（修改稿20230904）头部伽玛刀治疗肺腺癌脑转移瘤的专家共识

头部伽玛刀治疗肺腺癌脑转移瘤的专家共识脑转移瘤是一种恶性肿瘤，是原发肿瘤的癌细胞通过血管或淋巴系统转移到脑部，形成的肿瘤。由于肺腺癌脑转移瘤具有中等程度的放射敏感性，加上患者的病程和对系统治疗的反应具有自身特征，因此如何规范地采取头部伽玛刀治疗肺腺癌脑转移瘤，进而获得最优的肿瘤控制效果和最大程度的神经功能保护，仍有一系列问题需要明确。基于这个原因，世界华人神经外科协会放射外科专业委员会牵头，联合头部伽玛刀和相关学科的专家共同讨论，形成这一共识，为国内伽玛刀治疗中心规范治疗肺腺癌脑转移瘤提供参考。肺腺癌脑转移的流行病学脑转移瘤是成人颅内最常见的肿瘤之一ADDINEN.CITEADDINEN.CITE.DATA[1]。对原发肿瘤的有效控制使生存时间延长，同时，影像检查的进步使肺癌脑转移瘤的检出率增高，这些原因成为肺癌脑转移瘤发病率日益增长的因素ADDINEN.CITE<EndNote><Cite><Author>Riessk</Author><Year>2013</Year><RecNum>219</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>219</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">219</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Riessk,J.</author></authors></contributors><auth-address>4501XSt,Ste3016,Sacramento,CA95817.E-mail:Jonathan.Riess@.</auth-address><titles><title>Shiftingparadigmsinnon-smallcelllungcancer:anevolvingtherapeuticlandscape</title><secondary-title>AmJManagCare</secondary-title></titles><periodical><full-title>AmJManagCare</full-title></periodical><pages>s390-7</pages><volume>19</volume><number>19Suppl</number><edition>2014/02/06</edition><keywords><keyword>Carcinoma,Non-Small-CellLung/epidemiology/*secondary/*therapy</keyword><keyword>Chemotherapy,Adjuvant</keyword><keyword>CombinedModalityTherapy</keyword><keyword>Disease-FreeSurvival</keyword><keyword>Female</keyword><keyword>Genes,erbB-1/*drugeffects</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/epidemiology/*pathology/*therapy</keyword><keyword>Male</keyword><keyword>MolecularTargetedTherapy</keyword><keyword>NeoplasmInvasiveness/pathology</keyword><keyword>NeoplasmMetastasis</keyword><keyword>NeoplasmStaging</keyword><keyword>Pneumonectomy/methods</keyword><keyword>Prognosis</keyword><keyword>Radiotherapy,Adjuvant</keyword><keyword>SurvivalAnalysis</keyword></keywords><dates><year>2013</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1936-2692(Electronic) 1088-0224(Linking)</isbn><accession-num>24494720</accession-num><urls><related-urls><url>/pubmed/24494720</url></related-urls></urls></record></Cite></EndNote>[2]。在脑转移瘤对应的原发肿瘤中，肺癌占比最高，约30%-60%。同时，肺癌本身也是全球发病率最高的肿瘤，伴随的死亡率也为全球癌肿之最ADDINEN.CITEADDINEN.CITE.DATA[3]。原发肺癌可大致分为小细胞和非小细胞两种类型。而非小细胞肺癌约占肺癌的80%，又分为三种亚型：腺癌，鳞癌，大细胞癌。肺部各种亚型的癌肿都有向脑部转移的倾向。而其中，肺腺癌又是发生脑转移瘤的最常见的病理类型ADDINEN.CITE<EndNote><Cite><Author>Sorensen</Author><Year>1988</Year><RecNum>222</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>222</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">222</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sorensen,J.B.</author><author>Hansen,H.H.</author><author>Hansen,M.</author><author>Dombernowsky,P.</author></authors></contributors><auth-address>DepartmentofOncologyONB,FinsenInstitute,Copenhagen,Denmark.