In their overview of the management of medically inoperable but localized early-stage non-small-cell lung cancer (NSCLC), Decker and colleagues provide an excellent evaluation of the nonsurgical options for radical treatment, focusing particularly on radiotherapy as the current standard of care.

As becomes clear from the data cited by Decker et al, in the radical treatment of such patients, local control remains a major challenge. Indeed, among patients whose treatment fails—even though this may occur in the context of regional and distant metastasis—the majority will have evidence of local failure at the time of death. One intuitive response suggests that more effective radical treatment to the local primary site may have a significant impact on morbidity and mortality from the disease. Accepting that radical radiotherapy (potentially augmented by other treatment modalities) is likely to remain the standard of care, the question remains: How can the results of radical radiotherapy be improved for early-stage small volume NSCLC?

Conceptually there are a number of explanations for radiotherapy failure. These may be broadly divided into factors relating to geographic miss of the target and biologic factors resulting in radiation resistance within the tumor, which may be due to hypoxia, repopulation of tumor cells, or intrinsic cell resistance.

Geographic Miss

The first issue in determining a radiation treatment volume is to be confident of the distribution of the disease. As these authors state, staging of NSCLC has improved remarkably since the advent of three-dimensional cross-sectional imaging and functional imaging—in particular, ¹⁸F-fluorode-oxyglucose positron-emission tomography (FDG-PET) scanning. The latter has excluded a significant proportion of patients (around one in five) who previously would have undergone radical treatment but were already incurable by virtue of regional or distant metastasis undetected by conventional nonfunctional imaging techniques. Thus, the population of patients now treated is more favorable than in the past. Clearly, all patients in the group being considered in this review should undergo full computed tomography (CT) and PET staging prior to selection for treatment.

Similarly, advances in three-dimensional conformal and intensity-modulated radiotherapy planning have greatly improved our understanding of target definition and movement as well as normal tissue volumes within an irradiated area and their likely tolerance. The radiotherapy planning department can now define elegant radiation distributions to cover a defined tumor volume and minimize the dose to organs at risk.

In the lung, however, the major challenge is to transfer that sophisticated high-resolution mathematical exercise to a patient who is likely to be frail, anxious, and actively breathing while on the linear accelerator couch receiving radiation exposure. Internal organ movement presents a particular challenge in lung cancer. The simple, routine response to this problem is to allow wider margins around the defined microscopic and macroscopic tumor. The clinical target volume (CTV)-to-planning target volume (PTV) margin conventionally allows for 3- to 5-mm variations in patient setup even in the most rigorous radiation therapy facilities.

In a modern radiotherapy setting, it is unacceptable to omit some method of respiratory control when undertaking the radical treatment of lung cancer using either active breathing control (in which the patient controls respiration with positive physiologic feedback during radiation exposure) or respiratory gating (in which the treatment beam is pulsed with the respiratory cycle). Such considerations become increasingly critical for patients with small tumors and when techniques such as stereotactic radiotherapy and radiofrequency ablation—involving very high-dose treatment in a short time—are considered.

Hypoxia