吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌疗效及安全性的Meta分析

doi:10.3877/cma.j.issn.1674-0807.2022.03.005

目的

评估吡咯替尼联合新辅助化疗治疗HER-2阳性早期或局部晚期乳腺癌的疗效及安全性。

方法

检索中国知网、万方、维普、中国生物医学文献服务系统(SinoMed)及PubMed、Embase、Cochrane Library等数据库中吡咯替尼治疗HER-2阳性早期或局部晚期乳腺癌的随机对照研究，检索年限为建库以来至2022年2月9日，文献质量按照Cochrane Review Handbook 5.1.0进行评分，提取指标包括客观反应率、总病理完全缓解率、腹泻等不良事件发生率。对符合质量评价标准的研究使用RevMan 5.4.1软件进行数据提取及定量合成，并根据其异质性大小分别采用固定效应模型或随机效应模型的方法进行分析。

结果

最终纳入4项研究，共554例患者，其中吡咯替尼联合化疗组278例，单用化疗组276例。Meta分析结果显示，吡咯替尼联合化疗较单用化疗能明显提高患者的客观反应率(RR＝1.15，95%CI：1.07~1.24，P<0.001)和总病理完全缓解率(RR＝1.90，95%CI：1.45~2.50，P<0.001)。不良反应方面，吡咯替尼联合化疗组≥3级腹泻发生率及任何级别腹泻事件发生率均明显升高(RR＝7.67，95%CI：4.38~13.45，P<0.001；RR＝5.62，95%CI：3.95~8.00，P<0.001)；而2组患者白细胞减少、血小板减少、恶心/呕吐以及手足综合征发生率的差异均无统计学意义(RR＝1.02，95%CI：0.87~1.21，P＝0.790；RR＝1.00，95%CI：0.70~1.43，P＝0.990；RR＝1.30，95%CI：1.00~1.68，P＝0.050；RR＝1.46，95%CI：0.75~2.86，P＝0.270)。

结论

针对早期或局部晚期HER-2阳性乳腺癌患者，吡咯替尼联合化疗的新辅助治疗方案能够明显提高其客观反应率及总病理完全缓解率，但同时也增加患者≥3级腹泻的发生风险。在临床实践中需重视对腹泻等不良事件的管理，以保证患者治疗的顺利进行及提高其生活质量。

关键词: 吡咯替尼, 乳腺肿瘤, 新辅助治疗, 治疗结果, 安全

Objective

To evaluate the efficacy and safety of pyrotinib in the neoadjuvant therapy of HER-2-positive early or locally advanced breast cancer.

Methods

The databases including China National Knowledge Infrastructure(CNKI), Wanfang Data, VIP Med Online, SinoMed, PubMed, Embase and Cochrane Library were searched for the literatures on pyrotinib in the neoadjuvant therapy of HER-2-positive early or locally advanced breast cancer. The retrieval period was from the establishment of the database to February 9, 2022. The quality of the research was assessed according to the Cochrane Review Handbook 5.1.0. The objective response rate, total pCR rate and incidence of adverse events (such as diarrhea) were parameters to be extracted from the literature. Revman 5.4.1 software was used for data extraction and quantitative synthesis in the studies that met the quality assessment criteria. Random effect model or fixed effect model was utilized depending on the heterogeneity.

Results

Four trials were enrolled, including 554 patients. Totally 278 patients received pyrotinib combined with chemotherapy and 276 patients received chemotherapy alone. The results of meta-analysis revealed that compared with chemotherapy alone, pyrotinib combined with chemotherapy significantly improved the objective response rate (RR=1.15, 95%CI: 1.07-1.24, P<0.001) and total pCR rate(RR=1.90, 95%CI: 1.45-2.50, P<0.001). As for adverse events, the incidence of grade 3 or above diarrhea (RR=7.67, 95%CI: 4.38-13.45, P<0.001) and the incidence of diarrhea of any grade(RR=5.62, 95%CI: 3.95-8.00, P<0.001) in combined therapy group were significantly increased compared with chemotherapy, but there was no significant difference in the incidence of leucopenia (RR=1.02, 95%CI: 0.87-1.21, P=0.790), thrombocytopenia (RR=1.00, 95%CI: 0.70-1.43, P=0.990), nausea/vomiting(RR=1.30, 95%CI: 1.00-1.68, P=0.050) and hand-foot syndrome(RR=1.46, 95%CI: 0.75-2.86, P=0.270) between two groups.