</auth-address><titles><title>Brainmetastasesinadenocarcinomaofthelung:frequency,riskgroups,andprognosis</title><secondary-title>JClinOncol</secondary-title></titles><periodical><full-title>JClinOncol</full-title></periodical><pages>1474-80</pages><volume>6</volume><number>9</number><edition>1988/09/01</edition><keywords><keyword>Adenocarcinoma/drugtherapy/mortality/*secondary</keyword><keyword>AntineoplasticCombinedChemotherapyProtocols/therapeuticuse</keyword><keyword>BrainNeoplasms/mortality/*secondary</keyword><keyword>ClinicalTrialsasTopic</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*LungNeoplasms/drugtherapy</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>Prognosis</keyword><keyword>RandomAllocation</keyword><keyword>RiskFactors</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0732-183X(Print) 0732-183X(Linking)</isbn><accession-num>3047337</accession-num><urls><related-urls><url>/pubmed/3047337</url></related-urls></urls><electronic-resource-num>10.1200/JCO.19474</electronic-resource-num></record></Cite></EndNote>[4]。这种类型的肺癌发生脑转移瘤的概率约为其他病理类型肺癌的2倍ADDINEN.CITE<EndNote><Cite><Author>Liu</Author><Year>2017</Year><RecNum>223</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>223</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">223</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Liu,D.</author><author>Vokes,N.I.</author><author>VanAllen,E.M.</author></authors></contributors><auth-address>DepartmentofMedicalOncology,Dana-FarberCancerInstitute,Boston,Massachusetts. DepartmentofMedicalOncology,Dana-FarberCancerInstitute,Boston,Massachusetts.eliezerm_vanallen@.</auth-address><titles><title>TowardMolecularlyDrivenPrecisionMedicineinLungAdenocarcinoma</title><secondary-title>CancerDiscov</secondary-title></titles><periodical><full-title>CancerDiscov</full-title></periodical><pages>555-557</pages><volume>7</volume><number>6</number><edition>2017/06/04</edition><keywords><keyword>Adenocarcinoma/*genetics/*therapy</keyword><keyword>AdenocarcinomaofLung</keyword><keyword>Biomarkers,Tumor/genetics</keyword><keyword>DNA,Neoplasm</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/*genetics/*therapy</keyword><keyword>MolecularTargetedTherapy</keyword><keyword>PrecisionMedicine</keyword><keyword>SequenceAnalysis,DNA</keyword></keywords><dates><year>2017</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>2159-8290(Electronic) 2159-8274(Print) 2159-8274(Linking)</isbn><accession-num>28576842</accession-num><urls><related-urls><url>/pubmed/28576842</url></related-urls></urls><custom2>PMC7043263</custom2><electronic-resource-num>10.1158/2159-8290.CD-17-0355</electronic-resource-num></record></Cite></EndNote>[5]。因此有效控制肺腺癌脑转移瘤的进展，同时最大程度地保护神经功能具有重要意义。肺腺癌脑转移瘤的伽玛刀治疗技术特征伽玛刀采用立体定向几何原理，使60钴放射源产生的伽玛射线大剂量聚焦照射。靶区内放射剂量很高，靶区周围的正常组织放射剂量很小ADDINEN.CITEADDINEN.CITE.DATA[6]。Perfexion型伽玛刀使用通过在单个内部准直系统中圆柱锥形状地布置的192个放射性60钴源，将射线束聚焦到一个中心点。钨准直器含有8个扇区的钨准直器呈锥柱状排列，内含24个60钴源，每个扇区有4、8和16毫米的3种不同孔径。根据病灶的大小、形状和位置，使用一个或多个等中心点向靶区照射相应剂量。传统上，接受伽玛刀治疗的患者需安装一个具有定位功能的刚性立体定位头架，靶精度误差<0.5mm。伽玛刀的最新型号Icon可以基于面罩进行放射外科定位。在脑转移瘤的治疗中，肺腺癌并非放射敏感性显著的肿瘤，因此伽玛刀的集中高剂量的优势较传统放射治疗更为明显。而与传统开颅手术相比，头部伽玛刀则具有微创优势ADDINEN.CITE<EndNote><Cite><Author>Heck</Author><Year>2007</Year><RecNum>180</RecNum><DisplayText><styleface="superscript">[7]</style></DisplayText><record><rec-number>180</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">180</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Heck,B.