Aflibercept or Bevacizumab as Second-line Treatment of RAS Mutated Metastatic Colorectal Cancer

Colorectal cancer is the third most frequent neoplasm after prostate and lung in man and breast and lung cancers in woman from Western Countries. The intensive study of predictive factors has strongly ameliorated the therapeutic flow-chart of metastatic colorectal cancer (mCRC) by allowing the selection of patients who benefit from specific therapies. In this context, the assessment of RAS (N- and K-) oncogene mutations is able to predict the response to anti-EGFR agents being mutated RAS mCRC patients resistant to these drugs. In this group of patients the use of anti-angiogenic drugs (bevacizumab and aflibercept) is predominant. Still to date there are no studies to guide oncologists in the selection of the best anti-angiogenic drug (bevacizumab beyond progression vs aflibercept) after failure of the first-line chemotherapy in RAS-M mCRC patients. The present is the first observational, pragmatic, prospective study aimed to report outcomes of mCRC patients treated with folfiri plus bevacizumab versus folfiri plus aflibercept in second-line treatment of mRAS mCRC. Furthermore, the serum levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor-A and C (VEGF-A and C), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor beta (PDGF-β), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-C motif) ligand 5 (CCL5) and Placental Growth Factor (PlGF), will be evaluated before starting second-line chemotherapy with bevacizumab or aflibercept in order to evidence any pattern related to response and/or prognosis. The hypothesis is that knowledge of eventual unbalance of these factors could help to select the best anti-angiogenic drug in second-line treatment of mRAS mCRC patients.

在西方国家，结直肠癌（colorectal cancer）是男性群体中发病率排名第三的恶性肿瘤，仅次于前列腺癌与肺癌；在女性群体中则仅次于乳腺癌与肺癌。针对预测因素的深入研究极大优化了转移性结直肠癌（metastatic colorectal cancer, mCRC）的治疗流程，使得临床能够筛选出可从特定疗法中获益的患者。在此研究背景下，RAS（N型与K型）癌基因突变检测可用于预测患者对抗表皮生长因子受体（anti-EGFR）类药物的应答效果：携带RAS突变的mCRC患者对这类药物存在耐药性。对于该类患者，抗血管生成药物贝伐珠单抗（bevacizumab）与阿柏西普（aflibercept）的使用占据主导地位。迄今为止，尚无研究可指导肿瘤学家在RAS突变型mCRC患者一线化疗失败后，选择最优的抗血管生成药物（贝伐珠单抗跨线治疗（bevacizumab beyond progression）vs阿柏西普）。本研究为首个观察性、实用性、前瞻性研究，旨在报告RAS突变型mCRC患者二线治疗中，采用FOLFIRI方案联合贝伐珠单抗对比FOLFIRI方案联合阿柏西普的临床结局。此外，本研究将在患者接受贝伐珠单抗或阿柏西普二线化疗前，检测其血清中血管生成素-1（Ang-1）、血管生成素-2（Ang-2）、血管内皮生长因子-A与C（VEGF-A、VEGF-C）、基质细胞衍生因子-1（SDF-1）、血小板衍生生长因子β（PDGF-β）、碱性成纤维细胞生长因子（bFGF）、白细胞介素-8（IL-8）、趋化因子（C-C基序）配体2（CCL2）、趋化因子（C-C基序）配体5（CCL5）以及胎盘生长因子（PlGF）的水平，以探寻与治疗应答和/或预后相关的分子模式。本研究的核心假说为：明确上述细胞因子的失衡状态，可助力肿瘤学家在RAS突变型mCRC患者的二线治疗中选择最优抗血管生成药物。