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Brain metastases (BMs) represent the commonest intracranial tumours which occur approximately 30% of all adult patients presenting with solid cancers. The BMs do not only reduce the survival expectations but negatively alter the quality of life measures as well. For decades, surgery and whole-brain radiotherapy (WBRT) constituted the traditional treatment options with limited efficacy for the BMs. However, the unsatisfactory local control and ultimate survival outcomes led to a paradigm change, and stereotactic radiosurgery (SRS) has been executed as an alternative to surgery and WBRT or to augment the outcomes of each treatment when used in conjunction with them. In spite of the impressive improvements in the local control rates, yet the desired survival results were not achieved with SRS mainly due to the deaths ascribed to the extracranial systemic disease progression or unavoidably fatal distant brain recurrences. In this regard, as of late, numerous immunotherapeutics have been shown to improve the outcomes of various cancers, such as the locally advanced non-small-cell lung cancers. Recognizing the fact that the immunotherapy is becoming one of the indispensable components of standard treatment protocols for many tumour primaries, this review aimed to evaluate the efficacy and safety of the use of novel immunotherapeutics with standard SRS for BMs.
Schuette W. Treatment of brain metastases from lung cancer: Chemo-therapy. Lung Cancer. 2004;45(2):253-7.
D’Andrea G, Palombi L, Minniti G, Pesce A, Marchetti P. Brain metastases: Surgical treatment and overall survival. World Neurosurg. 2017;97:169-77.
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu. Rev. Immunol. 2005;23:515-48.
Zou W, Chen L. Inhibitory B7 family molecules in the tumour microenvironment. Nature Rev. Immunol. 2008;8:467-77.
Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 1996;14:233-58.
Rudd CE, Taylor A, Schneider H. CD28 and CTLA4 coreceptor expression and signal transduction. Immunol. Rev. 2009;229:12-26.
Hathcock KS, Laszlo G, Dickler HB, et al. Identification of an alternative CTLA4 ligand costimulatory for T cell activation. Science. 1993;262:905-7.
Freeman GJ, Gribben JG, Boussiotis VA, et al. Cloning of B7–2: A CTLA4 counter-receptor that costimulates human T cell proliferation. Science. 1993;262:909-11.
Linsley PS, Greene JL, Brady W, et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA4 receptors. Immunity. 1994;1(9):793-801.
Parry RV, Chemnitz JM, Frauwirthet KA, et al. CTLA4 and PD1 receptors inhibit T cell activation by distinct mechanisms. Mol. Cell Biol. 2005;25:9543-53.
Wing K, Onishi Y, Martin PP, et al. CTLA4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-5.
Keir ME, Liang SC, Guleria I, et al. Tissue expression of PDL1 mediates peripheral T-cell tolerance. J. Exp. Med. 2006;203(4): 883-95.
Okazaki T, Honjo T. PD1 and PD1 ligands: From discovery to clinical application. Int. Immunol. 2007;19:813-24.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
Chow MT, Moller A, Smyth MJ. Inflammation and immune surveillance in cancer. Semin Cancer Biol. 2012;22:23-32.
Zeng J, Harris TJ, Lim M, Drake CG, Tran PT. Immune modulation and stereotactic radiation: Improving local and abscopal responses. Biomed Res Int. 2013;658126.
Tang C, Wang X, Soh H, et al. Combining radiation and immunotherapy: A new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831-8.
Salama AK, Postow MA, Salama JK. Irradiation and immunotherapy: From concept to the clinic. Cancer. 2016;122: 1659-71.
Shahabi V, Postow MA, Tuck D, Wolchok JD. Immune priming of the tumor microenvironment by radiotherapy: Rationale for combination with immunotherapy to improve anticancer efficacy. Am J Clin Oncol. 2015;38: 90-7.
Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83(4):1306-10.
Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379-88.
Zhang I, Formenti SC, Knisely J. Immunotherapy plus stereotactic radiosurgery: Building on the promise of precision medicine for CNS malignancies-part 1: Principles of combined treatment. Oncology. 2018;32:e28.
Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: A synergistic combination. J Clin Invest. 2013;123(7):2756-63.
Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458-68.
Knisely JP, Yu JB, Flanigan J. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117(2):227-33.
Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD. Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med. 2013;2:899-906.
Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res. 2013;23(3): 191-5.
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):68-75.
Tazi K, Hathaway A, Chiuzan C, Shirai K. Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery. Cancer Med. 2015;4(1):1-6.
Schoenfeld JD, Mahadevan A, Floyd SR, et al. Ipilimumab and cranial radiation in metastatic melanoma patients: A case series and review. J Immunother Cancer. 2015;3:50.
Qian JM, Yu JB, Kluger HM, Chiang VL. Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer. 2016;122:3051-8.
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;27:434-41.
Ahmed KA, Kim S, Arrington J, et al. Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neurooncol. 2017;133: 331-8.
Patel KR, Shoukat S, Oliver DE, et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am J Clin Oncol. 2017;40: 444-50.
Cohen-Inbar O, Shih HH, Xu Z, Schlesinger D, et al. The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg. 2017;127:1007-14.
Skrepnik T, Sundararajan S, Cui H, Stea B. Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab. Oncoimmunology. 2017;6(3):e1283461.
Yusuf MB, Amsbaugh MJ, Burton E, et al. 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.
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;99:22-30.
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;5:76.
Rahman R, Cortes A, Niemierko A, et al The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: Intracranial progression, survival and toxicity. J Neurooncol. 2018;138(2):299-306.
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.
Diao K, Bian SX, Routman DM, et al. Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: Clinical outcomes and toxicity. J. Neurooncol. 2018;139(2):421- 9.
Schapira E, Hubbeling H, Yeap BY, et al. Improved overall survival and locoregional disease control with concurrent PD-1 pathway inhibitors and stereotactic radiosurgery for lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys. 2018;101(3):624-9.
Nardin C, Mateus C, Texier M, et al. Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases. Melanoma Res. 2018;28:111-9.
Minniti G, Anzellini D, Reverberi C, et al. Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: Evaluation of brain control and toxicity. J. Immuno-therapy Cancer. 2019;7:102.
Murphy B, Walker J, Bassale S, et al. Concurrent radiosurgery and immune checkpoint inhibition: Improving regional intracranial control for patients with metastatic melanoma. Am J Clin Oncol. 2019;42(3):253-7.
Galli G, Cavalieri S, Di Guardo L, et al. Combination of immunotherapy and brain radiotherapy in metastatic melanoma: A retrospective analysis. Oncol Res Treat. 2019;42:182-8.
Lu VM, Goyal A, Rovin RA, et al. Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: A systematic review and meta-analysis. J. Neurooncol. 2019;141(1):1-12.
Lehrer EJ, Peterson J, Brown PD, et al. Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data. Radiother Oncol. 2019;130:104-12.
Trapani S, Manicone M, Sikokis A, et al. Effectiveness and safety of “real” concurrent stereotactic radiotherapy and immunotherapy in metastatic solid tumors: A systematic review. Crit. Rev. Oncol. Hematol. 2019;142:9-15.
Eljalby M, Pannullo SC, Schwartz TH, et al. Optimal timing and sequence of immunotherapy when combined with stereotactic radiosurgery in the treatment of brain metastases. World Neurosurgery. 2019;127:397-404.
Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One. 2016;11(6):e0157164.
Robin TP, Breeze RE, Smith DE, et al. Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases. Journal of Neuro-Oncology. 2018;140:55– 62.
Martin IS, 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):1123-24.