</author><author>Jess-Hempen,A.</author><author>Kreiner,H.J.</author><author>Schopgens,H.</author><author>Mack,A.</author></authors></contributors><auth-address>GammaKnifeMunich,Ingolstadterstrasse166,80939Munich,Germany.b.heck@gammaks.de</auth-address><titles><title>Accuracyandstabilityofpositioninginradiosurgery:long-termresultsoftheGammaKnifesystem</title><secondary-title>MedPhys</secondary-title></titles><periodical><full-title>MedPhys</full-title></periodical><pages>1487-95</pages><volume>34</volume><number>4</number><edition>2007/05/16</edition><keywords><keyword>EquipmentDesign</keyword><keyword>EquipmentFailureAnalysis</keyword><keyword>*Motion</keyword><keyword>QualityAssurance,HealthCare/*methods</keyword><keyword>Radiosurgery/*instrumentation</keyword><keyword>ReproducibilityofResults</keyword><keyword>SensitivityandSpecificity</keyword></keywords><dates><year>2007</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0094-2405(Print) 0094-2405(Linking)</isbn><accession-num>17500479</accession-num><urls><related-urls><url>/pubmed/17500479</url></related-urls></urls><electronic-resource-num>10.1118/1.2710949</electronic-resource-num></record></Cite></EndNote>[7]。伽玛刀单次治疗肺腺癌脑转移瘤通常用于毗邻功能区的＜5cm3的病灶、或者位于非功能区的＜10cm3的病灶，单次处方剂量15-18Gy，采用40%-60%等剂量线覆盖病灶ADDINEN.CITEADDINEN.CITE.DATA[8]。当病灶毗邻功能区并且≥5cm3、或者位于非功能区并且≥10cm3，可采用分两次伽玛刀治疗，每次剂量10-12Gy，采用40%-50%等剂量线覆盖病灶ADDINEN.CITEADDINEN.CITE.DATA[9]，建议间隔时间为24-72小时。另一种针对体积≥10cm3的病灶的治疗方案采用分三阶段的自适应伽玛刀治疗，计划每阶段处方剂量10Gy，50%等剂量线覆盖病灶，时间间隔2-3周，如果治疗过程中病灶体积进行性缩小，则实际每阶段处方剂量分别为10、12和15GyADDINEN.CITE<EndNote><Cite><Author>Ma</Author><Year>2021</Year><RecNum>283</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>283</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1693576664">283</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ma,L.</author><author>Tseng,C.L.</author><author>Sahgal,A.</author></authors></contributors><auth-address>DepartmentofRadiationOncology,UniversityofCaliforniaSanFrancisco(UCSF),SanFrancisco,CA,USA.lijun.ma@. DepartmentofRadiationOncology,SunnybrookOdetteCancerCentre,PrincessMargaretHospital,UniversityofToronto,Toronto,ON,Canada.</auth-address><titles><title>PossibleOvercomingofTumorHypoxiawithAdaptiveHypofractionatedRadiosurgeryofLargeBrainMetastases:ABiologicalModelingStudy</title><secondary-title>ActaNeurochirSuppl</secondary-title></titles><periodical><full-title>ActaNeurochirSuppl</full-title></periodical><pages>107-112</pages><volume>128</volume><edition>2021/07/01</edition><keywords><keyword>*BrainNeoplasms/radiotherapy/surgery</keyword><keyword>Humans</keyword><keyword>*Radiosurgery</keyword><keyword>TreatmentOutcome</keyword><keyword>TumorBurden</keyword><keyword>TumorHypoxia</keyword><keyword>Biologicalmodeling</keyword><keyword>Biologicallyeffectivedose</keyword><keyword>Hypofractionatedstereotacticradiosurgery</keyword><keyword>Intracranialmetastases</keyword><keyword>Treatmentplanning</keyword></keywords><dates><year>2021</year></dates><isbn>0065-1419(Print) 0065-1419(Linking)</isbn><accession-num>34191066</accession-num><urls><related-urls><url>/pubmed/34191066</url></related-urls></urls><electronic-resource-num>10.1007/978-3-030-69217-9_11</electronic-resource-num></record></Cite></EndNote>[10]。