李曄雄

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胃腸道淋巴瘤放療進展

李曄雄

李曄雄 教授、主任醫(yī)師、博士生導(dǎo)師?，F(xiàn)任中國醫(yī)學(xué)科學(xué)院腫瘤醫(yī)院放療科主任。中華醫(yī)學(xué)會放射腫瘤治療學(xué)分會第七屆主任委員、中華醫(yī)學(xué)會腫瘤學(xué)分會委員、北京醫(yī)學(xué)會腫瘤學(xué)分會副主任委員、臨床腫瘤研究協(xié)會（CSCO）常務(wù)委員、國際淋巴瘤放射腫瘤研究組（ILROG）專家指導(dǎo)委員、國際結(jié)外淋巴瘤研究組（IELSG）委員，《中華放射腫瘤學(xué)雜志》主編。獲新世紀(jì)百千萬人才工程國家級人選，衛(wèi)計委突出貢獻中青年專家，和政府特殊津貼。2014年榮膺代表我國醫(yī)藥衛(wèi)生領(lǐng)域最具權(quán)威性的非政府獎項：吳階平-保羅?楊森醫(yī)學(xué)藥學(xué)獎。目前承擔(dān)“863”、國家自然科學(xué)基金和衛(wèi)生部臨床學(xué)科重點項目等多項國家和省部級研究課題，發(fā)表論文200余篇，系列研究發(fā)表于“J Clin Oncol”、“Blood”、“Leukemia”等著名的國際學(xué)術(shù)期刊和國內(nèi)核心期刊上，SCI論文累積影響因子200余分。

【摘要】原發(fā)胃腸道淋巴瘤是最常見的結(jié)外非霍奇金淋巴瘤。胃腸道淋巴瘤為異質(zhì)性的腫瘤，彌漫大B細胞淋巴瘤和粘膜相關(guān)淋巴瘤是最常見的病理類型，放療在不同部位和病理類型的淋巴瘤治療中地位不同。原發(fā)胃淋巴瘤接受保留胃功能的治療可取得良好預(yù)后，彌漫大B細胞淋巴瘤化療后（包括完全緩解）接受放療可提高局控率和生存率，美羅華時代大腫塊患者仍需要接受放療以提高局部控制率。早期胃MALT淋巴瘤抗HP失敗后，接受單純放療即可取得良好的預(yù)后。原發(fā)腸道侵襲性淋巴瘤的治愈手段仍為外科治療，惰性淋巴瘤亦可選擇放療。

【關(guān)鍵詞】胃腸道； 淋巴瘤，非霍奇金； 彌漫大B細胞淋巴瘤； 粘膜相關(guān)淋巴瘤

作者單位：100021 北京，中國醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院腫瘤醫(yī)院放療科

原發(fā)胃腸道的非霍奇金淋巴瘤（non-Hodgkin′s lymphoma，NHL）是最常見的結(jié)外NHL，占所有NHL的10%～15%。最常見的發(fā)病部位是胃（43%～75%），其次為小腸（9%～37%）、結(jié)腸（7%～21%）、直腸（2%～12%）［1］。彌漫大B細胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）是最常見的病理類型（45%～66%），其次為結(jié)外邊緣帶粘膜相關(guān)淋巴瘤（extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue，MALT）（30%～48%），其他類型如套細胞淋巴瘤、濾泡淋巴瘤、Burkitt淋巴瘤及T細胞淋巴瘤則相當(dāng)罕見。胃腸道原發(fā)NHL中位發(fā)病年齡為61～65歲左右，男女比例為1.1：1～1.7：1，臨床I～II期占80%～90%［2-3］。

胃腸道淋巴瘤為一組異質(zhì)性的腫瘤，不同部位和病理類型的淋巴瘤治療原則不同。原發(fā)胃淋巴瘤的治愈手段已經(jīng)從手術(shù)轉(zhuǎn)變?yōu)楸Ａ粑腹δ艿闹委?，原發(fā)腸道淋巴瘤的治愈手段仍為外科治療。

一、胃淋巴瘤

（一）胃彌漫大B細胞淋巴瘤

胃彌漫大B細胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）治療經(jīng)驗主要來自于對總體DLBCL的研究，早期患者應(yīng)接受化放療結(jié)合的綜合治療模式，晚期患者主要治療手段為化療，大腫塊患者應(yīng)接受放療。

1.放療在美羅華時代前后的角色

目前，已有多個研究證實化療后放療可提高NHL患者局部控制率（local control，LC）。Dorth等［4］報道化療（65%接受RCHOP方案）后完全緩解（complete remission，CR）患者（73% 為PET-CT證實）放療和不放療的5年LC分別為92%和69%（P=0.03）。芝加哥大學(xué)的研究［5］同樣顯示即使R-CHOP化療后，放療仍然顯著提高了CR患者（86%為PET證實）的局控率，5年LC分別為92%和49%（P＜0.0001）。

