Oligometastatic Non–Small-Cell Lung Cancer: How Should We Define and Manage It?

Recent years have seen a markedly increased interest in the concept of oligometastatic disease in non–small-cell lung cancer (NSCLC). Lacking a precise and consistent definition, oligometastatic disease is generally considered to represent a relatively favorable clinical state, with more indolent biology, a limited number of disease sites, and potential for prolonged periods of disease control. What factors have led to the heightened attention to this clinical scenario? For one, improved staging with highly sensitive imaging technologies such as positron emission tomography scans has resulted in more patients being diagnosed with stage IV disease with lower disease burden.1 In addition, major improvements in systemic therapy, including effective and well-tolerated cytotoxic agents, molecularly targeted therapies, and immune checkpoint inhibitors, are providing disease control to more patients, and for longer, than ever before. Discussions of oligometastatic NSCLC are inexorably linked with management considerations, specifically the use of local therapies such as surgery and radiation therapy. Indeed, it is the advent and widespread uptake of stereotactic radiation therapy to both brain and extracranial sites that have driven much of this recent work. In the setting of metastatic disease, even if relatively low burden, what are the clinical and biologic rationales for pursuing local therapy? Disease progression most often occurs in original sites of gross disease, suggesting that definitive treatment to these areas could impact clinical course.2 If metastatic sites can propagate secondary metastases (as proposed by the linear progression model), then local treatment to these areas may decrease future disease burden.3 Local therapy may also debulk a tumor, thereby improving efficacy of subsequent systemic therapy. In the setting of immunotherapy, focal radiation may increase tumor antigenicity (abscopal effect) and treatment efficacy. With molecularly targeted therapy, local treatment may prevent, delay, or treat the emergence of resistant clones. Because solid tumors are composed of faster growing cells, which are sensitive to therapy, and slower more resistant cells (Norton-Simon hypothesis4), the addition of local therapy to systemic treatments may provide maximum antitumor effect. Because resistance depends on spontaneous mutations and therefore increases with time (Goldie-Coldman hypothesis5), early use of non–cross-resistant therapies (eg, stereotactic radiation) may increase the likelihood of killing more cancer cells before resistance develops.