贝伐单抗维持治疗脑转移瘤疗效与安全性分析
2017-02-28石大友廖立潇熊超
石大友+廖立潇+熊超
摘要:目的 评估贝伐单抗治疗全脑放疗后复发或进展脑转移瘤的临床疗效。方法 回顾分析放疗后进展或复发脑转移瘤患者21例,共计28处病灶。患者有原发肿瘤病史且均取得病理,病灶均同时满足以下各项影像学证据:CT或MRI增强病灶表现为灶内强化且伴有明显水肿影;所有患者均给予贝伐单抗5 mg/kg,每14 d重复1次,治疗4~8个周期。每4周期治疗后第5周期治疗前均行MRI检查,比较治疗前后T1WI相增强病灶大小变化及T1WI相病灶水肿变化。记录患者治疗前、后临床症状、kps评分改变情况,治疗前、后病灶大小、水肿变化以及KPS评分行t检验。结果 21例患者均安全完成治疗,未见明显严重不良反应。自第1周期治疗结束患者临床症状明显改善,4周期后kps评分平均提高13.8分。MRI T1WI增强相可见强化区域病灶较治疗前平均缩小54.8%,(P=0.001),MRI T2WI相可见水肿区域较治疗前平均缩小80.7%(P=0.004)。结论 初步证实贝伐单抗能控制脑转移瘤,明显减轻颅内水肿,并改善脑转移瘤的临床症状。
关键词:贝伐单抗;脑转移瘤;颅脑水肿;全脑放疗
Abstract:Objective To evaluate the clinical effect of bevacizumab for recurrence or progression brain metastases after whole brain radiotherapy .Methods Retrospective analysis of 20 cases of recurrence or progession brain metastases after radiotherapy, a total of 28 lesions. Patients had primary tumor history and pathology were obtained, the lesions were also satisfy the following the image evidence: CT or MRI enhanced lesions showed foci in the strengthening and accompanied by edema; All patients were given bevacizumab 5mg / kg, every 14 days repeated 1 time for 8 cycles. After the forth cycles of treatment, MRI was examined before and after treatment, and the changes of T1WI phase and edema of T1WI phase were compared before and after treatment. The clinical symptoms, KPS score , the size of the lesion, edema were record respectively before and after treatment. Comarision before and afer treatment was perofomed by paried t test. Results All the 20 patients receive treatment successfully, and no serious adverse reactions were found. The clinical symptoms of the patients were significantly improved after first cycles of treatment, and the KPS score increased by 13.8 points on average after 4 cycles. The regional lesions of T1WI MRI enhanced phase were smaller average 54.8% than before treatment, (P= 0.001), T2WI MRI edema region were smaller average 80.7% compared with the before treatment (P= 0.004).Conclusion Bevacizumab is preliminary confirmed to control the brain metastatic tumor, alleviate cerebral edema, and improve clinical symptoms of brain metastases.
Key words:Bevacizumab; Brain metastases; Encephaledema;Whole brain radiotherapy
