R ESEARCH R EPORT 10.2217/14622416.8.4.319 © 2007 Future Medicine Ltd ISSN 1462-2416 Pharmacogenomics (2007) 8(4), 319–327 319 part of For reprint orders, please contact: reprints@futuremedicine.com Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan Bruno Vincenzi 1† , Daniele Santini 1 , Antonio Russo 2 , Michele Gavasci 3 , Fabrizio Battistoni 3 , Giordano Dicuonzo 3 , Laura Rocci 1 , Valerio Maria Rosaria 2 , Nicola Gebbia 2 & Giuseppe Tonini 1 † Author for correspondence 1 University Campus Bio-Medico, Medical Oncology, Via Emilio Longoni, 69, 00155, Rome, Italy Tel.: +39 062 254 1853; Fax: +39 062 254 1520; E-mail: b.vincenzi@ unicampus.it 2 Università di Palermo, Department of Oncology, Italy 3 University Campus Bio-Medico, Laboratory Medicine, Rome, Italy Keywords: angiogenesis, cetuximab, colorectal cancer, irinotecan, survival, vascular endothelial growth factor Objective: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion with respect to the basal time point. For patients with at least a 50% reduction in VEGF levels, the response rate was 45.5% compared with 8.7% in the nonreduced VEGF group (p = 0.014). The median time to progression was 6 months in the reduced VEGF group versus 3.9 months in the other patients (p < 0.0001). In addition, overall survival was longer in patients with VEGF reduction (11.0 months) than in patients without (9.6 months; p = 0.01). Conclusion: These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients. Colorectal cancer is the third most common cancer in the USA, with approximately 145,000 new cases expected in 2007 [101]. Esti- mated 5-year survival rates range from 90% for patients with Stage I disease to less than 10% for patients with metastatic colorectal cancer [1,101]. T he US FDA recently approved two tar- geted agents: an antivascular endothelial growth factor (anti-VEGF) monoclonal anti- body, bevacizumab, and a human epidermal growth factor receptor (HER-1/EGFR)-tar- geted monoclonal antibody, cetuximab, as first- and second-line metastatic coloretal can- cer therapy, respectively [2]. EGFR, a member of the ErbB family of receptors, is relevant in colorectal cancer because expression or upregu- lation of the EGFR gene occurs in 60–80% of cases [3]. EGFR overexpression has been associated with advanced stages of disease, resistance to conventional treatments and poor prognosis in colorectal cancer, head and neck cancer, glio- mas and pancreatic cancer [4–6] and, although due in part to the lack of a standardized method of measurement, a consensus has not been reached regarding this matter [7,8]. Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that binds to EGFR with high specificity and with a higher affinity than epidermal growth factor, thus blocking ligand-induced phosphorylation of EGFR [3]. Cetuximab’s mechanism of action in tumor cells is thought to involve the binding of cetux- imab to the EGFR, preventing normal ligand binding and subsequent activation of the recep- tor’s tyrosine kinase activity. T he consequence of this blockade is reflected in the disruption of any number of processes regulated by EGFR pathways in a given tumor cell. Several mecha- nisms have been identified in preclinical models whereby cetuximab inhibits the growth and sur- vival of EGFR-positive tumors. These include inhibition of survival pathways [9], inhibition of tumor cell motility and invasion [10], inhibition of angiogenesis [11,12] and interruption of EGFR-activated survival and proliferation sig- naling [13]. Moreover, the blockade of EGFR receptor seems to be able to enhance the radio- responsiveness [14] and chemosensitivity [15,16] in in vitro and in vivo models. Prewett and colleagues demonstrated that cetuximab combined with irinotecan shows a higher anticancer efficacy compared with