肺癌是全世界最常見且病死率最高的惡性腫瘤 ^［1］，其中非小細胞肺癌（NSCLC）約占肺癌的85%。初治的NSCLC患者有7.4%～10%伴腦轉移，初治沒有腦轉移的NSCLC患者30%～50%最終發生腦轉移 ^［2］，其中腺癌的腦轉移發生率最高。約30%局部晚期NSCLC患者在有效局部區域治療后腦轉移成為首個失敗部位 ^［3］，大部分患者明確診斷時腦轉移為多發。隨著影像技術的發展，局部區域治療手段的進步和各種靶向治療藥物的成功應用，腦轉移瘤的發生率有逐漸增高的趨勢。腦轉移瘤的原發部位亦以NSCLC為最常見。沒有對原發部位進行限定的腦轉移瘤臨床研究中，絕大多數包含了相當比例的NSCLC。因此，有關腦轉移瘤治療的臨床研究所得出的結論基本上適用于NSCLC腦轉移瘤患者。腦轉移瘤的治療手段包括：全腦放療（WBRT）、手術、立體定向外科（SRS）、化療、靶向治療等，也可以是上述治療手段的聯合。本文重點對非小細胞肺癌腦轉移瘤的治療進行綜述。

腦轉移瘤預后很差，腦轉移瘤不做治療中位生存期（OS）僅1個月，激素治療后中位OS約2個月，WBRT后中位OS 約3～6個月 ^［4，5］，SRS治療后中位OS約5～11個月。大部分NSCLC伴腦轉移患者腦內轉移瘤是多發的，WBRT是多發腦轉移瘤患者的標準治療 ^［6］。對于未經選擇的NSCLC腦轉移瘤患者，WBRT的客觀反應率約38%～45% ^［7，8］，中位OS約5個月。EGFR敏感突變的NSCLC腦轉移患者WBRT的客觀反應率高于EGFR野生型患者（54% vs. 24%），EGFR敏感突變是NSCLC腦轉移獨立的預后因子 ^［9，10］。多項前瞻性隨機對照研究 ^［11-19］未顯示出不同分割次數、不同劑量的WBRT之間的療效差異，30Gy/10F依然是當前WBRT的標準劑量。

手術治療亦是NSCLC腦轉移瘤的有效治療手段之一。手術治療可迅速解除顱高壓和壓迫癥狀，并明確病理診斷。隨著放療的普及，手術在腦轉移瘤中的應用逐漸減少，現主要作為RPA1級、癥狀明顯或對放療抗拒的患者的治療選擇。

SRS對于單發和多發腦轉移瘤治療有效，回顧性研究提示，SRS較WBRT改善了1～3個腦轉移瘤患者的中位OS ^［20-22］。盡管缺乏Ⅲ期臨床研究，多個回顧性研究提示，單發腦轉移瘤患者SRS ^［23-27］與手術 ^［28-30］療效相當。一般情況好的NSCLC單個腦轉移患者經手術或SRS后中位生存期超過10個月 ^{［29，31］}。因此，SRS可以作為1～3個腦轉移瘤患者的首先推薦治療。

兩個前瞻性隨機對照研究顯示，手術+WBRT較WBRT延長了可手術單個腦轉移瘤患者的中位生存期 ^{［28，30］}，而另一個隨機對照研究 ^［31］卻未能顯示手術+WBRT在OS上的優勢。此外，前瞻性非隨機研究和回顧性研究亦顯示手術+WBRT 的OS優于WBRT。與單純手術相比，術后輔助WBRT改善了PS評分≤2單個可手術腦轉移瘤患者的局部控制率，減少了神經系統相關死亡率 ^［29］，但入組病例數較少，無法回答術后WBRT是否改善了OS。因此，對于PS評分好的單個可手術切除的腦轉移瘤患者，手術+WBRT是首先推薦的治療。