但是上述相关的各种分阶段治疗方案尚缺乏I级循证医学证据佐证。根据Miller等推荐的公式计算BEDADDINEN.CITEADDINEN.CITE.DATA[11]，则有可能形成更规范的治疗方案评估指标。伽玛刀治疗肺腺癌脑转移瘤是否选择伽玛刀治疗脑转移瘤，应该围绕病灶大小、数目、位置、放射敏感性以及患者的一般情况来进行综合评估ADDINEN.CITEADDINEN.CITE.DATA[12,13]。通常根据病灶大小来选择伽玛刀或者开颅手术。按照肿瘤大小，脑转移瘤可以分为巨大肿瘤（最大直径＞3cm），中等大小肿瘤（5mm＜最大直径≤3cm），和小肿瘤（最大直径≤5mm）ADDINEN.CITEADDINEN.CITE.DATA[8,9]。巨大病灶若伴有明显水肿和颅高压，多数采用开颅手术而不是伽玛刀治疗。而绝大多数位于深部的病灶采用伽玛刀治疗。病灶数目可以用来帮助确定采取伽玛刀治疗的次数，通常10个以下的病灶采用单次伽玛刀治疗可以覆盖所有病灶，10个以上病灶可能需要采用薄层MR影像扫描再次确认病灶数目并且商讨治疗方案ADDINEN.CITEADDINEN.CITE.DATA[14]。此外，肺腺癌的剂量反应（α/β比值）不能保证其放射敏感性显著高于周围神经组织（α/β比值）ADDINEN.CITEADDINEN.CITE.DATA[15]，因此当病灶位于功能区，例如毗邻锥体束时，倾向采取剂量分割方案来平衡控制肿瘤和保护神经之间的矛盾。患者一般情况通常采用Karnofsky（KPS）评分进行评估。KPS评分较差的患者需要区分是脑转移瘤造成的低分值，还是由于颅外病灶进展造成低分值。由于颅外病灶进展导致一般情况恶化的患者往往生存时间有限，并且器官耐受手术打击的能力减退，因此倾向采用放射外科这种微侵袭方式治疗脑转移瘤ADDINEN.CITE<EndNote><Cite><Author>Harat</Author><Year>2020</Year><RecNum>230</RecNum><DisplayText><styleface="superscript">[16]</style></DisplayText><record><rec-number>230</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">230</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Harat,M.</author><author>Blok,M.</author><author>Miechowicz,I.</author><author>Kowalewska,J.</author></authors></contributors><auth-address>DepartmentofOncologyandBrachytherapy,CollegiumMedicumNicolausCopernicusUniversity,Bydgoszcz,Poland. DepartmentofRadiosurgeryandNeurooncology,Prof.FranciszekLukaszczykMemorialOncologyCenter,Bydgoszcz,Poland. DepartmentofRadiotherapy,Prof.FranciszekLukaszczykMemorialOncologyCenter,Bydgoszcz,Poland. DepartmentofComputerScienceandStatistics,PoznanUniversityofMedicalSciences,Poznan,Poland.</auth-address><titles><title>StereotacticRadiosurgeryofBrainMetastasisinPatientswithaPoorPrognosis:EffectiveorOvertreatment?</title><secondary-title>CancerManagRes</secondary-title></titles><periodical><full-title>CancerManagRes</full-title></periodical><pages>12569-12579</pages><volume>12</volume><edition>2020/12/17</edition><keywords><keyword>brain</keyword><keyword>metastasis</keyword><keyword>neoplasm</keyword><keyword>radiosurgery</keyword><keyword>radiotherapy</keyword><keyword>riskfactors</keyword></keywords><dates><year>2020</year></dates><isbn>1179-1322(Print) 1179-1322(Electronic) 1179-1322(Linking)</isbn><accession-num>33324101</accession-num><urls><related-urls><url>/pubmed/33324101</url></related-urls></urls><custom2>PMC7732755</custom2><electronic-resource-num>10.2147/CMAR.S272369</electronic-resource-num></record></Cite></EndNote>[16]。肺腺癌脑转移瘤的伽玛刀与手术治疗占位效应明显，常伴有颅内压增高。肿瘤体积增加可能导致伽玛刀治疗病灶的放射剂量下降，不利于肿瘤控制。因此巨大肿瘤更适合采用开颅手术治疗。小肿瘤或者位于深部的肿瘤倾向采用放射外科治疗。中等大小肿瘤可能既适合开颅手术，也适合放射外科治疗。哪一种治疗方式更好，存在争议。Auchter的一项前瞻性研究显示，放射外科联合全脑放疗治疗单发脑转移瘤的患者生存时间优于手术联合全脑放疗ADDINEN.CITEADDINEN.CITE.DATA[17]。而Bindal的回顾性研究结果则显示，手术治疗脑转移瘤的局部复发率低于放射外科ADDINEN.CITE<EndNote><Cite><Author>Bindal</Author><Year>1996</Year><RecNum>240</RecNum><DisplayText><styleface="superscript">[18]</style></DisplayText><record><rec-number>240</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">240</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bindal,A.K.