A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour that often presents
with extensive (metastatic) disease. It frequently has micrometastatic disease at
presentation. Chemotherapy is the mainstay of treatment with radiotherapy to the primary
tumour. It is now part of care to offer Prophylactic Cranial Irradiation (PCI)with 25 Gy in
10 fractions dependent on the extent of response in the primary tumour and the patient's
performance status. PCI is routine care for limited stage patients showing response and can
be considered in selected patients with limited stage disease showing good
response.Somnolence syndrome is a common intermediate side effect of cranial radiotherapy
that occurs about six weeks after treatment and manifests as lethargy, increased sleepiness
and poor attention or subtle memory changes and altered temperament.
The use of cranial irradiation is linked to neurocognitive complications such as long term
memory, mood and concentration issues. Decline in attention, executive function, motor,
language and general intellectual skills have all been reported. There is the suggestion of
a more rapid progression of dementing illness in patients receiving cranial irradiation
although the numbers of long term survivors is limited. Radiation mediates neurocognitive
effects by affecting glial cells, neural stem and progenitor cells[4, 5] and the vascular
structures[3, 6]. Cranial irradiation delivered to mice has been shown to reduce neural
proliferation translating to long term reduction in neurogenesis[7, 8]. Lithium confers
neuroprotection and is associated with less cognitive loss in various brain injury models
including after cranial irradiation[9, 10]. In addition, neural stem/progenitor cells
positively respond to Lithium treatment under basal conditions[11, 12]. In humans, 4 weeks
of Lithium increases brain grey matter content and hippocampal volume as evidenced
by MRI scanning. Lithium was found to protect irradiated hippocampal neurons in mice from
apoptosis resulting in better performance reflecting learning and memory function.
Lithium is known to reduce oxidative stress, specifically via the glutathione system.
Lithium is a standard part of the management of moderate to severe bipolar disorder and
schizoaffective disorders and its toxicity profile is well understood[15, 16]. In bipolar
disorder, lithium has been shown to prevent the loss of cortical grey matter that occurs as
part of the neuroprogressive cascade seen in the disorder. There is limited prospective
clinical data regarding the use of lithium as a neuroprotectant. A large Danish
observational cohort study, demonstrated that use of lithium (in those with mood disorders,
who display an increased risk for dementia) was associated with reduction of the rate of
dementia to the same level as that for the general population. A follow up study by the
same group showed similar findings. A metaanalysis of lithium on cognitive performance
demonstrated minor negative effects on cognition. There has been one early phase study
using lithium as a neuroprotective agent presented in abstract form at the 2007 American
Society for Therapeutic Radiology and Oncology (ASTRO) and updated at the 2008 annual
meeting of the Society of NeuroOncology (SNO).
Long term lithium treatment has also shown promise in amnestic mild cognitive impairment in
a study that randomized 45 participants to receive lithium (0.25-0.5 mmol/l) (n = 24) or
placebo (n = 21) in a 12 month, doubleblind trial. Lithium treatment was associated with
a significant decrease in CSF concentrations of Ptau(P =0.03) and better performance on the
cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. The
data support the notion that lithium has disease modifying properties with potential
clinical implications in the prevention of Alzheimer's disease.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Feasibility of a project design where the patients are randomized into lithium or placebo
Number of participants with adverse events
Mustafa Khasraw, MD
Australia: Department of Health and Ageing Therapeutic Goods Administration