RTOG9508研究 ^［32］顯示，WBRT聯合SRS較單用WBRT顯著提高了單發腦轉移瘤患者的OS（6.5 vs 4.9月），顯著改善了1～3個腦轉移瘤患者的腦內局部控制率和KPS評分。亞組分析提示，肺鱗癌腦轉移患者的OS亦可能從WBRT聯合SRS治療中獲益。薈萃分析顯示 ^［33］，SRS后輔助WBRT較單獨SRS顯著降低了腦轉移瘤復發率和新發腦轉移瘤發生率，但不改善1年生存率，且增加了晚期神經毒性。由于WBRT對認知功能潛在影響 ^［34］，對于1～4個腦轉移瘤患者，先行SRS治療，將WBRT作為挽救治療是一種合理的選擇。而對于RPA1級單發腦轉移瘤患者，手術+WBRT ^［28］和SRS+WBRT ^［35］均為可以首先考慮的治療選擇。

非小細胞肺癌腦轉移一線化療的有效率為17%～50% ^［36-42］，腦轉移瘤的化療有效率與腦外病灶的有效率相似。這可能是因為腦轉移瘤患者的血腦屏障（BBB）已部分破壞 ^［43］，腦內和腦外腫瘤組織中的化療藥物濃度相似 ^［44］。因此，NSCLC腦轉移的患者可以按照晚期NSCLC的化療方案進行化療。

替莫唑胺BBB穿透率高，腦脊液濃度可達血漿濃度的30%～40% ^［45］，其治療曾行一線化療NSCLC腦轉移的有效率為5%～10% ^［46-49］。因此，替莫唑胺可以作為NSCLC腦轉移的二線治療選擇。替莫唑胺具有良好的耐受性，與其他化療藥物的聯用是可行的 ^［50］，腦轉移瘤的客觀緩解率可進一步提高。

薈萃分析顯示 ^［51］，在EGFR敏感突變的晚期NSCLC中，一線TKI治療與化療相比顯著改善了客觀反應率和PFS，從而確立了TKI在晚期NSCLC中的地位，但這些研究大部分不包含腦轉移瘤患者。盡管TKI在腦脊液中的濃度很低 ^{［52，53］}，TKI可以在NSCLC腦轉移瘤中選擇性聚集 ^［54］，因此TKI可以有效治療腦轉移瘤。多個研究 ^［55］顯示TKI治療NSCLC腦轉移瘤療效顯著。CTONG0803 ^［56］顯示，EGFR基因敏感突變的患者（8例）厄洛替尼二線治療無顱外進展的NSCLC腦轉移患者的有效率為75%，中位無進展生存期15.2個月，中位OS37.5個月。多個研究顯示，原發灶的EGFR狀態是腦轉移瘤的療效預測因子 ^{［55，57-59］}。在EGFR敏感突變的患者中，腦轉移瘤TKI治療的有效率為75%～83% ^{［56，58，60］}，明顯高于化療和WBRT。EGFR不同基因型之間的NSCLC腦轉移患者TKI治療療效亦有所不同，Iuchi等報道 ^［61］，19外顯子缺失突變患者的PFS和OS均顯著優于21外顯子點突變的患者。

Kim等 ^［62］報道，TKI治療優勢人群NSCLC腦轉移瘤患者，腦轉移瘤和肺癌原發灶的有效率無顯著差異（74% vs. 70%）。而另有報道 ^{［63，64］}認為肺癌原發灶和腦轉移瘤之間的EGFR突變狀態可能不同。由于臨床上很難獲得腦轉移瘤的標本，NSCLC原發灶EGFR突變狀態是NSCLC腦轉移瘤有效實用的預測因子。上述研究入組的均為無癥狀腦轉移患者，因此TKI可以作為EGFR敏感突變無癥狀NSCLC腦轉移患者的一線治療選擇，一部分患者可能不需要WBRT的參與。

NSCLC腦轉移瘤中的EGFR突變率較高，有報道高達63% ^［65］。回顧性研究顯示，發生腦轉移的NSCLC患者EGFR的突變率高于未發生腦轉移的患者。EGFR突變的NSCLC患者腦轉移瘤發生率亦高于EGFR無突變者，伴EGFR突變的NSCLC腦轉移患者預后較好 ^［9］。

