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Radiation Brain Injury

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Book cover Acute Side Effects of Radiation Therapy

Abstract

Cranial irradiation has an important role in the treatment of brain tumors either with curative intent or for palliation. Cranial irradiation has a unique application in prevention of distant metastasis to brain parenchyma, and prophylactic cranial irradiation may be carried out in selected patients at high risk of neoplastic cranial involvement. Brain is also an organ at risk during radiotherapy of tumors which are located in base of skull and in some head and neck cancers. Cranial irradiation in any condition can cause brain injuries that are classified into three groups based on the timing of their occurrence after radiation exposure: acute (during radiation or up to 6 weeks after radiation), early delayed or subacute (up to 6 months after radiation), and late delayed (6 months or more after the completion of radiation). However in more trials, brain injury simply is defined as acute (within 90 days of the commencement of therapy) and late reactions (after 90 days of the commencement of therapy) [1]. Reports indicate that patients that undergo standard fractionated cranial irradiation and stereotactic radiosurgery may have acute brain reactions in the range of 2–40% [1–12]. However, up to 50% of patients with high doses per fraction (more than 3 Gy) to a large part of the brain may develop acute encephalopathy [3, 13].

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References

  1. Lawrence YR, Wang M, Dicker AP, Andrews D, Curran WJ, Michalski JM et al (2011) Early toxicity predicts long-term survival in high-grade glioma. Br J Cancer 104(9):1365–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Goetz P, Ebinu JO, Roberge D, Zadeh G (2012) Current standards in the management of cerebral metastases. Int J Surg Oncol 2012:493426

    PubMed  Google Scholar 

  3. Young DF, Posner JB, Chu F, Nisce L (1974) Rapid-course radiation therapy of cerebral metastases: results and complications. Cancer 34(4):1069–1076

    Article  CAS  PubMed  Google Scholar 

  4. Borgelt B, Gelber R, Larson M, Hendrickson F, Griffin T, Roth R (1981) Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 7(12):1633–1638

    Article  CAS  PubMed  Google Scholar 

  5. Harwood AR, Simpson WJ (1977) Radiation therapy of cerebral metastases: a randomized prospective clinical trial. Int J Radiat Oncol Biol Phys 2(11):1091–1094

    Article  CAS  PubMed  Google Scholar 

  6. Rades D, Haatanen T, Schild SE, Dunst J (2007) Dose escalation beyond 30 grays in 10 fractions for patients with multiple brain metastases. Cancer 110(6):1345–1350

    Article  PubMed  Google Scholar 

  7. Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH et al (1993) Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery. Ann Neurol 33(6):583–590

    Article  CAS  PubMed  Google Scholar 

  8. Rades D, Bohlen G, Pluemer A, Veninga T, Hanssens P, Dunst J et al (2007) Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer 109(12):2515–2521

    Article  PubMed  Google Scholar 

  9. O’Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O’Fallon JR (2003) A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55(5):1169–1176

    Article  PubMed  Google Scholar 

  10. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC et al (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363(9422):1665–1672

    Article  PubMed  Google Scholar 

  11. Muacevic A, Wowra B, Siefert A, Tonn J-C, Steiger H-J, Kreth FW (2008) Microsurgery plus whole brain irradiation versus gamma knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neuro-Oncol 87(3):299–307

    Article  Google Scholar 

  12. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H et al (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13(9):916–926

    Article  PubMed  Google Scholar 

  13. Posner JB (1995) Neurologic complications of cancer. Oxford University Press, Oxford

    Google Scholar 

  14. Ch’ien LT, Aur RJ, Stagner S, Cavallo K, Wood A, Goff J et al (1980) Long-term neurological implications of somnolence syndrome in children with acute lymphocytic leukemia. Ann Neurol 8(3):273–277

    Article  PubMed  Google Scholar 

  15. Freeman J, Johnston P, Voke J (1973) Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukaemia. Br Med J 4(5891):523–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garwicz S, Aronson A, Elmqvist D, Landberg T (1975) Postirradiation syndrome and EEG findings in children with acute lymphoblastic leukaemia. Acta Paediatr Scand 64(3):399–403

    Article  CAS  PubMed  Google Scholar 

  17. Siemes H, Rating D, Siegert M, Hanefeld F, Müller S, Gadner H et al (1980) Changes of CSF-protein pattern in children with acute lymphoblastic leukemia during prophylactic CNS therapy (Berlin protocol). Med Pediatr Oncol 8(1):25–34

