Non-small cell lung cancer (NSCLC) is the leading cause of cancer related morbidity and mortality in the U.S. With the increasing use of computed tomography scans and lung cancer screening, tumors are increasingly being detected at stage I disease, conferring a greater than 70% likelihood of cure. Surgery has been the traditional treatment for stage I NSCLC. However, population-based studies demonstrate a rapid increase in stereotactic body radiation therapy (SBRT) over the past decade. Retrospective studies comparing surgery and SBRT, including several publications from our group, have been hampered by relatively small sample sizes, lack of patient reported outcomes, and sparse information on comorbidities and cancer-related outcomes. Consequently, a recent systematic review concluded, “there is a need to compare both treatments in large prospective trials”. Unfortunately, multiple attempted randomized controlled trials comparing surgery to SBRT have failed to accrue and closed prematurely due to specialty bias and perceived lack of equipoise. Furthermore, our previous work has demonstrated that individual patient characteristics are crucial in the choice of therapy. In the absence of prospective comparative studies, treatment allocation is largely directed by institutional experience, retrospective data, and provider opinion. The lack of evidence-based treatment allocation in patients with stage I lung cancer remains a critical unmet need. To address this fundamental gap in knowledge, we will perform a prospective, pragmatic, multi-center cohort study to compare the effectiveness of surgery and SBRT for stage I NSCLC. This pragmatic study design is ideally suited to provide actionable results. Aim 1: To compare the effectiveness of surgery versus stereotactic body radiation therapy (SBRT) on stakeholder selected short and long-term outcomes in patients with clinical stage I lung cancer. Aim 1a: To compare 3-year disease-free survival (DFS) between surgery and SBRT. We will compare long-term DFS using propensity score matched cohorts. We hypothesize that SBRT will lead to fewer and less severe treatment- related complications, while surgery will result in longer DFS. Aim 1b: To compare patient reported outcomes (PRO) between surgery and SBRT. We will compare short and long-term PRO in propensity-matched cohorts using the Patient Reported Outcomes Measurement Information System. We hypothesize that SBRT will result in better short-term PRO with equivalent long-term PRO. Aim 2: To develop and validate prediction models for treatment outcomes for an individual patient with stage I lung cancer. In prospectively assembled cohorts of patients undergoing surgery or SBRT for stage I lung cancer, we will predict long-term DFS and PRO for an individual patient using regression techniques. These models will be validated and presented as a web-based tool for patients with stage I NSCLC. Our proposal will create a benchmark for personalized treatment allocat...