Omuro等 ^［66］報道，TKI治療后5年腦轉移發生率可以高達60%；Lee等 ^［67］報道TKI治療晚期NSCLC患者臨床獲益者腦轉移瘤發生率顯著高于TKI治療無效者（26% vs. 4%），提示TKI治療與腦轉移瘤發生率高相關。相反，Heon等 ^［68］報道，晚期NSCLC患者TKI治療后腦轉移瘤發生率顯著降低；Chen等和Ceresoli等 ^{［69，70］}報道，晚期NSCLC患者TKI治療后腦轉移瘤中位發生時間顯著長于未行TKI治療者；Heon等 ^［71］報道，對于EGFR敏感突變的NSCLC患者，一線TKI治療比化療的腦轉移瘤發生率低；這些研究提示晚期NSCLC患者TKI治療后腦轉移瘤發生率較低。因此，對于晚期NSCLC患者而言，TKI治療與腦轉移瘤的發生率之間的關系尚無定論。

在未經選擇的NSCLC腦轉移患者中 ^［72-74］，TKI的有效率波動范圍較大（10%～81%）。而以臨床病理特征選擇的優勢人群中 ^62，75，TKI的有效率較高且波動較小（69%和70%）。在EGFR野生型NSCLC腦轉移患者中，TKI治療腦轉移瘤的有效率約為10%。

回顧性研究提示 ^［76］，EGFR敏感突變的肺腺癌腦轉移患者WBRT與TKI治療后效果佳，OS可達33個月，與EGFR敏感突變而無腦轉移晚期NSCLC的OS相似。WBRT組的OS 與TKI組無差異，而腦內局控率和腦內病灶進展時間WBRT組優于TKI組。

上述小樣本Ⅱ期臨床研究和回顧性研究（包括個案報道）提示TKI在EGFR敏感突變NSCLC腦轉移中的治療結果令人鼓舞。但無TKI與腦放療或化療對比的Ⅲ期研究結果發表，亦無WBRT+TKI與單獨TKI、WBRT或化療對比的Ⅲ期研究發表，因此，EGFR敏感突變NSCLC腦轉移瘤患者TKI單用或聯合應用的價值有待大樣本的前瞻性研究進一步明確。

臨床前研究提示，放療和TKI聯合具有增敏作用。而多個研究提示，既往曾行全腦放療的患者TKI治療后疾病控制率提高，并有改善生存的趨勢，因而曾行全腦放療可能是NSCLC腦轉移患者好的預后因子。但這究竟是因為WBRT破壞了BBB，還是選擇偏倚或其他原因尚不得而知。

多個研究顯示，WBRT同步聯合TKI治療有增敏作用而且耐受性好。在EGFR基因突變狀態未明的患者中，WBRT+TKI的有效率為81%和71%，顯著高于單獨WBRT或化療 ^{［77，78］}。在EGFR基因敏感突變的患者中，WBRT+TKI的有效率高達84%，EGFR敏感突變的患者有效率顯著高于無突變者 ^［10］。

然而，RTOG 0320 ^［79］研究將NSCLC伴1～3個腦轉移瘤的患者隨機分為單純放療組（WBRT+SRS）和聯合治療組（WBRT+SRS+替莫唑胺或TKI），結果聯合治療組的OS差于單純放療組，盡管統計學無差異。該研究入組的患者未經EGFR基因選擇，而且不屬于EGFR基因敏感突變優勢人群，因此非EGFR敏感突變患者中腦放療聯合TKI治療需要謹慎。

對于無癥狀的腦轉移瘤患者，一線單獨化療與化療后WBRT相比，有效率和OS并無差異；接近1/3一線僅行化療的患者死于腦外疾病進展而腦轉移瘤獲得控制，在整個病程中并不需要WBRT ^［80］。兩個前瞻性隨機對照Ⅱ期 ^{［81，82］}研究顯示，WBRT聯合替莫唑胺較單用WBRT顯著提高了腦轉移瘤的有效率，但未顯著改善OS。RTOG 0320研究 ^［79］亦顯示，放療（WBRT+SRS）與替莫唑胺聯合不能改善NSCLC伴1～3個腦轉移瘤患者的OS。因此，WBRT聯合化療在NSCLC腦轉移瘤中的地位尚未確立。