在美羅華時代之前，有4個隨機分組研究比較了早期侵襲性NHL患者化療后放療和未放療生存結(jié)果（表1）［6-9］。多數(shù)研究證實，CHOP方案化療后放療可提高生存［6，8］，但老年無不良預(yù)后因素的患者可能不需要鞏固放療［9］，SWOG 8736顯示，3周期CHOP化療＋放療對比8周期CHOP化療提高了早期患者5年無進展生存（progression-free survival，PFS）和總生存（overall survival，OS）［6］。但隨著隨訪時間延長，二組患者生存無差別，該研究中出現(xiàn)晚期復(fù)發(fā)的情況提示3周期CHOP化療可能不夠，患者可能需要更強化療［10］。在此基礎(chǔ)上，ECOG 1484進一步探究了8周期CHOP 后CR患者是否需要鞏固放療，結(jié)果顯示鞏固放療可提高無病生存（disease-free survival，DFS），說明即使足量化療達到CR，放療仍占有重要地位［8］。但GELA LNH 93-4研究顯示，老年患者4周期CHOP可能已經(jīng)足夠，化療CR后放療未提高患者生存［9］。而GELA LNH 93-1研究顯示，對于年輕早期患者（≤60歲），更強的ACVBP化療方案優(yōu)于3周期CHOP＋放療，提示進一步提高化療強度可能使部分患者獲益［7］。然而，在美羅華時代，這些結(jié)果還需進一步更新與詮釋。

在美羅華時代，多個回顧性單中心研究［4-5，11-13］和大數(shù)據(jù)庫分析［14-16］，在多因素分析控制混雜因素后，RCHOP方案化療后放療的加入仍然可使DLBCL患者生存獲益（表1）。幾個瞻性研究亞組分析［17-19］和隨機對照研究［20-21］亦顯示放療的加入提高了患者生存。然而，在更強的RCHOP方案化療基礎(chǔ)上，放療未必使所有患者獲益，如何選擇美羅華時代放療獲益的亞組患者成為研究熱點。UNFOLDER研究及RICOVER-60顯示，放療可提高大腫塊（≥7.5 cm）或結(jié)外受累患者生存，故即使接受足量RCHOP化療，有大腫塊或結(jié)外受累患者仍需接受放療［17，21］。

III～IV期DLBCL患者治療以化療為主，但有證據(jù)顯示若化療取得CR，對化療前受累部位進行鞏固放療可提高局控率或總生存（表1）［4-5］，但結(jié)論目前尚不肯定，需要進一步研究證實。

2.放療在胃DLBCL中地位

針對胃DLBCL的多個前瞻性觀察研究［22-25］和回顧性分析［26-31］顯示，化療＋放療的綜合治療可取得良好的局控率、生存和生活質(zhì)量。

表1 侵襲性NHL放療與不放療比較性文獻總結(jié)表

日本和韓國分別開展的Ⅱ期多中心臨床研究顯示，早期患者3～4周期CHOP化療＋40 Gy受累野放療后，CR率均為92%，2年DFS和OS分別為88%～92%和92%～94%，且無出血、穿孔等嚴(yán)重并發(fā)癥發(fā)生［23-24］。德國的前瞻性觀察性研究中，393例早期患者中包括237例DLBCL，6周期CHOP方案化療±40 Gy受累野放療，5年P(guān)FS 和5年OS分別為84.5%和87.0%［32］。以上幾個研究的結(jié)果為保留胃功能的化放療代替手術(shù)提供了證據(jù)。ELSG 4研究是迄今唯一針對早期胃DLBCL化療后是否需要鞏固放療的隨機對照研究，結(jié)果顯示早期患者4～6周期CHOP化療CR后，放療可顯著提高DFS，降低局部復(fù)發(fā)，但未提高2年OS［25］。因此，在美羅華時代，早期胃DLBCL化療后鞏固放療可取得良好的療效［26，28-31］，但僅有回顧性研究顯示鞏固放療相比單純RCHOP化療可提高患者局控率［31］（表2），鞏固放療否能進一步提高生存還有待證實。

（二）胃結(jié)外邊緣帶粘膜相關(guān)淋巴瘤

早期胃MALT患者活檢標(biāo)本中抗幽門螺桿菌（HP）陽性率為90%［33］，患者接受HP清除治療后完全緩解（CR）率達77.5%，5年OS為90%，然而II期、HP陰性、API2-MALT1突變者患者抗HP治療的CR率僅為20%～50%［34-35］，因此目前I期、HP陽性患者首選抗HP治療。

MALT淋巴瘤對放射治療敏感，單純放療的CR率即可達到90%～100%，5年OS可達到83%～95%，無事件生存或無治療失敗生存在80%～100%［22，39-50］（表3）。SEER數(shù)據(jù)庫（n=1134）資料顯示，I期患者接受放療的5年淋巴瘤相關(guān)死亡率明顯低于化療（5.3% vs 19.1%，P＜0.001）［51］。目前，多個共識或指南均指出：II期、t（11；18）（q21；q21）基因突變、HP陰性、抗HP后腫瘤殘存或進展患者的標(biāo)準(zhǔn)治療為放射治療［36-38］。

