Cetuximab (IMC-C225) is a chimaeric IgG1 monoclonal antibody (Mab) that binds competitively to the extracellular domain of Epidermal Growth Factor Receptor (EGFR), inhibiting Epidermal Growth Factor (EGF) binding and subsequent activation of the receptor with receptor autophosphorylation, and inducing its internalization and degradation. The EGFR is a member of the ErbB family of tyrosine kinase cell-surface receptors that are dysregulated in many tumor types. The EGFR starts intracellular signalling and causes cellular proliferation when it is activated. Cetuximab blocks the production of proangiogenic factors such as VEG-F, interleukin-8 and basic fibroblast growth factor (bFGF).

It is well-tolerated, its main side effect being an acneiform rash, but can also cause asthenia, fever, nausea, elevation of aminotransferases, and allergic reactions. Cetuximab has shown single-agent antitumor activity, unlike the EGFR-tyrosine kinase inhibitors.

Cetuximab has been shown to improve the antitumor activity of irinotecan in preclinical studies (31). The mechanism of this enhancement is not clear but is thought to be due to pro-apoptotic effects or separate antiangiogenic effects caused by the inhibition of EGFR signalling inhibition.

This agent has been studied in patients with advanced disease that is refractory to irinote-can. It has been shown in such cases that the objective response rate with cetuximab alone is approximately 10% and in combination with irinotecan this rises to 22% (32). Cunningham's large randomized trial recently investigated the effect of single agent cetuximab compared with combination cetuximab and irinotecan in 329 patients with advanced, irinotecan-refractory disease (32). This allocated 218 patients who had progressed during or within three months after treatment with irinotecan based chemotherapy to the combination arm and 111 to monother-apy. Amongst other entry criteria patients required immunohistochemical evidence of EGFR expression. A clinically significant activity of cetuximab in both groups was revealed, but there was a higher rate of response in the combination therapy group compared to the cetuximab monotherapy group [22.9% (95% CI, 17.5-18.1%) vs. 10.8% (95% CI 5.7-18.1%) P = 0.007]. The median time to progression was greater in the combination-therapy group (4.1 vs. 1.5 months, P < 0.001 by log-rank test). The median survival time was 8.6 months in the monotherapy group and 6.9 in the combination arm (P = 0.48). The trial organizers felt that the effectiveness of the combination treatment suggested that EGFR inhibition by cetuximab may overcome irinotecan resistance, perhaps by annulling drug efflux, restoring apoptosis or impairing DNA-repair activity. They state that cetuximab may therefore be helpful for patients once the three usual chemotherapy options of 5-FU, oxaliplatin, and irinotecan have been used, by providing a 22.9% tumor response rate in the combination setting described above.

IFL + bevacizumab

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