晚期NSCLC患者很少僅有腦轉移瘤，經全腦放療后大部分患者最終并非死于腦轉移瘤，相當一部分患者死于肺癌原發灶進展 ^{［83，84］}。多項回顧性研究 ^［85-88］顯示，對于無縱隔淋巴結轉移（N0-1）的NSCLC腦轉移瘤患者，肺癌和腦轉移瘤的聯合手術切除可以提高生存率，異時腦轉移的患者預后優于同時腦轉移者。手術治療后中位生存期可達10～27個月，2年生存率28%～54%，5年生存率11%～24%。與之相仿，多個回顧性研究 ^{［5，89-93］}顯示，肺癌原發灶的積極放射治療同樣可以改善非小細胞肺癌腦轉移瘤患者的預后。這些患者的腦轉移瘤接受了全腦放療、SRS、手術或聯合治療，大部分研究只入組了單發腦轉移瘤的患者，也有部分研究包含了多發腦轉移瘤的患者。接受肺癌原發灶放療的患者生存與接受手術的患者相仿，中位生存期達15.5～31.8個月，2年生存率為16%～60%。在這些原發灶和腦轉移瘤均接受了積極治療的患者中，腺癌、初診時低CEA水平、KPS評分好、年輕、N0-1、無腦外轉移瘤和誘導化療反應率高等提示預后良好。因此，在預后較好的NSCLC腦轉移瘤患者中，既針對原發灶又針對腦轉移瘤的積極治療可能是有益的，但缺乏前瞻性隨機對照研究的證據。對于原發灶的處理，N0-1的患者可以選擇手術，N2-3的患者選擇放化療。

NSCLC腦轉移瘤的治療選擇主要包括WBRT、手術、SRS、TKI等。多發腦轉移瘤的標準治療為WBRT，不同劑量及分割的WBRT之間療效無顯著差異。SRS的療效與手術相當。手術/SRS+WBRT治療單個腦轉移瘤患者的有效率和腦內控制率最高。對于單個腦轉移瘤而言，手術/SRS+WBRT較單用WBRT改善了OS。SRS+WBRT治療1～4個腦轉移瘤較單用SRS改善了局部控制，但未顯著改善OS；由于WBRT的潛在神經毒性，單用SRS也是合理的選擇。按照NSCLC一線化療的方案治療NSCLC腦轉移瘤患者，腦轉移瘤與原發灶有效率相似。在EGFR敏感突變患者中，TKI治療NSCLC腦轉移療效突出，有效率顯著高于WBRT和化療。對于無癥狀NSCLC腦轉移患者，一線單用TKI可能是合理的，部分患者最終死于腦外疾病進展而無須WBRT。WBRT同期聯合TKI治療有效率高，是否能較一線單用TKI或WBRT改善OS值得進一步研究。WBRT同期聯合化療提高了NSCLC腦轉移瘤患者的有效率，但未改善OS。預后好的NSCLC腦轉移患者可能從原發灶的手術治療或放療中獲益，對于預后良好的患者可以考慮積極地治療原發灶。

1. Jemal A，Bray F，Center MM，et al. Global cancer statistics. CA：a cancer journal for clinicians. 2011；61（2）：69-90.

2. Schouten LJ，Rutten J，Huveneers HA，et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast，colon，kidney，and lung and melanoma. Cancer. 2002；94（10）：2698-2705.

3. Markesbery WR，Brooks WH，Gupta GD，et al. Treatment for patients with cerebral metastases. Archives of neurology. 1978；35（11）：754-756.

4. Gaspar LE，Mehta MP，Patchell RA，et al. The role of whole brain radiation therapy in the management of newly diagnosed brain metastases：a systematic review and evidence-based clinical practice guideline. Journal of neuro-oncology. 2010；96 （1）：17-32.

5. Arrieta O，Villarreal-Garza C，Zamora J，et al. Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiation oncology. 2011；6：166.

6. Tsao MN，Lloyd N，Wong RK，et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane database of systematic reviews. 2012；4：CD003869.