Conclusions

For patients with HER-2-positive early or locally advanced breast cancer, the neoadjuvant regimen of pyrotinib combined with chemotherapy can significantly improve the objective response rate and total pCR rate, and increase the risk of grade 3 or above diarrhea. In clinical practice, attention should be paid to the management of adverse events such as diarrhea, so as to ensure the efficacy and improve the quality of life.

Key words: Pyrotinib, Breast neoplasms, Neoadjuvant therapy, Treatment outcome, Safety

图1 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者的文献筛选流程

图2 纳入的吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌研究质量评价注：1代表Ding等^[12]的研究；2代表Li等^[13]的研究；3代表郑等^[14]的研究；4代表Wu等^[15]的研究；代表偏倚风险低；代表偏倚风险高；代表偏倚风险不明确

表1 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌研究中患者的基本特征

研究者	年份	试验组/对照组措施	例数	年龄[岁，±s或M(P₂₅，P₇₅) ]	结局指标	ORR(%)	tpCR率(%)	≥3级腹泻发生率(%)
Ding等^[12]	2021年	TCbH+P/TCbH	21	未提供^a	tpCR、ORR、腹泻发生率	100	71.4	28.6
			30			83.3	36.7	10.0
Li等^[13]	2021年	TCbH+P/TCbH	63	未提供^b	tpCR、ORR、腹泻发生率等	100	75.0	11.1
			53			75.0	25.0	0
郑向欣等^[14]	2021年	TCbH+P/TCbH	16	31.7±3.5	tpCR、ORR、腹泻发生率等	100	43.8	18.8
			16	32.4±3.9		75.0	25.0	0
Wu等^[15]	2021年	TH+P/TH	178	50(43，55)	tpCR、ORR、腹泻发生率等	91.6	41.0	44.4
			177	50(44，55)		81.9	22.0	5.1

表1 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌研究中患者的基本特征

研究者	年份	试验组/对照组措施	例数	年龄[岁，±s或M(P₂₅，P₇₅) ]	结局指标	ORR(%)	tpCR率(%)	≥3级腹泻发生率(%)
Ding等^[12]	2021年	TCbH+P/TCbH	21	未提供^a	tpCR、ORR、腹泻发生率	100	71.4	28.6
			30			83.3	36.7	10.0
Li等^[13]	2021年	TCbH+P/TCbH	63	未提供^b	tpCR、ORR、腹泻发生率等	100	75.0	11.1
			53			75.0	25.0	0
郑向欣等^[14]	2021年	TCbH+P/TCbH	16	31.7±3.5	tpCR、ORR、腹泻发生率等	100	43.8	18.8
			16	32.4±3.9		75.0	25.0	0
Wu等^[15]	2021年	TH+P/TH	178	50(43，55)	tpCR、ORR、腹泻发生率等	91.6	41.0	44.4
			177	50(44，55)		81.9	22.0	5.1

图3 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者的客观反应率森林图

图4 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者的总病理完全缓解率森林图

图5 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者的≥3级腹泻发生率森林图

表2 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者后出现的相关不良反应

不良反应	RR值	95%CI	P值
腹泻	5.62	3.95~8.00	<0.001
白细胞减低	1.02	0.87~1.21	0.790
血小板减低	1.00	0.70~1.43	0.990
恶心/呕吐	1.30	1.00~1.68	0.050
手足综合征	1.46	0.75~2.86	0.270

表2 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者后出现的相关不良反应

不良反应	RR值	95%CI	P值
腹泻	5.62	3.95~8.00	<0.001
白细胞减低	1.02	0.87~1.21	0.790
血小板减低	1.00	0.70~1.43	0.990
恶心/呕吐	1.30	1.00~1.68	0.050
手足综合征	1.46	0.75~2.86	0.270

图6 吡咯替尼新辅助治疗人表皮生长因子受体2阳性乳腺癌患者的研究发表偏倚漏斗图注：RR为相对危险度

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Efficacy and safety of pyrotinib in neoadjuvant therapy of HER-2-positive breast cancer: a meta-analysis

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Efficacy and safety of pyrotinib in neoadjuvant therapy of HER-2-positive breast cancer: a meta-analysis