    Article  CAS  PubMed  Google Scholar 

  18. Parker D, Malpas J, Sandland R, Sheaff P, Freeman J, Paxton A (1978) Outlook following “somnolence syndrome” after prophylactic cranial irradiation. Br Med J 1(6112):554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Littman P, Rosenstock J, Gale G, Krisch RE, Meadows A, Sather H et al (1984) The somnolence syndrome in leukemic children following reduced daily dose fractions of cranial radiation. Int J Radiat Oncol Biol Phys 10(10):1851–1853

    Article  CAS  PubMed  Google Scholar 

  20. Rahman AA, Mannan M, Sadeque S (2008) Acute and long-term neurological complications in children with acute lymphoblastic leukemia. Bangladesh Med Res Counc Bull 34(3):90–93

    PubMed  Google Scholar 

  21. Parvez K, Parvez A, Zadeh G (2014) The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci 15(7):11832–11846

    Article  PubMed  PubMed Central  Google Scholar 

  22. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9(5):453–461

    Article  PubMed  Google Scholar 

  23. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26(13):2192–2197

    Article  PubMed  Google Scholar 

  24. Boldrey E, Sheline G (1966) Delayed transitory clinical manifestations after radiation treatment of intracranial tumors. Acta Radiol Ther Phys Biol 5:5–10

    Article  CAS  PubMed  Google Scholar 

  25. Faithfull S, Brada M (1998) Somnolence syndrome in adults following cranial irradiation for primary brain tumours. Clin Oncol 10(4):250–254

    Article  CAS  Google Scholar 

  26. Armstrong C, Ruffer J, Corn B, DeVries K, Mollman J (1995) Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms. J Clin Oncol 13(9):2263–2271

    Article  CAS  PubMed  Google Scholar 

  27. Rider W (1963) Radiation damage to the brain—a new syndrome. J Can Assoc Radiol 14:67–69

    CAS  PubMed  Google Scholar 

  28. Kramer S, Lee KF (1974) Complications of radiation therapy: the central nervous system. Semin Roentgenol 9:75–83

    Article  CAS  PubMed  Google Scholar 

  29. Liang BC (1999) Radiation-associated neurotoxicity. Neurol Clin 35:54–58

    Google Scholar 

  30. Walker AJ, Ruzevick J, Malayeri AA, Rigamonti D, Lim M, Redmond KJ et al (2014) Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression? Future Oncol 10(7):1277–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Uzal D, Özyar E, Hayran M, Zorlu F, Atahan L, Yetkin S (1998) Reduced incidence of the somnolence syndrome after prophylactic cranial irradiation in children with acute lymphoblastic leukemia. Radiother Oncol 48(1):29–32

    Article  CAS  PubMed  Google Scholar 

  32. McTyre E, Scott J, Chinnaiyan P (2013) Whole brain radiotherapy for brain metastasis. Surg Neurol Int 4(Suppl 4):S236

    PubMed  PubMed Central  Google Scholar 

  33. Kiebert G, Curran D, Aaronson N, Bolla M, Menten J, Rutten E et al (1998) Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). Eur J Cancer 34(12):1902–1909

    Article  CAS  PubMed  Google Scholar 

  34. Garden AS, Maor MH, Yung WA, Bruner JM, Woo SY, Moser RP et al (1991) Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother Oncol 20(2):99–110

    Article  CAS  PubMed  Google Scholar 

  35. Chao JH, Phillips R, Nickson JJ (1954) Roentgen-ray therapy of cerebral metastases. Cancer 7(4):682–689

    Article  CAS  PubMed  Google Scholar 

  36. Mandell LR, Walker RW, Steinherz P, Fuks Z (1989) Reduced incidence of the somnolence syndrome in leukemic children with steroid coverage during prophylactic cranial radiation therapy. Results of a pilot study. Cancer 63(10):1975–1978

    Article  CAS  PubMed  Google Scholar 

  37. Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH et al (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303(23):1323–1329

    Article  CAS  PubMed  Google Scholar 

  38. Bleehen N, Stenning SA (1991) Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council brain tumour working party. Br J Cancer 64(4):769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taphoorn M, Stupp R, Coens C, Osoba D, Kortmann R, van den Bent M et al (2005) European organisation for research and treatment of cancer brain tumour group; EORTC radiotherapy group; national cancer institute of Canada clinical trials group. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 6(12):937–944

    Article  PubMed  Google Scholar 

  40. Kocher PM, Eich H-T, Semrau R, Güner SA, Müller R-P (2005) Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases. Strahlenther Onkol 181(1):20–25

    Article  PubMed  Google Scholar 

  41. Abrey LE, Christodoulou C (2001) Temozolomide for treating brain metastases. Semin Oncol 28:34–42

    Article  CAS  PubMed  Google Scholar 

  42. Suh JH, Stea B, Nabid A, Kresl JJ, Fortin A, Mercier J-P et al (2006) Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 24(1):106–114

