Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies

Abstract

Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design.

Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer

“…For example, familial renal cell cancer is dependent on angiogenesis, but in mCRC and most other cancers, angiogenesis contributes to but is not determinant of cancer progression. It is mediated by a balance between pro‐angiogenic and anti‐angiogenic factors and receptors, including vascular endothelial growth factor (VEGF), platelet‐derived growth factor, and fibroblast growth factor …”

“…As described in Table , toxicities of VEGF inhibition include hypertension, proteinuria, wound healing complications, mucosal bleeding, arterial thrombosis, and gastrointestinal perforation …”

“…It is mediated by a balance between pro-angiogenic and anti-angiogenic factors and receptors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and fibroblast growth factor. 13 Bevacizumab (Avastin; Genentech, Inc, South San Francisco, California) is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) directed against VEGF-A, as depicted in Figure 1. Its potential mechanisms of action are believed to include the depletion of tumor vasculature as well as the temporary normalization of the crazy-quilt pattern of tumor vasculature to enhance chemotherapy delivery.…”

“…As described in Table 1, toxicities of VEGF inhibition include hypertension, proteinuria, wound healing complications, mucosal bleeding, arterial thrombosis, and gastrointestinal perforation. 13 Lastly, regorafenib (Stivarga; Bayer HealthCare Pharmaceuticals, Inc, Berlin, Germany) is a tyrosine kinase inhibitor with inhibitory activity across a wide range of targets, including KIT and RET, in addition to those involved in the development of angiogenesis. 24 Its use in refractory mCRC is based on the phase 3 CORRECT trial, 28 which randomized 760 patients who had progressed on all other lines of standard therapy to receive best supportive care plus regorafenib or a placebo.…”

FDG-PET/CT-Positive Foreign Body Granuloma Mimicking Colon Cancer Recurrence: Case Report

“…Surgical resection of the primary tumor associated with 6 months of adjuvant chemotherapy is standard treatment in patients with stage III CRC. Nevertheless, even after treatment, systemic recurrence in particular is frequent and may affect half of these stage 3 patients [3].…”