Skip to main content

Advertisement

Log in

Neurologic Complications of Cranial Radiation Therapy and Strategies to Prevent or Reduce Radiation Toxicity

  • Neuro-Oncology (J.C.M. Brust, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Radiation therapy is an important treatment for patients with brain tumors but can have significant neurologic complications. This review highlights the broad spectrum of short-term and long-term neurologic complications that can occur in patients receiving cranial radiation therapy, and strategies to prevent and treat such complications.

Recent Findings

Despite significant improvements in radiotherapy delivery, there are neurologic complications that can result from treatment. With increased recognition and understanding of these neurologic complications, novel strategies to prevent and mitigate them are an area of active research with early promising results. Intensive efforts are ongoing to address the risk of radiation-induced neurocognitive changes through advances in radiation technique and therapies targeting relevant molecular pathways.

Summary

Neurologic complications from radiation therapy are an important consideration in counseling, treatment, and post-treatment management of patients with brain tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Chang EL, Brown PD, Lo SS, Sahgal A, Suh JH. Adult CNS radiation oncology: Principles and Practice. Berlin: Springer; 2018.

    Google Scholar 

  2. Farooqi A, Li J, de Groot J, Yeboa DN. Current role of radiation therapy in the management of malignant central nervous system tumors. Hematol Oncol Clin North Am. 2020;34:13–28.

    PubMed  Google Scholar 

  3. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand. 1951;102:316–9.

    CAS  PubMed  Google Scholar 

  4. Potters L, Kavanagh B, Galvin JM, Hevezi JM, Janjan NA, Larson DA, et al. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) Practice Guideline for the Performance of Stereotactic Body Radiation Therapy. Int J Radiat Oncol. 2010;76:326–32.

    Google Scholar 

  5. Kjellberg RN, Shintani A, Frantz AG, Kliman B. Proton-beam therapy in acromegaly. N Engl J Med. 1968;278:689–95.

    CAS  PubMed  Google Scholar 

  6. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. Philadelphia: Lippincott Williams & Wilkins; 2012.

    Google Scholar 

  7. Maier P, Hartmann L, Wenz F, Herskind C. Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization. Int J Mol Sci. 2016;17:102.

    PubMed Central  Google Scholar 

  8. Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci CMLS. 2016;73:2829–50.

    CAS  PubMed  Google Scholar 

  9. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys. 1980;6:1215–28.

    CAS  PubMed  Google Scholar 

  10. Harjani RR, Gururajachar JM, Krishnaswamy U. Comprehensive assessment of somnolence syndrome in patients undergoing radiation to the brain. Rep Pract Oncol Radiother. 2016;21:560–6.

    PubMed  PubMed Central  Google Scholar 

  11. Powell C, Guerrero D, Sardell S, Cumins S, Wharram B, Traish D, et al. Somnolence syndrome in patients receiving radical radiotherapy for primary brain tumours: a prospective study. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2011;100:131–6.

    Google Scholar 

  12. Brown PD, Ballman KV, Rummans TA, Maurer MJ, Sloan JA, Boeve BF, et al. Prospective study of quality of life in adults with newly diagnosed high-grade gliomas. J Neuro-Oncol. 2006;76:283–91.

    Google Scholar 

  13. Armstrong TS, Vera E, Zhou R, Acquaye AA, Sullaway CM, Berger AM, et al. Association of genetic variants with fatigue in patients with malignant glioma. Neuro-Oncol Pract. 2018;5:122–8.

    Google Scholar 

  14. Butler JM, Case LD, Atkins J, Frizzell B, Sanders G, Griffin P, et al. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2007;69:1496–501.

    CAS  PubMed  Google Scholar 

  15. Boele FW, Douw L, de Groot M, van Thuijl HF, Cleijne W, Heimans JJ, et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. Neuro-Oncol. 2013;15:1420–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee EQ, Muzikansky A, Drappatz J, Kesari S, Wong ET, Fadul CE, et al. A randomized, placebo-controlled pilot trial of armodafinil for fatigue in patients with gliomas undergoing radiotherapy. Neuro-Oncol. 2016;18:849–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Page BR, Shaw EG, Lu L, Bryant D, Grisell D, Lesser GJ, et al. Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-Oncol. 2015;17:1393–401.

