胃肠道淋巴瘤放疗进展

李晔雄



胃肠道淋巴瘤放疗进展

李晔雄

李晔雄 教授、主任医师、博士生导师。现任中国医学科学院肿瘤医院放疗科主任。中华医学会放射肿瘤治疗学分会第七届主任委员、中华医学会肿瘤学分会委员、北京医学会肿瘤学分会副主任委员、临床肿瘤研究协会（CSCO）常务委员、国际淋巴瘤放射肿瘤研究组（ILROG）专家指导委员、国际结外淋巴瘤研究组（IELSG）委员，《中华放射肿瘤学杂志》主编。获新世纪百千万人才工程国家级人选，卫计委突出贡献中青年专家，和政府特殊津贴。2014年荣膺代表我国医药卫生领域最具权威性的非政府奖项：吴阶平-保罗•杨森医学药学奖。目前承担“863”、国家自然科学基金和卫生部临床学科重点项目等多项国家和省部级研究课题，发表论文200余篇，系列研究发表于“J Clin Oncol”、“Blood”、“Leukemia”等著名的国际学术期刊和国内核心期刊上，SCI论文累积影响因子200余分。

【摘要】原发胃肠道淋巴瘤是最常见的结外非霍奇金淋巴瘤。胃肠道淋巴瘤为异质性的肿瘤，弥漫大B细胞淋巴瘤和粘膜相关淋巴瘤是最常见的病理类型，放疗在不同部位和病理类型的淋巴瘤治疗中地位不同。原发胃淋巴瘤接受保留胃功能的治疗可取得良好预后，弥漫大B细胞淋巴瘤化疗后（包括完全缓解）接受放疗可提高局控率和生存率，美罗华时代大肿块患者仍需要接受放疗以提高局部控制率。早期胃MALT淋巴瘤抗HP失败后，接受单纯放疗即可取得良好的预后。原发肠道侵袭性淋巴瘤的治愈手段仍为外科治疗，惰性淋巴瘤亦可选择放疗。

【关键词】胃肠道； 淋巴瘤，非霍奇金； 弥漫大B细胞淋巴瘤； 粘膜相关淋巴瘤

作者单位：100021 北京，中国医学科学院 北京协和医学院肿瘤医院放疗科

原发胃肠道的非霍奇金淋巴瘤（non-Hodgkin′s lymphoma，NHL）是最常见的结外NHL，占所有NHL的10%～15%。最常见的发病部位是胃（43%～75%），其次为小肠（9%～37%）、结肠（7%～21%）、直肠（2%～12%）［1］。弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）是最常见的病理类型（45%～66%），其次为结外边缘带粘膜相关淋巴瘤（extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue，MALT）（30%～48%），其他类型如套细胞淋巴瘤、滤泡淋巴瘤、Burkitt淋巴瘤及T细胞淋巴瘤则相当罕见。胃肠道原发NHL中位发病年龄为61～65岁左右，男女比例为1.1：1～1.7：1，临床I～II期占80%～90%［2-3］。

胃肠道淋巴瘤为一组异质性的肿瘤，不同部位和病理类型的淋巴瘤治疗原则不同。原发胃淋巴瘤的治愈手段已经从手术转变为保留胃功能的治疗，原发肠道淋巴瘤的治愈手段仍为外科治疗。

一、胃淋巴瘤

（一）胃弥漫大B细胞淋巴瘤

胃弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）治疗经验主要来自于对总体DLBCL的研究，早期患者应接受化放疗结合的综合治疗模式，晚期患者主要治疗手段为化疗，大肿块患者应接受放疗。

1.放疗在美罗华时代前后的角色

目前，已有多个研究证实化疗后放疗可提高NHL患者局部控制率（local control，LC）。Dorth等［4］报道化疗（65%接受RCHOP方案）后完全缓解（complete remission，CR）患者（73% 为PET-CT证实）放疗和不放疗的5年LC分别为92%和69%（P=0.03）。芝加哥大学的研究［5］同样显示即使R-CHOP化疗后，放疗仍然显著提高了CR患者（86%为PET证实）的局控率，5年LC分别为92%和49%（P＜0.0001）。

