Martins Diana, Rodrigues Jéssica, Redondo Patrícia, Julião Ivo, Faustino Cátia
Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Porto, PRT.
Cancer Epidemiology Group, IPO Porto Research Center of IPO Porto (CI-IPOP)RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)Porto Comprehensive Cancer Center (Porto.CCC), Porto, PRT.
Cureus. 2022 Mar 27;14(3):e23543. doi: 10.7759/cureus.23543. eCollection 2022 Mar.
Background Epithelial growth factor receptor inhibitors (EGFRi) and bevacizumab are the two main target therapies available for first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC). However, the optimal sequencing of these agents remains unclear. In this study, we aimed to evaluate the optimal sequence with EGFRi and bevacizumab in first- and second-line treatment. Methods This was a retrospective cohort study with RAS wt mCRC patients identified by extended RAS analysis between 2013 and 2020 at a comprehensive cancer center. All patients had to be treated with a sequence of systemic treatment that included an EGFRi and bevacizumab in first and second line, in either order. Two groups were defined according to treatment sequence: first-line EGFRi followed by second-line bevacizumab (cohort A) or the reverse sequence (cohort B). Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival with first-line treatment (PFS1), progression-free survival with second-line treatment (PFS2), objective response rate (ORR), and serious adverse events (grade ≥ 3). Survival was estimated using the Kaplan-Meier method, and survival differences between groups were compared using the log-rank test. Univariate analyses were performed using Cox proportional hazard model. Results A total of 124 patients were included (93 in cohort A and 31 in cohort B). There were no statistical significant differences in median OS (A: 34.9 months vs B: 29.2 months; p=0.590), PFS1 (A: 13.1 months vs B: 8.2 months; p=0.600), and PFS2 (A: 7.4 months vs B: 5.5 months; p=0.110) between groups. No significant differences were also found between treatment sequences in subgroups defined by age, gender, primary tumor location, sidedness, timing of metastasis, number of metastatic sites, multimodal therapy, primary tumor resection, and first-line chemotherapy backbone. ORR was significantly higher with first-line treatment with EGFRi (A: 55.9% vs B: 22.6%; p=0.001). At the final follow-up, the proportion of patients with SAEs was similar between treatment sequences (p=0.827). Discussion Our study showed no impact of the treatment sequence with EGFRi and bevacizumab in the survival of RAS wt mCRC. However, patients treated with first-line EGFRi had significantly higher response rates, thus favoring its use in patients with symptomatic tumors and borderline resectable metastasis. Prospective trials are warranted to define the optimal sequence of treatment in RAS wt mCRC patients.
背景 表皮生长因子受体抑制剂（EGFRi）和贝伐单抗是可用于一线治疗RAS野生型（wt）转移性结直肠癌（mCRC）的两种主要靶向治疗药物。然而，这些药物的最佳给药顺序仍不明确。在本研究中，我们旨在评估EGFRi和贝伐单抗在一线和二线治疗中的最佳给药顺序。
方法 这是一项回顾性队列研究，研究对象为2013年至2020年在一家综合癌症中心通过扩展RAS分析确定的RAS wt mCRC患者。所有患者必须接受一线和二线系统性治疗，治疗顺序为EGFRi和贝伐单抗中的一种，另一种药物随后使用，两种顺序均可。根据治疗顺序将患者分为两组：一线使用EGFRi，二线使用贝伐单抗（队列A）或相反顺序（队列B）。主要终点为总生存期（OS）。次要终点为一线治疗的无进展生存期（PFS1）、二线治疗的无进展生存期（PFS2）、客观缓解率（ORR）和严重不良事件（≥3级）。采用Kaplan-Meier法估计生存率，使用对数秩检验比较组间生存差异。使用Cox比例风险模型进行单因素分析。
结果 共纳入124例患者（队列A 93例，队列B 31例）。两组间的中位OS（A组：34.9个月 vs B组：29.2个月；p = 0.590）、PFS1（A组：13.1个月 vs B组：8.2个月；p = 0.600）和PFS2（A组：7.4个月 vs B组：5.5个月；p = 0.110）无统计学显著差异。在按年龄、性别、原发肿瘤部位、左右侧、转移时间、转移部位数量、多模式治疗、原发肿瘤切除和一线化疗方案定义的亚组中，治疗顺序之间也未发现显著差异。一线使用EGFRi治疗的ORR显著更高（A组：55.9% vs B组：22.6%；p = 0.001）。在最后一次随访时，治疗顺序之间严重不良事件患者的比例相似（p = 0.827）。
讨论 我们的研究表明，EGFRi和贝伐单抗的治疗顺序对RAS wt mCRC患者的生存无影响。然而，一线使用EGFRi治疗的患者缓解率显著更高，因此更适合用于有症状肿瘤和边缘可切除转移的患者。有必要进行前瞻性试验来确定RAS wt mCRC患者的最佳治疗顺序。
