Background <p>Hepatectomy for isolated colorectal liver metastases is associated with 5&#xa0;year overall survival (OS) of 58% and is accepted as standard of care. However, the role of liver resection with unresectable low-volume lung metastases is unknown. LUNA was a phase II randomized trial designed to study the survival benefit of hepatectomy with unresectable lung metastases.</p> Methods <p>After stratification by <i>KRAS</i> status and primary tumor in the colon versus rectum, patients were randomized 1:1 to hepatectomy plus chemotherapy or chemotherapy alone. The primary endpoint was 3&#xa0;year OS. Slow accrual led to early trial closure.</p> Results <p>In total, 29 patients were enrolled and 27 randomized to either the experimental hepatectomy group (<i>n</i>=10) or the control group of chemotherapy alone (<i>n</i>=17), comprising the intention-to-treat population. Three patients in the chemotherapy group crossed over to surgery, and five in the hepatectomy group crossed over to standard treatment. Thus, the as-treated population comprised eight patients who underwent surgery and 19 who were treated with chemotherapy alone. Intention-to-treat analysis demonstrated 3-year OS of 30% (95% confidence interval [CI] 12‒77) and 34% (95% CI 17–67) in the surgery and control arms, respectively (<i>p</i>=0.53). In the as-treated analysis, hepatectomy was associated with significantly higher 3&#xa0;year OS than chemotherapy alone (75% [95% CI 50–100] vs 16% [95% CI 6–45], <i>p </i>= 0.001).</p> Conclusions <p>LUNA is the first randomized study to evaluate the potential benefit of hepatectomy for patients with colorectal cancer with resectable liver and unresectable low-volume lung metastases. The trial was closed early and did not meet the primary endpoint. Findings from the as-treated analysis may warrant validation in a larger, multicenter cohort.</p>