Fluoxetine Prevention Trial

Systematic studies of adverse cognitive and neurobiological changes subsequent to
chemotherapy for lymphoma, breast, and other cancers have attracted substantial interest in
the past decade. Little is known, however, concerning the feasibility and effects of
potentially protective therapies on cerebral function in patients undergoing chemotherapy.
Animal models have recently proved useful in examining some of the toxic effects of
chemotherapy agents on working memory and other abilities, as well as on biological
properties such as proliferation and survival of neuronal precursors involved in hippocampal
neurogenesis. Such models have also proved useful for testing potential neuroprotective
properties of agents given before, during and/or after chemotherapy. For example, impairment
in spatial working memory and decreased hippocampal neurogenesis is induced in rats by the
chemotherapy agent methotrexate, but co-administration of the (FDA-cleared and commercially
available) drug fluoxetine has been shown to counteract the negative long-term effects on
memory and hippocampal neurogenesis otherwise occurring after methotrexate administration. To
determine whether such a strategy could be effective in counteracting effects that
chemotherapy may have on cerebral function in humans, well-controlled experimental data
obtained with cancer patients is needed.

This investigation will employ a prospective, randomized, double-blinded, placebo-controlled
design, to provide a rigorous test of whether fluoxetine, a drug with a long-standing
excellent safety profile in humans most commonly marketed as an antidepressant, can offer
protection to breast cancer or lymphoma patients against changes in cerebral function
occurring after chemotherapy (Specific Aim 1). It will further provide a test of the
durability of any protective effects beyond the period during which fluoxetine is used, by
re-assessing function approximately 6 months after completion of the regimen (Specific Aim
2). Cerebral function will be assessed by determining distributions of regional cerebral
metabolism, previously demonstrated to sensitively detect functional alterations and closely
reflect diminished cognitive abilities with high statistical power, using positron emission
tomography with the glucose analog radiotracer [F-18]fluorodeoxyglucose. Neuropsychologic
testing will be conducted in parallel with neuroimaging studies and, as a step towards
understanding mechanisms underlying neurotoxic effects of chemotherapy and potentially
related to protective effects of fluoxetine, peripheral markers of inflammatory cytokines
will be measured in blood samples drawn at the time of neuroimaging (Specific Aim 3). If use
of fluoxetine in cancer patients can be validated in this manner and lead to its adoption in
the clinical setting, it will constitute the first drug with demonstrated utility for the
prevention of cerebral dysfunction associated with exposure to chemotherapy. Moreover, as
this involves an agent that is already FDA-cleared for other indications, widely commercially
available throughout the U.S. and other parts of the world, and relatively inexpensive since
it is obtainable in generic formulations, it would represent a pharmacologic approach that is
amenable to rapid translation to the clinical setting.

Inclusion Criteria:

- Scheduled to undergo chemotherapy, or has completed chemotherapy no more than a month
prior to enrollment, for breast cancer or lymphoma

- Age 21 or above

- Geographically accessible for follow-up in one year

- English language proficient

- Able to provide informed consent

Exclusion Criteria:

- Pregnant

- Evidence of current or past disorder/disease of the central nervous system or any
medical condition that might be expected to impact cognitive functioning (e.g.
multiple sclerosis)

- History of head trauma with loss of consciousness greater than 30 minutes

- Epilepsy, dementia, or severe learning disability

- Current psychotic-spectrum disorder (e.g. schizophrenia, bipolar disorder, major
affective disorder) or current substance abuse or dependence

- History of whole brain irradiation or surgery

- Active diagnosis of autoimmune disorder e.g., systemic lupus erythematosis, rheumatoid
arthritis, vasculitis

- Insulin dependent diabetes

- Uncontrolled allergic condition or asthma

- Chronic use of oral steroid medication

- Hormone therapy (estrogen, progestin compounds) other than vaginal estrogen

- Due to the subtleties of neuropsychological test evaluation, including necessity for
repeated administration with alternate forms, we must also exclude non-English
language proficient subjects.