Targeted therapy in advanced colorectal cancer, an update

Targeted Oncology (Impact Factor: 4). 07/2007; 2(3):165-172. DOI: 10.1007/s11523-007-0052-7


The introduction of inhibitors of signal transduction pathways has increased the therapeutic arsenal for patients with advanced
colorectal cancer (ACC). Bevacizumab, a monoclonal vascular endothelial growth factor antibody, is currently part of the standard
first-line treatment in combination with fluoropyrimidine-based chemotherapy. Cetuximab, a chimeric monoclonal antibody against
the epidermal growth factor receptor, has shown efficacy in irinotecan-refractory ACC patients. Several experimental targeted
agents, including small molecules that inhibit receptor tyrosine kinase activity, are currently being tested. We review the
mechanism of action as well as the current status of targeted therapy in ACC.

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    • "The addition of bevacizumab (a humanized mAb against the vascular endothelial growth factor) to fluoropyrimidine-containing chemotherapy49 results in a significant survival benefit and it is currently considered as part of standard first-line therapy. In irinotecan monotherapy-resistant patients, the use of cetuximab improves mPFS. "
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    ABSTRACT: Worldwide, colorectal cancer (CRC) is the fourth most commonly diagnosed malignant disease and the second leading cause of cancer-related death in Western nations. In 2008 there were an estimated 148,810 new cases and 49,960 deaths in the US. For several years different chemotherapeutic regimens, based on fluoropyrimidines, irinotecan and oxaliplatin, have been used in advanced CRC, but survival is still unsatisfactory. New targeted therapies, including drugs and monoclonal antibodies (MoABs), show great promise in the fight against CRC and have shown activity in different disease settings. Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer (mCRC). As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The combination of this drug with classical chemotherapies has shown better clinical profiles reflected in an improvement in overall and progression-free survival. Clinical trials established the role of cetuximab, particularly with irinotecan, in irinotecan-refractory/heavily pretreated patients. Whereas cetuximab has a clear indication in the salvage setting, its role in first-line therapy remains investigational. It is particularly encouraging that cetuximab may enhance curative opportunities in patients with early metastatic disease, suggesting that adding cetuximab in first-line therapy may downstage disease in some patients, and, as a result, allow potentially curative resection of previously unresectable metastases. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit, and the role of cetuximab in first-line treatment of metastatic CRC.
    OncoTargets and Therapy 02/2009; 2:73-82. · 2.31 Impact Factor
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    ABSTRACT: Targeting the vascular endothelial growth factor or the epidermal growth factor receptor (EGFR) has shown efficacy in advanced colorectal cancer (ACC), but no data are available on the combination of these strategies with chemotherapy in the first-line treatment. The CAIRO2 study evaluates the effect of adding cetuximab, a chimeric mAb against EGFR, to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC. In all, 755 patients were randomly assigned between treatment with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. The primary end point is progression-free survival. We here present the toxicity results in the first 400 patients that entered the study. The incidence of overall grade 3-4 toxicity was significantly higher in arm B compared with arm A (81% versus 72%, P = 0.03). This difference is fully attributed to cetuximab-related skin toxicity. The addition of cetuximab did not result in an increase of gastrointestinal toxicity or treatment-related mortality. The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab in the first-line treatment of ACC appears to be safe and feasible. No excessive or unexpected toxicity in the cetuximab-containing treatment arm was observed.
    Annals of Oncology 05/2008; 19(4):734-8. DOI:10.1093/annonc/mdm607 · 7.04 Impact Factor
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    ABSTRACT: Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation.
    Investigational New Drugs 09/2008; 26(4):393-7. DOI:10.1007/s10637-008-9125-4 · 2.92 Impact Factor
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