Metastatic Brain Tumors: Viewpoint: Whole Brain Radiation Therapy

  • William F. RegineEmail author
  • Sarah F. Grabowski
  • Roy A. Patchell


Whole brain radiation therapy (WBRT) is the standard of care for most patients with greater than four brain metastases. WBRT in these patients has been shown to improve neurologic symptoms, decrease progression of intracranial disease, and lengthen survival. In patients with one to four brain metastases, the utility of focal therapies such as neurosurgery or stereotactic radiosurgery (SRS), as well as concern over the possible neurotoxicities of WBRT, has lead to questions regarding its use in this population. However, studies looking at combined regimens of focal treatment plus WBRT vs. WBRT alone have not been able to produce conclusive evidence of either increased neurotoxicity or improved survival with the use of WBRT due to issues of lack of power, significant crossover between the randomized groups, and inconsistent endpoints. Similarly, investigations into the neurocognitive functioning of patients being treated for brain metastases have not effectively taken into account confounding factors including baseline neurologic status, radiation dose and fractionation, the effects of other palliative and anti-cancer medications, and the definition of truly clinically relevant endpoints. Two findings that have been consistently shown in these trials are that progression of disease within the brain leads to a significant decline in neurocognitive functioning, and that WBRT significantly decreases recurrence of disease within the brain. Fortunately, studies looking at various fractionation schemes have shown that there is enough flexibility in the delivery of WBRT to accommodate the patient’s overall goals of therapy while somewhat mediating the risk of unwanted effects. Finally, it is important to understand that, the shortcomings of the current body of literature notwithstanding, the process of reconciling the benefits of WBRT with the risks must include a clear perspective regarding the fact that while the concerns surrounding this therapy remain unproven, the detrimental clinical consequences of omitting WBRT are clear.


