OBJECTIVES: We prepared this report on the comparative effectiveness and harms of lung-directed nonsurgical therapies for non-small-cell lung cancer (NSCLC) in three distinct patient populations: (1) patients with stage I NSCLC who are not surgical candidates (Key Question 1), (2) patients with stage I NSCLC who are deemed operable but decline surgery (Key Question 2), and (3) patients with endoluminal NSCLC causing obstruction (Key Question 3). For stage I NSCLC, the local nonsurgical interventions could include conformal radiotherapy modalities and radiofrequency ablation (RFA). For patients with airway obstruction due to an endoluminal NSCLC, local nonsurgical interventions could include those for the stage I setting, as well as conventional wide-field radiotherapy, brachytherapy, laser and mechanical debridement, endoluminal stents, cryoablation, and photodynamic therapy. Surgical resection of any type is not considered as a comparator for any of the Key Questions. DATA SOURCES: MEDLINE(r), Embase(r), and the Cochrane Controlled Trials Registry were searched from January 1, 1995, to July 25, 2012. A search of the gray literature included databases with regulatory information, clinical trial registries, abstracts and conference papers, and information from manufacturers. REVIEW METHODS: We sought studies reporting overall survival, cancer-specific survival, local control, symptom relief, adverse events, and quality of life among our populations of interest. Data were abstracted for each Key Question by a team of reviewers, with independent data verification. Study quality and the risk of bias of randomized controlled trials (RCTs) were assessed using the United States Preventive Services Task Force criteria. The quality and risk of bias of single-arm studies were assessed using the Carey and Boden criteria. The strength of the body of evidence was assessed according to the Agency for Healthcare Research and Quality Methods Guide. RESULTS: In our searches, we identified 4,648 unique titles and screened 1,178 in full text. Of the latter, 55 met the inclusion criteria. Thirty-five studies were relevant to Key Question 1, considering medically inoperable patients with stage I NSCLC; 6 were relevant to Key Question 2, considering medically operable patients with stage I NSCLC who decline surgery; and 17 were relevant to Key Question 3, considering patients with inoperable endoluminal NSCLC causing symptoms of obstruction. Three studies addressed both Key Questions 1 and 2. All studies relevant to Key Questions 1 and 2 were single-arm design, prospective (n=15), retrospective (n=21), or not specified (n=2). Among 17 papers included for Key Question 3, 5 were RCTs, 1 was a nonrandomized comparative study, and 11 were single-arm studies. Because comparative study evidence on RFA and debridement and stenting was unavailable for Key Question 3, we included evidence from two single-arm studies involving stents and one on RFA. All RCTs were of poor quality. Only one comparison was available per study, with no two studies examining the same set of interventions. Outcomes of therapy for all Key Questions included overall survival, adverse effects, and quality of life. CONCLUSIONS: Evidence on localized nonsurgical therapies for patients with stage I NSCLC who are not surgical candidates or who decline surgery consists only of single-arm studies, with no direct comparisons among interventions. The best evidence for NSCLC patients with endoluminal obstruction consists of poor-quality single RCTs for each comparison; we did not identify evidence that permitted us to draw conclusions based on indirect comparisons. Overall, evidence is insufficient to permit conclusions on the comparative effectiveness of local nonsurgical therapies for inoperable or operable patients with stage I NSCLC or inoperable NSCLC patients with endoluminal tumor causing pulmonary symptoms.