中樞神經系統轉移瘤放射外科治療指南
《RevAssoc Med Bras》2017年7月（ 63(7):559-563）刊登巴西放射治療學會立體定向放射治療專業組Gustavo Nader Marta1, Helena Espindola Baraldi, Fabio Ynoe de Moraes執筆撰寫的《放射外科治療中樞神經系統轉移瘤指南Guidelines for the treatment of central nervous system metastasesusing radiosurgery》。（DOI：10.1590/1806-9282.63.07.559）。
本指南是巴西醫學協會的建議，旨在將醫學領域的信息整合匯總，協助醫生進行規範循證和決策。
本指南所提供的信息須由負責醫療行為的醫生按照每個病人的具體情況和臨床表現進行評估，判別和採納。
指南的分級和循證等級
? A:實驗或觀察性研究的高度一致性。
?B:實驗或觀察性研究相對較低的一致性。
?C:(非對照的研究)病例報告。
?D:基於共識、生理研究、或動物模型，缺乏批判性評價。
背景
本指南的目的是評估治療中樞神經系統轉移性腫瘤的放射外科技術。
證據收集方法的描述
通過六個與提議的主題相關的臨床問題的闡述，作者試圖展示與放射外科治療中樞神經系統轉移瘤的安全性、副作用和有效性相關的主要證據。研究人群包括所有年齡段的男性和女性患者，不同組織學類型的中樞神經系統轉移瘤，伴有或未伴有合併疾病。為此目的，對原始科學資料庫(Medline – PubMed; Embase – Elsevier; Lilacs – Bireme; Cochrane Library – Record of Controlled Trials)中的文獻進行系統評價。所有作者分析引用的文獻出版日期截止到到2015年4月2日。在Medline搜索中所使用的搜索策略被描述在附錄一中。對檢索到的文獻根進行批評性評估，尋找最好的循證證據。由巴西放射治療學會的三名成員組成專業小組，經討論之後，提出了相關建議。本指南是由一個專業臨床循證指南的獨立團隊進行評價。指南完稿後,曾先發布，在15天內收集相關反饋意見，並由作者進行評估，作修訂和指南最後定稿。
介紹
腦轉移瘤是成年人中最常見的顱內腫瘤之一。據估計，6 - 30%被診斷患有惡性系統性疾病的患者會在其自然病程進展的某個時刻出現腦轉移瘤。1-3
近年來，腦轉移瘤的發病率一直呈上升趨勢。主要原因在於顱腦磁共振成像(MRI)在臨床實踐中的應用，能在中樞神經系統腫瘤病變早期就較好地準確發現。此外，對顱外疾病的控制也有了顯著的改善，原因與使用新的系統療法所治療的癌症有關。
在成年人中，與中樞神經系統（CNS）轉移瘤最相關的原發性腫瘤是肺癌、黑色素瘤、腎癌、乳腺癌和結直腸癌。
在發病機制上，中樞神經系統（CNS）轉移瘤最常見的原因是血源性擴散轉移。腦轉移瘤通常位於灰質和白質的交界處，該處血管的直徑變窄，有利於腫瘤細胞成簇聚集;80%的腦轉移瘤出現在大腦半球。
臨床表現因中樞神經系統轉移瘤的數目、體積和位置而各異。所描述的主要癥狀是頭痛、噁心、嘔吐、局灶性神經功能障礙和認知功能障礙。10,11
中樞神經系統轉移瘤的局部治療，預後主要取決於患者的臨床狀況和年齡。有一些手段可以幫助腦轉移瘤患者按預後因素及其對中位生存的影響進行分類。這些手段可以促進最為適當的對癌症局部治療的決策。
對於預後不良的患者，治療應集中在控制腦轉移瘤引起的癥狀，以維持神經功能和生活質量。對於預後良好的患者，局部治療應以根除和控制中樞神經系統轉移性病變為目標。在這種情況下，可供選擇的是單獨或聯合手術切除及放射治療(全腦放療或放射外科治療)。
放射外科治療是种放射治療技術，能夠在預設的小型靶體積內聚焦高劑量的輻射。這是種複雜的技術，利用匯聚(共面和非共面射束到)多個治療野覆蓋預定的靶區，並使鄰近的健康組織得到顯著的保護，從而能迅速、無創和安全地進行治療。12
1.放射治療腦轉移瘤產生的副反應會是哪些?
