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Abstract
Lung cancer is the leading cause of cancer deaths. Non-small cell lung cancer constitutes approximately 75% of lung cancers, and 40% present as advanced stage IIIa or IIIb, where primary surgery is ineffective. Radiation of the primary tumor and the regional lymphatics has been the traditional treatment for unresectable locally advanced disease, but few patients achieved a complete response. Because of the limited benefits provided by radiation therapy, the use of combined chemoradiotherapy in patients with locally advanced, unresectable NSCLC was explored. Combined chemoradiotherapy appears to have improved the outcome of patients with locally advanced unresectable stage III NSCLC, with a median survival of 13 to 14 months and 5-year survival rates as high as 15% to 20%, nearly three times that reported with radiation therapy alone and various agents have been used either sequentially or concomitantly in clinical trials of combined chemoradiotherapy for NSCLC. The interactions of chemotherapy and radiation therapy are complex. The texanes interact with radiation at many levels. Cell-cycle synchronization through mitotic arrest has been consistently shown to have a major role in radiation enhancement, but increased apoptosis and tumor reoxygenation may constitute additional mechanisms. Clearly, the interaction is multifactorial and the dominant mechanism may be affected by specific settings that include drug exposure and concentration, tumor type, and radiation dosimetry.
Recent studies have demonstrated that shorter high-dose radiotherapy schedules cause a statistically significant increase in local tumor control in NSCLC. Radiation dose escalation utilizing conventional fractionation techniques would likely cause prohibitive toxicity. Three-dimensional conformal radiation therapy (3-DCRT) had the potential to deliver high dose radiation (>70 Gy) with minimal underdosing and with a concomitant relative sparing of normal tissues. This technical demonstration of enhanced therapeutic ratio is the base for the evolving clinical utilization of 3-DCRT for NSCLC. Preliminary experience has resulted in promising survival following three-dimensional conformal radiation therapy alone for locally advanced NSCLC. More follow-up and experience will determine late toxicity, maximum dose, and efficacy of dose escalation with three-dimensional conformal radiation therapy. Strategies should be developed to integrate this modality into the combined treatment of locally advanced NSCLC.
Developments in biotechnology within the last decade have resulted in identification of important biological and biophysiological pathways in the lung carcinogenesis, and new agents are developed to target difficult levels of these important pathways.
Preclinical and clinical studies with these specific targeted therapies in lung cancer have been very promising. Targeted therapies in lung cancer and the potential of combining these agents with chemotherapy and radiotherapy are under investigation.
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