刘加军：原发中枢神经系统淋巴瘤治疗进展（上）_京智康,家庭健康智能终端,大健康,我淘健康

原发中枢神经系统淋巴瘤（PCNSL）是指起源于中枢神经系统且具有侵袭性的结外非霍奇金淋巴瘤，病灶原发且仅限于中枢神经系统（大脑、脑膜、眼及其附属器和脊髓）^[1]。该病发病率低，仅占颅内肿瘤的4%，占所有结外淋巴瘤的4%-6%，预后差，复发率高，近一半的患者2年内复发^[2,3]。PCNSL发病的主要危险因素之一是免疫缺陷，自2000年以来，PCNSL的发病率一直在以每年增加1.6％的速度增长，特别是在免疫功能正常的患者和老年人（＞60岁）中^[4]。因为血脑屏障的存在，标准淋巴瘤化疗对PCNSL的作用有限，大剂量甲氨蝶呤（HD-MTX）加或不加全脑放射治疗（WBRT）是最有效的治疗方法。尽管PCNSL对初始治疗的缓解率很高，但总体预后仍然很差。随着对PCNSL病理生理的不断深入研究，已经发现B细胞受体通路（BCR）、Toll样受体通路（TLR）、免疫逃避机制、肿瘤免疫微环境受抑制是PCNSL发病中的关键机制。PCNSL的治疗逐渐有了新的方向，靶向治疗和免疫治疗及与之相关的联合用药成为研究热点。本文从外科手术治疗、放疗、化疗、造血干细胞移植、靶向治疗及免疫治疗六个方面系统地回顾了PCNSL的治疗，并总结新型药物现有的临床证据，供广大读者参考。

外科手术治疗

PCNSL治疗的目标是消除病灶获得持久的完全缓解（CR），主要依靠化疗和放疗，手术在PCNSL中的作用仅限于获得肿瘤标本完成病理学诊断，且由于PCNSL的病灶多累及大脑深部且多发，因此手术的治疗作用十分有限。立体定向脑活检的应用更是让手术切除治疗的地位进一步下降。之前的研究提示^[5]，积极的手术治疗可能会增加术后神经系统功能缺损的风险，且无生存获益。但在最近的一项大型随机III期研究中发现，积极切除PCNSL可以改善无进展生存期（PFS）^[6]。另外也有研究证实PCNSL手术切除与活检相比具有生存优势^[7-9]。因此，有学者建议对于有显著占位效应且界限清楚的病灶，可采取积极的手术减瘤措施。另外，神经外科技术的进步也成为手术治疗在PCNSL中地位上升的原因之一。

放疗

PCNSL不同于其他颅内肿瘤，对放疗有较高的缓解率，但是单独放疗不能充分控制疾病，并且其延迟的神经毒性也会引起神经认知障碍，影响患者生活质量甚至生存期^[10,11]。一般认为WBRT局限于以下三点：（1）淋巴瘤的局部控制不足；（2）淋巴瘤细胞在脑脊液循环内、放射野外的播散；（3）放射疗法对脑功能的损害。在之前的研究中，使用WBRT（36-40Gy）作为PCNSL的唯一治疗方法产生了90%的总缓解率（ORR），但中位总生存期（OS）仅为11.6月，60%以上的患者淋巴瘤进展^[12]。随着时间推移，WBRT的长期神经毒性也逐渐显现，例如失禁、步态异常和记忆障碍。已有研究证实，60岁以上的患者最容易出现WBRT相关并发症。虽然，低剂量WBRT的神经毒性不明显，但辐射引起的神经毒性可能是一个连续变量^[13]，因此在过去的十年，WBRT不再被推崇为诱导治疗或首次CR患者的巩固治疗措施，但可以作为甲氨蝶呤耐药的一线抢救疗法^[12]。

化疗

PCNSL患者的生存率不如其他结外淋巴瘤，除了神经系统内淋巴瘤的独特生物学特征之外，血脑屏障（BBB）对化疗药物的阻隔也发挥了不小的作用。BBB是由周细胞、星形胶质细胞和内皮细胞紧密连接形成动态而又复杂的结构，调节大脑间质环境的生化成分并保护大脑免受有毒分子（包括外源性物质）的侵害。由于其物理化学特性，血脑屏障对许多水溶性化合物是相对不可渗透的,大多数进入大脑的细胞毒性药物通过被动扩散穿过BBB。除了药代动力学性质之外，影响这些化合物透过BBB的主要因素包括脂溶性、分子量、电荷和与血浆蛋白结合的能力。因此，这限制了某些化学治疗剂（如CHOP方案：环磷酰胺、多柔比星、长春新碱和强的松）、抗体和细胞疗法的递送以及癌细胞暴露。在20世纪70年代，HD-MTX单药治疗被认为可有效治疗PCNSL，ORR为35%-74%，中位PFS为10-12.8个月，中位OS为25–55个月^[14-16]，目前认为脑微环境中的大细胞淋巴瘤对HD-MTX为基础的治疗比同组织学的系统性淋巴瘤具有大约两倍的敏感性^[17]。因此HD-MTX成为了PCNSL绝大多数诱导方案的支柱。

甲氨蝶呤的最佳剂量尚未确定。Skarin等人的研究表明在脑实质中，MTX剂量≥1g/m²可达到杀瘤作用^[18]。大多数研究采用的剂量在3-8g/m²之间，美国国立综合癌症网络（NCCN）指南推荐MTX给药剂量为3.5g/m²或更高^[19]，但应同时注意MTX对肾功能的影响。之前的一项大型回顾性研究^[20]提示，MTX≥3g/m²可提高PCNSL患者的生存率。Batchelor T等^[14]的研究表明接受MTX剂量为8g/m²的患者CR率和ORR分别为52%和74%，中位PFS和中位OS分别为12.8个月和22.8个月，并且毒性中等。近期的一项对于73例新诊断PCNSL患者的回顾性研究^[21]比较了接受HD-MTX 8g/m²与3.5g/m²剂量患者的缓解情况，CR率分别为68.29%和43.75%（p=0.03），中位PFS分别为17.7个月和9.05个月（p=0.03），两组之间的OS没有显著差异，严重的不良反应较为少见。增加剂量的MTX对良好的体能状态和初诊时低风险预后分层的患者具有有利结果^[22]。

关于给药方式，glantz等研究表明，静脉注射甲氨蝶呤（8g/m²，4小时）在血清和脑脊液中产生的细胞毒性水平高于鞘内注射甲氨蝶呤（12mg）。纪念斯隆-凯特琳癌症中心对PCNSL结果的回顾性分析也表明^[23]，是否鞘内注射并不影响接受3.5g/m² HD-MTX治疗患者的疗效，因此不需要静脉注射联合鞘内注射甲氨蝶呤。

之前的研究显示，使用MTX单药化疗的缓解率为52%–88%，联合使用MTX和其他化疗药物的多药化疗的缓解率为70%–94%^[24]。联合用药包括替莫唑胺、利妥昔单抗、丙卡巴肼、阿糖胞苷、噻替派、长春新碱、卡莫司汀、依托泊苷、异环磷酰胺和环磷酰胺等。一项多中心Ⅱ期临床试验显示，将阿糖胞苷加入HD-MTX作为诱导治疗可提高CR率（46% vs 18%）、3年PFS率（38% vs 21%）和3年OS率（46% vs 32%）^[25]。另一项Ⅱ期临床试验显示，在HD-MTX+阿糖胞苷中加入噻替派和利妥昔单抗可提高CR率（49% vs 23%）、2年PFS率（61% vs 36%）和2年OS率（69% vs 42%）^[26]。替莫唑胺是一种口服烷基化剂，具有良好的安全性，透过BBB能力高，在25%的复发或难治PCNSL患者中该药可有效诱导CR，尤其适用于老年患者。最近的一项关于PCNSL患者接受基于HD-MTX联合治疗的荟萃分析显示^[27]，包含HD-MTX的联合化疗的CR率为41%，三药和四药方案的CR率均优于HD-MTX单药治疗。所有用药组合中，HD-MTX + 丙卡巴肼 + 长春新碱方案联合或不联合利妥昔单抗的CR率分别为63%和58%，利妥昔单抗 + HD-MTX + 替莫唑胺方案CR率为60%。另一项荟萃分析显示^[28]，与单独使用HD-MTX相比，接受HD-MTX+阿糖胞苷治疗的PCNSL患者在PFS、ORR和CR率方面均有获益（HR：0.54；95% CI：0.31-0.92；p=0.01），但在OS方面没有显著的统计学差异（HR：0.65；95% CI：0.38-1.13；p=0.07）。

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刘加军教授

教授、主任医师、博士生导师
中山大学附属第三医院血液内科主任
欧洲肿瘤协会抗癌分会会员
中国免疫协会会员
广东省医疗行业协会常委
广东省血液学会会员等
主研方向：白血病细胞凋亡信号转导机制、造血干细胞移植、血液肿瘤的分子靶向治疗、基因治疗及新型抗肿瘤药物的机制研究等。
医疗专长：从事内科血液学临床医疗工作20多年。多年来从事白血病细胞凋亡信号转导机制及血液肿瘤的分子靶向治疗研究。对各种贫血、出血性疾病及血液肿瘤有熟练的诊治能力。诊疗疾病包括血液病造血干细胞移植、白血病化疗、恶性淋巴瘤和多发性骨髓瘤等恶性血液疾病的个体化治疗方案选择、各种原因不明的贫血、不明原因的长期发热以及淋巴结肿大的鉴别诊断和治疗等。

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刘加军：原发中枢神经系统淋巴瘤治疗进展（上）

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