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Abstract：
Background: Evidence comparing the efficacy of different treatments for patients with unresectable colorectal liver metastases (CRLM) receiving first-line or maintenance therapy is sparse. We aimed to assess the efficacy and safety of these treatments, with a distinct focus on evaluating first-line and maintenance treatments separately. Methods: We conducted Bayesian network meta-analyses, sourcing English-language randomized controlled trials (RCTs) published through July 2023 from databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and key conference proceedings. Phase Ⅱ or Ⅲ trials that assessed two or more therapeutic regimens were included. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), adverse events graded as 3 or above (SAE), and R0 liver resection rate. Hazards Ratios (HRs) and 95% confidence intervals (CI) were used as effect size for OS and PFS, Odds Ratios (ORs) and 95% CI were used for ORR, SAEs and R0 resection rate. Subgroup and sensitive analyses were conducted to analysis the model uncertainty (PROSPERO: CRD42023420498). Results: 56 RCTs were included (50 for first-line treatment, six for maintenance therapies), with a total of 21,323 patients. Regarding first-line, for OS, the top three mechanisms were: local treatment + single-drug chemotherapy (SingleCT), Targeted therapy (TAR)+SingleCT, and TAR + multi-drug chemotherapy (MultiCT). Resection or ablation (R/A)+SingleCT, S1, and Cetuximab + intensified fluorouracil-based combination chemotherapy (ICTFU) were identified as the best treatments. For PFS, the top three mechanisms were: Immune therapy + TAR + MultiCT, multi-targeted therapy (MultiTAR), TAR + SingleCT. The top three treatments were: Atezolizumab + Bevacizumab + fluorouracil-based combination chemotherapy (CTFU), TAS-102+bevacizumab, Bevacizumab + ICTFU. Cetuximab + CTFU was the best choice for RAS/RAF wild-type patients. Regarding maintenance treatment, Bevacizumab + SingleCT and Adavosertib were the best options for OS and PFS, respectively. For safety, MultiCT was the safest, followed by local treatment + MultiCT, TAR + MultiCT caused the most SAEs. Bevacizumab plus chemotherapy was found to be the safest among all targeted combination therapies. Conclusion: In first-line, local treatment or targeted therapsy plus chemotherapy are the best mechanisms. R/A + SingleCT or CTFU performed the best for OS, Atezolizumab + Bevacizumab + ICTFU was the best option regarding PFS. For RAS/RAF wild-type patients, Cetuximab + CTFU was the optimal option. Monotherapy may be preferred choice for maintenance treatment. Combination therapy resulted in more SAEs when compared to standard chemotherapy.
摘要：
背景：比较接受一线或维持治疗的不可切除的结直肠癌肝转移（CRLM）患者不同治疗方法的疗效的证据很少。我们旨在评估这些治疗的疗效和安全性，特别注重分别评估一线和维持治疗。方法：我们进行了贝叶斯网络荟萃分析，从包括PubMed，Embase,Cochrane图书馆,ClinicalTrials.gov,和关键会议记录。包括评估两种或两种以上治疗方案的Ⅱ期或Ⅲ期试验。主要结果是总生存期（OS）。次要结局包括无进展生存期（PFS），客观反应率（ORR），不良事件分级为3级或以上（SAE），和R0肝切除率。使用危害比（HR）和95%置信区间（CI）作为OS和PFS的效应大小，ORR使用赔率(OR)和95%CI，SAEs和R0切除率。进行亚组和敏感性分析以分析模型的不确定性（PROSPERO：CRD42023420498）。结果：纳入56项RCT（一线治疗50项，六个用于维持治疗)，共有21,323名患者。关于第一行，对于操作系统，前三个机制是：局部治疗+单药化疗（SingleCT），靶向治疗（TAR）+单CT，TAR+多药化疗（MultiCT）。切除或消融术（R/A）+单CT，S1和西妥昔单抗+基于氟尿嘧啶的强化联合化疗(ICTFU)被确定为最佳治疗。对于PFS，前三种机制是：免疫治疗+TAR+MultiCT，多靶向治疗（MultiTAR），TAR+SingleCT。前三名的治疗方法是：阿替珠单抗+贝伐单抗+氟尿嘧啶联合化疗（CTFU），TAS-102+贝伐单抗，贝伐单抗+ICTFU。西妥昔单抗+CTFU是RAS/RAF野生型患者的最佳选择。关于维护处理，贝伐单抗+SingleCT和Adavosertib是OS和PFS的最佳选择，分别。为了安全,MultiCT是最安全的,其次是局部治疗+MultiCT，TAR+MultiCT引起的SAE最多。发现贝伐单抗加化疗是所有靶向联合疗法中最安全的。结论：在第一线，局部治疗或靶向治疗加化疗是最好的机制。R/A+SingleCT或CTFU在操作系统中表现最好，阿替珠单抗+贝伐单抗+ICTFU是PFS的最佳选择。对于RAS/RAF野生型患者，西妥昔单抗+CTFU是最佳选择。单一疗法可能是维持治疗的首选。与标准化疗相比，联合治疗导致更多的SAE。
