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HERALD OF MEDICINE, 2018, 37(5): 554-558
doi: 10.3870/j.issn.1004-0781.2018.05.011
贝伐珠单抗联合治疗晚期非小细胞肺癌的疗效和安全性
Efficacy and Safety of Bevacizumab Combination Therapy in Patients with Advanced Non-small Cell Lung Cancer
石磊, 蒋继宗, 刘青旭, 张莉, 夏曙, 陈元, 褚倩

摘要: 目的 探讨贝伐珠单抗联合治疗对晚期非小细胞肺癌(NSCLC)患者的疗效和安全性。方法 回顾性分析晚期NSCLC患者78例,根据治疗方案的不同分为4组,A组:一线化疗联合贝伐珠单抗治疗36例;B组:一线表皮生长因子受体酪氨酸激酶抑制药(EGFR-TKI)联合贝伐珠单抗治疗7例;C组:二线及二线以上化疗联合贝伐珠单抗治疗30例;D组:二线及二线以上EGFR-TKI联合贝伐珠单抗治疗5例。 统计联合应用贝伐珠单抗患者的无进展生存期(PFS)、总生存期及不良反应发生情况。结果 A、B、C、D组疾病控制分别为34,6,26和4例;平均无进展时间(mPFS)为8.9,10.8,7.2和7.8个月,总生存时间数据尚不成熟。化疗联合贝伐珠单抗的主要不良反应与所联合的方案高度相关,包括骨髓抑制、疲乏、腹泻、高血压等,3或4 级毒副反应主要为中性粒细胞减少15.2%(10/66)、腹泻4.5%(3/66)、疲乏7.6%(5/66)、高血压 6.1%(4/66)。EGFR-TKI联合贝伐珠单抗的主要不良反应为高血压2例(2/12)、皮疹3例(3/12)、腹泻5例(5/12)、无症状蛋白尿2例(2/12)、疲乏2例(2,12)。未观察到3级以上不良反应。结论 化疗或EGFR-TKI联合贝伐珠单抗是晚期NSCLC安全有效的治疗策略。
关键词: 贝伐珠单抗 ; ; ; 非小细胞 ; 抗肿瘤血管生成

Abstract:
Objective To investigate the efficacy and safety of bevacizumab in the systemic treatment of patients with advanced non-small cell lung cancer. Methods A total of 78 patients diagnosed with advanced non squamous non-small cell lung cancer were divided into 4 groups: 36 patients in group A(first-line chemotherapy combined with bevacizumab),7 patients in group B[first-line epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKI) combined with bevacizumab], 30 patients in group C(two or more lines of chemotherapy combined with bevacizumab)and 5 patients in group D(two or more lines of EGFR tyrosine kinase inhibitor combined with bevacizumab). The progression-free survival (PFS), overall survival (OS) and adverse reactions were retrospectively analyzed. Results The disease control cases in each group were 34,6,26 and 4, respectively. The mean progression free survival (mPFS) in each group were 8.9 months, 10.8 months, 7.2 months and 7.8 months, respectively. The overall survival data is not mature. The main adverse reactions of chemotherapy combined with bevacizumab were myelosuppression, fatigue, diarrhea, and hypertension etc. grade 3 or 4 toxicities include neutropenia (10/66,15.2% ), diarrhea (3/66,4.5%), fatigue (5/66,7.6%), hypertension(4/66,6.1%).The main adverse reactions of EGFR-TKI combined with bevacizumab were hypertension (2/12), rash (3/12), diarrhea (5/12) , asymptomatic proteinuria (2/12) and fatigue (2/12), without grade above 3 toxicities. Conclusion Chemotherapy or EGFR-TKI combined with bevacizumab are safe and effective treatment strategies for advanced non-small cell lung cancer.
Key words: Bevacizumab ; Cancer ; lung ; non-small cell ; Antiangiogenesis

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种内皮特异性血管生长因子,在多种肿瘤中表达强,在非小细胞肺癌(non-small cell lung cancer,NSCLC)中VEGF高表达与预后不良相关[1,2]。贝伐珠单抗(bevacizumab,贝伐珠单抗®)是一种新型血管生成抑制药,通过与VEGF特异性结合,阻止其与受体相互作用,从而持续抑制肿瘤的生长和转移。2015年8月1日,贝伐珠单抗的肺癌适应证正式在中国获批。笔者回顾性分析了2015年12月—2016年11月在我院就诊、临床资料完整、使用含贝伐珠单抗治疗方案的晚期非鳞NSCLC患者78例,报道如下。

