Stereotactic radiosurgery in the era of novel systemic therapy for lung cancer brain metastases

Abstract

The emergence of novel systemic therapies has spurred a dramatic paradigm shift in lung cancer treatment. Research has revealed greater intracranial efficacy in targeted agents and immune checkpoint inhibitors (ICI) compared to conventional chemotherapy. Concurrently, advances in stereotactic radiosurgery (SRS) have contributed to the increased use of this highly localized, minimally-invasive treatment modality for local tumor control. In this era of precision medicine, the combination of these novel agents and SRS demands further prospective exploration - particularly as questions regarding their sequence of administration and the risk of neurotoxicity remain unanswered. Presently, although data are limited and largely retrospective, literature supports the concurrent administration of ICI and radiation, with no observed increases in immune-related adverse events or acute neurologic toxicities. In the case of patients with driver mutations, newer generations of tyrosine kinase inhibitors (TKI) display improved intracranial efficacy and are currently preferred alone upfront in patients with asymptomatic brain metastases (BM) due to lack of data. Evidence of combining TKI and SRS is limited with mixed results. In this review, we explore the evidence regarding the use of novel systemic agents and SRS for treatment of lung cancer BM. Clinical practice will continue to be refined as larger, prospective studies yield results.

Keywords

Lung cancer / stereotactic radiosurgery / brain metastasis / tyrosine kinase inhibitors / immunotherapy

References

[1] Siegel RL,Jemal A.Cancer statistics, 2019..CA Cancer J Clin2019;69:7-34

[2] McGranahan T.A neuro-oncologist’s perspective on management of brain metastases in patients with EGFR mutant non-small cell lung cancer..Curr Treat Options Oncol2017;18:22 PMCID:PMC5385200

[3] Waqar SN,Robinson CG,Devarakonda S.Non-small-cell lung cancer with brain metastasis at presentation..Clin Lung Cancer2018;19:e373-e9

[4] Quan AL,Suh JH.Brain metastases in small cell lung cancer..Oncology (Williston Park)2004;18:961-72discussion 74, 79-80, 87

[5] Bui N,Johnson A.Novel treatment strategies for brain metastases in non-small-cell lung cancer..Curr Treat Options Oncol2016;17:25

[6] Wang YY,Liu T,Yang GQ.Efficacy study of CyberKnife stereotactic radiosurgery combined with CIK cell immunotherapy for advanced refractory lung cancer..Exp Ther Med2013;5:453-6 PMCID:PMC3570163

[7] Thapa B,Desai K,Ahluwalia MS.Novel systemic treatments for brain metastases from lung cancer..Curr Treat Options Neurol2018;20:48

[8] NCCN Clinical Practice Guidelines in Oncology..Non-Small Cell Lung Cancer, Version 2.2019. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)2018;

[9] Sperduto PW,Beal K,Brown PD.Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA)..JAMA Oncol2017;3:827-31 PMCID:PMC5824323

[10] Bergsma DP,Singh DP,Milano MT.Radiotherapy for oligometastatic lung cancer..Front Oncol2017;7:210 PMCID:PMC5610690

[11] Aly Z.Combination of radiotherapy and targeted agents in brain metastasis: an update..Curr Treat Options Neurol2016;18:32

[12] Linskey ME,Asher AL,Kondziolka D.The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline..J Neurooncol2010;96:45-68 PMCID:PMC2808519

[13] Fuentes R,Exposito Hernandez J,Martinez-Zapata MJ.Surgery versus stereotactic radiotherapy for people with single or solitary brain metastasis..Cochrane Database Syst Rev2018;8:Cd012086

[14] O’Neill BP,Link MJ,Ballman KV.A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases..Int J Radiat Oncol Biol Phys2003;55:1169-76

[15] Routman DM,Vora S,Mahajan A.Preoperative stereotactic radiosurgery for brain metastases..Front Neurol2018;9:959 PMCID:PMC6277885

[16] Asher AL,Wiggins WF,Boltes MO.A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence..Int J Radiat Oncol Biol Phys2014;88:899-906

[17] Patel KR,Asher AL,Fraser RW.Comparing preoperative with postoperative stereotactic radiosurgery for resectable brain metastases: A multi-institutional analysis..J Neurooncol2017;131:611-8

[18] Sperduto PW,Roberge D,Shanley R.Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases..J Clin Oncol2012;30:419-25 PMCID:PMC3269967

[19] Halasz LM,Hughes M,Dexter EU.Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer..Cancer2016;122:2091-100 PMCID:PMC4911286

[20] Yamamoto M,Shuto T,Higuchi Y.Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study..Lancet Oncol2014;15:387-95

[21] Sneed PK,Vemer-van den Hoek JG,Ma L.Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors..J Neurosurg2015;123:373-86

[22] Chin LS,Biggins T.Acute complications following Gamma Knife radiosurgery are rare..Surg Neurol2000;53:498-502discussion 502

[23] Miller JA,Xiao R,Chao ST.Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis..Int J Radiat Oncol Biol Phys2016;96:1060-9

[24] Shaw E,Souhami L,Kline R.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 Phys2000;47:291-8

[25] Yamamoto M,Higuchi Y,Kawagishi J.A multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901 Study Update): Irradiation-related complications and long-term maintenance of mini-mental state examination scores..Int J Radiat Oncol Biol Phys2017;99:31-40

[26] Minniti G,Paolini S,Romano A.Single-fraction versus multifraction (3 x 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 Phys2016;95:1142-8

[27] Masucci GL.Hypofractionated radiation therapy for large brain metastases..Front Oncol2018;8:379 PMCID:PMC6176274

[28] Margolin K,Hamid O,McDermott D.Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial..Lancet Oncol2012;13:459-65

