Late effects of chemotherapy on brain functioning in the elderly

Cancer patients who have been treated with chemotherapy frequently report
cognitive complaints that they consider to result from the therapy. These
cognitive complaints are of great concern to patients, and are a frequent topic
in cancer support groups where they are referred to as *chemobrain*. Over the
last few years, several neuropsychological studies indeed reported cognitive
impairment in series of cancer patients treated with adjuvant chemotherapy.
Moreover, several neurophysiological studies found abnormalities in brain
functioning up to five years after cessation of treatment with
chemotherapeutics and suggest that the cognitive problems in these patients may
not be transient. Furthermore, animal studies showed long lasting
dose-dependent decreases in cell proliferation in the hippocampal formation in
rats following single intravenous administration of methotrexate, one of the
frequently used cytotoxic agents. We hypothesize that also in humans cytotoxic
treatment may lead to long-lasting brain damage that can result in persistent
cognitive changes and accelerated cognitive decline at an older age. The
proposed study will investigate whether chemotherapy causes brain changes
different from the normal age related brain changes and increases the risk of
worse cognitive function and cognitive decline.
We will compare brain structure and cognitive function between
hundred-and-twenty women who are now aged 60 years or over and who were treated
with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy for
breast cancer 5 to 20 years ago, with controls without a history of cytotoxic
treatment. Patients will be recruited from the Daniel de Hoed Cancer Clinic and
the Antoni van Leeuwenhoek Hospital. Patients will be compared to participants
of the Rotterdam Study without a history of cytotoxic treatment. The Rotterdam
Study is a large on-going population based cohort study among persons aged 45
years and over living in Ommoord, Rotterdam. The standard examination protocol
in the Rotterdam Study includes a neuropsychological test battery to assess
cognitive function, and brain MRI scanning to assess total and regional volumes
of grey matter, white matter, and CSF and presence and severity of vascular
lesions (white matter lesions, lacunar infarcts, microbleeds). The cancer
patients will be assessed in exactly the same way as the control subjects
following the protocol of the Rotterdam Study. MRI scanning and the
neuropsychological testing will take place at the research centre of the
Rotterdam Study in Ommoord, Rotterdam.
This study will give insight in the long term effects of chemotherapy on
cognitive function in elderly women. Furthermore, by comparing specific brain
structures and brain lesions between women with and without previous
chemotherapy, this study may help elucidate the mechanisms that underlie the
deficits found in a number of patients treated with adjuvant chemotherapy. As
CMF chemotherapy has been the adjuvant regimen of choice for more than 20 years
world wide, very large number of survivors might be at risk for neurocognitive
late effects of treatment. In addition, this study can be regarded as a model
for the investigation of other frequently used cytotoxic regimens. It is
expected that in 2015 the incidence of breast cancer will be around 17.000 in
the Netherlands alone, and that in half of these patients chemotherapy will be
part of the treatment strategy. Therefore, it is important to systematically
investigate any potential late effect of chemotherapy that can seriously affect
the quality of the survival of these patients.

Cytotoxic treatment may lead to long-lasting brain damage that can result in
persistent cognitive changes and accelerated cognitive decline at an older age.
The proposed study will investigate whether chemotherapy causes brain changes
different from the normal, age-related brain changes and increases the risk of
worse cognitive function and cognitive decline.

Observational study, cross-sectional

Patients will be tested once. Each test assessment will last 2.5 hour and
consists of a semi-structured interview, a medical assessment in which weight,
length and bloodpressure will be measured. In addition, blood will be collected
and an ECG and ultrasound of coronary arteries will be performed; several
questionnaires and tests and an MRI scanning session.

The patient has to lie still in the scanner which is sometimes considered
inconvenient. Moreover, the scanner produces noise, which is effectively
reduced by the use of earplugs and headphones. When standard safety rules are
applied (no ferromagnetic objects inside the scanner room) no risks exist for
the patient. The addition medical examination are not harmful. Ample experience
with patient populations and with participants of the Rotterdam (ERGO study)
have indicated that this procedure is feasible and is not considered too
burdensome.