7. Antoniou D，Kyprianou K，Stathopoulos GP，et al. Response to radiotherapy in brain metastases and survival of patients with non-small cell lung cancer. Oncology reports. 2005；14（3）：733-736.

8. Nieder C，Niewald M，Hagen T.［Brain metastases of bronchial and breast carcinoma. Differences in metastatic behavior and prognosis］. Der Radiologe. 1995；35（11）：816-821.

9. Eichler AF，Kahle KT，Wang DL，et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro-oncology. 2010；12（11）：1193-1199.

10. Gow CH，Chien CR，Chang YL，et al. Radiotherapy in lung adenocarcinoma with brain metastases：effects of activating epidermal growth factor receptor mutations on clinical response. Clinical cancer research：an official journal of the American Association for Cancer Research. 2008；14（1）：162-168.

11. Borgelt B，Gelber R，Larson M，et al. Ultra-rapid high dose irradiation schedules for the palliation of brain metastases：final results of the first two studies by the Radiation Therapy Oncology Group. International journal of radiation oncology，biology，physics. 1981；7（12）：1633-1638.

12. Chatani M，Matayoshi Y，Masaki N，et al. Radiation therapy for brain metastases from lung carcinoma. Prospective randomized trial according to the level of lactate dehydrogenase. Strahlentherapie und Onkologie：Organ der Deutschen Rontgengesellschaft ［et al］. 1994；170（3）：155-161.

13. Chatani M，Teshima T，Hata K，et al. Whole brain irradiation for metastases from lung carcinoma. A clinical investigation. Acta radiologica Oncology. 1985；24（4）：311-314.

14. Davey P，Hoegler D，Ennis M，et al. A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excision. Radiotherapy and oncology：journal of the European Society for Therapeutic Radiology and Oncology. 2008；88（2）：173-176.

15. Haie-Meder C，Pellae-Cosset B，Laplanche A，et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiotherapy and oncology：journal of the European Society for Therapeutic Radiology and Oncology. 1993；26（2）：111-116.

16. Komarnicky LT，Phillips TL，Martz K，et al. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases（RTOG-7916）. International journal of radiation oncology，biology，physics. 1991；20（1）：53-58.

17. Kurtz JM，Gelber R，Brady LW，et al. The palliation of brain metastases in a favorable patient population：a randomized clinical trial by the Radiation Therapy Oncology Group. International journal of radiation oncology，biology，physics. 1981；7（7）：891-895.

18. Murray KJ，Scott C，Greenberg HM，et al. A randomized phaseⅢstudy of accelerated hyperfractionation versus standard in patients with unresected brain metastases：a report of the Radiation Therapy Oncology Group（RTOG）9104. International journal of radiation oncology，biology，physics. 1997；39（3）：571-574.

19. Priestman TJ，Dunn J，Brada M，et al. Final results of the Royal College of Radiologists' trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clinical oncology. 1996；8（5）：308-315.

20. Li B，Yu J，Suntharalingam M，et al. Comparison of three treatment options for single brain metastasis from lung cancer. International journal of cancer Journal international du cancer. 2000；90（1）：37-45.

21. Wang LG，Guo Y，Zhang X，et al. Brain metastasis： experience of the Xi-Jing hospital. Stereotactic and functional neurosurgery. 2002；78（2）：70-83.

22. Rades D，Pluemer A，Veninga T，et al. Whole-brain radiotherapy versus stereotactic radiosurgery for patients in recursive partitioning analysis classes 1 and 2 with 1 to 3 brain metastases. Cancer. 2007；110（10）：2285-2292.

23. Adler JR，Cox RS，Kaplan I，et al. Stereotactic radiosurgical treatment of brain metastases. Journal of neurosurgery. 1992；76（3）：444-449.

24. Alexander E，3rd，Moriarty TM，Davis RB，et al. Stereotactic radiosurgery for the definitive，noninvasive treatment of brain metastases. Journal of the National Cancer Institute. 1995；87 （1）：34-40.

25. Auchter RM，Lamond JP，Alexander E，et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. International journal of radiation oncology，biology，physics. 1996；35（1）：27-35.

