Neurological Surgery 脳神経外科44巻10号

2016年10月発行

連載 脳腫瘍Update

（11）Metastatic brain tumors（転移性脳腫瘍）

著者： 中洲庸子¹ 三矢幸一¹ 林央周¹

所属機関： ¹県立静岡がんセンター脳神経外科

ページ範囲：P.881 - P.895

Ⅰ．はじめに
　転移性脳腫瘍（metastatic brain tumors, brain metastasis［以下，BM］）の予防と治療は，今日のがん患者における重要な臨床課題である．BMは成人のがん患者の10〜20%に発生するとされ，原発性脳腫瘍の10倍の頻度とされている³¹⁾．最も頻度が高い原発がんは，肺がん，乳がん，さらに欧米では悪性黒色腫が挙げられるが，あらゆる悪性腫瘍が脳に転移する¹⁷⁾．BM患者が臨床現場で増加し，臨床課題として注目されている理由は，①空間分解能が高い画像検査，特に脳magnetic resonance（MR）が一般化したこと，②続々と臨床応用される新規薬剤によってがん患者の生存期間が延長したこと，③BMの治療方法が増え，治療後の長期生存者が認知されるようになったことなどによる．
　BMの診療は，ダイナミックに進歩しつつある臨床腫瘍学と集学的治療をリアルタイムで学ぶ機会を与えてくれる．象徴的な事例として，がんに対して新しい分子標的薬が全身的には治療効果を示している場合でも，最初の再発が脳に出現すること（isolated central nervous system［CNS］failure）が増えている^59,72)．また，がんの治療後，長い寛解期間を経て発症したBM患者に遭遇することがある．この遅発性再発の機序として，がん細胞が転移先の組織に潜伏し増殖休止の状態を保つ状態，すなわちがん休眠（cancer dormancy）が注目され，がん転移の生物学的機序や臨床的リスクに関して研究が進んでいる⁸⁰⁾．
　日本脳腫瘍学会ガイドライン委員会が2013年7月までの文献をもとに編纂した「成人転移性脳腫瘍ガイドライン」が完成している（『脳腫瘍診療ガイドライン1　2016年版』［金原出版］収載）．本稿では，これ以降の資料を中心に，脳神経外科医の視点からBM診療における変革の方向を探る．

参考文献

1) Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, Throuvalas N：Phase Ⅱ randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20：3644-3650, 2002

2) 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 WJ Jr：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 randomized trial. Lancet 363：1665-1672, 2004

3) 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 treatment of brain metastases. A randomized controlled trial. JAMA 295：2483-2491, 2006

4) 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 68：1388-1395, 2007

5) Asher AL, Burri SH, Wiggins WF, Kelly RP, Boltes MO, Mehrlich M, Norton HJ, Fraser RW：A new treatment paradigm：neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys 88：896-906, 2014

6) Baumert BG, Rutten I, Dehing-Oberije C, Twijnstra A, Dirx MJ, Debougnoux-Huppertz RM, Lambin P, Kubat B：A pathology-based substrate for target definition in radiosurgery of brain metastases. Int J Radiat Oncol Biol Phys 66：187-194, 2006

7) Bindal AK, Bindal RK, Hess KR, Shiu A, Hassenbusch SJ, Shi WM, Sawaya R：Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 84：748-754, 1996

8) Black PM, Johnson MD：Surgical resection for patients with solid brain metastases：current status. J Neurooncol 69：119-124, 2004

9) Bollig-Fischer A, Michelhaugh SK, Wijesinghe P, Dyson G, Kruger A, Palanisamy N, Choi L, Alosh B, Ali-Fehmi R, Mittal S：Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics. Oncotarget 10：14614-14624, 2015

10) Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG 2nd, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC：Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5：1164-1177, 2015

11) Brennan C, Yang TJ, Hilden P, Zhang Z, Chan K, Yamada Y, Chan TA, Lymberis SC, Narayana A, Tabar V, Gutin PH, Ballangrud Å, Lis E, Beal K：A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys 88：130-136, 2014

12) Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, Choucair A, Fox S, Suh JH, Roberge D, Kavadi V, Bentzen SM, Mehta MP, Watkins-Bruner D；Radiation Therapy Oncology Group（RTOG）：Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy：a randomized, double-blind, placebo-controlled trial. Neuro Oncol 15：1429-1437, 2013

13) Caine C, Deshmukh S, Gondi V, Mehta M, Tomö W, Corn BW, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Raben A, Shi W, Wendland M, Kachnic L：CogState computerized memory tests in patients with brain metastases：secondary endpoint results of NRG Oncology RTOG 0933. J Neurooncol 126：327-336, 2016

14) Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE：A phase Ⅲ randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab：updated efficacy and biomarker analyses. Breast Cancer Res Treat 112：533-543, 2008

15) Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal SA, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Griffin CA, Burton J, Swerdlow H, Quail MA, Stratton MR, Iacobuzio-Donahue C, Futreal PA：The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467：1109-1113, 2010

16) 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 randomized controlled trial. Lancet Oncol 10：1037-1044, 2009

17) Committee of Brain Tumor Registry of Japan：Report of brain tumor registry of Japan（2001-2004). 13th edition. Neurol Med Chir（Tokyo）54（Suppl 1）：1-102, 2014

18) Curry WT, Lim M：Immunomodulation：checkpoint blockade etc. Neuro Oncol 17 Suppl 7：vii26-vii31, 2015

19) DeAngelis LM, Delattre JY, Posner JB：Radiation-induced dementia in patients cured of brain metastases. Neurology 39：789-796, 1989

20) Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, Veronese L, Hilfiker PR, Felderer L, Rinderknecht JD：Vemurafenib in patients with BRAF（V600）mutation-positive melanoma with symptomatic brain metastases：final results of an open-label pilot study. Eur J Cancer 50：611-621, 2014

21) Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J：New response evaluation criteria in solid tumours：revised RECIST guideline（version 1.1). Eur J Cancer 45：228-247, 2009

22) Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE：Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 85：223-227, 2007

23) Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, Carlini P, Boni C, Di Sarra S：Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma：a prospective study. Cancer 85：1599-1605, 1999

24) Furuse M, Nonoguchi N, Kuroiwa T, Miyamoto S, Arakawa Y, Shinoda J, Miwa K, Iuchi T, Tsuboi K, Houkin K, Terasaka S, Tabei Y, Nakamura H, Nagane M, Sugiyama K, Terasaki M, Abe T, Narita Y, Saito N, Mukasa A, Ogasawara K, Beppu T, Kumabe T, Nariai T, Tsuyuguchi N, Nakatani E, Kurisu S, Nakagawa Y, Miyatake S：A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis. Neurooncol Pract, 2016, doi：10.1093/nop/npv064

25) Gans JH, Raper DM, Shah AH, Bregy A, Heros D, Lally BE, Morcos JJ, Heros RC, Komotar RJ：The role of radiosurgery to the tumor bed after resection of brain metastases. Neurosurgery 72：317-325, 2013

26) Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R：Recursive partitioning analysis（RPA）of prognostic factors in three Radiation Therapy Oncology Group（RTOG）brain metastases trials. Int J Radiat Oncol Biol Phys 37：745-751, 1997

27) Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic L, Mehta MP：Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases（RTOG 0933）:a phase Ⅱ multi-institutional trial. J Clin Oncol 32：3810-3816, 2014

28) Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, Clarke JL, Lassman AB：“Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 13：1364-1369, 2011

29) Harris S, Chan MD, Lovato JF, Ellis TL, Tatter SB, Bourland JD, Munley MT, deGuzman AF, Shaw EG, Urbanic JJ, McMullen KP：Gamma knife stereotactic radiosurgery as salvage therapy after failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys 83：e53-59, 2012

30) Hart MG, Grant R, Walker M, Dickinson H：Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases. Cochrane Database Syst Rev, 2005, CD003292

31) Hojo S, Hirano A：Pathology of metastases affecting the central nervous system. In Takakura K, Sano K, Hojo S, Hirano A（eds）：Metastatic tumors of the central nervous system. Igaku-Shoin, Tokyo, 1982, pp5-111

32) Hsieh J, Elson P, Otvos B, Rose J, Loftus C, Rahmathulla G, Angelov L, Barnett GH, Weil RJ, Vogelbaum MA：Tumor progression in patients receiving adjuvant whole-brain radiotherapy vs localized radiotherapy after surgical resection of brain metastases. Neurosurgery 76：411-420, 2015

33) Kano H, Kondziolka D, Lobato-Polo J, Zorro O, Flickinger JC, Lunsford LD：T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 66：486-492, 2010

34) Khasraw M, Holodny A, Goldlust SA, DeAngelis LM：Intracranial hemorrhage in patients with cancer treated with bevacizumab：the Memorial Sloan-Kettering experience. Ann Oncol 23：458-463, 2012

35) Kim KH, Lee J, Lee JI, Nam DH, Kong DS, Ahn YC, Park HC, Kwon OJ, Kim H, Chang MH, Yi SY, Ji SH, Park YH, Ahn JS, Park K, Ahn MJ：Can upfront systemic chemotherapy replace stereotactic radiosurgery or whole brain radiotherapy in the treatment of non-small cell lung cancer patients with asymptomatic brain metastases? Lung Caner 68：258-263, 2010

36) Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den 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 29：134-141, 2011

37) Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, Goto K：Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res 4：156-164, 2015

38) Kosaka N：Decoding the secret of cancer by means of extracellular vesicles. J Clin Med, 2016, doi：10.3390/jcm5020022

