Treatment of brain metastases in lung cancer: Strategies to avoid/reduce late complications of whole brain radiation therapy

Current Treatment Options in Oncology

Volumn 14, Issue 4, 2013, Pages 553-567

  Shaw, Mark G ^a   Ball, David L ^a  

^a PETER MACCALLUM CANCER CENTRE   (Australia)

Author keywords

Brain metastases; Hippocampus; Neurocognitive impairment; Neuroprotection; Quality of life; Whole brain radiation therapy

Indexed keywords

DONEPEZIL; LITHIUM CARBONATE; MEMANTINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PLACEBO;

ALOPECIA; AMNESIA; ARTICLE; BLOOD VESSEL INJURY; BRAIN METASTASIS; BRAIN SURGERY; CANCER RADIOTHERAPY; COGNITIVE DEFECT; DEMENTIA; DEMYELINATION; FATIGUE; HEADACHE; HUMAN; INTELLECTUAL IMPAIRMENT; INTERMETHOD COMPARISON; LEUKOENCEPHALOPATHY; LUNG CANCER; NEURAL STEM CELL TRANSPLANTATION; NONHUMAN; PATIENT SAFETY; RADIATION DOSE FRACTIONATION; RADIATION DOSE REDUCTION; RADIATION INJURY; RADIATION NECROSIS; RADIATION SICKNESS; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RISK REDUCTION; SKULL IRRADIATION; SOMNOLENCE; WHOLE BRAIN RADIATION THERAPY;

BRAIN NEOPLASMS; COGNITION DISORDERS; COMBINED MODALITY THERAPY; CRANIAL IRRADIATION; DOSE FRACTIONATION; FEMALE; HUMANS; LUNG NEOPLASMS; MALE; NEUROPROTECTIVE AGENTS; QUALITY OF LIFE; RADIATION-SENSITIZING AGENTS; RADIOSURGERY; SURVIVAL ANALYSIS; TIME FACTORS; TREATMENT OUTCOME;

EID: 84890805332     PISSN: 15272729     EISSN: 15346277     Source Type: Journal    
DOI: 10.1007/s11864-013-0258-0     Document Type: Article

References (100)

