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Abstract：
UNASSIGNED: To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis.
UNASSIGNED: The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
UNASSIGNED: A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
UNASSIGNED: Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
UNASSIGNED: The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies.
UNASSIGNED: A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state.
UNASSIGNED: Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.
摘要：
UNASSIGNED：为了对现有的疗效荟萃分析进行系统评价，新型Polo样激酶-1（Plk1）抑制剂在各种肿瘤治疗中的安全性和药代动力学，并评估纳入荟萃分析的方法学质量和证据强度。
未经批准：Medline，PubMed,Embase,等。于2022年6月30日进行了搜索和更新。纳入22项符合条件的临床试验，共涉及1256名患者进行分析。随机对照试验（RCT）比较了疗效或安全性，或两种Plk1抑制剂与安慰剂（活性或惰性）的参与者。要包括在内，研究必须是RCT，准RCT,和非随机比较研究。
UNASSIGNED：两项试验的荟萃分析报告了总体人群的无进展生存期（PFS）（效应大小（ES），1.01；95%置信区间(CI)，0.73-1.30，I2=0.0%，P<0.001）和总体人群的总生存期（OS）（ES，0.91；95%CIs，0.31-1.50，I2=77.6%，P=0.003)。18个不良事件（AEs）反映Plk1抑制剂组发生AEs的可能性比对照组高1.28倍（比值比（ORs），1.28；95%CIs，1.02-1.61)。荟萃分析结果显示,神经系统中AEs的发生率最高(ES,0.202；95%CIs，0.161-0.244)，其次是血液系统(ES，0.190；95%CI，0.178-0.201)和消化系统(ES，0.181；95%CIs，0.150-0.213）。Rigosertib（01910年。Na）与消化系统不良事件（ES，0.103；95%CIs，0.059-0.147),但BI2536和Volasertib(BI6727)增加了血液系统不良事件的风险(ES，0.399；95%CI，0.294-0.504）。5项符合条件的研究报告了低剂量（100mg）队列和高剂量（200mg）队列的药代动力学参数，总血浆清除率没有统计学差异，稳态时的终末半衰期和表观分布量。
UNASSIGNED：Plk1抑制剂在改善OS方面效果更好，耐受性良好，有效和安全地降低疾病的严重程度，同时提高生活质量，特别是在非特异性肿瘤患者中，呼吸系统肿瘤,肌肉骨骼系统肿瘤，和泌尿系统肿瘤.然而,他们无法延长PFS。从纵向整体水平分析，与身体中的其他系统相比，Plk1抑制剂应尽可能避免用于治疗与血液循环系统有关的肿瘤，消化系统和神经系统，这归因于Plk1抑制剂的干预与这些系统中AE的风险增加相关。应仔细考虑免疫治疗引起的毒性。相反，三种不同类型的Plk1抑制剂的水平比较表明Rigosertib（ON01910。Na）可能相对适合治疗与消化系统相关的肿瘤，而Volasertib（BI6727）可能更不适合治疗与血液循环系统相关的肿瘤。此外,在Plk1抑制剂的剂量选择中，100毫克的低剂量应该是优选的，同时,它还可以确保药代动力学功效与200mg的高剂量难以区分。
UNASSIGNED：https://www。crd.约克。AC.英国/普华永道/，标识符CRD42022343507。
未经批准：Medline，
UNASSIGNED：两项试验的荟萃分析报告了总体人群的无进展生存期（PFS）（效应大小（ES），
UNASSIGNED：Plk1抑制剂在改善OS方面效果更好，耐受性良好，
UNASSIGNED：https://www。