    Article  CAS  PubMed  Google Scholar 

  43. Powell C, Guerrero D, Sardell S, Cumins S, Wharram B, Traish D et al (2011) Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: a prospective study. Radiother Oncol 100(1):131–136

    Article  PubMed  Google Scholar 

  44. Leibel SA, Sheline GE (1987) Radiation therapy for neoplasms of the brain. J Neurosurg 66(1):1–22

    Article  CAS  PubMed  Google Scholar 

  45. Sanghvi D (2015) Post-treatment imaging of high-grade gliomas. Indian J Radiol Imaging 25(2):102

    Article  PubMed  PubMed Central  Google Scholar 

  46. Williams RL, Karacan IE, Moore CA (1998) Sleep disorders: diagnosis and treatment. Wiley, New York

    Google Scholar 

  47. Faithfull S (1991) Patients’ experiences following cranial radiotherapy: a study of the somnolence syndrome. J Adv Nurs 16(8):939–946

    Article  CAS  PubMed  Google Scholar 

  48. Druckmann A (1929) Schlafsucht als Folge der Röntgenbestrahlung. Beitrag zur Strahlenempfindlichkeit des Gehirns. Strahlentherapie 33(382–84):268

    Google Scholar 

  49. Vern TZ, Salvi S (2009) Somnolence syndrome and fever in pediatric patients with cranial irradiation. J Pediatr Hematol Oncol 31(2):118–120

    Article  PubMed  Google Scholar 

  50. Kelsey CR, Marks LB (2006) Somnolence syndrome after focal radiation therapy to the pineal region: case report and review of the literature. J Neuro-Oncol 78(2):153–156

    Article  Google Scholar 

  51. Ballonoff A. (2016) Acute complications of cranial irradiation. Available from https://www.uptodate.com/contents/acute-complications-of-cranial-irradiation. Accessed 10 Aug 2016

  52. Pampiglione G (1974) Letter: somnolence in children with acute leukemia. Br Med J 1(5899):158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tallet AV, Azria D, Barlesi F, Spano J-P, Carpentier AF, Gonçalves A et al (2012) Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol 7(1):1

    Article  Google Scholar 

  54. Halperin EC, Brady LW, Wazer DE, Perez CA (2013) Perez & Brady’s principles and practice of radiation oncology. Lippincott Williams & Wilkins, Philadelphia, PA

    Google Scholar 

  55. Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Sillevis Smitt PA et al (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113(2):405–410

    Article  CAS  PubMed  Google Scholar 

  56. Zeng Q-S, Li C-F, Liu H, Zhen J-H, Feng D-C (2007) Distinction between recurrent glioma and radiation injury using magnetic resonance spectroscopy in combination with diffusion-weighted imaging. Int J Radiat Oncol Biol Phys 68(1):151–158

    Article  PubMed  Google Scholar 

  57. Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the radiation therapy oncology group (RTOG) and the European organization for research and treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 31(5):1341–1346

    Article  CAS  PubMed  Google Scholar 

  58. Faithfull S (1992) The diary method for nursing research: a study of somnolence syndrome. Eur J Cancer Care 1(2):13–18

    Article  Google Scholar 

  59. Ryken TC, McDermott M, Robinson PD, Ammirati M, Andrews DW, Asher AL et al (2010) The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. J Neuro-Oncol 96(1):103–114

    Article  CAS  Google Scholar 

  60. Hempen C, Weiss E, Hess CF (2002) Dexamethasone treatment in patients with brain metastases and primary brain tumors: do the benefits outweigh the side-effects? Support Care Cancer 10(4):322–328

    Article  PubMed  Google Scholar 

  61. Woodford K (2007) Somnolence syndrome after cranial irradiation: a literature review. The Radiographer 54(3):30

    Google Scholar 

  62. Proctor S, Kernahan J, Taylor P (1981) Depression as component of post-cranial irradiation somnolence syndrome. Lancet 317(8231):1215–1216

    Article  Google Scholar 

  63. Roth P, Wick W, Weller M (2010) Steroids in neurooncology: actions, indications, side-effects. Curr Opin Neurol 23(6):597–602

    Article  CAS  PubMed  Google Scholar 

  64. Alberti E, Hartmann A, Schütz H-J, Schreckenberger F (1978) The effect of large doses of dexamethasone on the cerebrospinal fluid pressure in patients with supratentorial tumors. J Neurol 217(3):173–181

    Article  CAS  PubMed  Google Scholar 

  65. Jarden J, Dhawan V, Moeller J, Strother S, Rottenberg D (1989) The time course of steroid action on blood-to-brain and blood-to-tumor transport of 82Rb: a positron emission tomographic study. Ann Neurol 25(3):239–245

