Abstract Introduction Colorectal cancer (CRC) is one of the most common malig- nancies worldwide. It is estimated that approximately half of the patients with CRC develop metastases and eventually die. 1 Until a few years ago, treatment options for patients with metastatic CRC (mCRC) were limited to 5-fluorouracil (5-FU), with over- all response rates (ORRs) of 10%-15% and a median overall sur- vival (OS) of 10 months. 2,3 The introduction of 2 new cytotoxic drugs, irinotecan and oxaliplatin, in combination with 5-FU has resulted in significant progress in the treatment of patients with mCRC. The addition of irinotecan or oxaliplatin to 5-FU/leu- covorin (LV) has increased the median OS to 16 months and the ORR to approximately 50%. 4,5 Sequential exposure to various 1- or 2-drug combinations of fluoropyrimidines, irinotecan, and oxaliplatin has resulted in an extension of median OS to approximately 21 months. 6 Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target function- ally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR), expressed in 75% to 89% of CRCs, 7,8 or the vascular endothelial growth factor (VEGF; VEGFR). Cetuximab is a chimeric immunoglobulin (Ig) G1 monoclonal antibody (MoAb) that binds EGFR with high specificity and an approximately 10-fold higher affinity than its natural ligands. Its molecular weight is approximately 154 kDa. Competitive binding of cetuximab to EGFR prevents ligand-induced phosphorylation of the intracellular tyrosine kinase (TK) domain, thus inhibiting activation of the further downstream signaling cascade. 9 Furthermore, binding of cetuximab to EGFR leads to receptor dimerization followed by endocytosis and intracellular degradation of the antibody-receptor complex. Consequently, EGFR density on the cell surface is down- regulated (Figure 1). 10,11 Cetuximab has a number of molecular and biologic effects on CRC cells, each of which might contribute to anti- tumor activity: it inhibits TK receptor activity, inhibits cell cycle pro- gression, causes apoptosis, inhibits angiogenesis, inhibits invasion and Update on Novel Strategies to Optimize Cetuximab Therapy in Patients with Metastatic Colorectal Cancer Teresa Macarulla, Francisco Javier Ramos, Elena Élez, Jaume Capdevila, Sergio Peralta, Josep Tabernero The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward mo- lecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radi- ation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Clinical Colorectal Cancer, Vol. 7, No. 5, 300-308, 2008; DOI: 10.3816/CCC.2008.n.039 Keywords: Bevacizumab, Epidermal growth factor receptor, Panitumumab, Skin toxicity, Wild-type K-ras Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400. Comprehensive Review 300 • Clinical Colorectal Cancer September 2008 Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain Submitted: Feb 27, 2008; Accepted: Jun 23, 2008 Address for correspondence: Josep Tabernero, MD, Department of Medical Oncology, Vall d’Hebron University Hospital, P. Vall d’Hebron, 119-129, 08035, Barcelona, Spain Fax: 34-93-274-6059; e-mail: jtabernero@vhebron.net