在美罗华时代之前，有4个随机分组研究比较了早期侵袭性NHL患者化疗后放疗和未放疗生存结果（表1）［6-9］。多数研究证实，CHOP方案化疗后放疗可提高生存［6，8］，但老年无不良预后因素的患者可能不需要巩固放疗［9］，SWOG 8736显示，3周期CHOP化疗＋放疗对比8周期CHOP化疗提高了早期患者5年无进展生存（progression-free survival，PFS）和总生存（overall survival，OS）［6］。但随着随访时间延长，二组患者生存无差别，该研究中出现晚期复发的情况提示3周期CHOP化疗可能不够，患者可能需要更强化疗［10］。在此基础上，ECOG 1484进一步探究了8周期CHOP 后CR患者是否需要巩固放疗，结果显示巩固放疗可提高无病生存（disease-free survival，DFS），说明即使足量化疗达到CR，放疗仍占有重要地位［8］。但GELA LNH 93-4研究显示，老年患者4周期CHOP可能已经足够，化疗CR后放疗未提高患者生存［9］。而GELA LNH 93-1研究显示，对于年轻早期患者（≤60岁），更强的ACVBP化疗方案优于3周期CHOP＋放疗，提示进一步提高化疗强度可能使部分患者获益［7］。然而，在美罗华时代，这些结果还需进一步更新与诠释。

在美罗华时代，多个回顾性单中心研究［4-5，11-13］和大数据库分析［14-16］，在多因素分析控制混杂因素后，RCHOP方案化疗后放疗的加入仍然可使DLBCL患者生存获益（表1）。几个瞻性研究亚组分析［17-19］和随机对照研究［20-21］亦显示放疗的加入提高了患者生存。然而，在更强的RCHOP方案化疗基础上，放疗未必使所有患者获益，如何选择美罗华时代放疗获益的亚组患者成为研究热点。UNFOLDER研究及RICOVER-60显示，放疗可提高大肿块（≥7.5 cm）或结外受累患者生存，故即使接受足量RCHOP化疗，有大肿块或结外受累患者仍需接受放疗［17，21］。

III～IV期DLBCL患者治疗以化疗为主，但有证据显示若化疗取得CR，对化疗前受累部位进行巩固放疗可提高局控率或总生存（表1）［4-5］，但结论目前尚不肯定，需要进一步研究证实。

2.放疗在胃DLBCL中地位

针对胃DLBCL的多个前瞻性观察研究［22-25］和回顾性分析［26-31］显示，化疗＋放疗的综合治疗可取得良好的局控率、生存和生活质量。

表1 侵袭性NHL放疗与不放疗比较性文献总结表

日本和韩国分别开展的Ⅱ期多中心临床研究显示，早期患者3～4周期CHOP化疗＋40 Gy受累野放疗后，CR率均为92%，2年DFS和OS分别为88%～92%和92%～94%，且无出血、穿孔等严重并发症发生［23-24］。德国的前瞻性观察性研究中，393例早期患者中包括237例DLBCL，6周期CHOP方案化疗±40 Gy受累野放疗，5年PFS 和5年OS分别为84.5%和87.0%［32］。以上几个研究的结果为保留胃功能的化放疗代替手术提供了证据。ELSG 4研究是迄今唯一针对早期胃DLBCL化疗后是否需要巩固放疗的随机对照研究，结果显示早期患者4～6周期CHOP化疗CR后，放疗可显著提高DFS，降低局部复发，但未提高2年OS［25］。因此，在美罗华时代，早期胃DLBCL化疗后巩固放疗可取得良好的疗效［26，28-31］，但仅有回顾性研究显示巩固放疗相比单纯RCHOP化疗可提高患者局控率［31］（表2），巩固放疗否能进一步提高生存还有待证实。

（二）胃结外边缘带粘膜相关淋巴瘤

早期胃MALT患者活检标本中抗幽门螺杆菌（HP）阳性率为90%［33］，患者接受HP清除治疗后完全缓解（CR）率达77.5%，5年OS为90%，然而II期、HP阴性、API2-MALT1突变者患者抗HP治疗的CR率仅为20%～50%［34-35］，因此目前I期、HP阳性患者首选抗HP治疗。

