The role of surgery in the treatment of locally advanced non-small cell lung cancer: E07-02

Combined modality therapy for locally advanced NSCLC Choy, Hak Department of Radiation Oncology The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA There has certainly been a progression in the approach to locally advanced non-small cell lung cancer over the last two decades. Until the 1980s, radiation therapy alone had been the standard of care for locally advanced NSCLC despite the dismal survival data. During the early 1990s, results of multiple randomized phase III studies shifted the standard toward concurrent chemoradiation therapy. The mechanism of chemotherapeutic radiosensitization is thought to be direct inhibition of radiation-induced damage repair; elimination of radioresistant, chemosensitive clones; and/or suppression of inter-fraction tumor repopulation. Concurrent chemoradiation addresses both distant and locoregional disease simultaneously. The two modalities should act synergistically on tumor clonogens susceptible to both modality and in a complementary fashion on locoregional clonogens that are susceptible to only one of the modalities. A number of phase III randomized trials have shown a statistically significant improvement in clinical outcomes, including survival, with the concurrent approach. However, this aggressive strategy has also led to an increase in the incidence and severity of treatment-related toxicities. These innovations in treatment now begin to cooperate with improvements in the imaging of cancers like PET scanning and with the improvements in computers and automation that are allowing us to deliver radiation in a more conformal fashion than before to reduce toxicity while improving tumor control. The implication of these new technologies in treating lung cancers is really quite profound. New treatment planning systems allow for the delivery of more targeted radiation with multiple, non-traditional field arrangements when needed to protect normal structures. Areas of atelectatic lung remain a challenge for the radition oncologist to be able to adequately define the target volume. However, incorporation of the physiologic data provided by PET scanning may not only allow physicans to spare the collapsed lung but may allow them to deliver higher doses of radiation to more biologically active and presumably more aggressive areas of tumors as well. Advances in radiation therapy (RT) techniques, chemotherapeutic regimens, and different combined-modality approaches have yielded a modest impact on the prognosis of patients with advanced lung cancer. But the median survival for locally advanced NSCSL patients is only 18-24 month at best. There is clearly a need for additional strategies. Recent discoveries in molecular biology have identified a number of molecular determinants that may be responsible for resistance of cancer cells to radiation or other cytotoxic agents, and as such may serve as targets for augmentation of radioor chemo-response. Among these determinants are epidermal growth factor receptor (EGFR), Anti Angiogeneis agents, mutated ras, angiogenic molecules, and various other molecules that regulate different steps in their signal transduction pathways. Incorporating newer biologic agents into chemoradiotherapy is critical to further improve outcomes in this setting. One strategy should improve therapeutic outcomes by blocking receptors and pathways that help tumor cells survive radiation and repair damage without increasing normal tissue toxicity. In this meeting we will review the current research challenges in incorporating these agents into radiotherapy and chemoradiotherapy and preliminary data in patients with locally advanced NSCLC.