysfunction following chemotherapy.
All parameters that will be measured have also been measured in the ongoing
PROSPECT study (NL32148.031.10).
Background summary
Improvements in cancer therapy have increased survival in breast cancer
patients. Therefore, psychosocial aspects of breast cancer and its treatment
have become increasingly important. About half of the breast cancer survivors
report cognitive problems at some stage of their disease. The problems include
forgetfulness and lack of concentration and sometimes also occur long after
treatment (> 1 year), without signs of disease recurrence. Cognitive decline
can negatively impact quality of life after cancer and is one of the most
frequently reported problems in breast cancer survivors who are back at work.
At the level of self-report cognitive problems usually co-occur with
psychological problems like fatigue, anxiety and depression. However, when
cognitive functioning is evaluated with standardized neurocognitive tests,
cognitive decline, to some extent appears to be the result of the specific
type of treatment that breast cancer patients received. Particularly after
adjuvant chemotherapy cognitive decline occurs, in 19 -78 % of patients. Who
are the breast cancer patients that show cognitive decline after chemotherapy?
At the level of self-report cognitive problems usually co-occur with
psychological problems like fatigue, anxiety and depression. However, when
cognitive functioning is evaluated with standardized neurocognitive tests,
cognitive decline, to some extent appears to be the result of the specific
type of treatment that breast cancer patients received. Particularly after
adjuvant chemotherapy cognitive decline occurs, in about 30% of patients.
Animal studies and neuroimaging studies in humans, some conducted by our group,
point to measurable alterations in brain structure and function after
chemotherapy. Recent advanced neuroimaging techniques like diffusion MRI
indicate that particularly brain white matter is susceptible to neurotoxic side
effects of chemotherapy. This technique shows a reduction in white matter
integrity on a microstructural level. White matter consists of nerve tracts
that connect brain regions. Intact nerve tracts are essential for cognitive
functioning, which is supported by extensive neural networks. Injury to white
matter, therefore, is potentially very detrimental for cognitive functioning.
Study objective
As only a subgroup of breast cancer patients experience long-term cognitive
decline after adjuvant chemotherapy, it is critical to identify risk factors
for this decline. Some risk factor like higher age, lower cognitive reserve
(either defined as lower IQ, education or cognitive performance at baseline),
low levels of hemoglobin and high levels of anxiety have been identified but
none of them consistently. Because brain white matter is sensitive to toxic
effects of chemotherapy, and essential for cognitive functioning, our objective
in this study is to evaluate whether a low *white matter reserve* (before
chemotherapy is administered) is a risk factor for developing late cognitive
decline, 3 years after chemotherapy exposure.
White matter reserve is measured with diffusion MRI scans that have been
collected in the PROSPECT study (P10CDC/NL32148.031.10).
The identification of a low white matter reserve before treatment might
ultimately guide treatment strategies. For instance, when the administration of
a particular kind of chemotherapy is already questionable (in the case of an
elderly patient with a weak constitution, and/or a particular type of breast
cancer for which the added value of chemotherapy is unclear).
Secondary Objectives:
In addition to cognitive decline after 3 year, we also aim to investigate
whether a low white matter reserve (before chemotherapy administration) is a
risk factor for cognitive decline 2 years after chemotherapy.
In addition we aim to evaluate whether early decline of white matter integrity
after chemotherapy (6 months after chemotherapy exposure) is a risk factor for
late cognitive decline (2 and 3 years after chemotherapy).
Identifying early decline of white matter integrity after chemotherapy might
serve to inform the patient about potential side effects of chemotherapy and
early interventions after treatment (e.g., neurorehabilitation). Also the
patient might be advised to adapt their lifestyle in a way that is beneficial
to the quality of brain white matter (e.g., quit smoking and start exercising).
We also aim to investigate whether other aspects of brain structure and
function as measured with state of the art MRI scan sequences (before
chemotherapy and 6 months after chemotherapy) are predictive of late cognitive
decline, 2 and 3 years after chemotherapy. Finally we also aim to assess
various aspect of late brain decline 3 years after chemotherapy by repeating
the MRI sequences from the PROSPECT study (P10CDC/NL32148.031.10).
