Integration of Epidermal Growth Factor Receptor Inhibitors with Preoperative Chemoradiation

In many different cancer cell types, the epidermal growth factor receptor (EGFR) pathway becomes hyperactivated because of overproduction of the ligand, overproduction of the receptor, or constitutive activation of the receptor. The overproduction of EGFR and its ligands correlates with poor prognosis in several solid tumors such as lung, colon, and ovary. These observations led to the development of EGFR inhibitors for anticancer treatment. In the last few years, promising results have been obtained in several tumor types, with EGFR inhibitors given as monotherapy or in combined treatments. In particular, cetuximab in combination with curative-intent radiotherapy in head and neck cancer increases median survival over radiation alone. Similarly, the same approach might benefit patients with locally advanced rectal cancer. Unfortunately, the first clinical studies combining chemoradiation with cetuximab in rectal cancer gave disappointing results. Translational research suggested that the low response rate observed might have been due to the strong antiproliferative effect of cetuximab that may have compromised the activity of chemotherapeutics that target proliferating cells. This result indicates the need for more translational research to unravel how the molecular mechanisms might be manipulated to optimize the combined treatment regimen and to identify biomarkers that can select those patients who will derive most benefit. Clin Cancer Res; 16(10); 2709-14. (C) 2010 AACR.