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A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer

18 Years
Open (Enrolling)
Small Cell Lung Cancer

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Trial Information

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.[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]


1. Turrisi AT, 3rd, Kim K, Blum R et al. Twice daily compared with once daily thoracic
radiotherapy in limited small cell lung cancer treated concurrently with cisplatin and
etoposide. N England J Med 1999; 340: 265271.

2. Kelsey CR, Marks LB. Somnolence syndrome after focal radiation therapy to the pineal
region: case report and review of the literature. J Neurooncol 2006; 78: 153156.

3. Armstrong CL, Gyato K, Awadalla AW et al. A critical review of the clinical effects of
therapeutic irradiation damage to the brain: the roots of controversy. Neurophysiol Rev
2004; 14: 6586.

4. Monje ML, Vogel H, Masek M et al. Impaired human hippocampal neurogenesis after
treatment for central nevrous system malignancies. Ann Neurol. 2007; 62, 515520.

5. Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003; 129134.

6. Perry A, Schmidt RE. Cancer therapy associated CNS neuropathology: an update and review
of the literature. Acta Neuropathol 2006; 111: 197212.

7. Rola R, Raber J, Rizk A et al. Radiation induced impairment of hippocampal neurogenesis
is associated with cognitive deficits in young mice. Exp Neurol 2004; 188: 316330.

8. Vorhees CV, Williams MT. Morris water maze procedures for assessing spatial and related
forms of learning and memory. Nat Protoc 2006; 1: 848858.

9. Rowe MK, Chuang DM. Lithium neuroprotection: molecular mechanisms and clinical
implications. Expert Rev Mol. Med. 2004;6: 118.

10. Yazlovitskaya EM, Edwards E, Thotala D et al. Lithium treatment prevents neurocognitive
deficit resulting from cranial irradiation. Cancer Res 2006; 66: 1117911186.

11. Chen G, Rajokowska G, Du F et al. Enhancement of hippocampal neurogenesis by lithium.
J. Neurochem. 2000; 75: 17291734.

12. Yan XB, Hou HL, Wu LM et al. Lithium regulates hippocampal neurogenesis by ERK pathway
and facilitates recovery of spatial learning and memory in rats after transient global
cerebral ischemia. Neuropharmacology 2007;53: 487495.

13. Moore GJ, Bebchuk JM, WIlds IB et al. Lithium induced increase in human brain grey
matter. Lancet 2000; 356:12411242.

14. Foland LC, Altshuler LL, Sugar CA et al. Increased volume of the amygdala and
hippocampus in bipolar patients treated with lithium. Neuroreport 2008;19:221224.

15. Dowdan J. Therapeutic Guidelines: Psychotropic. (Version 5). Melbourne: 2003.

16. Foutoulakis KN, Vieta E, SanchezMoreno J et al. Treatment guidelines for bipolar
disorder: a critical review. J Affect Disord 2005; 86:110.

17. Berk M, Kapczinski F, Andreazza AC et al. Pathways underlying neuroprogression in
bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors.
Neurosci Biobehav Rev 2011; 35:804817.

18. Kessing LV, SOndergard L, Forman JL, Andersen PK. Lithium treatment and risk of
dimential. Arch Gen Psychiatry 2008; 65: 13311335.

19. Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar
Disord 2010; 12: 8794.

20. Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive
performance: a metaanalysis. J. Clin Psychiatry 2009; 70: 15881597.

21. Yang ES, Lu B, Hallahan DE. Lithium mediated neuroprotection during cranial
irradiation: A phase 1 trial. In ASTRO (American SOciety for Therapeutic Radiology and
Oncology) 49th Annual Conference. Los Angeles CA:

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 SCLC

- Patients can either have:

- Limited stage disease with CR or PR OR

- Extensive stage disease with CR or good PR

- Patients must have discontinued other chemotherapies at least 3 weeks prior to

- 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:

- Hemoglobin ≥ 9.0 g/dl

- Absolute neutrophil count (ANC) ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- Total bilirubin ≤ 2.0 times the upper limit of normal

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x
upper limit of normal (≤ 5x ULN for patients with liver involvement)

- International Normalized Ratio for Prothrombin Time (PT-INR) ≤ 1.5 and activated
partial prothrombin time (aPTT) within 5% of normal limits for patient NOT on

- Creatinine ≤ 2.0 times the upper limit of normal. Patients with ECOG performance
score 2 are ineligible if serum albumin is < 30 g/L.

- Age ≥ 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

- 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:

- Life expectancy less than 3 months.

- Substance abuse, medical, psychological, or social condition that may interfere with
the patient's participation in the study or evaluation of the study results.

- Severe cardiac or renal disease.

- Frank hypothyroidism.

- Hyponatraemia.

- Known or suspected allergy to lithium.

- Women who are pregnant or breast-feeding.

- Inability to comply with protocol and /or not willing or not available for follow-up

- Significant psychiatric or neurologic illness (prior known psych/cognitive/CNS
pathology eg CVA; known or prior brain metastases

- Current lithium therapy.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Feasibility of a project design where the patients are randomized into lithium or placebo

Outcome Description:

Number of participants with adverse events

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Mustafa Khasraw, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Barwon Health


Australia: Department of Health and Ageing Therapeutic Goods Administration

Study ID:

ALCC 11.01



Start Date:

November 2012

Completion Date:

December 2015

Related Keywords:

  • Small Cell Lung Cancer
  • Lung Neoplasms
  • Small Cell Lung Carcinoma