Therapeutic integration of new molecule-targeted therapies with radiotherapy in lung cancer

Lung cancer is the most common form of the disease and the leading cause of cancer deaths worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers. Forty percent of all cases present with stage III, and many of them are considered inoperable (staged IIIA with mediastinal lymph node involvement) or stage IIIB disease. Concurrent platinum-based chemotherapy and thoracic radiation has demonstrated survival benefits in these patients. We review the role of new target agents in combination with radiotherapy in stage III NSCLC. Antiangiogenics improve tumor oxygenation thereby improving the therapeutic efficacy of irradiation in models. Bevacizumab in combination with thoracic radiation has shown high toxicity. However, other antiangiogenic agents are more promising. Radiation activates epidermal growth factor receptor (EGFR) pathways, inducing radioresistance, cell proliferation and enhanced DNA repair. After promising data from preclinical models and early clinical trials, cetuximab did not show any benefit in a recent phase III trial. Panitumumab and nimotuzumab are under evaluation. Gefitinib has been investigated in combination with radiotherapy for unresectable stage III NSCLC, but results in maintenance treatment after chemoradiotherapy were not encouraging. Erlotinib has also been tested in a phase II trial with chemoradiotherapy. Other new pathways and agents are being studied, such as m-TOR pathway, bortezomib, heat shock protein 90 (Hsp90) inhibition, histone deacetylase inhibitors (HDACS), aurora kinases, mitogen activated protein kinases (MARK) and PARP inhibitors.