Study design
This prospective observational study is a collaboration between the
departments of Psychosocial Research and Epidemiology and Neuro-oncology of the
Netherlands Cancer Institute and the department of Radiology of the Academic
Medical Center of the University of Amsterdam. In this study, patients will
participate who were treated at the Netherlands Cancer Institute, VU University
medical center, Flevo Hospital and Reiner de Graaf Hospital. The current study
recruits patients from the ongoing PROSPECT study (NL32148.031.10) on brain
function and structure in breast cancer patients.
Study burden and risks
Participants will be assessed twice, 2 and 3 years after chemotherapy
completion, or matched intervals for breast cancer patients for whom
chemotherapy was not indicated en healthy controls. The assessment after 2
years lasts 1.5 hours and the assessment after 3 years lasts 3 to 3.5 hours.
The assessment after 2 years comprises the neurocognitive test administration
and several questionnaires. At the assessment after 3 years these data are also
collected. In addition the cortisol hairsample and a venipuncture will be
collected and the MRI scans will be acquired.
Burden of undergoing MRI scans (only the 3 year after chemotherapy assessment
or comparable intervals for patients who did not undergo chemotherapy and
healhy controls). About half of the total duration of MRI scan acquisition the
participant is actively involved in performing the fMRI tests. The remainder of
the MRI scan acquisition no active involvement of the participant is required.
De participant has to lie still in the scanner which is sometimes experienced
as unpleasant. In addition the scanner makes noise, but this is effectively
reduced by using earplugs and headphones. When standard safety rules are
applied (eg., no ferromagnetic objects inside the scanner room) no risks exist
for the participant. In our ongoing PROSPECT studie,
die identieke metingen heeft, weten we dat patiënten het onderzoek als niet te
belastend ervaren. Dat blijkt ook uit het lage percentage patiënten dat niet
aan de tweede meting van deze studie deelneemt om andere redenen dan dat zij
inmiddels voldoen aan de exclusiecriteria (<3%).
Only 3 year after chemotherapy (or comparable intervals for patients who did
not undergo chemotherapy and healhy controls), a small hair sample will be
collected to measure cortisol levels. The collected sample is very small. It is
not visible that this hair strand has been taken from the back of the head. We
also collect hair samples in the ongoing PROSPECT study that participants in
the present study are recruited from. In the PROSPECT study participants have
not expressed problems with collection of the sample. Venipuncture (also only
after 3 years) is performed by a certified research assistant to limit patient
burden to the minimum.
No information on individual test results and other outcomes measures will be
communicated to participants (except for serious incidental MRI findings), in
accordance with the approved PROSPECT protocol.
The measurement after 2 years takes place at the Antoni van Leeuwenhoek
Hospital or at home, if the participant prefers that.
The measurement after 3 years takes place at the Spinoza Centre for
Neuroimaging at the University of Amsterdam (Roeterseiland).
Travel and parking expenses will be reimbursed. Patients will also be paid an
additional 20 euros (2 year measurement) and 40 euros (3 year measurement) for
compensation. Participants will be given a short break during the assessment
and will receive a lunch voucher.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
-participation in study PROSPECT, NL32148.031.10;Inclusion criteria PROSPECT study (all groups):
-female
-age < 70 (to allow for the use of the same neuropsychological test battery in all participants)
-sufficient proficiency in the Dutch language;Experimental group:
-newly diagnosed breast cancer patients without distant metastases who will receive anthracycline-based adjuvant chemotherapy;Breast cancer control group:
-newly diagnosed breast cancer patients without distant metastases who do not require chemotherapy;Healthy control group:
-healthy females, matched for age
Exclusion criteria
All groups:
-new malignancies, except for basal cell carcinoma
-excessive use of alcohol of drugs
-use of psychotropic medication
-neurologic or psychiatric disorders that may influence cognitive functioning
-conditions that preclude MRI examination (e.g., pacemaker);Experimental group and breast cancer control group:
-relapse and/or metastases
-treatment with trastuzumab (Herceptin)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL44466.031.13 |