现代药物与临床  2016, Vol. 31 Issue (6): 873-877
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贝伐单抗与洛铂腹腔灌注治疗恶性腹腔积液的对比研究
牛楠, 陈威, 杨明丽, 吴荣, 曾越灿     
中国医科大学附属盛京医院 第二肿瘤科, 辽宁 沈阳 110022
摘要目的 比较贝伐珠单抗注射液与注射用洛铂腹腔灌注治疗恶性腹腔积液的疗效和毒副反应。 方法 选取2013年10月-2015年10月在中国医科大学附属盛京医院住院治疗的48例恶性腹腔积液患者,随机分为对照组和治疗组,每组各24例。对照组行腹腔灌注注射用洛铂,30 mg/m2用生理盐水50 mL稀释,1次/周。治疗组行腹腔灌注贝伐珠单抗注射液,5 mg/kg用生理盐水50 mL稀释,1次/周。两组患者均连续灌注2周,最多灌注3次。观察两组的临床疗效,用药前及用药后3 d检测血管内皮生长因子(VEGF)和癌胚抗原(CEA)水平,比较生活质量评分,评价毒副反应。 结果 治疗后,对照组、治疗组总有效率分别为50.0%、79.2%,两组比较差异有统计学意义(P<0.05)。治疗后,两组患者VEGF和CEA水平显著降低,同组治疗前后差异有统计学意义(P<0.05);且治疗组VEGF水平降低更明显,两组比较差异有统计学意义(P<0.05)。治疗后,治疗组患者腹胀评分、厌食评分均低于对照组,两组比较差异具有统计学意义(P<0.05、0.01)。两组患者均无严重的Ⅲ~Ⅳ度不良反应发生。 结论 贝伐珠单抗注射液腹腔灌注治疗恶性腹腔积液疗效优于注射用洛铂,且耐受性良好,具有一定的临床推广应用价值。
关键词贝伐珠单抗注射液     注射用洛铂     腹腔灌注     恶性腹腔积液     VEGF     CEA     生活质量评分     毒副反应    
Comparison on bevacizumab and lobaplatin by intraperitoneal perfusion in treatment of malignant ascites
NIU Nan, CHEN Wei, YANG Ming-li, WU Rong, ZENG Yue-can     
Second Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
Abstract: Objective To compare the efficacy and toxicities of Bevacizumab Injection and Lobaplatin for injection by intraperitoneal perfusion in treatment of malignant ascites. Methods Patients (48 cases) with malignant ascites in Shengjing Hospital of China Medical University from October 2013 to October 2015 were randomly divided into control and treatment group, and each group had 24 cases. Patients in the control group were received intraperitoneal perfusion with Lobaplatin for injection, 30 mg/m2 diluted with normal saline 50 mL, once weekly. Patients in the treatment group were received intraperitoneal perfusion with Bevacizumab Injection, 5 mg/kg diluted with normal saline 50 mL, once weekly. The patients in two groups were treated for 2 weeks, 3 times at most. After treatment, the efficacy was evaluated, and levels of VEGF and CEA in ascites were determined before treatment and treated for 3 d. Scores of life quality in two groups were compared, and adverse reactions between two groups were studied. Results After treatment, the clinical efficacies in the control and treatment groups were 50.0% and 79.2%, respectively, and there was difference between two groups (P < 0.05). After treatment, levels of VEGF and CEA in two groups were significantly decreased, and the difference was statistically significant in the same group (P < 0.05). After treatment, the levels of VEGF in the treatment group were significantly lower than those in the control group, with significant difference between two groups (P < 0.05). After treatment, abdominal distension score and anorexia score in two groups were significantly decreased, and the difference was statistically significant between group (P < 0.05). No grade Ⅲ - Ⅳ toxicities were found in two groups. Conclusion Bevacizumab Injection has better efficacy than Lobaplatin for injection in treatment of malignant ascites, and has good tolerance, which has a certain clinical application value.
Key words: Bevacizumab Injection     Lobaplatin for injection     intraperitoneal perfusion     malignant ascites     VEGF     CEA     scores of life quality     toxicities    