1 资料与方法
1.1 临床资料

Ⅳ期非鳞NSCLC患者78例,其中男35例,女43例。年龄37~72岁,平均(58.6±5.3)岁。所有患者均经病理组织学检查证实为肺腺癌,其中表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变20例,EGFR野生型21例,EGFR基因状态未知37例。间变性淋巴瘤激酶(anaplasticlymphoma kinase,ALK)融合基因阳性1例,该患者同时合并EGFR敏感突变(表1)。

1.2 分组与治疗方法

A组:一线化疗联合贝伐珠单抗治疗36例;B组:一线EGFR酪氨酸激酶抑制药 (EGFR-tyrosine kinase inhibitors,EGFR-TKI)联合贝伐珠单抗治疗7例;C组:二线及二线以上化疗联合贝伐珠单抗治疗30例;D组:二线及二线以上EGFR-TKI联合贝伐珠单抗治疗5例。一线化疗方案包括培美曲塞+顺铂/卡铂/奈达铂;二线及二线以上化疗方案包括:多西他赛+顺铂/奈达铂、吉西他滨+顺铂/卡铂/洛铂、伊立替康+奈达铂、多西他赛单药、培美曲塞单药、纳米白蛋白结合型紫杉醇单药;EGFR-TKI包括:吉非替尼、厄洛替尼和埃克替尼。贝伐珠单抗(上海罗氏制药有限公司,批准文号:S20100024)的使用剂量均为7.5 mg·kg-1,每3周重复。ALK阳性的患者因经济原因未使用ALK抑制药治疗(表1)。

4组患者基线特征和联合治疗方案

Baseline characteristics and combined regimens of four groups of patients 例,x¯±s

组别 例数 性别/例 年龄/
基因型 联合治疗方案
EGFR
M+
EGFR
M-
EGFR
未知
ALK
融合
培美曲塞+
铂类
伊立替康+
铂类
多西他赛+
铂类
A组 36 17 19 61.2±4.6 3 14 19 1 36 0 0
B组 7 4 3 57.2±3.8 6 0 1 0 0 0 0
C组 30 12 18 58.2±6.7 7 7 16 0 3 2 8
D组 5 2 3 59.1±2.6 4 0 1 0 0 0 0
组别 联合治疗方案 贝伐珠单抗平均
疗程/个月
吉西他滨+
铂类
多西他赛
单药
培美曲塞
单药
白蛋白结合型
紫杉醇
吉非
替尼
厄洛
替尼
埃克
替尼
A组 0 0 0 0 0 0 0 10.4±3.8
B组 0 0 0 0 5 0 2 11.2±2.5
C组 6 9 1 1 0 0 0 8.3±2.2
D组 0 0 0 0 1 2 2 8.1±1.9

1.3 疗效和毒副反应评价

疗效评价采用实体瘤疗效评价标准(response evaluation criteria in solid tumors,RECIST),分为完全缓解(complete response,CR)、部分缓解(partial response,PR)、稳定(stable disease,SD)和进展(progressive disease,PD),CR+PR 为有效(ORR),以 CR+PR+SD 计算疾病控制率(DCR)。记录无进展生存期(progression-free survival,PFS)及总生存期 (overall survival,OS)。按照国际癌症中心(National Cancer Center,NCI)制定的抗肿瘤药物常见毒性分级标准分析不良反应。

4组患者的疗效

Treatment efficacy of four groups of patients 例

组别 例数 完全
缓解
部分
缓解
疾病
稳定
疾病
进展
疾病控制 平均无进展
生存期/个月
A组 36 0 25 9 2 34 8.9
B组 7 0 5 1 1 6 10.8
C组 30 0 16 10 4 26 7.2
D组 5 0 4 0 1 4 7.8

1.4 随访

所有患者随访方式包括复习病历、住院记录、电话随访及信访,随访 1 年以上,患者死亡日期为截止日期,随访中断的患者剔除。

2 结果
2.1 疗效

4组患者疗效见表2。OS数据未成熟。

2.2 安全性

贝伐珠单抗联合化疗组主要的不良反应包括:骨髓抑制、疲乏、腹泻、高血压等,3或4 级不良反应以中性粒细胞减少15.2%(10/66)、高血压6.1%(4/66)、疲乏7.6%(5/66)、腹泻4.5%(3/66)为主,不良反应主要与化疗相关。EGFR-TKI联合贝伐珠单抗的主要不良反应为腹泻5例(5/12)、粒细胞减少3例(3/12)、皮疹3例(3/12)、高血压2例(2/12)、无症状蛋白尿2例(2/12)、疲乏2例(2/12),未观察到3级以上不良反应。出血及血栓并发症分别有3和1例,分别发生在一线化疗组和二线EGFR-TKI组,常见不良反应事件评价标准分级为1级,经治疗后迅速缓解。见表3。

贝伐珠单抗联合治疗的不良反应

Adverse reaction of bevacizumab combination chemotherapy

组别 例数 粒细胞减少 疲乏 腹泻 高血压 皮疹 蛋白尿 出血 血栓
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
1或
2级
3或
4级
A组 36 13 6 4 3 6 1 7 2 0 0 2 0 1 0 0 0
B组 7 2 0 2 0 3 0 2 0 1 0 1 0 1 0 0 0
C组 30 9 4 2 2 4 2 2 2 1 0 1 0 1 0 0 0
D组 5 1 0 0 0 2 0 0 0 2 0 1 0 0 0 1 0

3 讨论

肺癌是我国发病率及病死率均居首位的恶性肿瘤,根据国家癌症中心公布的《2015中国肿瘤登记年报》[3]我国每年肺癌新发病例约为65万例。其中,NSCLC是目前肺癌中最为常见的类型,约占所有肺癌病例的85%。肺癌患者就诊时多为中晚期,目前肺癌的5年生存率仅为16.1%[3]。肺癌患者的治疗需要根据肿瘤分期、组织学类型、分子分型和功能状态等因素综合来确定。基于驱动基因的状态制定精准的治疗策略,选用合适的分子靶向药物是晚期肺癌实施精准医疗的重要组成部分[4]

美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)指南推荐贝伐珠单抗在驱动基因阴性、细胞程序性死亡-配体低表达的晚期非鳞NSCLC患者的一线治疗中与紫杉醇/卡铂联合使用为1类证据,与培美曲塞/顺铂、培美曲塞/卡铂联合使用为2A类证据。在2005年报道的美国东部肿瘤协作组(ECOG) Ⅲ期随机临床研究(E4599)中,未经治疗的ⅢB期和Ⅳ期晚期非鳞NSCLC患者被随机分配接受化疗药物[卡铂的血药浓度-时间曲线下面积为6 mg·mL-1·min,紫杉醇的剂量为200 mg·(m2)-1,每3周1次,共6个周期]联合或不联合贝伐珠单抗(15 mg·kg-1每3周1次,持续至1年)。研究发现贝伐珠单抗联合紫杉醇/卡铂治疗组的中位PFS为6.2个月,本研究显示一线贝伐珠单抗联合化疗组患者(A组)的中位PFS为8.9个月,优于E4599研究的结果[5]。在2007年报道的AVAIL研究[6]中,ⅢB/Ⅳ期初治或复发的非鳞NSCLC患者被随机分配接受GP方案联合不同剂量组贝伐珠单抗或安慰药治疗。GP方案为吉西他滨[1 250 mg·(m2)-1,第1天,第8天]+顺铂[80 mg·(m2)-1,第1天],每3周为1周期,共6周期。贝伐珠单抗剂量为15 或7.5 mg·kg-1,第1天,每3周1次,直至疾病进展。研究发现与安慰药组相比,联合贝伐珠单抗组的有效率较高。安慰药组、小剂量贝伐珠单抗组、大剂量贝伐珠单抗组客观有效率分别为20%,34%和30%。联合贝伐珠单抗组PFS显著长于安慰药组。安慰药组、小剂量贝伐珠单抗组、大剂量贝伐珠单抗组PFS分别为6.2,6.8和6.6个月,差异有统计学意义。3组中位OS分别是13.1,13.6和13.4个月,GP方案联合贝伐珠单抗未能改善总生存。AVAIL研究是第二项显示贝伐珠单抗联合化疗可提高晚期NSCLC治疗有效率和延长PFS的Ⅲ期临床研究。贝伐珠单抗两种剂量(7.5 和15 mg·kg-1)的疗效相似,患者耐受性良好,严重咯血/肺出血发生率低。BEYOND研究[7]是一项随机、双盲、安慰药对照、多中心Ⅲ期研究,未经治疗的晚期非鳞NSCLC患者被随机分配接受贝伐珠单抗联合紫杉醇和卡铂对比紫杉醇和卡铂单纯化疗作为一线治疗。结果发现:贝伐珠单抗联合化疗组的PFS为9.2个月,OS为24.3个月。接受贝伐珠单抗联合化疗的患者较接受单纯化疗患者,疾病进展风险降低60%,死亡风险降低32%。BEYOND研究进一步对患者EGFR状态进行分层分析,结果显示,贝伐珠单抗组EGFR野生型患者PFS达8.3个月,EGFR突变型为12.4个月,与单纯化疗组比较,均差异有统计学意义,这提示晚期非鳞NSCLC患者EGFR无论有无突变,都会从贝伐珠单抗联合化疗方案中获益。基于4项大型试验的荟萃分析[8]显示,与单用化疗相比,加用贝伐珠单抗可显著延长OS和PFS,且对腺癌患者的OS影响更大,但加用贝伐珠单抗会增加3级及以上毒性反应的风险。本回顾性研究显示,贝伐珠单抗与一线或二线化疗联合使用的疾病控制率较高,中位PFS较长,亦证实了贝伐珠单抗与化疗联合使用的疗效较好。

对于EGFR敏感突变的患者,JO25567研究[9]是首个探索厄洛替尼联合贝伐珠单抗一线用于EGFR突变阳性非鳞NSCLC的前瞻随机研究,结果显示贝伐珠单抗联合厄洛替尼较厄洛替尼单药相比,PFS显著延长(16个月vs 9.7个月),联合治疗组客观缓解率达69%,疾病控制率达99%;研究中该种联合方案未发现新的安全性事件。我国正在进行的CTONG1509研究也进一步探索了厄洛替尼联合贝伐珠单抗的疗效,目前入组已经结束,希望能为我国肺癌患者提供新的治疗选择。本回顾性研究显示,在一线使用贝伐珠单抗联合EGFR-TKI治疗的7例患者中,疾病控制率及平均PFS略差于JO25567研究,可能与本单中心研究的患者例数较少,且有1例EGFR状态未知的患者接受了贝伐珠单抗联合EGFR-TKI治疗有关。

NSCLC患者应用贝伐珠单抗治疗常见的不良反应包括:高血压、蛋白尿、出血、血栓。国内外文献报道罕见不良反应包括:乏力、管瘘和变态反应等。而仅国外文献报道的罕见不良反应还包括口腔黏膜炎、皮疹、可逆性后脑白质病综合征、下颌骨坏死和厌食等。E4599研究[5]显示,贝伐珠单抗联合化疗组的整体耐受性良好。与化疗组相比,>3级的肺、胃肠道、中枢、鼻出血在贝伐珠单抗联合化疗组发生率较高(4.4% vs 0.7%,P<0.001)。治疗前肺内病灶空洞形成和近期咯血是贝伐珠单抗治疗后潜在出血的危险因素。除此之外,贝伐珠单抗联合化疗组在以下几方面不良事件发生率略高于对照组:4级中性粒细胞减少(25.5% vs 16.8%)、4级血小板减少(1.6% vs 0.2%)、≥3级中性粒细胞减少性发热(5.2% vs 2.0%)、≥3级的低钠血症(3.5% vs 1.1%)、≥3级高血压(7.0% vs 0.7%)、≥3级蛋白尿(3.1% vs 0)、≥3级的头痛(3.0% vs 0.5%)、≥3级皮疹(2.3% vs 0.5%)。亚组分析表明,毒性反应和治疗相关死亡在>70岁的老年患者更易发生。 AVAIL研究[6]同样显示,联合贝伐珠单抗治疗组的整体耐受性良好,安慰药组、小剂量贝伐珠单抗组、大剂量贝伐珠单抗组的3~5级不良事件发生率分别为75%,76%,81%;不良事件导致死亡发生率分别为4%,4%,5%。咯血发生率在联合贝伐珠单抗组和安慰药组之间差异无统计学意义,安慰药组、小剂量贝伐珠单抗组、大剂量贝伐珠单抗组患者的肺出血发生率分别为4.9%,7.0%,9.7%。但≥3级的肺出血、高血压和蛋白尿在联合贝伐珠单抗治疗组发生率较高,≥3级肺出血发生率分别为0.6%,1.5%,0.9%。在贝伐珠单抗联合化疗二线治疗的晚期NSCLC患者中,也发现联合贝伐珠单抗组的咯血、高血压、腹泻、鼻出血、致死性出血的发生率略高于单独化疗组。