放射外科治療後的副反應發生率一般較低。不太可能出現對患者生活質量產生負面影響的副作用。
Fokas等報道，在接受放射外科治療的患者中，急性副反應3級(頭痛、噁心和嘔吐)的發生率低至3%。同樣，慢性副反應3級(脫髮、頭痛、運動障礙和神經認知功能障礙、視覺和聽覺障礙)的發生率僅為6%。13(B級證據)
Kim等使用《不良反應的通用術語標準》（3.0版）來測量58例接受放射外科治療的中樞神經系統腦轉移瘤患者的副反應發生率。10例出現一定的副反應(5例為1級副反應，1例為2級反應，4例為3級副反應)。觀察到的癥狀包括頭痛、眩暈、偏癱、視力減退或腦壞死。14(B級證據)
Flickinger等表述，在116例評估的患者中，只有4例患者出現了灶周腦水腫，神經癥狀惡化，需要使用類固醇進行支持性治療。在整個隊列中，顱內腫瘤出血僅發生3例(2.5%)。15(B級證據)
Lim等對被1 - 4個非小細胞肺癌腦轉移瘤患者進行隨機3期臨床試驗，這些患者接受放射外科治療後進行化療，或單獨進行化療。放射外科治療耐受性好，兩組間神經認知功能無差異。16
即使腫瘤位於重要功能區域，放射外科治療也是可行的。Luther等觀察到，在接受放射外科治療的位於運動皮層的腦轉移瘤患者中，31%的患者運動功能改善，50%的患者運動功能保持穩定。17(B級證據)另有作者評價放射外科在腦幹轉移瘤患者中的作用。4%的患者出現無癥狀的灶周腦水腫，2.4%的患者在治療部位出現瘤內出血。18，19(B級證據)
建議
放射外科的致殘發生率低，且副作用的發生率也低。"
2.放射外科治療的腦轉移瘤病變的最大數目和最大體積是多少?
為減少放射副反應的風險，建立了單次放射外科治療的經驗性劑量閾值和瘤體積閾值。現有建議將四個以內的病灶和病灶最大直徑4厘米以內，作為主要的放射外科治療適應證中的理想對象,或全腦放療後的劑量補量20-23(A級證據)(表1)。然而，回顧性研究中有甚至多達15處腦轉移瘤病灶的患者接受放射外科治療後出現臨床進展、併發症和有效率與4個以內病灶患者的治療後結果類似。24,25有些文獻作者認為所治療的腦轉移瘤的總體積比腦轉移瘤的絕對數目更為重要，26-28但需要對這個說法進一步地研究。(B級證據)
建議
放射外科治療適用於4個以內病灶，且病灶最大直徑在4厘米以內。
3.與全腦放療相比，放射外科治療有什麼優勢?
放射外科的優勢在於提供了一種更適形的局部治療，其消融的劑量比全腦放療大得多。29-32
因此，放射外科最大限度地減少了全腦放療產生神經認知障礙和導致生活質量下降的有害影響。22,30(A級證據)
另一個關鍵點在於，與全腦放療相比，放射外科提供更高的局部控制率，甚至包括對組織學上具有放射耐受性的腫瘤(例如黑素瘤、腎臟腫瘤和肉瘤等需要更高劑量的電離輻射的腫瘤)。35，36(B級證據)
建議
放射外科治療降低神經認知功能下降的風險，並能積極改善患者的生活質量。
4.放射外科治療對腦轉移瘤患者的治療效果如何?
單獨放射外科治療腦轉移瘤的腫瘤局部控制率從65%-94%不等。15，37，38(B級證據)
放射外科治療後局部控制的主要因素有:腫瘤病變特點和治療劑量。劑量低於14Gy、囊性病灶和壞死病變與複發的可能性更大有關。39，40(B級證據)
放射外科治療的療效並不取決於原發腫瘤的組織學類型，因為放射敏感性腫瘤和放射抵抗性腫瘤的放射外科治療的局部控制率是相似的。41-43(B級證據)
建議
即使是在那些在組織學上具有抗放射性的原發腫瘤的患者，放射外科治療對腦轉移瘤患者的治療也是有效的。
5.對腦轉移瘤患者實施放射外科治療和全腦放射治療兩種治療方式的利弊是什麼?
