Skip to main content
SpringerLink
Log in
Book cover

Radiotherapy in Managing Brain Metastases pp 95–108Cite as

Integrating Systemic Therapy into the Management of Brain Metastases

  • Chapter
  • First Online:

  • 574 Accesses

Abstract

Physicians are often asked to integrate new oncologic agents with cranial radiation therapy in the treatment of brain metastases. These decisions are often made with incomplete information on safety. A pragmatic approach balances the needs to not delay systemic treatment with the theoretical risk of the agent based upon mechanism of action, distribution, and half-life in the context of treatment volume. This generally involves limited interruptions for radiosurgery for most classes of drugs including treatment during off weeks of cytotoxic chemotherapy and no interruption for immune checkpoint inhibitors. BRAF inhibitors and selected VEGF inhibitors may have higher rates of toxicity when combined with whole-brain radiation therapy. The potential overuse of corticosteroids during cranial radiation therapy may have detrimental impact on the efficacy of immunotherapy.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Shaw E, Scott C, Souhami L, et al. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90-05). Int J Radiat Oncol Biol Phys. 1996;34(3):647–54.

    Article  PubMed  CAS  Google Scholar 

  2. Shen CJ, Kummerlowe MN, Redmond KJ, Rigamonti D, Lim MK, Kleinberg LR. Stereotactic radiosurgery: treatment of brain metastasis without interruption of systemic therapy. Int J Radiat Oncol Biol Phys. 2016;95(2):735–42.

    Article  PubMed  Google Scholar 

  3. Kim JM, Miller JA, Kotecha R, et al. The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies. J Neuro-Oncol. 2017;133(2):357–68.

    Article  Google Scholar 

  4. Verduin M, Zindler JD, Martinussen HM, et al. Use of systemic therapy concurrent with cranial radiotherapy for cerebral metastases of solid tumors. Oncologist. 2017;22(2):222–35.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Quantin X, Bozonnat MC, Pujol JL. Recursive Partitioning Analysis Groups II–III brain metastases of non-small cell lung cancer: a phase II randomized study comparing two concurrent chemoradiotherapy regimens. J Thorac Oncol. 2010;5(6):846–51.

    Article  PubMed  Google Scholar 

  6. Jakacki RI, Burger PC, Zhou T, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children’s Oncology Group Phase I/II study. J Clin Oncol. 2012;30(21):2648–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Robinet G, Thomas P, Breton JL, et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) protocol 95-1. Ann Oncol. 2001;12(1):59–67.

    Article  PubMed  CAS  Google Scholar 

  8. Dinglin XX, Huang Y, Liu H, Zeng YD, Hou X, Chen LK. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J Neuro-Oncol. 2013;112(3):461–6.

    Article  CAS  Google Scholar 

  9. Cagney DN, Martin AM, Catalano PJ, et al. Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation. Radiother Oncol. 2018;126(3):511–8.

    Article  PubMed  CAS  Google Scholar 

  10. Glantz MJ, Choy H, Kearns CM, et al. Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. J Natl Cancer Inst. 1995;87(14):1077–81.

    Article  PubMed  CAS  Google Scholar 

  11. Glantz MJ, Chamberlain MC, Chang SM, Prados MD, Cole BF. The role of paclitaxel in the treatment of primary and metastatic brain tumors. Semin Radiat Oncol. 1999;9(2 Suppl 1):27–33.

    PubMed  CAS  Google Scholar 

  12. Lederman G, Wronski M, Arbit E, et al. Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol. 2000;23(2):155–9.

    Article  PubMed  CAS  Google Scholar 

  13. Maraveyas A, Sgouros J, Upadhyay S, Abdel-Hamid AH, Holmes M, Lind M. Gemcitabine twice weekly as a radiosensitiser for the treatment of brain metastases in patients with carcinoma: a phase I study. Br J Cancer. 2005;92(5):815–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Huang YJ, Wu YL, Xie SX, Yang JJ, Huang YS, Liao RQ. Weekly gemcitabine as a radiosensitiser for the treatment of brain metastases in patients with non-small cell lung cancer: phase I trial. Chin Med J. 2007;120(6):458–62.

    Article  PubMed  CAS  Google Scholar 

  15. Jeter MD, Janne PA, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53(2):394–400.

    Article  PubMed  Google Scholar 

  16. Grunda JM, Fiveash J, Palmer CA, et al. Rationally designed pharmacogenomic treatment using concurrent capecitabine and radiotherapy for glioblastoma; gene expression profiles associated with outcome. Clin Cancer Res. 2010;16(10):2890–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Niravath P, Tham YL, Wang T, et al. A phase II trial of capecitabine concomitantly with whole-brain radiotherapy followed by capecitabine and sunitinib for brain metastases from breast cancer. Oncologist. 2015;20(1):13.

    Article  PubMed  Google Scholar 

  18. Chargari C, Kirova YM, Dieras V, et al. Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients. J Neuro-Oncol. 2009;93(3):379–84.

    Article  CAS  Google Scholar 

  19. Low S, Han CH, Batchelor TT. Primary central nervous system lymphoma. Ther Adv Neurol Disord. 2018;11:1756286418793562.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pan Z, Yang G, He H, et al. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: a prospective and single-arm study. Int J Cancer. 2016;139(8):1864–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Qin H, Pan F, Li J, Zhang X, Liang H, Ruan Z. Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis. PLoS One. 2014;9(10):e111475.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Fiveash JB, Arafat WO, Naoum GE, et al. A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases. Adv Radiat Oncol. 2016;1(2):83–8.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87(5):586–92.

    Article  PubMed  CAS  Google Scholar 

  24. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672–81.

    Article  PubMed  CAS  Google Scholar 

  25. Li SH, Liu CY, Hsu PC, et al. Response to afatinib in treatment-naive patients with advanced mutant epidermal growth factor receptor lung adenocarcinoma with brain metastases. Expert Rev Anticancer Ther. 2018;18(1):81–9.

    Article  PubMed  CAS  Google Scholar 

  26. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018:JCO2018783118. https://doi.org/10.1200/JCO.2018.78.3118.

    Article  CAS  Google Scholar 

  27. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018;29(11):2214–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344(3):655–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Pulvirenti T, Hong A, Clements A, et al. Acute radiation skin toxicity associated with BRAF inhibitors. J Clin Oncol. 2016;34(3):e17–20.

    Article  PubMed  Google Scholar 

  30. Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys. 2016;95(2):632–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15.

    Article  PubMed  CAS  Google Scholar 

  32. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.

    Article  PubMed  CAS  Google Scholar 

  33. Lin NU, Freedman RA, Ramakrishna N, et al. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases. Breast Cancer Res Treat. 2013;142(2):405–14.

    Article  PubMed  CAS  Google Scholar 

  34. Chargari C, Idrissi HR, Pierga JY, et al. Preliminary results of whole brain radiotherapy with concurrent trastuzumab for treatment of brain metastases in breast cancer patients. Int J Radiat Oncol Biol Phys. 2011;81(3):631–6.

    Article  PubMed  Google Scholar 

  35. Carlson JA, Nooruddin Z, Rusthoven C, et al. Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema. Neuro-Oncology. 2014;16(7):1006–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Geraud A, Xu HP, Beuzeboc P, Kirova YM. Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer. J Neuro-Oncol. 2017;131(1):69–72.

    Article  CAS  Google Scholar 

  37. Vilela MD, Longstreth WT Jr, Pedrosa HAS, Gil GOB, Duarte JM, Filho MAD. Progressively enlarging cerebellar hematoma concurrent with T-DM1 treatment. World Neurosurg. 2018;111:109–14.

    Article  PubMed  Google Scholar 

  38. Fabi A, Alesini D, Valle E, et al. T-DM1 and brain metastases: clinical outcome in HER2-positive metastatic breast cancer. Breast. 2018;41:137–43.

    Article  PubMed  Google Scholar 

  39. Levy C, Allouache D, Lacroix J, et al. REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. Ann Oncol. 2014;25(12):2351–6.

    Article  PubMed  CAS  Google Scholar 

  40. Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16(1):269–78.

    Article  PubMed  CAS  Google Scholar 

  41. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27(31):5255–61.

    Article  PubMed  CAS  Google Scholar 

  42. Levin VA, Bidaut L, Hou P, 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(5):1487–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Abbas O, Shamseddin A, Temraz S, Haydar A. Posterior reversible encephalopathy syndrome after bevacizumab therapy in a normotensive patient. BMJ Case Rep. 2013;2013:1–4.

    Google Scholar 

  44. Ahluwalia MS, Chao ST, Parsons MW, et al. Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1–3 newly diagnosed brain metastases. J Neuro-Oncol. 2015;124(3):485–91.

    Article  CAS  Google Scholar 

  45. Pfannenstiel LW, McNeilly C, Xiang C, et al. Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma. Onco Targets Ther. 2019;8(1):e1507669.

    Google Scholar 

  46. Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Onco Targets Ther. 2014;3:e28780.

    Google Scholar 

  47. Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys. 2015;92(2):368–75.

    Article  PubMed  PubMed Central  Google Scholar 

  48. An Y, Jiang W, Kim BYS, et al. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol. 2017;125(1):80–8.

    Article  PubMed  CAS  Google Scholar 

  49. Williams NL, Wuthrick EJ, Kim H, et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol Biol Phys. 2017;99(1):22–30.

    Article  PubMed  CAS  Google Scholar 

  50. Chen L, Douglass J, Kleinberg L, et al. Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(4):916–25.

    Article  PubMed  Google Scholar 

  51. Anderson ES, Postow MA, Wolchok JD, et al. Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. J Immunother Cancer. 2017;5(1):76.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Stokes WA, Binder DC, Jones BL, et al. Impact of immunotherapy among patients with melanoma brain metastases managed with radiotherapy. J Neuroimmunol. 2017;313:118–22.

    Article  PubMed  CAS  Google Scholar 

  53. Martin AM, Cagney DN, Catalano PJ, et al. Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol. 2018;4(8):1123–4.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yusuf MB, Amsbaugh MJ, Burton E, Chesney J, Woo S. Peri-SRS administration of immune checkpoint therapy for melanoma metastatic to the brain: investigating efficacy and the effects of relative treatment timing on lesion response. World Neurosurg. 2017;100:632–40.. e634

    Article  PubMed  Google Scholar 

  55. Liniker E, Menzies AM, Kong BY, et al. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Onco Targets Ther. 2016;5(9):e1214788.

    CAS  Google Scholar 

  56. Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27(3):434–41.

    Article  PubMed  CAS  Google Scholar 

  57. Hubbeling HG, Schapira EF, Horick NK, et al. Safety of combined PD-1 pathway inhibition and intracranial radiation therapy in non-small cell lung cancer. J Thorac Oncol. 2018;13(4):550–8.

    Article  PubMed  Google Scholar 

  58. Chang EL, Wefel JS, Hess KR, 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.

    Article  PubMed  Google Scholar 

  59. Brown PD, Jaeckle K, Ballman KV, 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(4):401–9.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Blonigen BJ, Steinmetz RD, Levin L, Lamba MA, Warnick RE, Breneman JC. Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2010;77(4):996–1001.

    Article  PubMed  Google Scholar 

  62. Minniti G, Scaringi C, Paolini S, et al. Single-fraction versus multifraction (9 Gy x 3) 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(4):1142–8.

    Article  PubMed  Google Scholar 

  63. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Drago JZ, Lawrence D, Livingstone E, et al. Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. Melanoma Res. 2019;29(1):65–9.

    Article  PubMed  CAS  Google Scholar 

  65. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722–30.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Ellsworth SG. Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors. Adv Radiat Oncol. 2018;3(4):512–9.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Pike LRG, Bang A, Mahal BA, et al. The impact of radiation therapy on lymphocyte count and survival in metastatic cancer patients receiving PD-1 immune checkpoint inhibitors. Int J Radiat Oncol Biol Phys. 2019;103(1):142–51.

    Article  PubMed  CAS  Google Scholar 

  69. Arbour KC, Mezquita L, Long N, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36(28):2872–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    John B. Fiveash

  2. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Anatoly Nikolaev

  3. Division of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Robert M. Conry

Authors
  1. John B. Fiveash
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anatoly Nikolaev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert M. Conry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John B. Fiveash .

Editor information

Editors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yoshiya Yamada

  2. Department of Radiation Oncology, University of Southern California, Los Angeles, CA, USA

    Eric Chang

  3. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    John B. Fiveash

  4. Weill Cornell Medicine, NewYork–Presbyterian Hospital, New York, NY, USA

    Jonathan Knisely

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fiveash, J.B., Nikolaev, A., Conry, R.M. (2020). Integrating Systemic Therapy into the Management of Brain Metastases. In: Yamada, Y., Chang, E., Fiveash, J., Knisely, J. (eds) Radiotherapy in Managing Brain Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-43740-4_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-43740-4_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-43739-8

  • Online ISBN: 978-3-030-43740-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation