摘要
计算机检索PubMed、Web of science、Cochrane数据库、Embase、clinicaltrials.gov、中国知网、万方和CBM,收集传统化疗联合帕博利珠单抗(试验组)对比传统化疗联合安慰剂(对照组)或紫杉醇联合帕博利珠单抗(试验组)对比紫杉醇联合安慰剂(对照组)的临床试验,检索时间为从建库至2023年4月1日。筛选文献、提取数据和评价质量后,采用RevMan 5.3软件进行统计分析、敏感性分析。
共纳入3篇文献,合计1 509例患者,试验中结局指标(即3~5级不良事件)主要为腹泻、中性粒细胞减少、贫血、疲乏和皮肤反应。Meta分析结果显示,试验组患者3~5级腹泻(RR=1.83, 95% CI: 0.81~4.12, P=0.15)、中性粒细胞减少症(RR=1.03, 95% CI: 0.88~1.20, P=0.73)、贫血(RR=1.20, 95% CI: 0.92~1.55, P=0.18)、皮肤反应(RR=3.14, 95% CI: 0.28~35.41, P=0.35)的发生率与对照组比较,差异均无统计学意义;试验组疲乏发生率为3.4%,对照组疲乏发生率为1.3%,两组3~5级疲乏的发生率比较,差异有统计学意义(RR=2.21, 95% CI: 1.03~4.76, P=0.04)。
2022年2月,国家癌症中心发布了新一期全国癌症统计数据,我国每年新增乳腺癌患者约42万人,平均每76秒就有1例确诊,乳腺癌已成为中国女性高发恶性肿瘤之一,且发病人群逐渐年轻
近年来,免疫检查点抑制剂(immune checkpoint inhibitor, ICI)成为肿瘤治疗的关注焦点,包括细胞毒性T淋巴细胞相关抗原-4(cytotoxic T lymphocyte-associated antigen-4, CTLA-4)抑制剂、程序性死亡受体1(programmed death-1,PD-1)/程序性死亡受体配体1(programmed death-ligand 1, PD-L1)抑制剂等,能够改善肿瘤浸润淋巴细胞(tumor-infltrating lymphocyte, TIL)的细胞毒性和增殖能力。与其他乳腺癌亚型相比,一些独有的特征使得TNBC更有可能对免疫疗法产生反
2022年11月9日,默沙东宣布PD-1抑制剂帕博利珠单抗(pembrolizumab)在中国获批第十项适应证,用于治疗PD-L1高表达的早期三阴性乳腺癌(early triple-negative breast cancer,ETNBC)患
计算机检索PubMed、Web of science、Cochrane数据库、Embase、ClinicalTrials.gov、中国知网、万方数据和中国生物医学文献数据库(China Biology Medicine, CBM)。检索策略:主题词与自由词结合。中文数据库检索策略:“早期三阴性乳腺癌”AND(“帕博利珠单抗”OR“可瑞达”OR“K药”);外文数据库检索策略:(“early triple negative breast cancer” OR “ETNBC”) AND (“pembrolizumab” OR “SCH-900475” OR “lambrolizumab” OR “keytrude” OR “MK-3475”)。检索时间均为从建库至2023年4月1日。
由2名研究者按照纳入与排除标准对文献进行筛选及信息提取,如出现分歧,则通过第3位研究者协助解决。信息提取内容包括:第一作者姓名、文献发表年份、样本量、试验对象一般特征、研究类型、干预措施、结局指标和文献质量评价。
由2名研究者独立评价纳入研究的偏倚风险。偏倚风险评价采用Cochrane手册5.3.0推荐的随机对照试验(randomized controlled trial, RCT)偏倚风险评价工具,若有差异,则通过第三方讨论或裁决解决。
共检索到相关文献819篇,EndNote去重后,按照纳入与排除标准阅读题目、摘要和全文后,纳入文献351篇;进一步阅读全文,排除不符合纳入标准的文献348篇,最终纳入3篇文献,均为随机对照试验(
图1 文献筛选流程图
Fig.1 Flow diagram for selection of studies
本研究共纳入3篇文
纳入研究 | 研究类型 | 样本量 | 干预措施 | 结局指标 | |||
---|---|---|---|---|---|---|---|
试验组 | 对照组 | 试验组 | 对照组 | ||||
Nand | RCT | 69 | 181 | 传统化疗联合200 mg帕博利珠单抗 | 传统化疗联合200 mg安慰剂 | ①②③④⑤⑥ | |
Schmi | RCT | 783 | 389 | 传统化疗联合200 mg帕博利珠单抗 | 传统化疗联合200 mg安慰剂 | ①②③④⑤⑥ | |
Hattor | RCT | 61 | 26 | 紫杉醇联合200 mg帕博利珠单抗 | 紫杉醇联合200 mg安慰剂 | ①②③④⑤⑥ |
注: ①3~5级AEs发生总数;②腹泻发生数;③中性粒细胞减少症发生数;④贫血发生数;⑤疲乏发生数;⑥皮肤反应发生数。
Note: ① The total number of grade 3~5 AEs; ② The number of diarrhea; ③ The number of neutropenia; ④ The number of anemia; ⑤ The number of fatigue; ⑥ The number of skin reactions.