39) Kurtz G, Zadeh G, Gingras-Hill G, Millar BA, Laperriere NJ, Bernstein M, Jiang H, Mönard C, Chung C：Salvage radiosurgery for brain metastases：prognostic factors to consider in patient selection. Int J Radiat Oncol Biol Phys 88：137-142, 2014

40) Lassman AB, Abrey LE, Shah GG, Panageas KS, Begemann M, Malkin MG, Raizer JJ：Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol 78：255-260, 2006

41) Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN, Grewal J, Prabhu S, Loghin M, Gilbert MR, Jackson EF：Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79：1487-1495, 2011

42) 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 25：1260-1266, 2007

43) Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, Brown PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, Suh JH, van den Bent MJ, Vogelbaum MA, Wen PY；Response Assessment in Neuro-Oncology（RANO）group：Response assessment criteria for brain metastases：proposal from the RANO group. Lancet Oncol 16：e270-278, 2015

44) Lin X, DeAngelis LM：Treatment of brain metastases. J Clin Oncol 33：3475-3484, 2015

45) Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D：Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain（BREAK-MB）:a multicentre, open-label, phase 2 trial. Lancet Oncol 13：1087-1095, 2012

46) Lucas JT Jr, Colmer HG 4th, White L, Fitzgerald N, Isom S, Bourland JD, Laxton AW, Tatter SB, Chan MD：Competing risk analysis of neurologic versus nonneurologic death in patients undergoing radiosurgical salvage after whole-brain radiation therapy failure：who actually dies of their brain metastases? Int J Radiat Oncol Biol Phys 92：1008-1015, 2015

47) Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS：Ipilimumab in patients with melanoma and brain metastases：an open-label, phase 2 trial. Lancet Oncol 13：459-465, 2012

48) 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 22：157-165, 2004

49) Minniti G, Clarke E, Lanzetta G, Osti MF, Trasimeni G, Bozzao A, Romano A, Enrici RM：Stereotactic radiosurgery for brain metastases：analysis of outcome and risk of brain radionecrosis. Radiat Oncol 6：48, 2011

50) Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, Duncan G, Skingley P, Foster G, Levine M：A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78：1470-1476, 1996

51) Mitsuya K, Nakasu Y, Horiguchi S, Harada H, Nishimura T, Bando E, Okawa H, Furukawa Y, Hirai T, Endo M：Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery. J Neurooncol 99：81-88, 2010

52) Mitsuya K, Nakasu Y, Narita Y, Nakasu S, Ohno M, Miyakita Y, Abe M, Ito I, Hayashi N, Endo M：“Comet tail sign”：a pitfall of post-gadolinium magnetic resonance imaging findings for metastatic brain tumors. J Neurooncol 127：589-595, 2016

53) 宮北康二，成田善孝，田部井勇助，中西幸浩，渋井壮一郎，野村和弘：転移性脳腫瘍の浸潤能とMatrix metalloproteinaseの発現について．Brain Tumor Pathol 22 Suppl：55, 2005

54) Muacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW：Microsurgery plus whole brain irradiation versus gamma knife surgery alone for treatment of single metastases to the brain：a randomized controlled multicentre phase Ⅲ trial. J Neurooncol 87：299-307, 2008

55) 中洲庸子，三矢幸一，林　央周，伊藤以知郎：転移性脳腫瘍の「最小限摘出」と「安全域付き切除」—浸潤境界を基にした摘出術の使い分け．No Shinkei Geka 44：221-226, 2016

56) Obermueller T, Schaeffner M, Gerhardt J, Meyer B, Ringel F, Krieg SM：Risks of postoperative paresis in motor eloquently and non-eloquently located brain metastases. BMC Cancer 14：21, 2014

57) Okuda T, Kataoka K, Yabuuchi T, Yugami H, Kato A：Fluorescence-guided surgery of metastatic brain tumors using fluorescein sodium. J Clin Neurosci 17：118-121, 2010

58) Okuda T, Fujita M, Yoshioka H, Tasaki T, Kato A：Novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue for complete resection. Surg Neurol Int 5：100, 2014

59) Omuro AMP, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, Abrey LE：High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103：2344-2348, 2005

60) O'Neill BP, Iturria NJ, Link MJ, Pollock BE, Ballman KV, O'Fallon JR：A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55：1169-1176, 2003

61) Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B：A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322：494-500, 1990

62) 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 280：1485-1489, 1998

63) Patel KR, Lawson DH, Kudchadkar RR, Carthon BC, Oliver DE, Okwan-Duodu D, Ahmed R, Khan MK：Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases. Neuro Oncol 17：1312-1321, 2015

