Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic brokers. In phase II trials, antiangiogenic therapy has exhibited benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients. focal adhesion kinase, mitogen-activated protein kinase, phosphoinositide 3-kinase, protein kinase B, vascular endothelial growth factor Research has exhibited that both neuropilin-1 and neuropilin-2 act as accessory receptors for the VEGF165 isoform [33], and also that overexpression of neuropilin-1 in colorectal cancer cells increases tumor growth and angiogenesis [34]. Another characteristic of neuropilin-1 is usually that this molecule is usually upregulated by the activation of EGFR, another therapeutic target for colorectal cancer. Bevacizumab exerts its action against VEGF-A, which results in the prevention of VEGFR activation and the subsequent signaling cascades [35]. Aflibercept prevents VEGFR activation by binding to VEGF-A and PlGF [36]. Main antiangiogenic brokers in colorectal cancer Three main antiangiogenic agents have been shown to improve the outcomes of patients with mCRC when given in combination with chemotherapy, namely, bevacizumab, aflibercept, and regorafenib. Some of the main studies involved in the clinical development of bevacizumab are described briefly below. Hurwitz et al. conducted a phase III trial in 813 patients with previously untreated mCRC [37]. Patients were randomized to receive irinotecan plus bolus 5-fluorouracil and leucovorin (IFL) with or without bevacizumab. The addition of bevacizumab resulted in a statistical and clinical improvement in terms of median OS (20.3 vs 15.6?months, respectively; complete response, early tumor shrinkage, irinotecan, 5-fluorouracil and leucovorin, oxaliplatin, 5-fluorouracil and leucovorin, oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin, months, metastatic colorectal cancer, not reported, patients, progression-free Emodin survival, pathological response rate, response rate, overall survival, survival, capecitabine and irinotecan, capecitabine and oxaliplatin Retrospective studies Several retrospective analyses have provided evidence for the efficacy of bevacizumab when added to neoadjuvant and conversion chemotherapy for the Emodin treatment of patients with CRLM. The randomized phase III trial NO16966 compared the safety and efficacy of oxaliplatin-based chemotherapy with or without bevacizumab in 1400 patients with mCRC. A subsequent retrospective analysis of the resection rate in this study was performed [17]. In the intention-to-treat (ITT) population, 44 out of 699 (6.3?%) patients treated with chemotherapy plus bevacizumab underwent R0 metastasectomy, compared with 34 out of 701 (4.9?%; (%)Leukopenia145 (37)NeutropeniaC (37)Proteinuria3 (1)4 (1)C (8)7 (1)Nonhematologic toxicity, (%)Arterial thrombosis12 (2)C (2)Bleeding12 (3)13 (2)C (3)Diarrhea126 (32)C (19)36 (7)Fatigue48 (10)Fistula/intra-abdominal abscess6 (1)C (1)Gastrointestinal perforation6 (2)4 (1)C (1)Hand-foot skin reactionC (3)83 (17)Hyperbilirubinemia40 (8)Hypertension43 (11)26 (4)C (19)36 (7)Thrombophlebitis35 (9)Venous thrombosis54 (8)C (8)Wound healing complications1 (1)Any grade 3/4 toxicity, (%)334 (85)555 (80)C (83)270 (54) Open in a separate window adverse event, best supportive care, metastatic colorectal cancer, irinotecan plus bolus 5-fluorouracil and leucovorin, irinotecan plus infusional 5-fluorouracil and leucovorin, 5-fluorouracil, leucovorin, and oxaliplatin, capecitabine and oxaliplatin Conclusions Perioperative treatment of patients with CRLM results in longer PFS and OS. In addition, in patients with high-risk features, neoadjuvant and conversion treatment provides an opportunity to gather information on the biological activity of the tumor Emodin and its response to treatment, as well as improving resectability rates. To date, three antiangiogenic brokers have been exhibited to improve the outcomes of patients with mCRC in prospective randomized trials. Aflibercept in combination with FOLFIRI as second-line treatment improves OS and PFS in patients with mCRC after first-line treatment with an oxaliplatin-based regimen, with or without an antiangiogenic agent. Regorafenib has also exhibited promising results in patients with mCRC who had progressed after receiving all approved standard treatments. However, bevacizumab is currently the only antiangiogenic drug which has exhibited benefits in the presurgical treatment of CRLM as well as in patients with mCRC. For patients with initially unresectable CRLM, chemotherapy with or without a targeted agent may downsize metastases and facilitate secondary resection. For these patients, the combination of FOLFOX or FOLFOXIRI plus bevacizumab has led to high RRs and resection rates, as well as an acceptable safety profile. FOLFOX plus bevacizumab is also effective for patients with unresectable CRLM and has a favorable safety profile, ACTB whereas irinotecan carries a higher risk of hepatic toxicity. Encouraging results regarding the impact of bevacizumab plus chemotherapy on pathological response have been reported, with a clear benefit on OS. Additionally, several studies have shown that bevacizumab may have a protective effect against liver injury, in particular steatohepatitis and vascular parenchymal injuries, which are associated with the preoperative.
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