Nanda
图2 纳入研究的质量评价结果
Fig. 2 Quality assessment of the included studies
3项研
图3 帕博利珠单抗治疗ETNBC 3~5级AEs发生率Meta分析森林图
Fig. 3 Meta analysis forest chart of the incidence of 3~5 grade AEs of ETNBC treated with pabolizumab
本研究进一步分析了包括腹泻、中性粒细胞减少症、贫血、疲乏和皮肤反应在内的3~5级AEs的发生率。结果显示,对于3~5级腹泻的发生率,3项研究间异质性较小(
图4 帕博利珠单抗治疗ETNBC 3~5级腹泻发生率Meta分析森林图
Fig. 4 Meta analysis forest chart of the incidence of 3~5 grade diarrhea in ETNBC treated with pabolizumab
对于3~5级中性粒细胞减少症的发生率,3项研究间异质性较小(
图5 帕博利珠单抗治疗ETNBC 3~5级中性粒细胞减少症发生率Meta分析森林图
Fig. 5 Meta analysis forest chart of the incidence of 3~5 grade neutropenia in ETNBC treated with pabolizumab
对于3~5级贫血的发生率,3项研究间异质性较小(
图6 帕博利珠单抗治疗早期三阴性乳腺癌3~5级贫血发生率Meta分析森林图
Fig. 6 Meta analysis forest chart of the incidence of 3~5 grade anemia in ETNBC treated with pabolizumab
对于3~5级疲乏的发生率,3项研究间异质性较小(
图7 帕博利珠单抗治疗ETNBC 3~5级疲乏发生率Meta分析森林图
Fig. 7 Meta analysis forest chart of the incidence of 3~5 grade fatigue in ETNBC treated with pabolizumab
对于3~5级皮肤反应的发生率,3项研究间异质性较大(
图8 帕博利珠单抗治疗ETNBC 3~5级皮肤反应发生率Meta分析森林图
Fig. 8 Meta analysis forest chart of the incidence of 3~5 grade skin reactions in ETNBC treated with pabolizumab
TNBC的治疗具有挑战性,近年来,化疗联合PD-1/PD-L1抑制剂治疗TNBC开始得到应用。本研究纳入的3篇文献报告了患者接受传统化疗联合帕博利珠单抗或紫杉醇联合帕博利珠单抗治疗ETNBC的研究,涉及1 509例患者,评估了传统化疗联合帕博利珠单抗及紫杉醇联合帕博利珠单抗治疗ETNBC的安全性,有望为ETNBC的临床治疗提供指导意见。
Schmid
本研究对5种常见AEs进行了Meta分析,结果显示,无论是化疗联合帕博利珠单抗还是紫杉醇联合帕博利珠单抗,试验组患者3~5级腹泻、中性粒细胞减少症、贫血及皮肤反应的发生率与对照组比较,差异均无统计学意义(P>0.05);而试验组患者3~5级疲乏的发生率与对照组比较,差异有统计学意义(P<0.05),其中试验组患者疲乏发生率为3.4%,对照组疲乏发生率为1.3%,提示加用帕博利珠单抗可能增加患者发生疲乏的概率。
此外,帕博利珠单抗单药治疗在ETNBC患者中表现出良好的耐受性,3级以上AEs的发生率为9.5%~19
本研究的主要局限性是纳入的RCT数量有限及针对疾病的不同阶段采用的治疗方案不同。但本系统评价提供了帕博利珠单抗不同治疗方案治疗ETNBC的安全性信息,为未来使用帕博利珠单抗治疗ETNBC的安全性提供了强有力的证据。
在常见AEs方面,帕博利珠单抗可能会增加患者发生疲乏的概率,但并不会增加总体AEs及其他常见AEs的风险,具有可接受的安全性,在ETNBC患者中耐受性良好。然而,仍需要更多帕博利珠单抗相关大型多中心、随机、双盲试验来证实这些结果,并且需要开展更多帕博利珠单抗与紫杉醇等不同组合的试验。
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