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8. Proposed Study Measures - Introduction This study will examine the
following hypotheses in patients with early stage breast cancer who are treated
with adjuvant cytotoxic drugs as part of their standard care.
Further details are below: The proposed study will be
divided into two phases. The first phase, for which applications for
funding from the Cancer Council Australia (see Attachment QCF Grant Application
Form) and Wesley Research Institute have been submitted, will document the
cognitive profiles of patients with early stage breast cancer who are
candidates for adjuvant cytotoxic drug treatment. Objective
neuropsychologic testing will be undertaken on these patients prior to, and at
the completion of adjuvant cytotoxic drug treatment, and at six months and one
year after completion of treatment. Self report measures of quality of
life, fatigue, anxiety and depression will be administered at the time of
neuropsychologic testing. This initial phase of the study will identify
endophenotypes of cognitive function. The second phase will seek
additional funding for the longer term follow-up necessary to identify the
presence of persistent cognitive dysfunction, as well as genotyping.
Blood samples will be taken at baseline. Genotyping will build on our
published experience of Apo E allele expression and novel genotypes identified
in the QIMR twin study. First Phase (Hypotheses 2, 3) To identify profiles of
cognitive function before and at completion of adjuvant cytotoxic drug
treatment, and in follow-up at six months and one year. To evaluate the impact
of self report measures of quality of life, distress, anxiety and depression on
cognitive measures. Second Phase (Hypotheses 1,
2, 3) To assess whether common
genetic factors, including Apo E allele expression and novel alleles identified
in the QIMR twin cognition study, influence loss of cognitive function during
and after treatment with cytotoxic drugs. To evaluate cognitive function and
self report measures of quality of life, distress, anxiety and depression at a
follow-up interval of two years. Approximately 120 will be
recruited for the study. Eligible candidates will be
treated with conventional doses of standard cytotoxic drug regimens. Participants will be
recruited from clinics of the investigators (EW, NM, HJ, GB, DG). The
sources of recruitment will be the Histologically proven breast
cancer treated initially by definitive surgery that includes axillary lymph
node assessment. 18 years and less than 70
years. No past history of cancer,
except for non-melanoma skin cancer, carcinoma in-situ of cervix, lobular
carcinoma in-situ. No previous cytotoxic drug
treatment. Written informed consent
provided according to participating institutional requirements. Proficiency in English
language since childhood. Patients must be accessible
for treatment and follow-up. Adequate haematological and
biochemical function. Karnofsky performance status
index 80% Plan to receive adjuvant
cytotoxic chemotherapy The presence of metastatic
disease. A history of
neurologic/psychiatric symptoms or signs that may lead to deviant
neuropsychologic test results. Medications that might lead
to deviant neuropsychological test results. Alcohol and/or drug
addiction. Concurrent treatment with
other experimental drugs. Male patients, as no data
base exists for cognitive function testing in breast cancer. Participants who meet the
eligibility criteria will be treated initially with definitive surgery,
including sentinel lymph node biopsy and/or axillary dissection.
Cytotoxic drug regimens will be documented and can include the following drugs:
Adriamycin, Epirubicin, Cyclophosphamide, Methotrexate, 5-Fluorouracil,
Paclitaxel, Docetaxel. Patients will be eligible if they are treated with
endocrine treatments and Herceptin. Radiation treatment, if indicated,
will be administered after completion of cytotoxic drug treatment. 8.
Proposed Study Measures - Introduction Demographic data will be
collected on patients invited to participate in this study. These data
will include the following: - age, menopausal status, use of hormone
replacement therapy, medications, and plan of cytotoxic drug, endocrine and
radiation treatments. These variables will be treated as covariates and
will be documented at baseline and at each follow-up interval.
Demographic data will be collected prior to the study by hospital based data
managers or research nurses. Cognitive testing will take place in a quiet
room either at one of the hospitals or at the participant’s homes.
Self-report questionnaires for anxiety, depression, fatigue and quality of life
will be administered immediately following the cognitive testing. All
tests and questionnaires will be administered to each participant in the same
order and will take approximately 2 hours to complete. Assessments will
be made at baseline, at the end of adjuvant cytotoxic drug treatment, and at 6
and 12 months after cessation of therapy. Neuropsychologic tests will be
administered by a registered psychologist in accordance with standard practice
procedures. Clinical data, cognitive
measures, self report scales and genetic results will be stored in a purpose
designed relational database. The database will be held at the Queensland
Institute of Medical Research. Mean changes in cognitive profiles,
fatigue, anxiety and depression scores from baseline to post-treatment and for
each follow-up will be presented as percentage changes, and tested using paired
Student t-tests and repeated measures analysis of variance (ANOVA). Differences
in the degree of cognitive decline between genetic groups of women will also be
assessed using independent sample t-tests on mean differences, and repeated
measures ANOVA by including a time by genotype interaction term. Multivariate
linear regression will be used to assess the independent predictors of
cognitive decline, including terms for age, treatment schedule (eg doses),
disease characteristics (such as stage), menopausal status, fatigue, anxiety, depression
and, after genotyping, genetic polymorphisms. Power and sample size
calculations have been conducted using means and standard deviations of changes
in cognitive profiles, anxiety and depression derived from patients undergoing
cardiac surgery55 and population Apo E allele
frequencies as reported by Gelernter et al. To allow for patient withdrawal,
120 subjects will be invited to participate in the study. For phase 1,
100 subjects will provide 90% power to detect a significant (at the 5% level) 10%
decrease in Rey Auditory Verbal Learning scores (sd diff=2.00); 9% change in
Trail Making Tests (sd diff=12.23); 5% change in WAIS III Digit Symbols (sd
diff=6.36); 13% change in anxiety (sd diff=3.2); and a 15% change in depression
(sd diff=2.5). The sizes of these changes are consistent with those reported in
previous studies of cognitive function after treatment with cytotoxic drugs.
For phase 2, 100 subjects will provide 90% power to detect a significantly
greater decline in women who carry the Apo E allele
(prevalence=20%) than those who do not carry this allele, with fold-difference
in the order of: 2.0 for Rey Auditory Verbal Learning scores; 2.5 for Trail
Making Tests. |