Combining EGFR inhibitors with radiation or chemotherapy: Will preclinical studies predict clinical results?

Purpose: To highlight some of the preclinical data that examine the interaction of epidermal growth factor receptor (EGFR) inhibitors with radiotherapy and chemotherapy. Methods and Materials: Recognition of the EGFR as an important regulator of tumor cell growth in the early 1980s stimulated the development of a series of molecules specifically designed to inhibit EGFR signaling as anticancer agents. Many of these agents have now matured and are in advanced clinical trial investigations, with tumor response rates on the order of 10-20% identified across a variety of human malignancies. Initially designed primarily as "cytostatic" agents, as opposed to "cytotoxic" agents, it is possible that the EGFR inhibitors will realize their optimal clinical impact when delivered in concert with conventional cytotoxic modalities such as radiotherapy and/or chemotherapy. Results: Despite very strong in vitro and in vivo preclinical results, several major gaps remain in our knowledge regarding the EGFR inhibitor mechanisms of interaction with radiotherapy and chemotherapy, with considerable selection bias in the publication of preclinical data available to date. Conclusion: By acknowledging the limitations of the available preclinical data and by expanding our mechanistic understanding of EGFR inhibitor function in representative tumor model systems, we should enhance our capacity to predict the most rational and successful methods to combine EGFR inhibitors with cytotoxic modalities in future clinical trials. (C) 2004 Elsevier Inc.