恶性腹腔积液是晚期恶性肿瘤常见并发症,常引起患者腹胀腹痛、厌食、呼吸困难,严重的可导致恶病质,严重影响患者的生活质量与生存期[1]。恶性腹腔积液的预后差,一年生存率低于10%[2]。恶性腹腔积液的治疗除全身化疗外,多采取腹腔置管引流、腔内注药等,常用的药物包括白介素、铂类药物、贝伐单抗等。贝伐单抗是一种血管内皮生长因子的单克隆抗体,自2004年经美国食品与药品管理局批准上市以来,已被用于多种实体肿瘤的治疗。血管生成是肿瘤生成、生长和转移的关键。血管内皮生长因子(vascular endothelial growth factor,VEGF)是肿瘤生长中最重要的血管形成因子的前体之一,在肿瘤的发病机制中起着关键作用。贝伐单抗是一种由93%的人类IgG片段和7%的鼠源结构重组的人源化单克隆抗体,鼠源结构组成的轻链可变区可以特异性地结合VEGF,竞争性地阻断了其与内源性VEGFR的结合,从而抑制其生物学活性,抑制内皮细胞的有丝分裂,减少新生血管形成,降低血管通透性,进而达到抑制肿瘤生长的目的[3]。洛铂是最新的第3代铂类抗肿瘤药物,2005年3月经国家食品药品监督管理局批准,率先在我国获准上市。洛铂的化学名称为1,2-二氨甲基-环丁烷乳酸合铂,分子式为C9H18N2O3Pt。洛铂抗癌作用主要是通过与DNA以共价键结合形成DNA—药物加合物,与DNA链内、链间交叉连接,阻碍DNA的复制与转录,从而诱导肿瘤细胞凋亡[4]。本研究收集了在中国医科大学附属盛京医院就诊的恶性腹腔积液患者,比较观察贝伐单抗与洛铂腹腔灌注治疗恶性腹腔积液的疗效及毒副反应。

1 材料与方法 1.1 一般资料

选取2013年10月—2015年10月在中国医科大学附属盛京医院住院治疗的48例恶性腹腔积液患者。其中男29例,女19例;年龄39~69岁,中位年龄60岁,平均年龄59.5岁;17例ECOG评分2分;胃癌15例,肠癌11例,肝癌7例,卵巢癌7例,胰腺癌6例,前列腺癌2例。

所有患者原发肿瘤均经病理或细胞学确诊,且均经B超或X线证实伴有中量以上的恶性腹腔积液,积液中均找到癌细胞;年龄≤69岁,ECOG评分≤2分,预计生存期≥12周;血常规、肝肾功能、凝血功能及心功能基本正常;距末次全身静脉化疗或腹腔灌注治疗至少1个月;治疗前均知情同意并签署知情同意书。

1.2 分组

所有患者随机分为对照组和治疗组,每组各24例。对照组男14例,女10例;年龄41~69岁,中位年龄60.5岁,平均年龄59岁;9例ECOG评分2分;胃癌8例,肠癌6例,肝癌3例,卵巢癌4例,胰腺癌3例。治疗组男15例,女9例,年龄39~68岁,中位年龄59岁,平均年龄60岁;8例ECOG评分2分;胃癌7例,肠癌5例,肝癌4例,卵巢癌3例,胰腺癌3例,前列腺癌2例。两组患者在性别比例、年龄、ECOG评分、原发疾病等方面差异均无统计学意义,具有可比性。

1.3 治疗方法

经B超检查定位后腹腔穿刺留置中心静脉导管充分引流积液,积液明显减少(引流量<100 mL/d)时,行腹腔灌注术。两组患者注药前均腹腔灌注地塞米松5 mg以减轻腹腔局部反应。对照组行腹腔灌注注射用洛铂(海南长安国际制药有限公司生产,规格50 mg/支,批号20140301),30mg/m2用生理盐水50 mL稀释,1次/周。治疗组行腹腔灌注贝伐珠单抗注射液(罗氏制药公司生产,规格100 mg/瓶,批号H0145B08),5mg/kg用生理盐水50 mL稀释,1次/周。嘱患者注药后2 h内依照患侧位-健侧位-仰卧位-俯卧位-直立位的顺序15 min变换一次体位,使得药物与腹腔充分接触。两组患者均连续灌注2周,最多灌注3次。

1.4 疗效判定标准

参照WHO制定的Millar标准[5]评价。完全缓解(CR):积液完全消失,并至少维持4周以上;部分缓解(PR):积液显著减少(>50%),并维持4周以上;无变化(NS):积液仍持续或迅速产生,或积液量减少<50%。

总有效率=(CR+PR)/总例数

1.5 疗效观察 1.5.1 腹腔积液中血管内皮生长因子(VEGF)和癌胚抗原(CEA)水平的测定

用药前及用药后3 d抽取腹腔积液5 mL,采用全自动酶联免疫分析仪检测VEGF和CEA水平。

1.5.2 生活质量评分

参照恶性腹腔积液患者生活质量量表(FACIT-AI)[2]制定调查问卷,每项指标评分为0~4分,完全没有为0分,非常为4分,分值越高提示患者生存质量越差。分别于治疗前及治疗后1周对患者进行问卷调查,询问患者最近1周是否有乏力、失眠、腹痛、恶心等症状。

1.5.3 毒副反应

毒副反应按美国国家癌症研究所的常见药物毒性反应分级标准[6]分为0~Ⅳ级。

1.6 统计学方法

采用SPSS 17.0软件进行统计分析。计数资料采用χ2检验。计量资料采用x±s表示,组间比较采用独立样本t检验,组内比较采用配对t检验。

2 结果 2.1 两组临床疗效比较

治疗后,对照组CR 5例,PR7例,总有效率为50.0%;治疗组CR 11例,PR8例,总有效率为79.2%,两组总有效率比较差异有统计学意义(P<0.05),见表 1