26. Flickinger JC，Kondziolka D，Lunsford LD，et al. A multiinstitutional experience with stereotactic radiosurgery for solitary brain metastasis. International journal of radiation oncology，biology，physics. 1994；28（4）：797-802.

27. Mehta MP，Rozental JM，Levin AB，et al. Defining the role of radiosurgery in the management of brain metastases. International journal of radiation oncology，biology，physics. 1992；24（4）：619-625.

28. Patchell RA，Tibbs PA，Walsh JW，et al. A randomized trial of surgery in the treatment of single metastases to the brain. The New England journal of medicine. 1990；322（8）：494-500.

29. Patchell RA，Tibbs PA，Regine WF，et al. Postoperative radiotherapy in the treatment of single metastases to the brain：a randomized trial. JAMA：the journal of the American Medical Association. 1998；280（17）：1485-1489.

30. Vecht CJ，Haaxma-Reiche H，Noordijk EM，et al. Treatment of single brain metastasis：radiotherapy alone or combined with neurosurgery？ Annals of neurology. 1993；33（6）：583-590.

31. Mintz AH，Kestle J，Rathbone MP，et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer. 1996；78 （7）：1470-1476.

32. 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：phaseⅢresults of the RTOG 9508 randomised trial. Lancet. 2004；363 （9422）：1665-1672.

33. Duan L，Zeng R，Yang KH，et al. Whole brain radiotherapy combined with stereotactic radiotherapy versus stereotactic radiotherapy alone for brain metastases：a meta-analysis. Asian Pacific journal of cancer prevention：APJCP. 2014；15 （2）：911-915.

34. 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. The lancet oncology. 2009；10（11）：1037-1044.

35. Kihlstrom L，Karlsson B，Lindquist C. Gamma Knife surgery for cerebral metastases. Implications for survival based on 16 years experience. Stereotactic and functional neurosurgery. 1993；61 Suppl 1：45-50.

36. Yamanaka R. Medical management of brain metastases from lung cancer（Review）. Oncology reports. 2009；22（6）：1269-1276.

37. Bailon O，Chouahnia K，Augier A，et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro-oncology. 2012；14（4）：491-495.

38. Barlesi F，Gervais R，Lena H，et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer（NSCLC）with asymptomatic inoperable brain metastases：a multicenter phase II trial（GFPC 07-01）. Annals of oncology：official journal of the European Society for Medical Oncology / ESMO. 2011；22（11）：2466-2470.

39. Alberola V，Camps C，Provencio M，et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-smallcell lung cancer：a Spanish Lung Cancer Group phase III randomized trial. Journal of clinical oncology：official journal of the American Society of Clinical Oncology. 2003；21（17）：3207-3213.

40. Bearz A，Garassino I，Tiseo M，et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung cancer. 2010；68（2）：264-268.

41. Cortes J，Rodriguez J，Aramendia JM，et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology. 2003；64（1）：28-35.

42. Crino L，Scagliotti GV，Ricci S，et al. Gemcitabine and cisplatin versus mitomycin，ifosfamide，and cisplatin in advanced non-small-cell lung cancer：A randomized phase Ⅲstudy of the Italian Lung Cancer Project. Journal of clinical oncology：official journal of the American Society of Clinical Oncology. 1999；17（11）：3522-3530.

43. Lesser GJ. Chemotherapy of cerebral metastases from solid tumors. Neurosurgery clinics of North America. 1996；7（3）：527-536.

44. Stewart DJ，Leavens M，Maor M，et al. Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer research. 1982；42（6）：2474-2479.

45. Ostermann S，Csajka C，Buclin T，et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clinical cancer research：an official journal of the American Association for Cancer Research. 2004；10（11）：3728-3736.

46. Giorgio CG，Giuffrida D，Pappalardo A，et al. Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer：phaseⅡstudy. Lung cancer. 2005；50（2）：247-254.

47. Kouroussis C，Vamvakas L，Vardakis N，et al. Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer：a phaseⅡstudy. Oncology. 2009；76（2）：112-117.

48. Abrey LE，Olson JD，Raizer JJ，et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. Journal of neuro-oncology. 2001；53（3）：259-265.