64) Patel KR, Burri SH, Asher AL, Crocker IR, Fraser RW, Zhang C, Chen Z, Kandula S, Zhong J, Press RH, Olson JJ, Oyesiku NM, Wait SD, Curran WJ, Shu HG, Prabhu RS：Comparing preoperative with postoperative stereotactic radiosurgery for resectable brain metastases：a multi-institutional analysis. Neurosurgery 79：279-285, 2016

65) Rades D, Bohlen G, Pluemer A, Veninga T, Hanssens P, Dunst J, Schild SE：Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer 109：2515-2521, 2007

66) Rapp SR, Case LD, Peiffer A, Naughton MM, Chan MD, Stieber VW, Moore DF Jr, Falchuk SC, Piephoff JV, Edenfield WJ, Giguere JK, Loghin ME, Shaw EG：Donepezil for irradiated brain tumor survivors：a phase Ⅲ randomized placebo-controlled clinical trial. J Clin Oncol 33：1653-1659, 2015

67) Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, Shaw P, Beyene J, Chang EL：Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases：individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 91：710-717, 2015

68) Schöggl A, Kitz K, Reddy M, Wolfsberger S, Schneider B, Dieckmann K, Ungersböck K：Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases. Acta Neurochir（Wien）142：621-626, 2000

69) Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S：Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461：809-813, 2009

70) Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N：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 Phys 47：291-298, 2000

71) Shimato S, Mitsudomi T, Kosaka T, Yatabe Y, Wakabayashi T, Mizuno M, Nakahara N, Hatano H, Natsume A, Ishii D, Yoshida J：EGFR mutations in patients with brain metastases from lung cancer：association with the efficacy of gefitinib. Neuro Oncol 8：137-144, 2006

72) Shukuya T, Takahashi T, Naito T, Kaira R, Ono A, Nakamura Y, Tsuya A, Kenmotsu H, Murakami H, Harada H, Mitsuya K, Endo M, Nakasu Y, Takahashi K, Yamamoto N：Continuous EGFR-TKI administration following radiotherapy for non-small cell lung cancer patients with isolated CNS failure. Lung Cancer 74：457-461, 2011

73) Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A：A European Organization for Research and Treatment of Cancer phase Ⅲ trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery：quality-of-life results. J Clin Oncol 31：65-72, 2013

74) Soffietti R, Rudà R, Trakul N, Chang EL：Point/counterpoint：is stereotactic radiosurgery needed following resection of brain metastases? Neuro Oncol 18：12-15, 2016

75) Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M：Summary report on the graded prognostic assessment：an accurate and facile diagnosis specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30：419-425, 2012

76) Terakawa Y, Tsuyuguchi N, Iwai Y, Yamanaka K, Higashiyama S, Takami T, Ohata K：Diagnostic accuracy of 11C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med 49：694-699, 2008

77) Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M：Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366：2443-2454, 2012

78) Tsao MN, Rades D, Wirth A, Lo SS, Danielson BL, Gaspar LE, Sperduto PW, Vogelbaum MA, Radawski JD, Wang JZ, Gillin MT, Mohideen N, Hahn CA, Chang EL：Radiotherapeutic and surgical management for newly diagnosed brain metastasis（es）：an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2：210-225, 2012

79) Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, Tans JT, Lambooij N, Metsaars JA, Wattendorff AR, Brand R, Hermans J：Treatment of single brain metastasis：radiotherapy alone or combined with neurosurgery? Ann Neurol 33：583-590, 1993

80) Vishnoi M, Peddibhotla S, Yin W, Scamardo AT, George GC, Hong DS, Marchetti D：The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep 5：17533, 2015

81) Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, Chang JY, Wefel JS, McGovern SL, Garland LL, Chen SS, Holt J, Liao Z, Brown P, Sulman E, Heymach JV, Kim ES, Stea B：Phase Ⅱ trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31：895-902, 2013

82) Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M：Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369：122-133, 2013

83) Wrobel JK, Toborek M：Blood-brain barrier remodeling during brain metastasis formation. Mol Med, 2016, doi：10.2119/molmed. 2015.00207

84) Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, Yamanaka K, Sato Y, Jokura H, Yomo S, Nagano O, Kenai H, Moriki A, Suzuki S, Kida Y, Iwai Y, Hayashi M, Onishi H, Gondo M, Sato M, Akimitsu T, Kubo K, Kikuchi Y, Shibasaki T, Goto T, Takanashi M, Mori Y, Takakura K, Saeki N, Kunieda E, Aoyama H, Momoshima S, Tsuchiya K：Stereotactic radiosurgery for patients with multiple brain metastases（JLGK0901）:a multi-institutional prospective observational study. Lancet Oncol 15：387-395, 2014

85) Yoo H, Kim YZ, Nam BH, Shin SH, Yang HS, Lee JS, Zo JI, Lee SH：Reduced local recurrence of a single brain metastasis through microscopic total resection. J Neurosurg 110：730-736, 2009