表 1 两组临床疗效比较 Table 1 Comparison on clinical efficacies between two groups

2.2 两组腹腔积液中VEGF和CEA水平比较

治疗后,两组患者VEGF和CEA水平显著降低,同组治疗前后差异有统计学意义(P<0.05);且治疗组VEGF水平降低更明显,两组比较差异有统计学意义(P<0.05),见表 2

表 2 两组腹腔积液中VEGF和CEA水平比较 (x±s,n = 24) Table 2 Comparison on levels of VEGF and CEA in ascites (x±s,n =24)

2.3 两组生活质量评分比较

两组患者最主要的主诉均为乏力、腹胀、腹痛、厌食及少量进食后饱腹感,而恶心、呕吐及呼吸困难发生率均较低。治疗前两组患者各项指标差异均无统计学意义。治疗后,治疗组患者腹胀评分、厌食评分均低于对照组,两组比较差异具有统计学意义(P<0.05、0.01),见表 3

表 3 两组生活质量评分比较(x±sn = 24) Table 3 Comparison on scores of life quality between two groups (x±s,n = 24 )

2.4 毒副反应

两组患者均无严重的Ⅲ~Ⅳ度不良反应发生;无贝伐单抗相关性恶性高血压、胃肠道穿孔及出血等严重不良事件发生。两组的不良反应,如粒细胞减少、贫血、血小板计数减少,乏力等均无显著性差异。治疗组恶心呕吐发生率低于对照组,但差异无统计学意义,见表 4

表 4 两组患者毒副反应比较 Table 4 Comparison on adverse reactions between two groups

3 讨论

恶性腹腔积液严重影响肿瘤患者的生存期和生活质量。腹腔穿刺引流腹腔积液可改善患者的腹胀、腹痛、厌食及呼吸困难等症状,但是腹腔积液通常会短时间内再次增加。姑息治疗腹腔积液的主要目的在于减少腹腔积液量,提高患者的生存质量[7]。国外多项试验[8-10]证实VEGF可促进肿瘤血管的生成和调节血管通透性,与腹腔积液的产生密切相关。Byrne等[11]证实对大鼠的腹膜植入VEGF可引起腹腔积液。贝伐单抗是VEGF的抗体,可以与VEGF结合,抑制VEGF的作用,从而抑制血管内皮细胞的新生,显著减少肿瘤内部血管的生成,阻碍肿瘤的生长及迁移。Pichelmayer等[12]报道了贝伐单抗可有效治疗恶性腹腔积液。洛铂是最新的第3代铂类抗肿瘤药物,灌注治疗恶性胸腔、腹腔、心包腔积液疗效显著[4]

研究结果显示治疗后,对照组、治疗组总有效率分别为50.0%、79.2%,两组总有效率比较差异有统计学意义(P<0.05)。分别于治疗前及治疗后检测两组腹腔积液中VEGF、CEA水平,结果治疗组VEGF水平降至(156.05±59.05)pg/mL,与国外同类报道相当[13-18]。对照组VEGF下降值明显少于治疗组,治疗后两组VEGF水平差异有统计学意义。多项临床试验报道VEGF水平与患者的预后相关,VEGF水平越高往往提示预后越差[18-20]。Zhan等[18]报道腹腔积液中VEGF水平≥613.38 pg/mL,患者中位生存期较短。本研究中VEGF高于800pg/mL的患者预后均较差,与此报道结果相当。詹娜等的研究还发现卵巢癌所导致的恶性腹腔积液中VEGF水平高于其他肿瘤,可用于鉴别诊断良恶性腹腔积液[18]。因此,在今后的临床工作中,应重视开展VEGF的检测,以便为患者提供更优质的诊治。

本研究依据FACIT-AI制定调查问卷评价患者生活质量,FACIT-AI是目前为止唯一一个评价腹腔积液患者生存质量的量表,它由Cella等制定[2],娄燕妮等验证该表适用于我国患者[21]。研究显示治疗组患者腹胀评分、厌食评分均低于对照组,提示贝伐单抗能够更显著改善患者的生活质量。

Hamilton等报道一例88岁的高龄卵巢癌患者连续两周接受贝伐单抗5 mg/kg腹腔灌注治疗腹腔积液[22]。Joshua等也报道过一例82岁卵巢癌患者应用贝伐单抗腹腔灌注[23]。2例报道结果均显示患者腹腔积液量明显减少,生存质量显著提高。本研究采用贝伐单抗5 mg/kg,灌注1次/周,连续2周,最多灌注3次。无贝伐单抗相关恶性事件发生,而且治疗组恶心呕吐发生率低于对照组。治疗组患者最大年龄68岁,耐受良好,未出现恶性高血压、胃肠道穿孔及出血等不良事件。今后,对于70岁以上的高龄患者,可试行应用贝伐单抗腹腔灌注治疗以改善老年患者的生存质量。

综上所述,贝伐单抗腹腔灌注治疗恶性腹腔积液疗效优于洛铂,且耐受性良好,具有一定的临床推广应用价值。

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