[29] El Rassy E,Kattan J,Besse B.Non-small cell lung cancer brain metastases and the immune system: from brain metastases development to treatment..Cancer Treat Rev2018;68:69-79

[30] Berghoff AS,Ricken G,Bindea G.Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases..Oncoimmunology2015;5:e1057388 PMCID:PMC4760339

[31] Frey B,Kulzer L,Weiss EM.Antitumor immune responses induced by ionizing irradiation and further immune stimulation..Cancer Immunol Immunother2014;63:29-36

[32] Schaue D,Iwamoto KS.Maximizing tumor immunity with fractionated radiation..Int J Radiat Oncol Biol Phys2012;83:1306-10 PMCID:PMC3337972

[33] Dewan MZ,Kawashima N,Babb JS.Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody..Clin Cancer Res2009;15:5379-88 PMCID:PMC2746048

[34] Chicas-Sett R,Rodriguez-Abreu D.Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review..Clin Transl Radiat Oncol2017;9:5-11 PMCID:PMC5862682

[35] Knisely JP,Flanigan J,Kluger HM.Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival..J Neurosurg2012;117:227-33 PMCID:PMC6098938

[36] Ngwa W,Schoenfeld JD,Demaria S.Using immunotherapy to boost the abscopal effect..Nat Rev Cancer2018;18:313-22 PMCID:PMC5912991

[37] Hubbeling HG,Horick NK,Lin JJ.Safety of combined pd-1 pathway inhibition and intracranial radiation therapy in non-small cell lung cancer..J Thorac Oncol2018;13:550-8

[38] Chen L,Kleinberg L,Marciscano AE.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 Phys2018;100:916-25

[39] Martin AM,Catalano PJ,Redig AJ.Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation..JAMA Oncol2018;4:1123-4 PMCID:PMC5885198

[40] Ahmed Kamran AK,Arrington J,Dilling TJ.Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases..J Neurooncol2017;133:331-8

[41] Hirsch FR.EGFR testing in lung cancer is ready for prime time..Lancet Oncol2009;10:432-3

[42] Kwak EL,Camidge DR,Solomon B.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer..N Engl J Med2010;363:1693-703 PMCID:PMC3014291

[43] Dugay F,Gournay M,Mazet F.Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations..Oncotarget2017;8:53336-51 PMCID:PMC5581114

[44] Rangachari D,VanderLaan PA,Mahadevan A.Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers..Lung Cancer2015;88:108-11 PMCID:PMC4355240

[45] Patil T,Bunn PA,Le AT.The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib..J Thorac Oncol2018;13:1717-26 PMCID:PMC6204290

[46] Soria JC,Vansteenkiste J,Chewaskulyong B.Osimertinib in untreated EGFR-Mutated advanced non-small-cell lung cancer..N Engl J Med2018;378:113-25

[47] Reungwetwattana T,Cho BC,Cho EK.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 Oncol2018;

[48] Akimoto T,Buchmiller L,Ang KK.Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas..Clin Cancer Res1999;5:2884-90

[49] Chinnaiyan P,Vallabhaneni G,Varambally S.Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva)..Cancer Res2005;65:3328-35

[50] Soon YY,Koh WY.EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis..Radiother Oncol2015;114:167-72

[51] Magnuson WJ,Wu AJ,Lockney NA.Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: A retrospective multi-institutional analysis..J Clin Oncol2017;35:1070-7

[52] Sperduto PW,Robins HI,Werner-Wasik M.A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320..Int J Radiat Oncol Biol Phys2013;85:1312-8 PMCID:PMC3740376

[53] Wang W,Zhang Y.Efficacy of brain radiotherapy plus EGFR-TKI for EGFR-mutated non-small cell lung cancer patients who develop brain metastasis..Arch Med Sci2018;14:1298-307 PMCID:PMC6209704

[54] Costa DB,Ou SH,Riely GJ.Clinical experience with crizotinib in patients with advanced alk-rearranged non-small-cell lung cancer and brain metastases..J Clin Oncol2015;33:1881-8 PMCID:PMC4451171

[55] Peters S,Shaw AT,Ahn JS.Alectinib versus crizotinib in untreated alk-positive non-small-cell lung cancer..N Engl J Med2017;377:829-38

[56] Hida T,Kondo M,Azuma K.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial..Lancet2017;390:29-39

[57] Gadgeel S,Mok T,Kim DW.Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study..Ann Oncol2018;29:2214-22 PMCID:PMC6290889

[58] Kim DW,Ahn MJ,Hansen KH.Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase ii trial..J Clin Oncol2017;35:2490-8

[59] Gainor JF,Willoughby K,Kennedy E.Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib..J Thorac Oncol2015;10:232-6 PMCID:PMC4304931

[60] Solomon BJ,Bauer TM,Soo RA.Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study..Lancet Oncol2018;19:1654-67

[61] Griesinger F,Pottgen C,Eberhardt WEE.Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms..Oncotarget2018;9:35181-94 PMCID:PMC6205553

[62] Lim SM,Lee JS,Lee YG.Open-label, multicenter, phase ii study of ceritinib in patients with non-small-cell lung cancer harboring ros1 rearrangement..J Clin Oncol2017;35:2613-8

[63] Solomon B,Ou S,Felip E.OA 05.06 phase 2 study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer..J Thorac Oncol2017;12:S1756

[64] Weickhardt AJ,Burke JM,Lu X.Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer..J Thorac Oncol2012;7:1807-14 PMCID:PMC3506112

[65] Gan GN,Scheier B,Gaspar LE.Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib..Int J Radiat Oncol Biol Phys2014;88:892-8 PMCID:PMC4160890

[66] Johung KL,Desai NB,Lautenschlaeger T.Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis..J Clin Oncol2016;34:123-9 PMCID:PMC5070549