Background: Liver resection for metastatic colorectal cancer is associated with 5-year overall survival (OS) of 58% and accepted as standard of care. However, the role of liver resection with unresectable low-volume lung metastases is unknown. A recent retrospective study showed that resection of liver metastases was associated with statistically improved OS compared to a matched group of patients treated with systemic therapy alone for lung and liver metastases (3-year OS 43% vs. 14%; Mise Y, Ann Surg Oncol 2015). LUNA is a single-institution phase 2 randomized trial designed to determine the overall survival benefit of liver resection in patients with unresectable lung metastases and to integrate biological surrogates to risk stratify patients and optimize patient selection for hepatectomy. Methods: Eligibility criteria include resectable liver metastases, defined as sufficient liver remnant volume, adequate vascular inflow and outflow, and preservation of 2 contiguous liver segments. Low-volume lung metastases are defined as solid pulmonary nodules < 2 cm in size and < 15 in number. Chest computed tomography is reviewed by an attending thoracic surgeon, and lung metastases are deemed unresectable due to anatomic location, distribution, or patients’ comorbidities. Previous treatment with systemic chemotherapy and/or biologic agents is permitted. After stratification by KRAS status and primary tumor location in the colon vs. rectum, patients are randomized 1:1 to liver resection plus chemotherapy or no liver resection with chemotherapy at the discretion of the treating oncologist as routine standard of care. Patients are restaged every 3‒6 months until 3 years after randomization or death. The primary endpoint is OS. Secondary endpoints include quality of life and identification of biological surrogates in blood and resected liver tissue associated with response to chemotherapy, time to tumor progression, and survival. Targeting an effect size of extending median OS from 17 to 34 months will provide 80% power with 0.05 one-sided alpha with a sample size of 80 patients. Clinical trial information: NCT02738606