有一些隨機3期試驗評估放射外科(RS)治療與全腦放射治療(WBRT)或單獨的全腦放射治療WBRT在腦轉移瘤和有限病灶(1到4個腦實質內病變)患者中的應用。20，21
Aoyama等報道WBRT+RS組12個月的CNS複發率為46.8%，單獨RS組的複發率為76.4% (p29
Chang等報道，接受WBRT+RS治療後的患者學習能力下降，平均功能性記憶率分別為52%和24%。雖然WBRT+RS組一年無腦轉移瘤生存率(73%)高於RS組(23%)，但總體生存率沒有差異，RS患者更容易通過新療法而獲救。30
Brown等發表的報告中，接受WBRT+RS，儘管能改善局部控制率(單獨RS和WBRT + RS治療後一年局部控制率分別為50.5%和84.9%)，並沒有總體生存率提高，而與認知能力出現下降卻呈負相關,尤其是WBRT + RS組對記憶、語言流暢和即時記憶存在負面影響(p 44(A級證據)
在包括對隨機臨床試驗的個人數據進行薈萃分析的系統評價中,作者指出,年齡小於50歲、1-4個腦轉移瘤病灶和良好的機能評分的患者，利用單獨RS治療，能提高總體存活率，而在先前未行WBRT不會引起CNS的更多疾病表現。45(A級證據)
此外，儘管RS局部控制率較低，且需挽救性治療率較高，但衛生經濟分析表明，RS成本效益比WBRT+RS要好。46(B級證據)
建議
對接受放射外科治療的患者聯合全腦放療，雖然對提高總體生存率沒有作用，但可以很大程度改善顱內局部控制。全腦放療可能和減低認知、語言功能和記憶能力退化有關。
6.手術切除腦轉移瘤後，術後瘤床輔助放射外科治療是否有作用?
在術後輔助方案中，標準的治療方案之一是進行全腦放射治療。47-48
然而，為了避免全腦放療的不利影響，一些作者提倡對手術後瘤床使用輔助放射外科治療。
評估使用18 Gy中等劑量的放射外科治療2期臨床研究中患者機能狀態評分≥70和所切除腦轉移瘤≤2。在治療後12個月時，局灶和區域的複發率分別為22%和44%。對於病灶小於3cm及深部病灶有更好的療效。49(B級證據)其他幾項研究顯示，對同樣的患者治療後，隨訪1年和2年，局部控制率分別為75 - 90%和60 - 80%。這些結果與術後接受全腦放射治療的患者的局部控制率相似。50-54(B級證據)
此外，與完全切除腦轉移瘤後單純觀察相比，術後放射外科治療改善了局部控制。隨機3期試驗的數據顯示，接受放射外科治療的患者的局部控制率在統計學上顯著較高(治療後6個月和12個月的放射外科治療組和觀察組的局部控制率分別為83%、57%；和72%、45%)。55(A級證據)
最近，在ASCO和ASTRO上報告了兩項重要的研究。Kayama等進行了一項非劣效性3期試驗(JCOG0504)，以評估放射外科治療術後殘留複發腦轉移瘤的有效性。患者隨機接受放射外科手術或全腦放射治療。兩組患者的總體生存率相似。56(A級證據)
同樣，Brown等隨機選擇1 - 4個腦轉移瘤患者進行全腦放療或手術切除後放科治療。全腦放療組認知能力下降比例較高。兩組患者的總體生存率沒有差異，放射外科治療組的生活質量較好。57(A級證據)
建議
術後可採用輔助放射外科治療替代全腦放療。
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(Central Nervous System [Mesh] OR Central Nervous Systems OR Nervous System, Central OR Nervous Systems, Central OR System, Central Nervous OR Systems, Central Nervous) AND (Neoplasm Metastasis [Mesh] OR Metastases, Neoplasm OR Neoplasm Metastases OR Metastasis OR Metastases OR Metastasis, Neoplasm) AND (Radiosurgery [Mesh] OR Radiosurgeries OR Radiosurgery, Stereotactic OR Radiosurgeries, Stereotactic OR Stereotactic Radiosurgeries OR Stereotactic Radiosurgery OR Gamma Knife Radiosurgery OR Gamma Knife Radiosurgeries OR Radiosurgeries, Gamma Knife OR Radiosurgery, Gamma Knife OR Stereotactic Body Radiotherapy OR Body Radiotherapies, Stereotactic OR Body Radiotherapy, Stereotactic OR Radiotherapies, Stereotactic Body OR Radiotherapy, Stereotactic Body OR Stereotactic Body Radiotherapies OR CyberKnife Radiosurgery OR CyberKnife Radiosurgeries OR Radiosurgeries, CyberKnife OR Radiosurgery, CyberKnife OR Radiosurgery, Linear Accelerator OR Linear Accelerator Radiosurgeries OR Radiosurgeries, Linear Accelerator OR Linear Accelerator Radiosurgery OR Radiosurgery, Linac OR Radiosurgeries, Linac OR LINAC Radiosurgery OR Radiosurgeries, LINAC)
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