Rossini Daniele, Boccaccino Alessandra, Carullo Martina, Antoniotti Carlotta, Dima Giovanni, Ciracì Paolo, Marmorino Federica, Moretto Roberto, Masi Gianluca, Cremolini Chiara
Unit of Oncology, University Hospital of Pisa, Via Roma 67, 56126, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 67, 56126, Pisa, Italy.
Azienda Ospedaliero Universitaria Pisana, Unit of Medical Oncology 2, Pisa, Via Roma 67, 56126, Italy.
Eur J Cancer. 2023 May;184:106-116. doi: 10.1016/j.ejca.2023.02.006. Epub 2023 Feb 17.
Retrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented.
We searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed.
We identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39-2.26-0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68-0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12-1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness.
Our updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided.
既往一线治疗RAS野生型转移性结直肠癌（mCRC）试验的回顾性亚组分析提示，原发肿瘤部位对抗表皮生长因子受体（EGFR）药物疗效有预测作用。近期，公布了关于双联方案/贝伐单抗对比双联方案/抗EGFR的新的头对头试验，即PARADIGM和CAIRO5试验。
我们检索了比较双联化疗联合抗EGFR或贝伐单抗作为RAS野生型mCRC患者一线治疗的II期和III期试验。汇总了总体研究人群的总生存期（OS）、无进展生存期（PFS）、总缓解率（ORR）和根治性切除率结果，并根据原发部位，采用随机效应和固定效应模型进行两阶段分析。然后分析部位与治疗效果之间的相互作用。
我们纳入了5项试验（PEAK、CALGB/SWOG 80405、FIRE-3、PARADIGM和CAIRO5），共2739例患者，其中77%为左侧肿瘤，23%为右侧肿瘤。在左侧mCRC患者中，使用抗EGFR药物与更高的ORR（74%对62%，OR = 1.77 [95%置信区间{CI} 1.39 - 2.26 - 0.88]，p < 0.0001）、更长的OS（风险比[HR] = 0.77 [95% CI 0.68 - 0.88]，p < 0.0001）相关，PFS无显著延长（HR = 0.92，p = 0.19）。在右侧mCRC患者中，使用贝伐单抗与更长的PFS（HR = 1.36 [95% CI 1.12 - 1.65]，p = 0.002）相关，OS无显著延长（HR = 1.17，p = 0.14）。亚组分析证实，原发肿瘤部位与治疗组之间在ORR（p = 0.02）、PFS（p = 0.0004）和OS（p = 0.001）方面存在显著的相互作用效应。根据治疗和部位，根治性切除率未发现差异。
我们更新的荟萃分析证实了原发肿瘤部位在RAS野生型mCRC患者一线治疗选择中的作用，强烈推荐在左侧肿瘤中使用抗EGFR药物，在右侧肿瘤中优先选择贝伐单抗。