贝伐珠单抗引起高血压发生的可能机制:①内皮细胞一氧化氮的含量减少,外周血管一氧化氮密度降低从而引起血管收缩;②血管壁通透性增加,从而增加血容量,导致血压升高[10]。患者在接受贝伐珠单抗第1 次治疗后发生血压升高的比例较低,一般在治疗开始后的4~12 个月发生率较高。Meta 分析表明,剂量分别为7.5 和15 mg·kg-1的两组患者,大剂量组发生高血压的相对风险更大(P<0.05);但是我国的用药剂量相对欧美各国偏低,通常是7.5 mg·kg-1,每3周1次,发生血压升高的风险可能低于文献报道。本回顾性分析中仅4例患者用药期间发生3级以上高血压,其他11例用药期间血压波动的患者均为轻度异常波动。如果患者出现2或3级高血压应暂停用药,同时给予降压药,待血压恢复到治疗前水平,若治疗1个月仍未控制,则不应该再使用贝伐珠单抗。

贝伐珠单抗引起蛋白尿的发生率为18%~41%[11],蛋白尿发生的原因包括:抑制肾小球脏层上皮细胞VEGF 的表达,导致肾小球滤过膜的通透性增高;引起肾小球微血管血栓的形成,导致肾小球内压增高、滤过膜的通透性增加。大多数研究认为此损伤是可逆的,故可在治疗期间监测尿常规,如果尿蛋白结果是++,则应行24 h 尿蛋白的定量检查,定量结果>2 g则暂停治疗,至24 h尿蛋白<1 g 再恢复贝伐珠单抗的治疗,但如发生肾病综合征(4级蛋白尿),则应永久停用贝伐珠单抗。本研究中仅有6.4%(5/78)出现无症状的蛋白尿,其中3例为++,2例为+;治疗期间密切随访无相关症状发生,无需处理。

应用贝伐珠单抗发生出血的临床表现主要为皮肤、黏膜出血,以鼻出血最为常见。肺鳞癌、既往有出血病史的患者使用贝伐珠单抗后出血风险高,目前已不推荐贝伐珠单抗用于此类人群。使用贝伐珠单抗引起出血的机制与肿瘤靠近大血管、肿瘤的坏死、肿瘤的病理类型、空洞的形成相关[12]。患者用药前应先对肿瘤的病理类型、位置、浸润深度进行充分评估。另外,对于有中枢神经系统转移的患者,如需使用贝伐珠单抗,应先行手术或放疗预处理,以降低出血的风险。本项回顾性分析发现3例患者有出血性事件,分别为鼻出血、咯血和牙龈出血,后2例患者因此中断贝伐珠单抗治疗。鼻腔出血患者因出血量少,间断出现,持续用药未明显加重从而未中断贝伐珠单抗治疗。贝伐珠单抗治疗期间若出现任何级别的动脉血栓都应该永久停用贝伐珠单抗。若发生静脉血栓,应给予低分子肝素钠治疗5~10 d,并监测患者凝血功能及国际标准化比值。本项回顾性分析中有1例患者用药期间发生静脉血栓,应用抗凝药物后稳定。

尽管多项Ⅲ期临床研究的结果显示贝伐珠单抗联合一线化疗或TKI,以及在二线及以上治疗方案中可改善患者生存,但实际临床应用该药时仍需考虑成本效益和药物可及性的问题。贝伐珠单抗作为一种重要抗肿瘤机制的代表药物,联合化疗、分子靶向治疗等其他抗肿瘤药物治疗非鳞NSCLC,显示出卓越的疗效和安全性。随着贝伐珠单抗纳入国家医疗保险目录,将使更多晚期肺癌患者获益。

The authors have declared that no competing interests exist.

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关键词(key words)
贝伐珠单抗
非小细胞
抗肿瘤血管生成

Bevacizumab
Cancer
lung
non-small cell
Antiangiogenesis

作者
石磊
蒋继宗
刘青旭
张莉
夏曙
陈元
褚倩

SHI Lei
JIANG Jizong
LIU Qingxu
ZHANG Li
XIA Shu
CHEN Yuan
CHU Qian