</author><author>Bindal,R.K.</author><author>Hess,K.R.</author><author>Shiu,A.</author><author>Hassenbusch,S.J.</author><author>Shi,W.M.</author><author>Sawaya,R.</author></authors></contributors><auth-address>DepartmentofNeurosurgery,UniversityofTexasM.D.AndersonCancerCenter,Houston,USA.</auth-address><titles><title>Surgeryversusradiosurgeryinthetreatmentofbrainmetastasis</title><secondary-title>JNeurosurg</secondary-title></titles><periodical><full-title>JNeurosurg</full-title></periodical><pages>748-54</pages><volume>84</volume><number>5</number><edition>1996/05/01</edition><keywords><keyword>Adult</keyword><keyword>BrainNeoplasms/mortality/*secondary/*surgery</keyword><keyword>Female</keyword><keyword>Follow-UpStudies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>NeoplasmRecurrence,Local</keyword><keyword>Radiosurgery</keyword><keyword>SurvivalAnalysis</keyword></keywords><dates><year>1996</year><pub-dates><date>May</date></pub-dates></dates><isbn>0022-3085(Print) 0022-3085(Linking)</isbn><accession-num>8622147</accession-num><urls><related-urls><url>/pubmed/8622147</url></related-urls></urls><electronic-resource-num>10.3171/jns.19748</electronic-resource-num></record></Cite></EndNote>[18]。Muacevic的前瞻性研究发现，手术与放射外科的神经系统相关死亡率无显著差异，但放射外科治疗的患者发生远处转移的概率高于手术治疗ADDINEN.CITE<EndNote><Cite><Author>Muacevic</Author><Year>2008</Year><RecNum>241</RecNum><DisplayText><styleface="superscript">[19]</style></DisplayText><record><rec-number>241</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">241</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Muacevic,A.</author><author>Wowra,B.</author><author>Siefert,A.</author><author>Tonn,J.C.</author><author>Steiger,H.J.</author><author>Kreth,F.W.</author></authors></contributors><auth-address>DepartmentofNeurosurgery,Ludwig-Maximilians-University,KlinikumGrosshadern,Munich81377,Germany.</auth-address><titles><title>MicrosurgerypluswholebrainirradiationversusGammaKnifesurgeryalonefortreatmentofsinglemetastasestothebrain:arandomizedcontrolledmulticentrephaseIIItrial</title><secondary-title>JNeurooncol</secondary-title></titles><periodical><full-title>JNeurooncol</full-title></periodical><pages>299-307</pages><volume>87</volume><number>3</number><edition>2007/12/25</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>BrainNeoplasms/*radiotherapy/*secondary/*surgery</keyword><keyword>CombinedModalityTherapy</keyword><keyword>CranialIrradiation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kaplan-MeierEstimate</keyword><keyword>Male</keyword><keyword>Microsurgery</keyword><keyword>MiddleAged</keyword><keyword>NeurosurgicalProcedures</keyword><keyword>Prognosis</keyword><keyword>QualityofLife</keyword><keyword>*Radiosurgery</keyword></keywords><dates><year>2008</year><pub-dates><date>May</date></pub-dates></dates><isbn>0167-594X(Print) 0167-594X(Linking)</isbn><accession-num>18157648</accession-num><urls><related-urls><url>/pubmed/18157648</url></related-urls></urls><electronic-resource-num>10.1007/s11060-007-9510-4</electronic-resource-num></record></Cite></EndNote>[19]。