49. Christodoulou C，Bafaloukos D，Kosmidis P，et al. PhaseⅡstudy of temozolomide in heavily pretreated cancer patients with brain metastases. Annals of oncology：official journal of the European Society for Medical Oncology / ESMO. 2001；12（2）：249-254.

50. Ebert BL，Niemierko E，Shaffer K，et al. Use of temozolomide with other cytotoxic chemotherapy in the treatment of patients with recurrent brain metastases from lung cancer. The oncologist. 2003；8（1）：69-75.

51. Petrelli F，Borgonovo K，Cabiddu M，et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer：a meta-analysis of 13 randomized trials. Clinical lung cancer. 2012；13（2）：107-114.

52. Masuda T，Hattori N，Hamada A，et al. Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy. Cancer chemotherapy and pharmacology. 2011；67（6）：1465-1469.

53. Togashi Y，Masago K，Fukudo M，et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of nonsmall cell lung cancer. Journal of thoracic oncology：official publication of the International Association for the Study of Lung Cancer. 2010；5（7）：950-955.

54. Weber B，Winterdahl M，Memon A，et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer：visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. Journal of thoracic oncology：official publication of the International Association for the Study of Lung Cancer. 2011；6（7）：1287-1289.

55. Hotta K，Kiura K，Ueoka H，et al. Effect of gefitinib （‘Iressa’，ZD1839）on brain metastases in patients with advanced nonsmall-cell lung cancer. Lung cancer. 2004；46（2）：255-261.

56. Wu YL，Zhou C，Cheng Y，et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases：a phaseⅡstudy（CTONG-0803）. Annals of oncology：official journal of the European Society for Medical Oncology / ESMO. 2013；24（4）：993-999.

57. Shimato S，Mitsudomi T，Kosaka T，et al. EGFR mutations in patients with brain metastases from lung cancer：association with the efficacy of gefitinib. Neuro-oncology. 2006；8（2）：137-144.

58. Porta R，Sanchez-Torres JM，Paz-Ares L，et al. Brain metastases from lung cancer responding to erlotinib：the importance of EGFR mutation. The European respiratory journal. 2011；37（3）：624-631.

59. Benedetti G，Latini L，Galetta D，et al. Epidermal growth factor receptor exon 19 deletions predict complete regression of multiple intracranial metastases in two cases of non-small cell lung cancer treated with erlotinib. Journal of thoracic oncology：official publication of the International Association for the Study of Lung Cancer. 2009；4（7）：936-937.

60. Park SJ，Kim HT，Lee DH，et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung cancer. 2012；77（3）：556-560.

61. Iuchi T，Shingyoji M，Sakaida T，et al. PhaseⅡtrial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung cancer. 2013；82（2）：282-287.

62. Kim JE，Lee DH，Choi Y，et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung cancer. 2009；65（3）：351-354.

63. Jackman DM，Holmes AJ，Lindeman N，et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. Journal of clinical oncology：official journal of the American Society of Clinical Oncology. 2006；24（27）：4517-4520.

64. Ruppert AM，Beau-Faller M，Neuville A，et al. EGFR-TKI and lung adenocarcinoma with CNS relapse：interest of molecular follow-up. The European respiratory journal. 2009；33（2）：436-440.

65. Matsumoto S，Takahashi K，Iwakawa R，et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. International journal of cancer Journal international du cancer. 2006；119（6）：1491-1494.

66. Omuro AM，Kris MG，Miller VA，et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 2005；103（11）：2344-2348.

67. Lee YJ，Choi HJ，Kim SK，et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer. 2010；116（5）：1336-1343.

68. Heon S，Yeap BY，Britt GJ，et al. Development of central nervous system metastases in patients with advanced nonsmall cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clinical cancer research：an official journal of the American Association for Cancer Research. 2010；16（23）：5873-5882.

69. Chen AM，Jahan TM，Jablons DM，et al. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer：clinical implications for the subsequent management of the brain. Cancer. 2007；109（8）：1668-1675.

70. Ceresoli GL，Reni M，Chiesa G，et al. Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment：risk factors analysis. Cancer. 2002；95（3）：605-612.