1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2009 Incidence and Mortality Web-based Report. Available at http://www.cdc.gov/cancer/lung/statistics/. Accessed July 2013.
2. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865-72. doi: 10.1200/JCO.2004.12.149.
3. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698-705.
4. Nugent JL, Bunn Jr PA, Matthews MJ, Ihde DC, Cohen MH, Gazdar A, et al. CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer. 1979;44(5):1885-93.
5. Shi AA, Digumarthy SR, Temel JS, Halpern EF, Kuester LB, Aquino SL. Does initial staging or tumor histology better identify asymptomatic brain metastases in patients with non-small cell lung cancer? J Thorac Oncol. 2006;1(3):205-10.
6. Smedby KE, Brandt L, Backlund ML, Blomqvist P. Brain metastases admissions in Sweden between 1987 and 2006. Br J Cancer. 2009;101(11):1919-24. doi: 10.1038/sj.bjc.6605373.
7. Hirsh V. Systemic therapies in metastatic non-small-cell lung cancer with emphasis on targeted therapies: the rational approach. Curr Oncol. 2010;17(2):13-23.
8. Zimm S, Wampler GL, Stablein D, Hazra T, Young HF. Intracerebral metastases in solid-tumor patients: natural history and results of treatment. Cancer. 1981;48(2):384-94.
9. Posner JB. Management of central nervous system metastases. Semin Oncol. 1977;4(1):81-91.
10. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys. 1980;6(9):1215-28.
11. Tofilon PJ, Fike JR. The radioresponse of the central nervous system: a dynamic process. Radiat Res. 2000;153(4):357-70.
12. Crossen JR, Garwood D, Glatstein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol. 1994;12(3):627-42.
13. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology. 1989;39(6):789-96.
14. Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M, Hirota S, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68(5):1388-95. doi: 10.1016/j.ijrobp.2007.03. 048.
15. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol. 2006;24(8):1305-9. doi: 10.1200/JCO.2005.04.6086.
16. Gondi V, Paulus R, Bruner DW, Meyers CA, Gore EM, Wolfson A, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of radiation therapy oncology group randomized trials 0212 and 0214. Int J Radiat oncol biol Phys. 2013;86(4):656-64. doi: 10.1016/j.ijrobp.2013.02.033.
17. Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(19):3557-8. doi: 10.1200/JCO.2003.07.080.
18. Liu R, Page M, Solheim K, Fox S, Chang SM. Quality of life in adults with brain tumors: current knowledge and future directions. Neuro-Oncol. 2009;11(3):330-9. doi: 10.1215/15228517-2008-093.
19. Scoccianti S, Detti B, Cipressi S, Iannalfi A, Franzese C, Biti G. Changes in neurocognitive functioning and quality of life in adult patients with brain tumors treated with radiotherapy. J Neuro-Oncol. 2012;108(2):291-308. doi: 10.1007/s11060-012-0821-8.
20. Tallet AV, Azria D, Barlesi F, Spano JP, Carpentier AF, Goncalves A, et al. Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol. 2012;7:77. doi: 10.1186/1748-717X-7-77. This concise paper is a review of current literature on radiation-induced neurocognitive impairment with an exploration of different assessment techniques. The paper also explores the differences between therapeutic and prophylactic cranial irradiation.
21. Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04. Int J Radiat Oncol Biol Phys. 2001;51(3):711-7.
22. Gregor A, Cull A, Stephens RJ, Kirkpatrick JA, Yarnold JR, Girling DJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer. 1997;33(11):1752-8.
23. Komaki R, Meyers CA, Shin DM, Garden AS, Byrne K, Nickens JA, et al. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys. 1995;33(1):179-82. doi: 10.1016/0360-3016(95)00026-U.
24. Collins B, Mackenzie J, Stewart A, Bielajew C, Verma S. Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study. Psycho-Oncol. 2009;18(8):811-21. doi: 10.1002/pon.1453.
25. Hodgson KD, Hutchinson AD, Wilson CJ, Nettelbeck T. A meta-analysis of the effects of chemotherapy on cognition in patients with cancer. Cancer Treat Rev. 2013;39(3):297-304. doi: 10.1016/j.ctrv.2012.11.001.
26. Newcomer JW, Craft S, Hershey T, Askins K, Bardgett ME. Glucocorticoid-induced impairment in declarative memory performance in adult humans. J Neurosci: Off J Soc Neurosci. 1994;14(4):2047-53.
27. Zacny JP, Gutierrez S. Characterizing the subjective, psychomotor, and physiological effects of oral oxycodone in non-drug-abusing volunteers. Psychopharmacology. 2003;170(3):242-54. doi: 10.1007/s00213-003-1540-9.
28. Keime-Guibert F, Napolitano M, Delattre JY. Neurological complications of radiotherapy and chemotherapy. J Neurol. 1998;245(11):695-708.
29. Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY. CNS complications of radiotherapy and chemotherapy. Lancet. 2009;374(9701):1639-51. doi: 10.1016/S0140-6736(09)61299-X. This paper describes in great detail the treatment induced neurological complications of radiotherapy, chemotherapy, and combined treatment and the pathophysiological basis of these injuries.
30. Belka C, Budach W, Kortmann RD, Bamberg M. Radiation induced CNS toxicity-molecular and cellular mechanisms. Br J Cancer. 2001;85(9):1233-9. doi: 10.1054/bjoc.2001.2100.
31. Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73. doi: 10.3389/fonc.2012.00073. This review provides excellent coverage of the theories of radiation-induced brain injury and the pathophysiological mechanisms behind injury. Potential targets for ameliorating injury are discussed.
32. Arriagada R, Le Chevalier T, Borie F, Riviere A, Chomy P, Monnet I, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst. 1995;87(3):183-90.
33. Sun A, Bae K, Gore EM, Movsas B, Wong SJ, Meyers CA, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol. 2011;29(3):279-86. doi: 10.1200/JCO.2010.29.6053.
34. Le Pechoux C, Laplanche A, Faivre-Finn C, Ciuleanu T, Wanders R, Lerouge D, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol. 2011;22(5):1154-63. doi: 10.1093/annonc/mdq576.
35. Wolfson AH, Bae K, Komaki R, Meyers C, Movsas B, Le Pechoux C, et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;81(1):77-84. doi: 10.1016/j.ijrobp.2010.05.013.
36. Ball DL, Matthews JP. Prophylactic cranial irradiation: more questions than answers. Semin Radiat Oncol. 1995;5(1):61-8. doi: 10.1054/SRAO00500061.
37. Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;4, CD003869. doi: 10.1002/14651858.CD003869.pub3.
38. Young DF, Posner JB, Chu F, Nisce L. Rapid-course radiation therapy of cerebral metastases: results and complications. Cancer. 1974;34(4):1069-76.
39. Hindo WA, DeTrana 3rd FA, Lee MS, Hendrickson FR. Large dose increment irradiation in treatment of cerebral metastases. Cancer. 1970;26(1):138-41.
40. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313-7. doi: 10.1038/3305.
41. Colicos MA, Dash PK. Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits. Brain Res. 1996;739(1-2):120-31.
42. Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res. 2004;162(1):39-47.
43. Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol. 2004;188(2):316-30. doi: 10.1016/j.expneurol.2004.05.005.
44. Wan JF, Zhang SJ, Wang L, Zhao KL. Implications for preserving neural stem cells in whole brain radiotherapy and prophylactic cranial irradiation: a review of 2270 metastases in 488 patients. J Radiat Res. 2013;54(2):285-91. doi: 10.1093/jrr/rrs085.
45. Gondi V, Tome WA, Marsh J, Struck A, Ghia A, Turian JV, et al. Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933. Radiother Oncol. 2010;95(3):327-31. doi: 10.1016/j.radonc.2010.02.030.
46. Mehta MP. Radiation Therapy Oncology Group: RTOG 0933 Protocol. Available at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study= 0933 Accessed July 2013. This article, the RTOG 0933 protocol, describes the rationale behind hippocampal sparing radiation and provides an excellent stepwise guide on how to contour and plan for hippocampal sparing radiotherapy.
47. Gondi V, Hermann BP, Mehta MP, Tome WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348-54. doi: 10.1016/j.ijrobp.2012.11.031.
48. Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63(14):4021-7.
49. Barani IJ, Benedict SH, Lin PS. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys. 2007;68(2):324-33. doi: 10.1016/j.ijrobp.2007.01.033.
50. Marsh JC, Gielda BT, Herskovic AM, Wendt JA, Turian JV. Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: a dosimetric study using helical tomotherapy. J Med Imaging Radiat Oncol. 2010;54(4):375-82. doi: 10.1111/j.1754-9485.2010.02184.x.
51. Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: current concepts and approaches. J Oncol. 2010;2010:198208. doi: 10.1155/2010/198208. This paper describes the mechanisms of CNS toxicity and explores the role of hippocampal sparing, limbic circuit sparing, and neural stem cell sparing radiotherapy.
52. Barani IJ, Larson DA, Berger MS. Future directions in treatment of brain metastases. Surg Neurol Int. 2013;4 Suppl 4:S220-30. doi: 10.4103/2152-7806. 111299. An excellent review of recent studies investigating the role of WBRT and SRS with a focus on multiple brain metastases and projections for future treatment regimes.
53. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483-91. doi: 10.1001/jama.295.21.2483.
54. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037-44. doi: 10.1016/S1470-2045(09)70263-3. The only phase III RCT of SRS versus SRS with WBRT with a primary endpoint of neurocognitive function. The study was closed early according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function.
55. Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134-41. doi: 10.1200/JCO.2010.30. 1655. This paper reports the EORTC phase III RCT of WBRT versus observation after local therapy for 1-3 brain metastases. This large 359 patient trial provides a definitive statement on the impact of WBRT after local therapy.
56. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA: J Am Med Assoc. 1998;280(17):1485-9.
57. Mahmood U, Kwok Y, Regine WF, Patchell RA. Whole-brain irradiation for patients with brain metastases: still the standard of care. Lancet Oncol. 2010;11(3):221-2. doi: 10.1016/S1470-2045(09)70389-4. author reply 3.
58. Weiss SE, Kelly PJ. Neurocognitive function after WBRT plus SRS or SRS alone. Lancet Oncol. 2010;11(3):220-1. doi: 10.1016/S1470-2045(09)70387-0.
59. Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013;31(1):65-72. doi: 10.1200/JCO.2011.41.0639. This paper reports the QOL outcomes from [55]. It is the first such analysis and reveals a generally lower, albeit mild and transitory, change in QOL after WBRT.
60. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol. 2007;25(10):1260-6. doi: 10.1200/JCO.2006.09.2536.
61. Brown WR, Blair RM, Moody DM, Thore CR, Ahmed S, Robbins ME, et al. Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J Neurol Sci. 2007;257(1-2):67-71. doi: 10.1016/j.jns.2007.01.014.
62. Wilcock G, Mobius HJ, Stoffler A, Group MMM. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6):297-305.
63. Tsien JZ. Building a brainier mouse. Sci Am. 2000;282(4):62-8.
64. Brown PD, Shook S, Laack NN, Wefel JS, Choucair A, Suh JH, et al. Memantine for the Prevention of Cognitive Dysfunction in Patients Receiving Whole-brain Radiation Therapy (WBRT): First Report of RTOG 0614, a Placebo-controlled, Double-blind, Randomized Trial. Int J Radiat Oncol Biol Phys. 2012;84(3):S1-2.
65. Shaw EG, Rosdhal R, D'Agostino Jr RB, Lovato J, Naughton MJ, Robbins ME, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24(9):1415-20. doi: 10.1200/JCO.2005.03.3001.
66. Rapp SR, Case D, Peiffer A, Naughton MJ, Stieber VW, Bayer GK et al. Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors. 2013 ASCO Annual Meeting. Oral Abstract Session, Central Nervous System Tumours. J Clin Oncol 31, 2013 (suppl; abstr 2006).
67. Nonaka S, Chuang DM. Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport. 1998;9(9):2081-4.
68. Rowe MK, Chuang DM. Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med. 2004;6(21):1-18. doi: 10.1017/S1462399404008385.
69. Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell Jr WO, et al. Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res. 2006;66(23):11179-86. doi: 10.1158/0008-5472.CAN-06- 2740.
70. Khasraw M, Ashley D, Wheeler G, Berk M. Using lithium as a neuroprotective agent in patients with cancer. BMC Med. 2012;10:131. doi: 10.1186/1741-7015-10-131. This summary article describes the role of lithium for neurocognitive dysfunction and its potential role in radiation neuroprotection.
71. Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J, et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport. 2008;19(2):221-4. doi: 10.1097/WNR.0b013e3282f48108.
72. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal neurogenesis by lithium. J Neurochem. 2000;75(4):1729-34.
73. Huo K, Sun Y, Li H, Du X, Wang X, Karlsson N, et al. Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain. Mol Cell Neurosci. 2012;51(1-2):32-42. doi: 10.1016/j.mcn.2012.07.002.
74. Barwon Health, Deakin University, Peter MacCallum Cancer Centre; Australia. A Feasibility Trial Using Lithium As A Neuroprotective Agent In Patients Undergoing Prophylactic Cranial Irradiation For Small Cell Lung Cancer (TULIP). Available at http://clinicaltrials.gov/ct2/show/NCT01486459 NLM identifier: NCT01486459. Accessed July, 2013.
75. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86(3):747-803. doi: 10.1152/physrev.00036.2005.
76. Ghosh SN, Zhang R, Fish BL, Semenenko VA, Li XA, Moulder JE, et al. Renin-Angiotensin system suppression mitigates experimental radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2009;75(5):1528-36. doi: 10.1016/j.ijrobp.2009.07.1743.
77. Moulder JE, Cohen EP, Fish BL. Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation. Radiat Res. 2011;175(1):29-36. doi: 10.1667/RR2400.1.