    Article  CAS  PubMed  Google Scholar 

  66. Soffietti R, Cornu P, Delattre J, Grant R, Graus F, Grisold W et al (2006) EFNS guidelines on diagnosis and treatment of brain metastases: report of an EFNS task force. Eur J Neurol 13(7):674–681

    Article  CAS  PubMed  Google Scholar 

  67. Miller JD, Leech P (1975) Effects of mannitol and steroid therapy on intracranial volume-pressure relationships in patients. J Neurosurg 42(3):274–281

    Article  CAS  PubMed  Google Scholar 

  68. Nahaczewski AE, Fowler SB, Hariharan S (2004) Dexamethasone therapy in patients with brain tumors-a focus on tapering. J Neurosurg Nurs 36(6):340–343

    Article  Google Scholar 

  69. Vecht CJ, Hovestadt A, Verbiest H, Van Vliet J, Van Putten W (1994) Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors a randomized study of doses of 4, 8, and 16 mg per day. Neurology 44(4):675

    Article  CAS  PubMed  Google Scholar 

  70. Dietrich J, Rao K, Pastorino S, Kesari S (2011) Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol 4(2):233–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. BCCA protocol summary for dexamethasone as treatment for cerebral edema or CNS swelling. http://www.bccancer.bc.ca/chemotherapy-protocolssite/Documents/Supportive%20Care/SCDEXA_Protocol_1May09.pdf

  72. Ruegg S (2002) Dexamethasone/phenytoin interactions: neurooncological concerns. Swiss Med Wkly 132(29/30):425–426

    PubMed  Google Scholar 

  73. Lawson LA, Blouin RA, Smith RB, Rapp RP, Young AB (1981) Phenytoin-dexamethasone interaction: a previously unreported observation. Surg Neurol 16(1):23–24

    Article  CAS  PubMed  Google Scholar 

  74. Weissman DE, Janjan NA, Erickson B, Wilson FJ, Greenberg M, Ritch PS et al (1991) Twice-daily tapering dexamethasone treatment during cranial radiation for newly diagnosed brain metastases. J Neuro-Oncol 11(3):235–239

    Article  CAS  Google Scholar 

  75. Szabo GC, Winkler SR (1995) Withdrawal of glucocorticoid therapy in neurosurgical patients. Surg Neurol 44(5):498

    Article  CAS  PubMed  Google Scholar 

  76. Guidelines for use of steroids in cancer patients. Available from ttps://www.researchgate.net/file.PostFileLoader.html?id=569a63f35f7f71a5da8b4587&assetKey=AS%3A318546062577664%401452958707609

  77. Kostaras X, Cusano F, Kline G, Roa W, Easaw J (2014) Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol 21(3):e493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Recht L, Mechtler LL, Wong ET, O’Connor PC, Rodda BE (2013) Steroid-sparing effect of corticorelin acetate in peritumoral cerebral edema is associated with improvement in steroid-induced myopathy. J Clin Oncol 31(9):1182–1187

    Article  CAS  PubMed  Google Scholar 

  79. Tjuvajev J, Uehara H, Desai R, Beattie B, Matei C, Zhou Y et al (1996) Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res 56(6):1352–1360

    CAS  PubMed  Google Scholar 

  80. Villalona-Calero M, Eckardt J, Burris H, Kraynak M, Fields-Jones S, Bazan C et al (1998) A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema. Ann Oncol 9(1):71–77

    Article  CAS  PubMed  Google Scholar 

  81. Moliterno JA, Henry E, Pannullo SC (2009) Corticorelin acetate injections for the treatment of peritumoral brain edema. Expert Opin Investig Drugs 18(9):1413–1419

    Article  CAS  PubMed  Google Scholar 

  82. Vredenburgh JJ, Cloughesy T, Samant M, Prados M, Wen PY, Mikkelsen T et al (2010) Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist 15(12):1329–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Batchelor TT, Sorensen AG, di Tomaso E, Zhang W-T, Duda DG, Cohen KS et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Portnow J, Suleman S, Grossman SA, Eller S, Carson K (2002) A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomas. Neuro-Oncology 4(1):22–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Oncology, Imam Hossein Educational Hospital, Shahid Beheshti University of Medical Sciences (SBMU), Shahid Madani Street, Tehran, Iran

    Ainaz Sourati & Ahmad Ameri

  2. Department of Radiotherapy and Oncology, Shohadaye Tajrish Educational Hospital Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran

    Mona Malekzadeh

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Sourati, A., Ameri, A., Malekzadeh, M. (2017). Radiation Brain Injury. In: Acute Side Effects of Radiation Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-55950-6_3

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