The treatment of stage III non–small-cell lung cancer has evolved over the last two decades, with combined-modality therapy the current standard of care. As a result, intermediate and long-term survival has improved for patients in this common stage category, compared to the poor outcomes achieved with the historical standard of once-daily radiation therapy alone. This review summarizes two decades of clinical research regarding bimodality and trimodality approaches for the heterogenous stage subsets within the stage III designation, discusses the rationale and status of prophylactic brain irradiation, and concludes with perspectives on progress and future directions. Chemotherapy plus radiotherapy given concurrently is the optimal treatment for the group of patients with advanced stage III disease. The potential role of a surgical resection following chemotherapy (with or without radiation) in this setting is still controversial. The only subsets for which trimodality treatments are clearly preferred include T4N0-1 disease and superior sulcus tumors. The other major stage III subgroup has a minimal disease burden with low tumor volume and/or microscopic N2 disease, thus technically could undergo a surgical resection upfront. Induction chemotherapy before surgery may yield a survival advantage, although the phase III trials in this area are not conclusive. Given the marked survival benefit from adjuvant chemotherapy after surgery in even earlier stages of non–small-cell lung cancer, the proper sequence of surgery and chemotherapy (before v after surgery) remains an important unresolved question in this subgroup. Furthermore, how to incorporate radiation therapy, as well as whether it should be given at all in this subset of patients, are other important issues actively under study in ongoing trials.