二、腸道淋巴瘤

表2 美羅華時代胃淋巴瘤放療相關(guān)研究表

腸道NHL預(yù)后顯著差于胃淋巴瘤（50% vs 85%，P=0.0001）［52］，回盲部NHL預(yù)后顯著優(yōu)于小腸或大腸NHL［52-53］。早期侵襲性腸道淋巴瘤患者應(yīng)接受根治性手術(shù)＋化療。多個研究均顯示，接受根治性手術(shù)可顯著提高患者生存［53-55］。一項韓國的研究（n=345）顯示，小腸DLBCL接受手術(shù)＋化療（CHOP 或RCHOP）生存顯著優(yōu)于單純化療，3年OS分別為91%和62%（P＜0.001）；但美羅華加入后，手術(shù)作為初始治療未提高生存。另外，多因素分析顯示手術(shù)＋化療是唯一獨立預(yù)后因素。手術(shù)＋化療的生活質(zhì)量低于單純化療，但差異可接受［54］。腸道MALT預(yù)后顯著高于其他病理類型［53］，可行放療或手術(shù)，但因病例數(shù)較少，目前尚無二者比較性研究。

三、放療靶區(qū)、劑量和技術(shù)

近年來，淋巴瘤放療靶區(qū)已從過去的受累野放療（involved-field radiotherapy，IFRT）發(fā)展為受累淋巴結(jié)（involved-node radiotherapy，INRT）或受累區(qū)域放療（involved-site radiotherapy，ISRT）［56-57］。在更強的化療基礎(chǔ)上，照射體積的減少并未降低疾病控制率［58］。英國的隨機分組研究顯示：對于侵襲性NHL 30 Gy鞏固放療療效不劣于40～45 Gy；對于惰性淋巴瘤24 Gy鞏固放療療效不劣于40～45 Gy［59］。另外，現(xiàn)代放療技術(shù)在提高靶區(qū)覆蓋度同時減少了正常組織受量。胃淋巴瘤劑量學(xué)研究顯示調(diào)強放療（intensity modulated radiotherapy，IMRT）可降低肝臟或腎臟劑量［60-61］。降低放療靶區(qū)體積、劑量和應(yīng)用現(xiàn)代適形放療技術(shù)均有助于減少毒副反應(yīng)和提高患者生活質(zhì)量。最近的一項回顧性分析顯示，胃DLBCL患者化療后接受IMRT可取得良好的局控、生存，毒副反應(yīng)少，長期生活質(zhì)量好［62］。

表3 胃MALT淋巴瘤放射治療研究表

綜上，胃腸道淋巴瘤為異質(zhì)性的腫瘤，放療在不同部位和病理類型的淋巴瘤治療中地位不同。原發(fā)胃淋巴瘤接受保留胃功能的治療可取得良好預(yù)后，DLBCL化療后（包括CR）接受放療可提高局控率和生存，美羅華時代大腫塊患者仍需要接受放療以提高局部控制率。早期胃MALT淋巴瘤抗HP失敗后，接受單純放療即可取得良好的預(yù)后。原發(fā)腸道侵襲性淋巴瘤的治愈手段仍為外科治療，惰性淋巴瘤亦可選擇放療。

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（本文編輯：劉正）

李曄雄. 胃腸道淋巴瘤放療進展[J/CD]. 中華結(jié)直腸疾病電子雜志, 2016, 5(2): 114-120.

?專家論壇?

Recent progress in radiation therapy for primary gastrointestinal lymphoma

Li Yexiong. Department of Radiotherapy, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China Corresponding author: Li Yexiong, Email: yexiong12@163.com

【Abstract】The gastrointestinal tract is the most common extranodal site of non-Hodgkin lymphoma. The gastrointestinal lymphoma represents a heterogeneous disease, where diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are the most common subtypes. The role of radiotherapy varies in the treatment of lymphomas from different sites or with different subtypes. Conservative treatment using chemotherapy and/or radiotherapy produced favorable outcomes in gastric lymphoma. In gastric DLBCL, radiotherapy after chemotherapy improved locoregional control and survival, even for patients who achieved complete response after chemotherapy. In the era of rituximab, radiotherapy also improved locoregional control in patients with bulky disease. In gastric MALT lymphoma,radiotherapy alone could yield excellent outcomes for patients who are unresponsive to H. pylori eradication. However, surgery remains the mainstay of radical treatment for intestinal lymphoma, and radiotherapy is also a choice for indolent subtypes.

【Key words】Gastrointestinal tract; Lymphoma, non-Hodgkin; Diffuse large B cell lymphoma; Mucosa-associated lymphoid tissue

DOI：10.3877/cma.j.issn.2095-3224.2016.02.02

基金項目：國家863計劃（國家高技術(shù)研究發(fā)展計劃）子課題（863-306-ZD13-03-2）；衛(wèi)生部/吳階平醫(yī)學(xué)基金會（WKJ2005-3-006）；國家自然科學(xué)基金重點項目（10335050）；衛(wèi)生部臨床學(xué)科重點項目（07090010）；國家863課題（2006AA02Z345）

通信作者：李曄雄，Email：yexiong12@163.com

收稿日期：（2016-2-10）