MALT淋巴瘤对放射治疗敏感，单纯放疗的CR率即可达到90%～100%，5年OS可达到83%～95%，无事件生存或无治疗失败生存在80%～100%［22，39-50］（表3）。SEER数据库（n=1134）资料显示，I期患者接受放疗的5年淋巴瘤相关死亡率明显低于化疗（5.3% vs 19.1%，P＜0.001）［51］。目前，多个共识或指南均指出：II期、t（11；18）（q21；q21）基因突变、HP阴性、抗HP后肿瘤残存或进展患者的标准治疗为放射治疗［36-38］。

二、肠道淋巴瘤

表2 美罗华时代胃淋巴瘤放疗相关研究表

肠道NHL预后显著差于胃淋巴瘤（50% vs 85%，P=0.0001）［52］，回盲部NHL预后显著优于小肠或大肠NHL［52-53］。早期侵袭性肠道淋巴瘤患者应接受根治性手术＋化疗。多个研究均显示，接受根治性手术可显著提高患者生存［53-55］。一项韩国的研究（n=345）显示，小肠DLBCL接受手术＋化疗（CHOP 或RCHOP）生存显著优于单纯化疗，3年OS分别为91%和62%（P＜0.001）；但美罗华加入后，手术作为初始治疗未提高生存。另外，多因素分析显示手术＋化疗是唯一独立预后因素。手术＋化疗的生活质量低于单纯化疗，但差异可接受［54］。肠道MALT预后显著高于其他病理类型［53］，可行放疗或手术，但因病例数较少，目前尚无二者比较性研究。

三、放疗靶区、剂量和技术

近年来，淋巴瘤放疗靶区已从过去的受累野放疗（involved-field radiotherapy，IFRT）发展为受累淋巴结（involved-node radiotherapy，INRT）或受累区域放疗（involved-site radiotherapy，ISRT）［56-57］。在更强的化疗基础上，照射体积的减少并未降低疾病控制率［58］。英国的随机分组研究显示：对于侵袭性NHL 30 Gy巩固放疗疗效不劣于40～45 Gy；对于惰性淋巴瘤24 Gy巩固放疗疗效不劣于40～45 Gy［59］。另外，现代放疗技术在提高靶区覆盖度同时减少了正常组织受量。胃淋巴瘤剂量学研究显示调强放疗（intensity modulated radiotherapy，IMRT）可降低肝脏或肾脏剂量［60-61］。降低放疗靶区体积、剂量和应用现代适形放疗技术均有助于减少毒副反应和提高患者生活质量。最近的一项回顾性分析显示，胃DLBCL患者化疗后接受IMRT可取得良好的局控、生存，毒副反应少，长期生活质量好［62］。

表3 胃MALT淋巴瘤放射治疗研究表

综上，胃肠道淋巴瘤为异质性的肿瘤，放疗在不同部位和病理类型的淋巴瘤治疗中地位不同。原发胃淋巴瘤接受保留胃功能的治疗可取得良好预后，DLBCL化疗后（包括CR）接受放疗可提高局控率和生存，美罗华时代大肿块患者仍需要接受放疗以提高局部控制率。早期胃MALT淋巴瘤抗HP失败后，接受单纯放疗即可取得良好的预后。原发肠道侵袭性淋巴瘤的治愈手段仍为外科治疗，惰性淋巴瘤亦可选择放疗。

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（本文编辑：刘正）

李晔雄. 胃肠道淋巴瘤放疗进展[J/CD]. 中华结直肠疾病电子杂志, 2016, 5(2): 114-120.

•专家论坛•

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

基金项目：国家863计划（国家高技术研究发展计划）子课题（863-306-ZD13-03-2）；卫生部/吴阶平医学基金会（WKJ2005-3-006）；国家自然科学基金重点项目（10335050）；卫生部临床学科重点项目（07090010）；国家863课题（2006AA02Z345）

通信作者：李晔雄，Email：yexiong12@163.com

收稿日期：（2016-2-10）