A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer
A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer
Small cell lung cancer is an aggressive neuroendocrine tumour that often presents with extensive (metastatic) disease. Chemotherapy is the mainstay of treatment, with radiotherapy to the primary tumour. It is now part of care to also offer Prophylactic Cranial Irradiation (PCI) in order to prevent spread of the cancer into the brain.
Cognitive impairment can result after cranial irradiation. Lithium is thought to be neuroprotective. It is hypothesized that lithium administration with PCI will be safe, tolerable and feasible, and can be studied to prevent or ameliorate the ensuing cognitive impairment.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumour that often presents with extensive (metastatic) disease.[1] 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[2].
The use of cranial irradiation is linked to neurocognitive complications such as long term memory, mood and concentration issues[3]. 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[3]. 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[13] and hippocampal volume[14] 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[10]. 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[17]. 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[18]. A follow up study by the same group showed similar findings[19]. A metaanalysis of lithium on cognitive performance demonstrated minor negative effects on cognition[20]. 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)[21] and updated at the 2008 annual meeting of the Society of NeuroOncology (SNO)[22].
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[23]. 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.[23]
References:
2007 [22] Xia F, Yang E, Hallahan D, Lu B. Lithium mediated neuroprotection during cranial irradiation: a phase I trial. Neurooncology 2008; 10: 887887.
[23] Forlenza OV, Diniz BS, Radanovic M et al. Disease modifying properties of long term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. The British Journal of Psychiatry: The Journal of Mental Science 2011; 198: 351356.
Inclusion Criteria:
Histologically or cytologically confirmed high grade small cell neuroendocrine carcinoma.
Patients can either have:
Patients must have discontinued other chemotherapies at least 3 weeks prior to randomisation.
Prior radiation therapy to the chest is allowed but must be completed at least 3 weeks prior to randomisation.
ECOG Performance Status 0 to 2.
Adequate bone marrow, liver, and renal function as assessed by the following:
Male or female aged >18 years
Patients must be able and willing to sign a written informed consent. A signed informed consent must be appropriately obtained prior to any study specific procedures.
Patients must be able to swallow and retain oral medication.
Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomisation and must agree to use adequate contraception prior to randomisation and for the duration of study participation.
Exclusion Criteria: