Application of stereotactic radiosurgery combined with immune checkpoint inhibitors in brain metastasis_West China Medical Journal

Authors：

DENG Yifei ^1,2 , SU Zhou ¹ ,  XUE Jianxin ¹

1. Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Radiation Oncology, Chengdu Seventh People’s Hospital, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

XUE Jianxin, Email: killercell@163.com

Keywords：

Stereotactic radiosurgery; Immunotherapy; Immune checkpoint inhibitors; Brain metastases

DOI：

10.7507/1002-0179.201910072

Video：

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Brain metastases are the most common intracranial malignant tumors in adults. Radiotherapy isa common treatment for brain metastases. In particular, stereotactic radiosurgery can control tumors well, and can significantly reduce the impact on cognitive function compared with whole brain radiation therapy. Immune checkpoint inhibitors have less toxic side effects in the treatment of patients with advanced tumors, and show good survival advantages. This article introduces radiotherapy, immunotherapy, stereotactic radiosurgery combined with immune checkpoint inhibitors for brain metastases, discusses the mechanism of stereotactic radiosurgery combined with immune checkpoint inhibitors, and its therapeutic value and research progress in brain metastases, aiming to provide a theoretical basis for the better application of stereotactic radiosurgery combined with immune checkpoint inhibitors to brain metastases.

Citation： DENG Yifei, SU Zhou, XUE Jianxin. Application of stereotactic radiosurgery combined with immune checkpoint inhibitors in brain metastasis. West China Medical Journal, 2021, 36(1): 125-130. doi: 10.7507/1002-0179.201910072 Copy

1.	Tabouret E, Chinot O, Metellus P, et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res, 2012, 32(11): 4655-4662.
2.	Kamath SD, Kumthekar PU. Immune checkpoint inhibitors for the treatment of central nervous system (CNS) metastatic disease. Front Oncol, 2018, 8: 414.
3.	Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol, 2017, 19(11): 1511-1521.
4.	Fox BD, Cheung VJ, Patel AJ, et al. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am, 2011, 22(1): 1-6.
5.	Rahmathulla G, Toms SA, Weil RJ. The molecular biology of brain metastasis. J Oncol, 2012, 2012: 723541.
6.	Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov, 2015, 5(11): 1164-1177.
7.	Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep, 2012, 14(1): 48-54.
8.	Schabath MB, Thompson ZJ, Gray JE. Temporal trends in demographics and overall survival of non-small-cell lung cancer patients at Moffitt Cancer Center from 1986 to 2008. Cancer Control, 2014, 21(1): 51-56.
9.	Brown PD, Ballman KV, Cerhan JH, 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(8): 1049-1060.
10.	Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol, 2017, 18(8): 1040-1048.
11.	Sneed PK, Larson DA, Wara WM. Radiotherapy for cerebral metastases. Neurosurg Clin N Am, 1996, 7(3): 505-515.
12.	Jenrow KA, Brown SL, Lapanowski K, et al. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res, 2013, 179(5): 549-556.
13.	Andrews DW, Scott CB, Sperduto PW, et al. 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, 2004, 363(9422): 1665-1672.
14.	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): 401-409.
15.	National Comprehensive Cancer Network. Non-small cell lung cancer NCCN guidelines. (2019-01-18)[2019-10-12]. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
16.	Berghoff AS, Venur VA, Preusser M, et al. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book, 2016, 35: e116-e122.
17.	Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer, 2012, 12(4): 298-306.
18.	Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep, 2015, 13(2): 412-424.
19.	Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol, 2016, 37(3): 193-207.
20.	Berghoff AS, Ricken G, Wilhelm D, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol, 2016, 130(1): 19-29.
21.	Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology, 2015, 5(1): e1057388.
22.	He BP, Wang JJ, Zhang X, et al. Differential reactions of microglia to brain metastasis of lung cancer. Mol Med, 2006, 12(7/8): 161-170.
23.	Kuol N, Stojanovska L, Nurgali K, et al. PD-1/PD-L1 in disease. Immunotherapy, 2018, 10(2): 149-160.
24.	Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med, 2015, 373(1): 23-34.
25.	Kvistborg P, Philips D, Kelderman S, et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med, 2014, 6(254): 254ra128.
26.	Duchnowska R, Pęksa R, Radecka B, et al. Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res, 2016, 18(1): 43.
27.	Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010, 363(8): 711-723.
28.	Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol, 2012, 13(5): 459-465.
29.	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): 722-730.
30.	Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018, 378(22): 2078-2092.
31.	Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy, 2018, 10(2): 93-105.
32.	Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2017, 389(10066): 255-265.
33.	Crinò L, Bidoli P, Ulivi P, et al. Italian nivolumab expanded access programme (EAP): data from patients with advanced non-squamous NSCLC and brain metastases. J Thoracic Oncol, 2017, 12: S1915.
34.	Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol, 2016, 17(7): 976-983.
35.	Gauvain C, Vauléon E, Chouaid C, et al. Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. Lung Cancer, 2018, 116: 62-66.
36.	Tran TT, Mahajan A, Chiang VL, et al. Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy. J Immunother Cancer, 2019, 7(1): 200.
37.	Constantinidou A, Alifieris C, Trafalis DT. Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): a new era in cancer active immunotherapy. Pharmacol Ther, 2019, 194: 84-106.
38.	Murphy JB, Morton JJ. The effect of roentgen rays on the rate of growth of spontaneous tumors in mice. J Exp Med, 1915, 22(6): 800-803.
39.	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): 589-595.
40.	Wennerberg E, Lhuillier C, Vanpouille-Box C, et al. Barriers to radiation-induced in situ tumor vaccination. Front Immunol, 2017, 8: 229.
41.	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): 5379-5388.
42.	Chongsathidkiet P, Jackson C, Koyama S, et al. Sequestration ofT cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med, 2018, 24(9): 1459-1468.
43.	Jackson CM, Kochel CM, Nirschl CJ, et al. Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clin Cancer Res, 2016, 22(5): 1161-1172.
44.	Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer:a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol, 2017, 18(7): 895-903.
45.	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): 368-375.
46.	Lehrer EJ, McGee HM, Peterson JL, et al. Stereotactic radiosurgery and immune checkpoint inhibitors in the management of brain metastases. Int J Mol Sci, 2018, 19(10): E3054.
47.	Diao K, Bian SX, Routman DM, et al. Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg, 2018, 129(6): 1397-1406.
48.	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): 1123-1124.
49.	Colaco RJ, Martin P, Kluger HM, et al. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?. J Neurosurg, 2016, 125(1): 17-23.

1. Tabouret E, Chinot O, Metellus P, et al. Recent trends in epidemiology of brain metastases: an overview. Anticancer Res, 2012, 32(11): 4655-4662.
2. Kamath SD, Kumthekar PU. Immune checkpoint inhibitors for the treatment of central nervous system (CNS) metastatic disease. Front Oncol, 2018, 8: 414.
3. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol, 2017, 19(11): 1511-1521.
4. Fox BD, Cheung VJ, Patel AJ, et al. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am, 2011, 22(1): 1-6.
5. Rahmathulla G, Toms SA, Weil RJ. The molecular biology of brain metastasis. J Oncol, 2012, 2012: 723541.
6. Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov, 2015, 5(11): 1164-1177.
7. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep, 2012, 14(1): 48-54.
8. Schabath MB, Thompson ZJ, Gray JE. Temporal trends in demographics and overall survival of non-small-cell lung cancer patients at Moffitt Cancer Center from 1986 to 2008. Cancer Control, 2014, 21(1): 51-56.
9. Brown PD, Ballman KV, Cerhan JH, 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(8): 1049-1060.
10. Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol, 2017, 18(8): 1040-1048.
11. Sneed PK, Larson DA, Wara WM. Radiotherapy for cerebral metastases. Neurosurg Clin N Am, 1996, 7(3): 505-515.
12. Jenrow KA, Brown SL, Lapanowski K, et al. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res, 2013, 179(5): 549-556.
13. Andrews DW, Scott CB, Sperduto PW, et al. 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, 2004, 363(9422): 1665-1672.
14. 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): 401-409.
15. National Comprehensive Cancer Network. Non-small cell lung cancer NCCN guidelines. (2019-01-18)[2019-10-12]. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
16. Berghoff AS, Venur VA, Preusser M, et al. Immune checkpoint inhibitors in brain metastases: from biology to treatment. Am Soc Clin Oncol Educ Book, 2016, 35: e116-e122.
17. Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer, 2012, 12(4): 298-306.
18. Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep, 2015, 13(2): 412-424.
19. Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol, 2016, 37(3): 193-207.
20. Berghoff AS, Ricken G, Wilhelm D, et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J Neurooncol, 2016, 130(1): 19-29.
21. Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology, 2015, 5(1): e1057388.
22. He BP, Wang JJ, Zhang X, et al. Differential reactions of microglia to brain metastasis of lung cancer. Mol Med, 2006, 12(7/8): 161-170.
23. Kuol N, Stojanovska L, Nurgali K, et al. PD-1/PD-L1 in disease. Immunotherapy, 2018, 10(2): 149-160.
24. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med, 2015, 373(1): 23-34.
25. Kvistborg P, Philips D, Kelderman S, et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med, 2014, 6(254): 254ra128.
26. Duchnowska R, Pęksa R, Radecka B, et al. Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res, 2016, 18(1): 43.
27. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010, 363(8): 711-723.
28. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol, 2012, 13(5): 459-465.
29. 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): 722-730.
30. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018, 378(22): 2078-2092.
31. Reck M. Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Immunotherapy, 2018, 10(2): 93-105.
32. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2017, 389(10066): 255-265.
33. Crinò L, Bidoli P, Ulivi P, et al. Italian nivolumab expanded access programme (EAP): data from patients with advanced non-squamous NSCLC and brain metastases. J Thoracic Oncol, 2017, 12: S1915.
34. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol, 2016, 17(7): 976-983.
35. Gauvain C, Vauléon E, Chouaid C, et al. Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. Lung Cancer, 2018, 116: 62-66.
36. Tran TT, Mahajan A, Chiang VL, et al. Perilesional edema in brain metastases: potential causes and implications for treatment with immune therapy. J Immunother Cancer, 2019, 7(1): 200.
37. Constantinidou A, Alifieris C, Trafalis DT. Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): a new era in cancer active immunotherapy. Pharmacol Ther, 2019, 194: 84-106.
38. Murphy JB, Morton JJ. The effect of roentgen rays on the rate of growth of spontaneous tumors in mice. J Exp Med, 1915, 22(6): 800-803.
39. 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): 589-595.
40. Wennerberg E, Lhuillier C, Vanpouille-Box C, et al. Barriers to radiation-induced in situ tumor vaccination. Front Immunol, 2017, 8: 229.
41. 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): 5379-5388.
42. Chongsathidkiet P, Jackson C, Koyama S, et al. Sequestration ofT cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med, 2018, 24(9): 1459-1468.
43. Jackson CM, Kochel CM, Nirschl CJ, et al. Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clin Cancer Res, 2016, 22(5): 1161-1172.
44. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer:a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol, 2017, 18(7): 895-903.
45. 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): 368-375.
46. Lehrer EJ, McGee HM, Peterson JL, et al. Stereotactic radiosurgery and immune checkpoint inhibitors in the management of brain metastases. Int J Mol Sci, 2018, 19(10): E3054.
47. Diao K, Bian SX, Routman DM, et al. Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg, 2018, 129(6): 1397-1406.
48. 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): 1123-1124.
49. Colaco RJ, Martin P, Kluger HM, et al. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?. J Neurosurg, 2016, 125(1): 17-23.

West China Medical Journal

Application of stereotactic radiosurgery combined with immune checkpoint inhibitors in brain metastasis

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