    PubMed  PubMed Central  Google Scholar 

  18. Ho M-L, Rojas R, Eisenberg RL. Cerebral Edema. Am J Roentgenol. 2012;199:W258–73.

    Google Scholar 

  19. Werner-Wasik M, Rudoler S, Preston PE, Hauck WW, Downes BM, Leeper D, et al. Immediate side effects of stereotactic radiotherapy and radiosurgery. Int J Radiat Oncol Biol Phys. 1999;43:299–304.

    CAS  PubMed  Google Scholar 

  20. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47:291–8.

    CAS  PubMed  Google Scholar 

  21. Milano MT, Sharma M, Soltys SG, Sahgal A, Usuki KY, Saenz J-M, et al. Radiation-induced edema after single-fraction or multifraction stereotactic radiosurgery for meningioma: a critical review. Int J Radiat Oncol Biol Phys. 2018;101:344–57.

    PubMed  Google Scholar 

  22. Unger KR, Lominska CE, Chanyasulkit J, Randolph-Jackson P, White RL, Aulisi E, et al. Risk factors for posttreatment edema in patients treated with stereotactic radiosurgery for meningiomas. Neurosurgery. 2012;70:639–45.

    PubMed  Google Scholar 

  23. Han M-S, Jang W-Y, Moon K-S, Lim S-H, Kim I-Y, Jung T-Y, et al. Is fractionated gamma knife radiosurgery a safe and effective treatment approach for large-volume (>10 cm3) intracranial meningiomas? World Neurosurg. 2017;99:477–83.

    PubMed  Google Scholar 

  24. Galicich JH, French LA, Melby JC. Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet. 1961;81:46–53.

    CAS  PubMed  Google Scholar 

  25. Arvold ND, Pinnell NE, Mahadevan A, Connelly S, Silverman R, Weiss SE, et al. Steroid and anticonvulsant prophylaxis for stereotactic radiosurgery: large variation in physician recommendations. Pract Radiat Oncol. 2016;6:e89–96.

    PubMed  Google Scholar 

  26. Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain J Neurol. 2016;139:1458–71.

    Google Scholar 

  27. • Fleischmann DF, Jenn J, Corradini S, Ruf V, Herms J, Forbrig R, et al. Bevacizumab reduces toxicity of reirradiation in recurrent high-grade glioma. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2019;138:99–105 This paper demonstrates that concomitant bevacizumab with re-irradiation for recurrent high-grade gliomas reduces treatment toxicity.

    CAS  Google Scholar 

  28. Arratibel-Echarren I, Albright K, Dalmau J, Rosenfeld MR. Use of Bevacizumab for neurological complications during initial treatment of malignant gliomas. Neurol Barc Spain. 2011;26:74–80.

    CAS  Google Scholar 

  29. Deibert CP, Ahluwalia MS, Sheehan JP, Link MJ, Hasegawa T, Yomo S, et al. Bevacizumab for refractory adverse radiation effects after stereotactic radiosurgery. J Neuro-Oncol. 2013;115:217–23.

    CAS  Google Scholar 

  30. Fanous AA, Fabiano AJ. Bevacizumab for the treatment of post-stereotactic radiosurgery adverse radiation effect. Surg Neurol Int. 2016;7:S542–4.

    PubMed  PubMed Central  Google Scholar 

  31. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9:453–61.

    PubMed  Google Scholar 

  32. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:1963–72.

    Google Scholar 

  33. Strauss SB, Meng A, Ebani EJ, Chiang GC. Imaging Glioblastoma Posttreatment: Progression, Pseudoprogression, Pseudoresponse. Radiation Necrosis Radiol Clin North Am. 2019;57:1199–216.

    PubMed  Google Scholar 

  34. Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22:633–8.

    PubMed  Google Scholar 

  35. Régis J, Delsanti C, Roche P-H. Editorial: Vestibular schwannoma radiosurgery: progression or pseudoprogression? J Neurosurg. 2017;127:374–9.

    PubMed  Google Scholar 

  36. Patel TR, McHugh BJ, Bi WL, Minja FJ, Knisely JPS, Chiang VL. A comprehensive review of MR imaging changes following radiosurgery to 500 brain metastases. AJNR Am J Neuroradiol. 2011;32:1885–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wiggenraad R, Bos P, Verbeek-de Kanter A, Lycklama À, Nijeholt G, van Santvoort J, et al. Pseudo-progression after stereotactic radiotherapy of brain metastases: lesion analysis using MRI cine-loops. J Neuro-Oncol. 2014;119:437–43.

    Google Scholar 

  38. Radbruch A, Fladt J, Kickingereder P, Wiestler B, Nowosielski M, Bäumer P, et al. Pseudoprogression in patients with glioblastoma: clinical relevance despite low incidence. Neuro-Oncol. 2015;17:151–9.

    PubMed  Google Scholar 

  39. Ellingson BM, Chung C, Pope WB, Boxerman JL, Kaufmann TJ. Pseudoprogression, radionecrosis, inflammation or true tumor progression? Challenges associated with glioblastoma response assessment in an evolving therapeutic landscape. J Neuro-Oncol. 2017;134:495–504.

    CAS  Google Scholar 

  40. Patel P, Baradaran H, Delgado D, Askin G, Christos P, John Tsiouris A, et al. MR perfusion-weighted imaging in the evaluation of high-grade gliomas after treatment: a systematic review and meta-analysis. Neuro-Oncol. 2017;19:118–27.

    PubMed  Google Scholar 

  41. Galldiks N, Rapp M, Stoffels G, Fink GR, Shah NJ, Coenen HH, et al. Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-L-tyrosine PET in comparison to MRI. Eur J Nucl Med Mol Imaging. 2013;40:22–33.

    CAS  PubMed  Google Scholar 

  42. Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, et al. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncol. 2016;18:1199–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Haider AS, van den Bent M, Wen PY, Vogelbaum MA, Chang S, Canoll PD, et al. Towards a standard pathological and molecular characterization of recurrent glioma in adults: a RANO effort. Neuro-Oncol. 2019.

  44. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:2192–7.

    Google Scholar 

  45. Wick W, Chinot OL, Bendszus M, Mason W, Henriksson R, Saran F, et al. Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma. Neuro-Oncol. 2016;18:1434–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ellingson BM, Wen PY, Cloughesy TF. Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurother J Am Soc Exp Neurother. 2017;14:307–20.

    Google Scholar 

  47. Dörr W. Radiobiology of tissue reactions. Ann ICRP. 2015;44:58–68.

    PubMed  Google Scholar 

  48. Trifiletti DM, Lee C-C, Schlesinger D, Larner JM, Xu Z, Sheehan JP. Leukoencephalopathy after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2015;93:870–8.

    PubMed  Google Scholar 

  49. Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A comprehensive review. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2010;97:370–6.

    Google Scholar 

  50. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8:955–62.

    CAS  PubMed  Google Scholar 

  51. Wilke C, Grosshans D, Duman J, Brown P, Li J. Radiation-induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults. Neuro-Oncol. 2018;20:597–607.

    CAS  PubMed  Google Scholar 

  52. Hong JH, Chiang CS, Campbell IL, Sun JR, Withers HR, McBride WH. Induction of acute phase gene expression by brain irradiation. Int J Radiat Oncol Biol Phys. 1995;33:619–26.

    CAS  PubMed  Google Scholar 

  53. Parihar VK, Limoli CL. Cranial irradiation compromises neuronal architecture in the hippocampus. Proc Natl Acad Sci U S A. 2013;110:12822–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:1305–9.

    Google Scholar 

  55. 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 Off J Am Soc Clin Oncol. 2011;29:279–86.

    Google Scholar 

  56. Onodera S, Aoyama H, Tha KK, Hashimoto N, Toyomaki A, Terae S, et al. The value of 4-month neurocognitive function as an endpoint in brain metastases trials. J Neuro-Oncol. 2014;120:311–9.

    Google Scholar 

  57. 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;21:3557–8.

    Google Scholar 

  58. Avanzo M, Stavinoha P, Brodin P, Aridgides PD, Naqa IE, McGovern SL, et al. Modeling the risk of neurocognitive effects from radiation therapy in childhood cancer survivors: initial results from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) CNS Task Force. Int J Radiat Oncol Biol Phys. 2018;102:S175.

    Google Scholar 

  59. Merchant TE, Schreiber JE, Wu S, Lukose R, Xiong X, Gajjar A. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys. 2014;90:554–61.

    PubMed  PubMed Central  Google Scholar 

  60. Ma TM, Grimm J, McIntyre R, Anderson-Keightly H, Kleinberg LR, Hales RK, et al. A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2017;125:234–40.

    Google Scholar 

  61. • Acharya S, Wu S, Ashford JM, Tinkle CL, Lucas JT, Qaddoumi I, et al. Association between hippocampal dose and memory in survivors of childhood or adolescent low-grade glioma: a 10-year neurocognitive longitudinal study. Neuro-Oncol. 2019;21:1175–83 A longitudinal study evaluating the association between hippocampal radiotherapy dose and memory in survivors of childhood low grade glioma.

    PubMed  PubMed Central  Google Scholar 

  62. Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27:3691–7.

    Google Scholar 

  63. •• Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316:401–9 The authors report a randomized trial evaluating cognitive function in patients receiving radiosurgery alone or radiosurgery with whole brain radiation therapy.

    PubMed  PubMed Central  Google Scholar 

  64. 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;10:1037–44.

    PubMed  Google Scholar 

  65. • Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:1049–60 The authors report a randomized trial evaluating the use of stereotactic radiosurgery vs. whole brain radiation therapy after resection of metastatic brain disease with less cognitive effects in radiosurgery patients.

    PubMed  PubMed Central  Google Scholar 

  66. 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 Off J Am Soc Clin Oncol. 2013;31:65–72.

    Google Scholar 

  67. Brown PD, Buckner JC, O’Fallon JR, Iturria NL, Brown CA, O’Neill BP, et al. Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21:2519–24.

    Google Scholar 

  68. Klein M, Heimans JJ, Aaronson NK, van der Ploeg HM, Grit J, Muller M, et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet Lond Engl. 2002;360:1361–8.

    CAS  Google Scholar 

  69. Douw L, Klein M, Fagel SS, van den Heuvel J, Taphoorn MJ, Aaronson NK, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol. 2009;8:810–8.

    PubMed  Google Scholar 

  70. Bovi JA, Pugh SL, Sabsevitz D, Robinson CG, Paulson E, Mehta MP, et al. Pretreatment volume of MRI-determined white matter injury predicts neurocognitive decline after hippocampal avoidant whole-brain radiation therapy for brain metastases: secondary analysis of NRG oncology radiation therapy oncology group 0933. Adv Radiat Oncol. 2019;4:579–86.

    PubMed  PubMed Central  Google Scholar 

  71. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15:387–95.

    PubMed  Google Scholar 

  72. Moravan MJ, Fecci PE, Anders CK, Clarke JM, AKS S, Adamson JD, et al. Current multidisciplinary management of brain metastases. Cancer. 2020.

  73. Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncol. 2013;15:1429–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rapp SR, Case LD, Peiffer A, Naughton MM, Chan MD, Stieber VW, et al. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33:1653–9.

    CAS  Google Scholar 

  75. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32:3810–6.

    PubMed  PubMed Central  Google Scholar 

  76. •• Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG Oncology CC001. J Clin Oncol Off J Am Soc Clin Oncol. 2020;JCO1902767. The authors report a phase III randomized trial demonstrating benefit in hippocampal-avoidance whole brain radiation relative to conventional whole-brain radiation.

  77. Gross JP, Powell S, Zelko F, Hartsell W, Goldman S, Fangusaro J, et al. Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients. Neuro-Oncol. 2019;21:934–43.

    PubMed  PubMed Central  Google Scholar 

  78. •• Kahalley LS, Ris MD, Grosshans DR, Okcu MF, Paulino AC, Chintagumpala M, et al. Comparing intelligence quotient change after treatment with proton versus photon radiation therapy for pediatric brain tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34:1043–9 The authors report a longitudinal analysis of intellectual trajectories between pediatric patients treated with contemporary treatment paradigms with proton vs. photon-based radiotherapy. Improved outcomes are noted in patients treated with proton radiotherapy.

    CAS  Google Scholar 

  79. Kahalley LS, Peterson R, Ris MD, Janzen L, Okcu MF, Grosshans DR, et al. Superior intellectual outcomes after proton radiotherapy compared with photon radiotherapy for pediatric medulloblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 2020;38:454–61.

    Google Scholar 

  80. Robbins ME, Payne V, Tommasi E, Diz DI, Hsu F-C, 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;73:499–505.

    CAS  PubMed  Google Scholar 

  81. Zhao W, Payne V, Tommasi E, Diz DI, Hsu F-C, 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;67:6–9.

    CAS  PubMed  Google Scholar 

  82. Cramer CK, Alphonse-Sullivan N, Isom S, Metheny-Barlow LJ, Cummings TL, Page BR, et al. Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial. J Cancer Res Clin Oncol. 2019;145:337–44.

    CAS  PubMed  Google Scholar 

  83. Remler MP, Marcussen WH, Tiller-Borsich J. The late effects of radiation on the blood brain barrier. Int J Radiat Oncol Biol Phys. 1986;12:1965–9.

    CAS  PubMed  Google Scholar 

  84. Panagiotakos G, Alshamy G, Chan B, Abrams R, Greenberg E, Saxena A, et al. Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain. PLoS One. 2007;2:e588.

    PubMed  PubMed Central  Google Scholar 

  85. Muto M, Frauenfelder G, Senese R, Zeccolini F, Schena E, Giurazza F, et al. Dynamic susceptibility contrast (DSC) perfusion MRI in differential diagnosis between radionecrosis and neoangiogenesis in cerebral metastases using rCBV, rCBF and K2. Radiol Med (Torino). 2018;123:545–52.

    Google Scholar 

  86. Zakhari N, Taccone MS, Torres CH, Chakraborty S, Sinclair J, Woulfe J, et al. Prospective comparative diagnostic accuracy evaluation of dynamic contrast-enhanced (DCE) vs. dynamic susceptibility contrast (DSC) MR perfusion in differentiating tumor recurrence from radiation necrosis in treated high-grade gliomas. J Magn Reson Imaging JMRI. 2019;50:573–82.

    PubMed  Google Scholar 

  87. Zeng Q-S, Li C-F, Liu H, Zhen J-H, Feng D-C. Distinction between recurrent glioma and radiation injury using magnetic resonance spectroscopy in combination with diffusion-weighted imaging. Int J Radiat Oncol Biol Phys. 2007;68:151–8.

    PubMed  Google Scholar 

  88. Mehrabian H, Desmond KL, Soliman H, Sahgal A, Stanisz GJ. Differentiation between radiation necrosis and tumor progression using chemical exchange saturation transfer. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23:3667–75.

    CAS  Google Scholar 

  89. Horky LL, Hsiao EM, Weiss SE, Drappatz J, Gerbaudo VH. Dual phase FDG-PET imaging of brain metastases provides superior assessment of recurrence versus post-treatment necrosis. J Neuro-Oncol. 2011;103:137–46.

    Google Scholar 

  90. Shanker M, Chua B, Bettington C, Foote MC, Pinkham MB. Re-irradiation for recurrent high-grade gliomas: a systematic review and analysis of treatment technique with respect to survival and risk of radionecrosis. Neuro-Oncol Pract. 2019;6:144–55.

