抗血管生成药物联合化疗对恶性胸膜间皮瘤的疗效和安全性:更新的系统评价与meta分析

doi:10.3969/j.issn.1004-583X.2025.04.002

摘要/Abstract

摘要：

目的对抗血管生成药物在恶性胸膜间皮瘤(malignant pleural mesothelioma, MPM)中的疗效和安全性进行系统评价。方法检索Pubmed,Cochrane,知网等数据库检索建库至2024年11月发表的关于抗血管生成药物在MPM中的疗效及安全性的相关文献,应用RevMan 5.4进行meta分析。结果纳入6篇高质量RCT,涉及1 632例患者,其中研究组(血管生成抑制剂+化疗)814例,对照组(安慰剂+ 化疗或单独化疗)818例。结果显示:与对照组相比,研究组在远期生存与近期疗效有积极意义(HR=0.83,95%CI: 0.73~0.96,P=0.009;HR=0.77,95%CI: 0.64~0.93,P=0.007)且不良反应发生率在可接受范围内(RR=1.21, 95%CI: 1.12~1.30,P<0.00001)。结论在化疗中联合血管生成抑制剂相对于安慰剂联合化疗和单独化疗在治疗MPM中更具有优势,且不良反应控制在可接受范围内。

关键词: 恶性间皮瘤, 血管生成抑制剂, 有效性, 安全性

Abstract:

Objective This systematic review and meta-analysis aims to assess the efficacy and safety of anti-angiogenic drugs in treating malignant pleural mesothelioma (MPM). Methods Articles reporting the efficacy and safety of anti-angiogenic drugs in treating MPM from database inception through November 2024 were searched in the PubMed, Cochrane, and CNKI. Meta-analysis was performed using RevMan 5.4. Results Six high-quality randomized clinical trials (RCTs) involving 1, 632 patients were enrolled, including 814 in the experimental group (angiogenesis inhibitors+chemotherapy) and 818 in the control group (placebo+chemotherapy or chemotherapy alone). Compared with the control group, patients in the experimental group showed superior long-term survival (HR=0.83, 95%CI: 0.73-0.96, P=0.009) and short-term efficacy (HR=0.77, 95%CI: 0.64-0.93, P=0.007). The incidence of adverse reactions remained within acceptable limits (RR=1.21, 95%CI: 1.12-1.30, P<0.00001). Conclusion Anti-angiogenetic drugs combined with chemotherapy provides significant clinical benefits over placebo plus chemotherapy or chemotherapy alone in MPM treatment, with manageable toxicity profiles.

Key words: mesothelioma, malignant, angiogenesis inhibitors, efficacy, safety

中图分类号:

R730.262.7

唐旭, 左庄, 杨凯, 张志源, 王淇, 董信春, 苟云久. 抗血管生成药物联合化疗对恶性胸膜间皮瘤的疗效和安全性:更新的系统评价与meta分析[J]. 临床荟萃, 2025, 40(4): 304-312.

Tang Xu, Zuo Zhuang, Yang Kai, Zhang Zhiyuan, Wang Qi, Dong Xinchun, Gou Yunjiu. The efficacy and safety of anti-angiogenic drugs combined with chemotherapy in treating malignant pleural mesothelioma: An updated systematic review and meta-analysis[J]. Clinical Focus, 2025, 40(4): 304-312.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://lchc.magtechjournal.com/CN/10.3969/j.issn.1004-583X.2025.04.002

https://lchc.magtechjournal.com/CN/Y2025/V40/I4/304

图/表 13

图1 检索流程图

Fig. 1 Flowchart of the retrieval process

表1 纳入文献基本信息

Tab. 1 Basic information of the included literature

第一作者	时间	例数^*	治疗方式		HR(95%CI)		三级不良反应发生率
第一作者	时间	例数^*	对照组	研究组	PFS	OS	对照组	研究组
Zalcman^[6]	2016	223/225	AP	贝伐珠单抗+AP	0.61(0.50~0.75)	0.77(0.62~0.95)	139/224	158/222
Gregorc^[14]	2018	193/193	安慰剂+最佳治疗	NGF-hTNF+最佳治疗	0.95(0.78~1.17)	0.94(0.75~1.18)	118/193	136/193
Scagliotti^[15]	2019	229/229	安慰剂+AP	尼达尼布+AP	1.01(0.79~1.30)	1.12(0.79~1.58)	127/228	153/227
Tsao^[16]	2019	45/47	安慰剂+AP	西地尼布+AP	0.70(0.46~1.09)	0.88(0.57~1.35)	27/47	31/45
Pinto^[17]	2021	80/81	吉西他滨加安慰剂	吉西他滨+ramucirumab	0.79(0.66~0.94)	0.71(0.59~0.85)	24/81	35/80
Grosso^[18]	2017	44/43	尼达尼布	培美曲塞+顺铂+尼达尼布	0.54(0.33~0.87)	0.77(0.46~1.29)	22/43	35/44