Brain Metastasis Radiation Therapy Oncology Group Whole Brain Radiation Therapy Observation Group Neurocognitive Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Berk L. An overview of radiotherapy trials for the treatment of brain metastases. Oncology. 1995;9(11):1205–19.PubMedGoogle Scholar
  2. 2.
    Horton J, Baxter DH, Olson KB. The management of metastases to the brain by irradiation and corticosteroids. Am J Roentgenol Radium Ther Nucl Med. 1971;111(2):334–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Posner JB. Management of brain metastases. Rev Neurol. 1992;148(6–7):477–87.PubMedGoogle Scholar
  4. 4.
    Cairncross JG, Posner JB. The management of brain metastases. In: Walker MD, editor. Oncology of the nervous system. Boston: Martinus Nijhoff; 1983.Google Scholar
  5. 5.
    Markesbery WR, Brooks WH, Gupta GD, Young AB. Treatment for patients with cerebral metastases. Arch Neurol. 1978;35(11):754–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Ruderman NB, Hall TC. Use of glucocorticoids in the palliative treatment of metastatic brain tumors. Cancer. 1965;18(3):298–306.CrossRefPubMedGoogle Scholar
  7. 7.
    Chang DB, Yang PC, Luh KT, Kuo SH, Hong RL, Lee LN. Late survival of non-small cell lung cancer patients with brain metastases. Chest. 1992;101(5):1293–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, Perez CA, Hendrickson FR. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1980;6(1):1–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Kwok Y, Pathchell RA, Regine WF. Management of overt central nervous system metastases: brain and spinal cord. In: Pass HI, editor. Principles and practice of lung cancer. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2010.Google Scholar
  10. 10.
    Gelber RD, Larson M, Borgelt BB, Kramer S. Equivalence of radiation schedules for the palliative treatment of brain metastases in patients with favorable prognosis. Cancer. 1981;48(8):1749–53.CrossRefPubMedGoogle Scholar
  11. 11.
    Kurtz JM, Gelber RD, Brady LW, Carella RJ, Cooper JS. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1981;7(7):891–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Deiner-West M, Dobbins TW, Phillips TL, Nelson DF. Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys. 1989;16(3):669–73.CrossRefGoogle Scholar
  13. 13.
    Epstein BE, Scott CB, Sause WT, Rotman M, Sneed PK, Janjan NA, Davis LW, Selim H, Mohiuddin M, Wasserman TH. Improved survival duration in patients with unresected solitary brain metastasis using accelerated hyperfractionated radiation therapy at total doses of 54.4 gray and greater. Results of the Radiation Therapy Oncology Group 85-28. Cancer. 1993;71(4):1362–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Murray KJ, Scott C, Greenberg HM, Emami B, Seider M, Vora NL, Olson C, Whitton A, Movsas B, Curran W. A randomized phase III study of accelerated hyperfractionated versus standard radiation in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys. 1997;39(3):571–4.CrossRefPubMedGoogle Scholar
  15. 15.
    Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, Kunkler I, Caudrelier JM, Eisenberg PD, Meerwaldt J, Siemers R, Carrie C, Gaspar LE, Curran W, Phan SC, Miller RA, Renschler MF. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 2004;22(1):157–65.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    DeAngelis LM, Mandell LR, Thaler HT, Kimmel DW, Galicich JH, Fuks Z, Posner JB. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24(6): 798–805.CrossRefPubMedGoogle Scholar
  18. 18.
    Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30(10):1080–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, Verhoeven JS, Christiaens MR, Vandenberghe J, Vandenbulcke M, Sunaert S. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012;30(3):274–81.CrossRefPubMedGoogle Scholar
  20. 20.
    Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys. 1999;45(2):427–34.CrossRefPubMedGoogle Scholar
  21. 21.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran Jr WJ. Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial. Lancet. 2004;363(9422):1665–72.CrossRefPubMedGoogle Scholar
  22. 22.
    Elveen T, Andrews DW. Summary of RTOG 95-01 phase III randomized trial of whole brain radiation with and without stereotactic radiosurgery boost, including presentation of a clinical case study. Am J Oncol Rev. 2004;3:592–600.Google Scholar
  23. 23.
    Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery WR, Foon KA, Young B. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for the treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA. 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.CrossRefPubMedGoogle Scholar
  26. 26.
    Raizer J. Radiosurgery and whole-brain radiation therapy for brain metastases. JAMA. 2006;295(21):2535–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M, Hirota S, Shioura H, Inomata T, Kunieda E, Hayakawa K, Nakagawa K, Kobashi G, Shirato H. 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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Regine WF, Schmitt FA, Scott CB, Dearth C, Patchell RA, Nichols Jr RC, Gore EM, Franklin 3rd RL, Suh JH, Mehta MP. Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: results of Radiation Therapy Oncology Group trial BR-0018. Int J Radiat Oncol Biol Phys. 2004;58(5):1346–52.CrossRefPubMedGoogle Scholar
  30. 30.
    Armstrong CL, Corn BW, Ruffer JE, Pruitt AA, Mollman JE, Phillips PC. Radiotherapeutic effects on brain function: double dissociation of memory systems. Neuropsychiatry Neuropsychol Behav Neurol. 2000;13(2):101–11.PubMedGoogle Scholar
  31. 31.
    Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van de Berge D, Collette S, Collette L, Mueller RP. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer. 1997;79(4):835–42.CrossRefPubMedGoogle Scholar
  33. 33.
    Lawlor PG, Gagnon B, Mancini IL, Pereira JL, Hanson J, Suarez-Almazor ME, Bruera ED. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med. 2000;160(6):786–94.CrossRefPubMedGoogle Scholar
  34. 34.
    Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fraction 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.CrossRefPubMedGoogle Scholar
  35. 35.
    Regine WF, Huhn JL, Patchell RA, St Clair WH, Strottmann J, Meigooni A, Sanders M, Young AB. Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery al in patients with newly diagnosed brain metastases: results and implications. Int J Radiat Oncol Biol Phys. 2002;52(2):333–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Taylor BV, Buckner JC, Cascino TL, O’Fallon JR, Schaefer PL, Dinapoli RP, Schomberg P. Effects of radiation and chemotherapy on cognitive function in patients with high-grade gliomas. J Clin Oncol. 1998;16(6):2195–201.PubMedGoogle Scholar
  37. 37.
    Hocht S, Wiegel T, Hinkelbein W. Reirradiation for recurrent brain metastases. Controversies in Neuro-Oncology. Front Radiat Oncol Basal. 1999;33:327–31.CrossRefGoogle Scholar
  38. 38.
    Hazuka MB, Kinzie JJ. Brain metastases: results and effects of re-irradiation. Int J Radiat Oncol Biol Phys. 1988;15(2):433–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Kurup P, Reddy S, Hendrickson FR. Results of re-irradiation for cerebral metastases. Cancer. 1980;46(12):2587–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Wong WW, Schild SE, Sawyer TE, Shaw EG. Analysis of outcome in patients reirradiated for brain metastases. Int J Radiat Oncol Biol Phys. 1996;34(3):585–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Cooper JS, Steinfeld AD, Lerch IA. Cerebral metastases: value of reirradiation in selected patients. Radiology. 1990;174(3 Pt 1):883–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • William F. Regine
    • 1
    Email author
  • Sarah F. Grabowski
    • 1
  • Roy A. Patchell
    • 2
  1. 1.Department of Radiation OncologyUniversity of Maryland Medical CenterBaltimoreUSA
  2. 2.National Brain Tumor Center, Capital Institute for NeurosciencesCapital Health Medical Center-HopewellPenningtonUSA

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