Advanced non-small cell lung cancer therapy: historical and future perspectives

Before the 1980s, radiotherapy was the principal treatment for advanced non-small cell lung cancer (NSCLC). Radiotherapy is primarily effective for local disease control and in early stage disease, or as palliative therapy in inoperable disease. Prior to 1990, only a few cytotoxic drugs had confirmed activity against NSCLC, but a series of trials had established platinum-based chemotherapy as the most effective treatment regimen. Since then, newer chemotherapeutic agents have been found to be effective, and superior to traditional platinum combinations. Recently, chemotherapy-based regimens appear to have reached a therapeutic plateau, and effective, better-tolerated treatments are needed. Improved understanding of the molecular biology and genetics of the tumor has led to the development of more selective, less toxic, targeted therapies. Vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor both play a key role in tumor growth and proliferation, and are logical targets for therapy. Bevacizumab, a monoclonal antibody against VEGF, has demonstrated significant improvements in survival and response rates when combined with chemotherapy (versus chemotherapy alone) as first-line therapy. In the second-line setting, the tyrosine kinase inhibitor erlotinib has demonstrated improved survival compared with placebo. This paper reviews the principal treatments used for NSCLC in the past two decades, provides an overview of current treatment options and considers future challenges. Prolongation of survival, reduced toxicity and improved quality of life are the main objectives. Key challenges for the future are patient-specific tailored therapy and expansion of the eligible patient population for novel therapies.