图2 偏倚风险比例

Fig. 2 Proportion of risk of bias

图3 偏倚风险总结

Fig. 3 Summary of risk of bias

图4 OS的meta分析森林图

Fig. 4 Forest plot of the meta-analysis for overall survival

图5 PFS的meta分析森林图

Fig. 5 Forest map of meta-analysis for progression-free survival

图6 3~5级不良反应meta分析森林图

Fig. 6 Forest map of meta-analysis of grade 3 to 5 adverse reactions

图7 上皮样亚组OS的meta分析森林图

Fig. 7 Forest map of Meta-analysis of overall survival in the epithelioid subgroup

图8 非上皮样亚组OS的meta分析森林图

Fig. 8 Forest map of meta-analysis of total survival in the non-epithelioid subgroups

图9 上皮样亚组PFS的meta分析森林图

Fig. 9 Forest map of meta-analysis of progression-free survival in the epithelioid subgroup

图10 非上皮样亚组PFS的meta分析森林图

Fig. 10 Forest map of meta-analysis of progression-free survival in non-epithelioid subgroups

图11 3~5级各组不良反应亚组meta分析森林图

Fig. 11 Forest map of meta-analysis of grade 3 to 5 adverse reactions in groups

图12 发表偏倚漏斗图

Fig. 12 Funnel polt of publication bias

参考文献 30

[1]	Sauter JL, Dacic S, Galateau-Salle F, et al. The 2021 WHO classification of tumors of the pleura: Advances since the 2015 classification[J]. J Thorac Oncol, 2022, 17(5): 608-622.
[2]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[3]	Attanoos RL, Churg A, Galateau-Salle F, et al. Malignant mesothelioma and its non-asbestos causes[J]. Arch Pathol Lab Med, 2018, 142(6): 753-760. doi: 10.5858/arpa.2017-0365-RA pmid: 29480760
[4]	Nicolini F, Bocchini M, Bronte G, et al. Malignant pleural mesothelioma: State-of-the-art on current therapies and promises for the future[J]. Front Oncol, 2019, 9: 1519. doi: 10.3389/fonc.2019.01519 pmid: 32039010
[5]	Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase Ⅲ study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma[J]. J Clin Oncol, 2023, 41(12): 2125-2133. doi: 10.1200/JCO.22.02542 pmid: 37068377
[6]	Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A randomised, controlled, open-label, phase 3 trial[J]. Lancet, 2016, 387(10026): 1405-1414. doi: S0140-6736(15)01238-6 pmid: 26719230
[7]	Tsao A, Nakano T, Nowak AK, et al. Targeting angiogenesis for patients with unresectable malignant pleural mesothelioma[J]. Semin Oncol, 2019, 46(2): 145-154. doi: S0093-7754(19)30060-0 pmid: 31280996
[8]	Cinausero M, Rihawi K, Cortiula F, et al. Emerging therapies in malignant pleural mesothelioma[J]. Crit Rev Oncol Hematol, 2019, 144: 102815.
[9]	Disselhorst MJ, Baas P. Chemotherapy options versus “novel” therapies: how should we treat patients with malignant pleural mesothelioma[J]. Transl Lung Cancer Res, 2020, 9(Suppl 1): S77-s85.
[10]	Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma[J]. J Pathol, 2001, 193(4): 468-475. doi: 10.1002/path.824 pmid: 11276005
[11]	Cacciotti P, Strizzi L, Vianale G, et al. The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor[J]. Am J Respir Cell Mol Biol, 2002, 26(2): 189-193.
[12]	李晶, 张彩苹. 血管生成抑制剂治疗恶性胸膜间皮瘤的有效性及安全性的Meta分析[J]. 实用药物与临床, 2022, 25(2): 128-132.
[13]	Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis[J]. Trials, 2007, 8: 16. pmid: 17555582
[14]	Gregorc V, Gaafar RM, Favaretto A, et al. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): A randomised, double-blind, placebo-controlled phase 3 trial[J]. Lancet Oncol, 2018, 19(6): 799-811. doi: S1470-2045(18)30193-1 pmid: 29753703