尽管存在上述争议，目前临床共识认为，选择手术还是放射外科需要综合病灶大小、部位，以及患者的临床表现。直径＞3cm的肿瘤适合开颅手术治疗，而直径＜1cm-2cm的肿瘤，位于脑深部的肿瘤适合放射外科治疗。占位效应明显，合并因肿瘤压迫导致的神经功能障碍患者适合采用开颅手术去除病灶，及时解除占位效应，有助于患者功能恢复ADDINEN.CITEADDINEN.CITE.DATA[20]。由于肿瘤颅外进展导致临床状态差的患者可能无法耐受手术者，因此应考虑采用放射外科治疗。肺腺癌脑转移瘤的伽玛刀与全脑放疗由于肺腺癌相对较长的生存期，是否选择全脑放疗除了考虑是否有效控制所有病灶之外，还需要考虑治疗是否导致神经认知功能障碍，以及是否影响长期生存者的生活质量。必须指出的是，放射外科的广泛应用正在减少WBRT的使用。针对多发脑转移瘤，立体定向放射外科治疗病灶数目上限呈增长趋势。推荐单次治疗病灶上限由4个逐渐增加到10个以上ADDINEN.CITE<EndNote><Cite><Author>Scoccianti</Author><Year>2012</Year><RecNum>232</RecNum><DisplayText><styleface="superscript">[21]</style></DisplayText><record><rec-number>232</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">232</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Scoccianti,S.</author><author>Ricardi,U.</author></authors></contributors><auth-address>RadiationOncology,AziendaOspedalieroUniversitariaCareggi,Florence,Italy.silvia.scoccianti@unifi.it</auth-address><titles><title>Treatmentofbrainmetastases:reviewofphaseIIIrandomizedcontrolledtrials</title><secondary-title>RadiotherOncol</secondary-title></titles><periodical><full-title>RadiotherOncol</full-title></periodical><pages>168-79</pages><volume>102</volume><number>2</number><edition>2011/10/15</edition><keywords><keyword>BrainNeoplasms/*radiotherapy/*secondary/surgery</keyword><keyword>ClinicalTrials,PhaseIIIasTopic</keyword><keyword>CombinedModalityTherapy</keyword><keyword>CranialIrradiation/*methods</keyword><keyword>Humans</keyword><keyword>QualityofLife</keyword><keyword>Radiosurgery/methods</keyword><keyword>RandomizedControlledTrialsasTopic</keyword></keywords><dates><year>2012</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1879-0887(Electronic) 0167-8140(Linking)</isbn><accession-num>21996522</accession-num><urls><related-urls><url>/pubmed/21996522</url></related-urls></urls><electronic-resource-num>10.1016/j.radonc.2011.08.041</electronic-resource-num></record></Cite></EndNote>[21]。以往B型和C型伽玛刀由于头部定位框架的范围限制，数目多且位置分散的脑转移瘤病灶难以用单次头架安全模式治疗所有病灶。采用移动头架或多次治疗，有可能全面覆盖颅脑范围，完成所有病灶的治疗。但多次治疗会显著增加患者住院时间和治疗费用。而增加头部框架固定次数也意味着增加患者的不适感ADDINEN.CITEADDINEN.CITE.DATA[22]。这些因素促使临床医师面临多发病灶时可能倾向选择全脑放射治疗，尤其是在颅内病灶≥20个时ADDINEN.CITEADDINEN.CITE.DATA[23]。而新生代伽玛刀Perfexion型或者Icon型治疗仪则显著扩大了治疗的覆盖范围，单次治疗可及范围较B型和C型伽玛刀明显增大，并且无框架定位技术也有效地用于这两种新型伽玛刀，显著降低病灶数目的限制。这种情况下，全脑放射治疗更适合治疗可能存在的隐匿脑转移瘤，即对增强MR等影像学检查尚不能发现的病灶进行治疗。但是，与小细胞肺癌脑转移瘤不同，肺腺癌脑转移瘤发生隐匿脑转移瘤的可能性较小，因此倾向采取多次伽玛刀结合密切随访来完成所有病灶治疗，也包括隐匿脑转移瘤病灶的治疗。合并脑膜播散转移的肺腺癌脑转移瘤则应考虑采用全脑放疗而不是伽玛刀。放射外科治疗后放射损伤的防治放射损伤导致的神经功能障碍发生率决于放射剂量高低和神经组织的放射耐受性。神经功能保护相关的放射外科剂量不仅适用于肺腺癌脑转移瘤的放射外科治疗，也适用于其他与神经相毗邻的病灶。但需要注意的是，如果放射剂量不能有效控制肿瘤生长，逐渐进展的肿瘤压迫同样会导致神经功能障碍。因此，一方面，伽玛刀治疗产生的放射生物学效应要有效杀灭肺腺癌脑转移瘤的肿瘤细胞，另一方面，正常神经组织要耐受这种放射生物效应ADDINEN.CITE<EndNote><Cite><Author>Hopewell</Author><Year>2012</Year><RecNum>58</RecNum><DisplayText><styleface="superscript">[24]</style></DisplayText><record><rec-number>58</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">58</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hopewell,J.W.</author><author>Millar,W.T.</author><author>Lindquist,C.