中国循证医学杂志

中国循证医学杂志

CDK4/6 抑制剂联合内分泌治疗晚期乳腺癌有效性和安全性的 Meta 分析

查看全文

目的系统评价 CDK4/6 抑制剂联合内分泌治疗晚期乳腺癌的有效性和安全性。方法计算机检索 PubMed、EMbase、The Cochrane Library、CNKI、WanFang Data 和 VIP 数据库,搜集有关 CDK4/6 抑制剂联合内分泌治疗晚期乳腺癌的随机对照试验(RCT),检索时限均从建库至 2017 年 10 月 13 日。由 2 名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用 RevMan 5.3 软件进行 Meta 分析。结果共纳入 4 个 RCT,共计 2 524 例患者。Meta 分析结果显示:与安慰剂联合内分泌治疗相比,CDK4/6 抑制剂联合内分泌治疗可提高晚期乳腺癌患者中位无进展生存率[RR=0.53,95%CI(0.47,0.60),P<0.000 01]和客观缓解率[RR=1.67,95%CI(1.47,1.91),P<0.000 01]。但两组在临床获益率[RR=0.59,95%CI(0.75,1.19),P=0.64]差异无统计学意义。在不良反应方面,CDK4/6 抑制剂联合内分泌治疗的嗜中性粒细胞减少[RR=49.76,95%CI(26.85,92.21),P<0.000 01]、白细胞减少[RR=48.69,95%CI(17.74,133.61),P<0.000 01]、贫血[RR=2.96,95%CI(1.61,5.42),P=0.000 5]和乏力[RR=3.11,95%CI(1.37,7.08),P=0.007]等不良反应发生率较高;而在恶心、腹泻及食欲降低发生率等方面,两组差异均无统计学意义。结论CDK4/6 抑制剂联合内分泌治疗晚期乳腺癌患者可提高治疗客观缓解率和中位无进展生存率,但该方案可能导致嗜中性粒细胞减少、白细胞减少、贫血和乏力等不良反应的发生率升高。受纳入研究数量和质量的限制,上述结论尚待更多高质量研究予以验证。

ObjectiveTo systematically review the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer.MethodsPubMed, EMBase, The Cochrane Library, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer from inception to October 13th, 2017. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software.ResultsA total of 4 RCTs involving 2 524 patients were included. The results of meta-analysis showed that: compared with placebo combined with endocrine therapy, CDK4/6 inhibitors combined with endocrine therapy could improve the median progression free survival rate (RR=0.53, 95%CI 0.47 to 0.60, P<0.000 01) and the objective response rate (RR=1.67, 95%CI 1.47 to 1.91,P<0.000 01). While there was no statistical difference in clinical benefit rate (RR=0.59, 95%CI 0.75 to 1.19,P=0.64). In terms of adverse reactions, CDK4/6 inhibitors combined with endocrine therapy had higher rates of neutropenia (RR=49.76, 95%CI 26.85 to 90.21, P<0.000 01), leukopenia (RR=48.69, 95%CI 18.74 to 133.61,P<0.000 01), fatigue (RR=3.11, 95%CI 1.37 to 7.08,P=0.007) and anemia (RR=2.96, 95%CI 1.61 to 5.42, P=0.000 3). There were no significant differences between two groups in nausea, diarrhea and decreased appetite.ConclusionCDK4/6 inhibitors combined with endocrine therapy for the patients with advanced breast cancer can improve median progression free survival and objective response rate, while increase the incidence of adverse events such as neutropenia, leukopenia, fatigue and anemia. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify above conclusion.

关键词: 晚期乳腺癌; CDK4/6 抑制剂; 内分泌治疗; 系统评价; Meta 分析; 随机对照试验

Key words: Advanced breast cancer; CDK4/6 inhibitor; Endocrine therapy; Systematic review; Meta-analysis; Randomized controlled trial

引用本文: 秦泽敏, 易凡, 刘满想, 关泉林, 袁文臻. CDK4/6 抑制剂联合内分泌治疗晚期乳腺癌有效性和安全性的 Meta 分析. 中国循证医学杂志, 2018, 18(4): 333-339. doi: 10.7507/1672-2531.201710030 复制

登录后 ,请手动点击刷新查看全文内容。 没有账号,
登录后 ,请手动点击刷新查看图表内容。 没有账号,
1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
3. Lobbezoo DJ, van Kampen RJ, Voogd AC, et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat, 2013, 141(3): 507-514.
4. Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol, 2016, 34(25): 3069-3103.
5. Chlebowski RT. Changing concepts of hormone receptor-positive advanced breast cancer therapy. Clin Breast Cancer, 2013, 13(3): 159-166.
6. Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer, 2011, 18(3): 333-345.
7. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol, 2015, 16(1): 25-35.
8. Ekholm SV, Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol, 2000, 12(6): 676-684.
9. Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
10. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med, 2016, 375(20): 1925-1936.
11. Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med, 2015, 373(3): 209-219.
12. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med, 2016, 375(18): 1738-1748.
13. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol, 2017, 35(25): 2875-2884.
14. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
15. Dukelow T, Kishan D, Khasraw M, et al. CDK4/6 inhibitors in breast cancer. Anticancer Drugs, 2015, 26(8): 797-806.
16. 王浩, 田超. CDK4/6 抑制剂在乳腺癌治疗中的研究进展. 药品评价, 2017, 14(12): 12-19.
17. 姜秀, 赵文辉. CDK4/6 抑制剂在乳腺癌中的研究进展. 中国肿瘤, 2017, 26(2): 125-129.
18. Finn RS, Dering J, Conklin D, et al. PD0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res, 2009, 11(5): R77.
19. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol, 2016, 13(7): 417-430.
20. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res, 2016, 18(1): 17.
21. Mullard A. FDA approves Novartis’s CDK4/6 inhibitor. Nat Rev Drug Discov, 2017, 16(4): 229.
22. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet, 2014, 384(9938): 164-172.
23. Prat A, Fan C, Fernández A, et al. Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med, 2015, 13: 303.
24. Costa R, Costa RB, Talamantes SM, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: palbociclib and ribociclib. Breast, 2017, 35: 1-7.
25. Hu W, Sung T, Jessen BA, et al. Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res, 2016, 22(8): 2000-2008.