[15]	Scagliotti GV, Gaafar R, Nowak AK, et al. Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): A double-blind, randomised, placebo-controlled phase 3 trial[J]. Lancet Respir Med, 2019, 7(7): 569-580. doi: 10.1016/S2213-2600(19)30139-0 pmid: 31103412
[16]	Tsao AS, Miao J, Wistuba LI, et al. Phase II trial of cediranib in combination with cisplatin and pemetrexed in chemotherapy-naïve patients with unresectable malignant pleural mesothelioma (SWOG S0905)[J]. J Clin Oncol, 2019, 37(28): 2537-2547. doi: 10.1200/JCO.19.00269 pmid: 31386610
[17]	Pinto C, Zucali PA, Pagano M, et al. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): A randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet Oncol, 2021, 22(10): 1438-1447. doi: 10.1016/S1470-2045(21)00404-6 pmid: 34499874
[18]	Grosso F, Steele N, Novello S, et al. Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: Phase II results from the randomized, placebo-controlled LUME-Meso Trial[J]. J Clin Oncol, 2017, 35(31): 3591-600. doi: 10.1200/JCO.2017.72.9012 pmid: 28892431
[19]	Buikhuisen WA, Burgers JA, Vincent AD, et al. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): An open-label, multicentre, randomised phase 3 study[J]. Lancet Oncol, 2013, 14(6): 543-551. doi: 10.1016/S1470-2045(13)70125-6 pmid: 23583604
[20]	Ohta Y, Shridhar V, Bright RK, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours[J]. Br J Cancer, 1999, 81(1): 54-61.
[21]	Kumar-Singh S, Vermeulen P B, Weyler J, et al. Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma[J]. J Pathol, 1997, 182(2): 211-216. pmid: 9274533
[22]	Chan N, Bristow R G. “Contextual” synthetic lethality and/or loss of heterozygosity: Tumor hypoxia and modification of DNA repair[J]. Clin Cancer Res, 2010, 16(18): 4553-4560.
[23]	张洋, 杨帆, 王景景. 沙利度胺联合XELOX方案化疗治疗转移性结直肠癌的疗效及对生存率的影响[J]. 癌症进展, 2022, 20(7): 727-730.
[24]	Howells LM, Iwuji COO, Irving GRB, et al. Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized phase iia trial[J]. J Nutr, 2019, 149(7): 1133-1139. doi: 10.1093/jn/nxz029 pmid: 31132111
[25]	Yıldırım E, Yıldırım N, Cengiz M, et al. Protective effect of adenosine triphosphate and benidipine separately or together against cardiotoxicity caused by bevacizumab[J]. Biotech Histochem, 2023, 98(3): 193-200.
[26]	Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma[J]. J Clin Oncol, 2012, 30(20): 2509-2515. doi: 10.1200/JCO.2011.41.5869 pmid: 22665541
[27]	Gad ES, Salama AAA, El-Shafie MF, et al. The anti-fibrotic and anti-inflammatory potential of bone marrow-derived mesenchymal stem cells and nintedanib in bleomycin-induced lung fibrosis in rats[J]. Inflammation, 2020, 43(1): 123-134. doi: 10.1007/s10753-019-01101-2 pmid: 31646446
[28]	Fan Y, Li X, Fang X, et al. Antifibrotic role of nintedanib in tracheal stenosis after a tracheal wound[J]. Laryngoscope, 2021, 131(9): E2496-e505.
[29]	Wozniak AJ, Schneider B, Kalemkerian GP, et al. Short report of a phase ii trial of nintedanib in recurrent malignant pleural mesothelioma (MPM)[J]. Clin Lung Cancer, 2023, 24(6): 563-567. doi: 10.1016/j.cllc.2023.04.004 pmid: 37301693
[30]	Randall LM, Monk BJ. Bevacizumab toxicities and their management in ovarian cancer[J]. Gynecol Oncol, 2010, 117(3): 497-504. doi: 10.1016/j.ygyno.2010.02.021 pmid: 20363017