78. George AJ, Thomas WG, Hannan RD. The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer. 2010;10(11):745-59. doi: 10.1038/nrc2945.
79. Robbins ME, Zhao W, Garcia-Espinosa MA, Diz DI. Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets. 2010;11(11):1413-22. This comprehensive paper describes the role of RAS in the brain and the potential role of RAS blockers in amelioration of radiation-induced brain injury.
80. Kim JH, Brown SL, Kolozsvary A, Jenrow KA, Ryu S, Rosenblum ML, et al. Modification of radiation injury by ramipril, inhibitor of angiotensin- converting enzyme, on optic neuropathy in the rat. Radiat Res. 2004;161(2):137-42.
81. Robbins ME, Payne V, Tommasi E, Diz DI, Hsu FC, Brown WR, et al. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2009;73(2):499-505. doi: 10.1016/j.ijrobp.2008.09.058.
82. Conner KR, Forbes ME, Lee WH, Lee YW, Riddle DR. AT1 receptor antagonism does not influence early radiation-induced changes in microglial activation or neurogenesis in the normal rat brain. Radiat Res. 2011;176(1):71-83.
83. Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, et al. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res. 2012;178(1):46-56.
84. Jenrow KA, Liu J, Brown SL, Kolozsvary A, Lapanowski K, Kim JH. Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis. J Neuro-Oncol. 2011;101(3):449-56. doi: 10.1007/s11060-010-0282- x.
85. Bordet R, Ouk T, Petrault O, Gele P, Gautier S, Laprais M, et al. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans. 2006;34(Pt 6):1341-6. doi: 10.1042/BST0341341.
86. Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME. The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys. 2009;75(3):870-7. doi: 10.1016/j.ijrobp.2009.06.059.
87. Schnegg CI, Greene-Schloesser D, Kooshki M, Payne VS, Hsu FC, Robbins ME. The PPARdelta agonist GW0742 inhibits neuroinflammation, but does not restore neurogenesis or prevent early delayed hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radic Biol Med. 2013;61C:1-9. doi: 10.1016/j.freeradbiomed.2013.03.002.
88. Zhao W, Payne V, Tommasi E, Diz DI, Hsu FC, Robbins ME. Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2007;67(1):6-9. doi: 10.1016/j.ijrobp.2006.09.036.
89. Wake Forest University. Pioglitazone Hydrochloride in preventing radiation-induced cognitive dysfunction in treating patients with brain tumors. Available from: http://clinicaltrials.gov/ct2/show/NCT01151670 NLM identifier: NCT0115670. Accessed July, 2013.
90. Stessin AM, Gursel DB, Schwartz A, Parashar B, Kulidzhanov FG, Sabbas AM, et al. FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells. Neurosci Lett. 2012;516(2):253-8. doi: 10.1016/j.neulet.2012.04.004.
91. Zorrilla Zubilete MA, Guelman LR, Maur DG, Caceres LG, Rios H, Zieher LM, et al. Partial neuroprotection by 17-β-estradiol in neonatal gamma-irradiated rat cerebellum. Neurochem Int. 2011;58(3):273-80.
92. Mehrotra S, Pecaut MJ, Gridley DS. Analysis of minocycline as a countermeasure against acute radiation syndrome. In Vivo. 2012;26(5):743-58.
93. Oh SB, Park HR, Jang YJ, Choi SY, Son TG, Lee J. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by gamma-ray radiation. Br J Pharmacol. 2013;168(2):421-31. doi: 10.1111/j.1476-5381.2012.02142.x.
94. Attia A, Rapp SR, Case LD, D'Agostino R, Lesser G, Naughton M, et al. Phase II study of Ginkgo biloba in irradiated brain tumor patients: effect on cognitive function, quality of life, and mood. J Neuro-Oncol. 2012;109(2):357-63. doi: 10.1007/s11060-012-0901-9.
95. Said UZ, Saada HN, Abd-Alla MS, Elsayed ME, Amin AM. Hesperidin attenuates brain biochemical changes of irradiated rats. Int J Radiat Biol. 2012;88(8):613-8. doi: 10.3109/09553002.2012.694008.
96. Xin N, Li YJ, Li X, Wang X, Li Y, Zhang X, et al. Dragon's blood may have radioprotective effects in radiation-induced rat brain injury. Radiat Res. 2012;178(1):75-85.
97. Liu JL, Tian DS, Li ZW, Qu WS, Zhan Y, Xie MJ, et al. Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo. Brain Res. 2010;1316:101-11. doi: 10.1016/j.brainres.2009.12.055.
98. Wong-Goodrich SJ, Pfau ML, Flores CT, Fraser JA, Williams CL, Jones LW. Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation. Cancer Res. 2010;70(22):9329-38. doi: 10.1158/0008-5472.CAN-10- 1854.
99. Acharya MM, Christie LA, Lan ML, Donovan PJ, Cotman CW, Fike JR, et al. Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc Natl Acad Sci U S A. 2009;106(45):19150-5. doi: 10.1073/pnas.0909293106.
100. Daley GQ, Ahrlund Richter L, Auerbach JM, Benvenisty N, Charo RA, Chen G, et al. Ethics. The ISSCR guidelines for human embryonic stem cell research. Science. 2007;315(5812):603-4. doi: 10.1126/science.1139337.