71. Heon S，Yeap BY，Lindeman NI，et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clinical cancer research：an official journal of the American Association for Cancer Research. 2012；18（16）：4406-4414.

72. Ceresoli GL，Cappuzzo F，Gregorc V，et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer：a prospective trial. Annals of oncology：official journal of the European Society for Medical Oncology / ESMO. 2004；15（7）：1042-1047.

73. Chiu CH，Tsai CM，Chen YM，et al. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. Lung cancer. 2005；47 （1）：129-138.

74. Wu C，Li YL，Wang ZM，et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung cancer. 2007；57（3）：359-364.

75. Lee DH，Han JY，Lee HG，et al. Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clinical cancer research：an official journal of the American Association for Cancer Research. 2005；11（8）：3032-3037.

76. Gerber NK，Yamada Y，Rimner A，et al. Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma. International journal of radiation oncology，biology，physics. 2014；89（2）：322-329.

77. Lind JS，Lagerwaard FJ，Smit EF，et al. Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer. International journal of radiation oncology，biology，physics. 2009；74（5）：1391-1396.

78. Ma S，Xu Y，Deng Q，et al. Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung cancer. 2009；65（2）：198-203.

79. Sperduto PW，Wang M，Robins HI，et al. 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. International journal of radiation oncology，biology，physics. 2013；85（5）：1312-1318.

80. Lee DH，Han JY，Kim HT，et al. Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first：result of a randomized pilot study. Cancer. 2008；113（1）：143-149.

81. Antonadou D，Paraskevaidis M，Sarris G，et al. PhaseⅡrandomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. Journal of clinical oncology：official journal of the American Society of Clinical Oncology. 2002；20（17）：3644-3650.

82. Hofmann M，Kiecker F，Wurm R，et al. Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases. Journal of neuro-oncology. 2006；76（1）：59-64.

83. Villarreal-Garza C，de la Mata D，Zavala DG，et al. Aggressive treatment of primary tumor in patients with non-small-cell lung cancer and exclusively brain metastases. Clinical lung cancer. 2013；14（1）：6-13.

84. Modi A，Vohra HA，Weeden DF. Does surgery for primary non-small cell lung cancer and cerebral metastasis have any impact on survival？ Interactive cardiovascular and thoracic surgery. 2009；8（4）：467-473.

85. Iwasaki A，Shirakusa T，Yoshinaga Y，et al. Evaluation of the treatment of non-small cell lung cancer with brain metastasis and the role of risk score as a survival predictor. European journal of cardio-thoracic surgery：official journal of the European Association for Cardio-thoracic Surgery. 2004；26 （3）：488-493.

86. Bonnette P，Puyo P，Gabriel C，et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest. 2001；119（5）：1469-1475.

87. Mussi A，Pistolesi M，Lucchi M，et al. Resection of single brain metastasis in non-small-cell lung cancer：prognostic factors. The Journal of thoracic and cardiovascular surgery. 1996；112（1）：146-153.

88. Wronski M，Arbit E，Burt M，et al. Survival after surgical treatment of brain metastases from lung cancer：a follow-up study of 231 patients treated between 1976 and 1991. Journal of neurosurgery. 1995；83（4）：605-616.

89. Chidel MA，Suh JH，Greskovich JF，et al. Treatment outcome for patients with primary nonsmall-cell lung cancer and synchronous brain metastasis. Radiation oncology investigations. 1999；7（5）：313-319.

90. Moazami N，Rice TW，Rybicki LA，et al. Stage III non-small cell lung cancer and metachronous brain metastases. The Journal of thoracic and cardiovascular surgery. 2002；124（1）：113-122.

91. Hu C，Chang EL，Hassenbusch SJ，3rd，et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006；106（9）：1998-2004.

92. Flannery TW，Suntharalingam M，Regine WF，et al. Long-term survival in patients with synchronous，solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery. International journal of radiation oncology，biology，physics. 2008；72（1）：19-23.

93. Louie AV，Rodrigues G，Yaremko B，et al. Management and prognosis in synchronous solitary resected brain metastasis from non-small-cell lung cancer. Clinical lung cancer. 2009；10（3）：174-179.