恶性肿瘤脑转移是肿瘤常见的并发症,约20%~40%的癌症患者发生脑转移,尤其是好发生于肺癌和乳腺癌患者[1]。发生脑转移患者预后极差,自然生存时间1~3个月,全脑放疗(whole brain therapy,WBT)中位生存时间延长至3~6个月。故50年来全脑放疗一直是脑转移癌的标准治疗手段。但是全脑放疗有效率60%~80%,多数肿瘤短暂缓解后再次进展,中位生存期4~6个月,1年生存率14%~20%[2-3]。且再次复发后患者生活质量受到严重影响,治疗手段有限,常规再次放疗易造成正常神经组织坏死,预后极差。VEGF是目前发现的最重要的促进肿瘤血管生成的因子。在肿瘤的生长、复发、转移以及改变血脑屏障的通透性有重要的作用[4-6]。文献报道,晚期肿瘤患者外周血VEGF水平明显高于早期肺癌,VEGF可刺激肿瘤组织中微血管的生成,从而促进血管通透性增加肿瘤的进展与转移。肿瘤患者中高浓度的VEGF往往有更差的预后[7]。贝伐单抗是VEGF的单克隆抗体,可阻断VEGF的生物学的作用,并可透过血脑屏障,從而控制肿瘤,同时减轻颅内水肿作用改善患者脑转移症状,延长生存时间[8-12]。本研究试从分析贝伐珠单抗治疗放疗后脑转移瘤进展或者复发患者疗效。
1 资料与方法
1.1一般资料 2012年1月~2016年6月经过全脑放疗后脑转移瘤再次进展患者21例,其中肺癌脑转移6 例、胃癌脑转移5例、脑胶质瘤4例、乳腺癌脑转移3例、结肠癌脑转移2例、卵巢癌脑转移1例。男12例、女9 例,年龄45~71岁(平均55.3岁)。临床表现为颅内高压、肌力减退、共济失调以及认知功能障碍。脑转移病灶有全脑放疗治疗史。接受放疗平均生物剂量(40.4±5)Gy。
1.2诊断依据 所有脑转移瘤患者原发病灶有病理支持。同时所有的脑转移病灶符合以下影像学表现:CT或者MRI T1增强相表现为强化灶明确且水肿影明显。从接受放疗到脑转移再次出现进展平均时间为6~22个月,平均时间9.2个月。
1.3方法 针对脑转移瘤患者接受贝伐单抗5 mg/kg,每2周期重复1次,每2周期后第3周期治疗前行MRI评价疗效。症状严重者辅助予以甘露醇以及地塞米松控制水肿。
1.4观察指标 每周期治疗前记录患者临床症状及KPS评分,每2周期后第3周期前行MRI检查,比较治疗前后T1WI增强相病灶体积及水肿体积(水肿区体积-病灶区体积)把患者头颅磁共振 T1WI增强相序列和 T2WI相序列分别通过网络传输至TPS,分别勾画每层增强病灶区或水肿区,通过UNICORN-3D 软件计算体积。
1.5统计方法 采用 SPSS 16.0 软件对治疗前后肿瘤体积大小变化和水肿区体积变化行配对t检验,P<0.05为差异有统计学意义。
2 结果
2.1脑转移瘤病灶MRI T1WI增强相变化 所有患者均完成至少4个周期贝伐朱单抗维持治疗。第5周期前(即贝伐珠单抗使用第9 w)行头颅MRI评价。20例患者的头颅病灶及水肿均有不同程度的减小,治疗之前头颅病灶体积(9.6±3.2)cm3,治疗4周期后体积为(4.9±1.8)cm3。治疗前后体积行t检验有统计学差异(P=0.001)。肿瘤病灶周边水肿MRI T2WI变化:贝伐珠单抗治疗第3周期前(即贝伐珠单抗使用第9 w)行头颅MRI评价。20例患者的头颅病灶周边水肿均有不同程度的减小,治疗之前头颅病灶体积(21.6±9.2)cm3,治疗后体积为(12.8±4.2)cm3。治疗前后体积行t检验有统计学差异。(p=0.004)。治疗前患者KPS评分(65±7.2), 4周期治疗后第5周期治疗前KPS评分(78±4.9)(P=0.002)。
2.2经过2个周期贝伐珠单抗治疗后患者临床症状(头晕,恶心、共济失调)较前均有不同程度的明显改善。
2.3不良反应 20例患者行贝伐珠单抗治疗中均未出现脑出血。其中有1例出现2级高血压,经予以贝那普利对症治疗后控制症状。1例出现鼻出血,出血量约5 ml。
3 讨论
贝伐珠单抗是一种单克隆抗体,主要抑制血管内皮生长因子,主要用于转移性癌症[8]。在1997年,1例29岁女性肝癌脑转移患者在接受贝伐珠单抗I期临床实验过程中出现致命性的脑出血,之后贝伐珠单抗一直被排除应用在脑转移瘤患者[13]。但FDA并无此禁忌,部分患者为脑转移癌进展期,是否可用贝伐珠单抗值得探讨。II期PASSPORT研究显示入组脑转移治疗无进展或出血的非鳞癌患者,二线治疗给予贝伐珠单抗联合化疗或厄洛替尼,可评价的106例患者中,未见到2度以上脑出血。结果显示贝伐珠单抗治疗脑转移瘤是安全可行的[14]。之后研究发现在肺癌脑转移患者中,接受贝伐珠单抗治疗与否患者脑出血的发生几率无明显差异[15]。Levy采用全脑放疗联合贝伐珠单抗治疗脑转移瘤发现贝伐珠单抗的加入并没有增加脑转移瘤出血的风险[16]。Ranpura和中國学者在发现荟萃分析中发现贝伐珠单抗可增加心肌缺血的发作,但较对照组中并未增加脑出血发生[17-18]。贝伐单抗是一种重组人源化抗VEGF单克隆抗体,可抑制内皮细胞增殖和新生血管形成,使异常的血管内皮正常。从而阻止肿瘤血管生成和肿瘤生长,同时具有减少渗出,减轻颅内高压作用[19-20]。而不良毒副反应较化疗药物明显减轻,现已经广泛应用在结直肠癌、非小细胞肺癌、脑胶质瘤等恶性肿瘤的治疗。血管的生成是肿瘤恶化的特征之一,肿瘤的恶性程度越高,组织中的VEGF的表达也越高,常提示预后不良[21-22]。
本研究采用经过放疗后脑转移瘤进展患者,经过贝伐珠单抗应用后患者颅脑肿瘤较前均有明显减小,且瘤周水肿较治疗前均有明显缓解。患者的生活质量,中位生存时间和1年生存率较目前常规的治疗有明显改善。
综上所述,针对放疗后脑转移瘤复发或者转移患者贝伐珠单抗可以有效控制脑转移瘤的发展,减轻颅内水肿。明显改善脑转移瘤患者脑占位的症状以及生活质量,在治疗过程中并未出现明显的致命脑出血等副反应。因此贝伐珠单抗应用脑转移瘤患者临床疗效较好,毒副反应较轻。可能是一种较为理想且有效的治疗手段。
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