Jiang Yunlin, Shao Taihang, Zhao Mingye, Xue Yahong, Zheng Xueping
Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
Graduate School of Nanjing University of Chinese Medicine, Nanjing, China.
Front Pharmacol. 2024 Jul 26;15:1374136. doi: 10.3389/fphar.2024.1374136. eCollection 2024.
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. 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). 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. 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.
比较不同治疗方法对接受一线或维持治疗的不可切除结直肠癌肝转移（CRLM）患者疗效的证据很少。我们旨在评估这些治疗方法的疗效和安全性，特别着重于分别评估一线治疗和维持治疗。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以及主要会议论文集在内的数据库中获取截至2023年7月发表的英文随机对照试验（RCT）。纳入评估两种或更多治疗方案的Ⅱ期或Ⅲ期试验。主要结局是总生存期（OS）。次要结局包括无进展生存期（PFS）、客观缓解率（ORR）、3级及以上不良事件（SAE）和R0肝切除率。风险比（HRs）和95%置信区间（CI）用作OS和PFS的效应量，优势比（ORs）和95%CI用于ORR、SAEs和R0切除率。进行亚组分析和敏感性分析以分析模型不确定性（国际前瞻性系统评价注册库：CRD42023420498）。纳入了56项RCT（50项用于一线治疗，6项用于维持治疗），共21323例患者。关于一线治疗，对于OS，排名前三的治疗机制是：局部治疗+单药化疗（SingleCT）、靶向治疗（TAR）+SingleCT以及TAR+多药化疗（MultiCT）。切除或消融（R/A）+SingleCT、S1以及西妥昔单抗+强化氟尿嘧啶类联合化疗（ICTFU）被确定为最佳治疗方法。对于PFS，排名前三的治疗机制是：免疫治疗+TAR+MultiCT、多靶点治疗（MultiTAR）、TAR+SingleCT。排名前三的治疗方法是：阿替利珠单抗+贝伐珠单抗+氟尿嘧啶类联合化疗（CTFU）、TAS-102+贝伐珠单抗、贝伐珠单抗+ICTFU。西妥昔单抗+CTFU是RAS/RAF野生型患者最佳选择。关于维持治疗，贝伐珠单抗+SingleCT和阿扎沃替比分别是OS和PFS的最佳选择。在安全性方面，MultiCT最安全，其次是局部治疗+MultiCT，TAR+MultiCT导致的SAEs最多。在所有靶向联合治疗中，发现贝伐珠单抗联合化疗最安全。在一线治疗中，局部治疗或靶向治疗联合化疗是最佳治疗机制。R/A+SingleCT或CTFU在OS方面表现最佳，阿替利珠单抗+贝伐珠单抗+ICTFU是PFS方面的最佳选择。对于RAS/RAF野生型患者，西妥昔单抗+CTFU是最佳选择。维持治疗可能首选单药治疗。与标准化疗相比，联合治疗导致更多SAEs。