</author></authors></contributors><auth-address>GreenTempletonCollegeandParticleTherapyCancerResearchInstitute,UniversityofOxford,Oxford,UK.john.hopewell@gtc.ox.ac.uk</auth-address><titles><title>Radiobiologicalprinciples:theirapplicationtogammaknifetherapy</title><secondary-title>ProgNeurolSurg</secondary-title></titles><periodical><full-title>ProgNeurolSurg</full-title></periodical><pages>39-54</pages><volume>25</volume><edition>2012/01/13</edition><keywords><keyword>Dose-ResponseRelationship,Radiation</keyword><keyword>Humans</keyword><keyword>RadiationDosage</keyword><keyword>Radiobiology/*methods</keyword><keyword>Radiosurgery/adverseeffects/instrumentation/*methods</keyword></keywords><dates><year>2012</year></dates><isbn>1662-3924(Electronic) 0079-6492(Linking)</isbn><accession-num>22236667</accession-num><urls><related-urls><url>/pubmed/22236667</url></related-urls></urls><electronic-resource-num>10.1159/000331173</electronic-resource-num></record></Cite></EndNote>[24]。由于放射生物效应是细胞放射损伤和细胞修复作用的共同结果ADDINEN.CITEADDINEN.CITE.DATA[25]。在伽玛刀治疗中，这种结果受物理剂量高低、剂量率快慢、射线照射间隔时间长短、以及组织剂量反应是否敏感等因素影响ADDINEN.CITEADDINEN.CITE.DATA[26]。此外，伽玛刀的剂量分割方案也增加了产生放射生物效应的复杂性。放射生物效应剂量（BED）的计算模型有助于形成规范的肿瘤控制和神经保护评价指标。肺腺癌的剂量反应/比值约为8.2(7.0-9.4)，正常神经组织的剂量反应/比值约为2.47(0.8-3.9)ADDINEN.CITEADDINEN.CITE.DATA[15]，根据Miller等推荐的公式计算BEDADDINEN.CITEADDINEN.CITE.DATA[11]，有可能为伽玛刀治疗肺腺癌脑转移瘤的神经功能保护提供重要参考依据。一般推荐锥体束或者其他重要的脑白质纤维束单次放射外科接受剂量不超过15Gy。多次放射外科治疗计算生物效应剂量不超过45Gy2.47；或者40Gy2.47覆盖锥体束或者其他重要的脑白质纤维束的体积不超过1cm3。脑放射性坏死是放射外科治疗脑转移瘤的迟发并发症ADDINEN.CITEADDINEN.CITE.DATA[27]，其原因是包括血管内皮损伤和胶质损伤在内的组织损伤，血脑屏障破坏可能是其中一个关键组成部分。正常组织脑实质破坏通常与周围脑水肿有关。放射性脑水肿或坏死可以是有症状的也可以是无症状的。症状包括头痛、恶心、癫痫、共济失调和局部神经功能障碍。这些局部症状取决于受影响的大脑区域，可能完全或部分可逆，需要进行脱水、皮质类固醇激素、抗癫痫等治疗。严重的脑放射性坏死可能伴随显著的占位效应，导致肢体瘫痪和昏迷，需要进行手术治疗。肺腺癌脑转移瘤的多学科合作肺腺癌脑转移瘤伽玛刀治疗后发生局部复发时，首先需要与影像诊断专业医师合作，鉴别局部进展或放射性坏死。同时需要与开颅手术专家合作，商讨是否切除局部复发的病灶，或者切除难以控制的放射性坏死。患者一般情况不能耐受开颅手术而需要采取放射外科治疗时，当病灶位于功能区，或者病灶以往经历放射治疗，需要降低放射剂量。但是降低放射剂量可能导致局部控制率的降低。这种情况下，需要联合肿瘤专业医师，共同商讨如何联合药物治疗肺腺癌脑转移瘤。肺腺癌相关分子病理信息需要与病理科专家共同商讨获悉。例如表皮生长因子受体（EGFR）的相关分子病理检测可以为肺腺癌转移瘤的放射敏感性提供参考ADDINEN.CITEADDINEN.CITE.DATA[28]。由于肺癌发病率很高，肿瘤发生相关的分子生物学研究很多ADDINEN.CITE<EndNote><Cite><Author>Pao</Author><Year>2011</Year><RecNum>233</RecNum><DisplayText><styleface="superscript">[29]</style></DisplayText><record><rec-number>233</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">233</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Pao,W.</author><author>Girard,N.</author></authors></contributors><auth-address>DepartmentofMedicine,Vanderbilt-IngramCancerCenter,Nashville,TN37232-6307,USA.william.pao@</auth-address><titles><title>Newdrivermutationsinnon-small-celllungcancer</title><secondary-title>LancetOncol</secondary-title></titles><periodical><full-title>LancetOncol</full-title></periodical><pages>175-80</pages><volume>12</volume><number>2</number><edition>2011/02/01</edition><keywords><keyword>AdaptorProteins,SignalTransducing/*genetics</keyword><keyword>AnaplasticLymphomaKinase</keyword><keyword>Carcinoma,Non-Small-CellLung/*genetics/physiopathology</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/*genetics/physiopathology</keyword><keyword>Mutation</keyword><keyword>OncogeneProteinv-akt/*genetics</keyword><keyword>Protein-TyrosineKinases/*genetics</keyword><keyword>Proto-OncogeneProteinsB-raf/*genetics</keyword><keyword>ReceptorProtein-TyrosineKinases</keyword><keyword>Receptor,ErbB-2/*genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-5488(Electronic) 