Non-small-cell lung cancer (NSCLC) refers to any type of epithelial lung cancer other than small-cell lung cancer. The disease arises from epithelial cells of the lung, from the central bronchi to terminal alveoli. The histological type correlates with site of origin, reflecting the variation in respiratory tract epithelium by location. The most common types of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Several other types occur less frequently; all can occur in unusual histological variants. Squamous cell carcinoma typically originates near a central bronchus. Adenocarcinoma and adenocarcinoma in situ (formerly called bronchioalveolar carcinoma) usually arise in peripheral lung tissue. Adenocarcinomas are frequently associated with cigarette smoke but may also occur in patients who have never smoked. NSCLC may be symptomatic at presentation or it may be incidentally discovered at a routine chest imaging examination. The most common symptoms at presentation are progressive cough or chest pain. Other presenting symptoms include hemoptysis, malaise, weight loss, dyspnea, and hoarseness. Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression of the esophagus causing dysphagia, compression of the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease, such as chronic obstructive pulmonary disease or pulmonary fibrosis. The prognosis of an NSCLC patient and the subsequent treatment plan are a function of disease stage. NSCLC stage is defined by the TNM system, which was initially developed by the Union Internationale Contre le Cancer (UICC) and the American Joint Committee for Cancer Staging (AJCC). The Key Questions and CER analytical frameworks are structured to be consistent with the populations, interventions, comparisons, outcomes, timing, and settings (PICOTS) framework, as laid out in the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) "Methods Guide for Effectiveness and Comparative Effectiveness Reviews" (Methods Guide). The Key Questions are: KQ1. What are the comparative benefits and harms of local nonsurgical definitive therapies for documented (clinical or biopsy) stage I (T1N0M0, T2N0M0) NSCLC in adult patients (age 18 years or older) who are not surgical candidates because of the presence of contraindications to major surgery-for example, cardiac insufficiency, poor pulmonary function, presence of severe intercurrent illness, or poor performance status? KQ2. What are the comparative benefits and harms of local nonsurgical definitive therapies for documented (clinical or biopsy) stage I (T1N0M0, T2N0M0) NSCLC in adult patients (age 18 years or older) who are deemed operable but decline surgery? KQ3. What are the comparative short- and long-term benefits and harms of local nonsurgical therapies given with palliative or curative intent to patients with endoluminal NSCLC causing obstruction of the trachea, main stem, or lobar bronchi and recurrent or persistent thoracic symptoms such as hemoptysis, cough, dyspnea, and postobstructive pneumonitis?