    Google Scholar 

  91. Tsien C, Moughan J, Michalski JM, Gilbert MR, Purdy J, Simpson J, et al. Phase I 3D conformal radiation dose escalation study in newly diagnosed Glioblastoma: RTOG 9803. Int J Radiat Oncol Biol Phys. 2009;73:699–708.

    PubMed  Google Scholar 

  92. Kohutek ZA, Yamada Y, Chan TA, Brennan CW, Tabar V, Gutin PH, et al. Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neuro-Oncol. 2015;125:149–56.

    Google Scholar 

  93. Martin AM, Cagney DN, Catalano PJ, Alexander BM, Redig AJ, Schoenfeld JD, et al. Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol. 2018;4:1123–4.

    PubMed  PubMed Central  Google Scholar 

  94. Calvo W, Hopewell JW, Reinhold HS, Yeung TK. Time- and dose-related changes in the white matter of the rat brain after single doses of X rays. Br J Radiol. 1988;61:1043–52.

    CAS  PubMed  Google Scholar 

  95. Korytko T, Radivoyevitch T, Colussi V, Wessels BW, Pillai K, Maciunas RJ, et al. 12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors. Int J Radiat Oncol Biol Phys. 2006;64:419–24.

    PubMed  Google Scholar 

  96. Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, et al. Diagnosis and management of radiation necrosis in patients with brain metastases. Front Oncol. 2018;8:395.

    PubMed  PubMed Central  Google Scholar 

  97. • Lehrer EJ, Peterson JL, Zaorsky NG, Brown PD, Sahgal A, Chiang VL, et al. Single versus multifraction stereotactic radiosurgery for large brain metastases: an international meta-analysis of 24 trials. Int J Radiat Oncol Biol Phys. 2019;103:618–30 The authors report a large meta-analysis assessing the utility of multi-fraction stereotactic radiotherapy compared to single fraction radiotherapy with respect radionecrosis and local control.

    PubMed  Google Scholar 

  98. Minniti G, Scaringi C, Paolini S, Lanzetta G, Romano A, Cicone F, et al. Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis. Int J Radiat Oncol Biol Phys. 2016;95:1142–8.

    PubMed  Google Scholar 

  99. Tye K, Engelhard HH, Slavin KV, Nicholas MK, Chmura SJ, Kwok Y, et al. An analysis of radiation necrosis of the central nervous system treated with bevacizumab. J Neuro-Oncol. 2014;117:321–7.

    CAS  Google Scholar 

  100. Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79:1487–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Chuba PJ, Aronin P, Bhambhani K, Eichenhorn M, Zamarano L, Cianci P, et al. Hyperbaric oxygen therapy for radiation-induced brain injury in children. Cancer. 1997;80:2005–12.

    CAS  PubMed  Google Scholar 

  102. Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW, Schold SC. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology. 1994;44:2020–7.

    CAS  PubMed  Google Scholar 

  103. Ahluwalia M, Barnett GH, Deng D, Tatter SB, Laxton AW, Mohammadi AM, et al. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. J Neurosurg. 2018;130:804–11.

    PubMed  Google Scholar 

  104. Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. J Neuro-Oncol. 2015;122:421–9.

    CAS  Google Scholar 

  105. Sanford NN, Yeap BY, Larvie M, Daartz J, Munzenrider JE, Liebsch NJ, et al. Prospective, randomized study of radiation dose escalation with combined proton-photon therapy for benign Meningiomas. Int J Radiat Oncol Biol Phys. 2017;99:787–96.

    PubMed  PubMed Central  Google Scholar 

  106. Campen CJ, Kranick SM, Kasner SE, Kessler SK, Zimmerman RA, Lustig R, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke. 2012;43:3035–40.

    PubMed  PubMed Central  Google Scholar 

  107. Aizer AA, Du R, Wen PY, Arvold ND. Radiotherapy and death from cerebrovascular disease in patients with primary brain tumors. J Neuro-Oncol. 2015;124:291–7.