1470-2045(Linking)</isbn><accession-num>21277552</accession-num><urls><related-urls><url>/pubmed/21277552</url></related-urls></urls><electronic-resource-num>10.1016/S1470-2045(10)70087-5</electronic-resource-num></record></Cite></EndNote>[29]。研究聚焦于促使肿瘤基因突变的分子机制ADDINEN.CITEADDINEN.CITE.DATA[30]，从而研发出靶向药物，抑制肿瘤小分子和突变蛋白，来延缓肿瘤耐药，延长生存时间ADDINEN.CITE<EndNote><Cite><Author>Mayekar</Author><Year>2017</Year><RecNum>234</RecNum><DisplayText><styleface="superscript">[31]</style></DisplayText><record><rec-number>234</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">234</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mayekar,M.K.</author><author>Bivona,T.G.</author></authors></contributors><auth-address>DepartmentofMedicine,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA. DepartmentofCellularandMolecularPharmacology,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA. HelenDillerFamilyComprehensiveCancerCenter,UniversityofCalifornia,SanFrancisco,SanFrancisco,USA.</auth-address><titles><title>CurrentLandscapeofTargetedTherapyinLungCancer</title><secondary-title>ClinPharmacolTher</secondary-title></titles><periodical><full-title>ClinPharmacolTher</full-title></periodical><pages>757-764</pages><volume>102</volume><number>5</number><edition>2017/08/09</edition><keywords><keyword>AntineoplasticAgents/*administration&dosage/metabolism</keyword><keyword>ClinicalTrialsasTopic/methods</keyword><keyword>ErbBReceptors/antagonists&inhibitors/metabolism</keyword><keyword>Humans</keyword><keyword>LungNeoplasms/*drugtherapy/genetics/metabolism</keyword><keyword>MolecularTargetedTherapy/methods/*trends</keyword><keyword>Mutation/genetics</keyword></keywords><dates><year>2017</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1532-6535(Electronic) 0009-9236(Linking)</isbn><accession-num>28786099</accession-num><urls><related-urls><url>/pubmed/28786099</url></related-urls></urls><electronic-resource-num>10.1002/cpt.810</electronic-resource-num></record></Cite></EndNote>[31]。其中，EGFR突变患者在联合靶向药物治疗后，降低放射外科剂量仍可获得较好的肿瘤局部控制率ADDINEN.CITEADDINEN.CITE.DATA[32]。Alzate等在非小细胞肺癌患者队列中发现，低剂量的放射外科联合靶向治疗与较长的生存期和无进展生存期相关ADDINEN.CITE<EndNote><Cite><Author>Alzate</Author><Year>2023</Year><RecNum>236</RecNum><DisplayText><styleface="superscript">[33]</style></DisplayText><record><rec-number>236</rec-number><foreign-keys><keyapp="EN"db-id="2af0zw9tnas2pgevz0150dzsxwr52xrxtv0a"timestamp="1691271664">236</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Alzate,J.D.</author><author>Mashiach,E.</author><author>Berger,A.</author><author>Bernstein,K.</author><author>Mullen,R.</author><author>NigrisVasconcellos,F.</author><author>Qu,T.</author><author>Silverman,J.S.</author><author>Donahue,B.R.