Key Points

• Nonoperative management of locoregionally confined non–small cell lung cancer is potentially curative.
• In patients with anatomically inoperable stage III disease, survival is improved when concurrent chemotherapy is given along with a definitive course of radiation therapy.
• Consolidation therapy with 1-year of the immune checkpoint inhibitor durvalumab improves overall survival in patients with inoperable stage III disease after concurrent chemoradiation.
• In patients with recurrent disease or distant metastases, radiation therapy can have significant palliative benefit.
• Systemic chemotherapy improves survival in patients with advanced non–small cell lung cancer.
• Immunotherapy and molecularly targeted therapies are rapidly developing treatment areas and have both been incorporated into first-line treatments for metastatic non–small cell lung cancer.

Non-small cell lung cancer (NSCLC) in the curative setting can broadly be divided into early stage (stages I and II) and locally advanced, non-metastatic disease (stage III).[1],[2] These entities are further subdivided based on surgical considerations, with the definition of inoperability having both anatomic and medical underpinnings. Anatomically, patients with stage I-II disease are considered resectable with curative intent, whereas those with stage IIIB/IIIC are generally considered unresectable on presentation. For stage IIIA disease in particular, there is considerable variability from surgeon to surgeon in the definition of resectability. As detailed by Andre and colleagues, patients with microscopic single nodal station N2 involvement have a 5-year survival of 34% after primary surgical therapy.[3] On the other hand, patients with clinical evidence of mediastinal lymph node involvement or with multiple positive lymph nodes identified at surgery have a poor prognosis, with a 5-year survival after surgery of 11% or less.[4] Historically, such patients have not been considered appropriate candidates for surgical intervention. The development of successful induction chemotherapy and chemoradiotherapy treatment regimens, as well as the benefit demonstrated after postoperative adjuvant chemotherapy, are identifying a greater subset of patients with stage IIIA disease who might benefit from surgical resection.[4],[5],[6],[7],[8],[9],[10]

The nonsurgical approach to patients with advanced inoperable lung cancer is the primary focus of this chapter. The use of Stereotactic Body Radiotherapy (SBRT) for definitive management in patients with early stage lung cancer who are not surgical candidates will be discussed in a separate chapter. In patients with unresectable stage III disease, the standard of care is concurrent chemoradiation (CRT) in appropriately selected patients. The use of immune checkpoint inhibitors in stage III disease after CRT is a major recent breakthrough, producing durable remissions whereas recurrence was previously the norm. Systemic therapies for advanced metastatic disease have evolved rapidly in recent years. The advent of targeted therapies and immune checkpoint inhbitors has dramatically improved the survival and quality of life of NSCLC patients with metastatic disease. The clinical trial data discussed in this section represents a compendium of studies. It is important to note that these trials provide only guidelines in managing patients with inoperable NSCLC.