    CAS  Google Scholar 

  108. Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the childhood Cancer survivor study. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:5277–82.

    Google Scholar 

  109. Burn S, Gunny R, Phipps K, Gaze M, Hayward R. Incidence of cavernoma development in children after radiotherapy for brain tumors. J Neurosurg. 2007;106:379–83.

    PubMed  Google Scholar 

  110. Lew SM, Morgan JN, Psaty E, Lefton DR, Allen JC, Abbott R. Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma. J Neurosurg. 2006;104:103–7.

    PubMed  Google Scholar 

  111. Kikuchi A, Maeda M, Hanada R, Okimoto Y, Ishimoto K, Kaneko T, et al. Moyamoya syndrome following childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2007;48:268–72.

    PubMed  Google Scholar 

  112. Lessell S. Friendly fire: neurogenic visual loss from radiation therapy. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc. 2004;24:243–50.

    Google Scholar 

  113. Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys. 2010;76:S28–35.

    PubMed  Google Scholar 

  114. Li PC, Liebsch NJ, Niemierko A, Giantsoudi D, Lessell S, Fullerton BC, et al. Radiation tolerance of the optic pathway in patients treated with proton and photon radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2019;131:112–9.

    Google Scholar 

  115. Leber KA, Berglöff J, Pendl G. Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg. 1998;88:43–50.

    CAS  PubMed  Google Scholar 

  116. Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, et al. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2003;55:1177–81.

    PubMed  Google Scholar 

  117. Kerklaan JP. Lycklama á Nijeholt GJ, Wiggenraad RGJ, Berghuis B, Postma TJ, Taphoorn MJB. SMART syndrome: a late reversible complication after radiation therapy for brain tumours. J Neurol. 2011;258:1098–104.

    PubMed  PubMed Central  Google Scholar 

  118. Constine LS, Woolf PD, Cann D, Mick G, McCormick K, Raubertas RF, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med. 1993;328:87–94.

    CAS  PubMed  Google Scholar 

  119. Appelman-Dijkstra NM, Kokshoorn NE, Dekkers OM, Neelis KJ, Biermasz NR, Romijn JA, et al. Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:2330–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Pai HH, Thornton A, Katznelson L, Finkelstein DM, Adams JA, Fullerton BC, et al. Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis. Int J Radiat Oncol Biol Phys. 2001;49:1079–92.

    CAS  PubMed  Google Scholar 

  121. Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM. Ototoxicity after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys. 2007;67:469–79.

    PubMed  Google Scholar 

  122. Pan CC, Eisbruch A, Lee JS, Snorrason RM, Ten Haken RK, Kileny PR. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol. 2005;61:1393–402.

    Google Scholar 

  123. Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood Cancer survivor study. J Natl Cancer Inst. 2006;98:1528–37.

    PubMed  Google Scholar 

  124. Bowers DC, Nathan PC, Constine L, Woodman C, Bhatia S, Keller K, et al. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol. 2013;14:e321–8.

    PubMed  PubMed Central  Google Scholar 

  125. • Wolf A, Naylor K, Tam M, Habibi A, Novotny J, Liščák R, et al. Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 2019;20:159–64 The authors report low rates of secondary malignancy in a large multi-institutional analysis of patients treated with radiosurgery.

    PubMed  Google Scholar 

  126. Pollock BE, Link MJ, Stafford SL, Parney IF, Garces YI, Foote RL. The risk of radiation-induced tumors or malignant transformation after single-fraction intracranial radiosurgery: results based on a 25-year experience. Int J Radiat Oncol Biol Phys. 2017;97:919–23.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rifaquat Rahman.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuro-Oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahman, R., Alexander, B.M. & Wen, P.Y. Neurologic Complications of Cranial Radiation Therapy and Strategies to Prevent or Reduce Radiation Toxicity. Curr Neurol Neurosci Rep 20, 34 (2020). https://doi.org/10.1007/s11910-020-01051-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-020-01051-5

Keywords

Navigation