Radiotherapy for Locally Advanced Lung Cancer

Park, Charn II; Choi, Eun Kyung

Abstract

Lung cancer is the leading cause of cancer deaths. Non-small cell lung cancer constitutes approximately 75% of lung cancers, and 40% will present as advanced stage IIIa or IIIb, which are ineffectively treated by primary surgery. Radiation of a primary tumor, and the regional lymphatics, has been the traditional treatment for an unresectable locally advanced disease, but few patients achieved a complete response. Due to the limited benefits provided by radiation therapy, we explored the use of combined chemoradiotherapy in patients with locally advanced, unresectable NSCLC. 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, with 5 year survival rates as high as 15 to 20%, nearly three times that reported with radiation therapy alone. 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, and Texanes interact with radiation at many levels. Cell-cycle synchronization, through mitotic arrest, has been consistently shown to play a major role in radiation enhancement, but increased apoptosis and tumor reoxygenation may be additional mechanisms. Clearly, the interaction is multifactorial, and the dominant mechanism may be affected by specific settings, which 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 the control of a local tumor in NSCLC. Radiation dose escalation, utilizing conventional fractionation techniques, would be likely to cause prohibitive toxicity. Threedimensional conformal radiation therapy (3-DCRT) has the potential to deliver high dose radiation >70 Gy), with minimal under-dosing and concomitant relative sparing of normal tissues. This technical demonstration of the enhanced therapeutic ratio is used as the basis for the evolving clinical utilization of 3-DCRT for NSCLC. Preliminary experience of the technique has resulted in promising survival rates, following three-dimensional conformal radiation therapy alone, for locally advanced NSCLC. A greater follow-up and experience will help determine its late toxicity, maximum dose and efficacy of dose escalation. Strategies should be developed to integrate this modality into combined treatments for locally advanced NSCLC. Biotechnological developments within the last decade have resulted in the identification of important biological and biophysiological pathways in lung carcinogenesis, and new agents are being developed to target difficult levels of these important pathways. Preclinical and clinical studies using 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.