Simple SummaryPatients with early-stage BCLC 0/A hepatocellular carcinoma (HCC) who are not candidates for liver transplantation or resection are treated with percutaneous ablation according to guidelines. Nevertheless, these patients are at high risk of HCC recurrence and physicians must apply different criteria to choose the salvage treatment as part of the Clinical Decision-Making process. This study analyzed the outcome of 225 BCLC 0/A HCC patients treated with ablation, focusing beyond the classical factors of tumor burden, liver function, and/or performance status. We found that the risk of death is two times higher (HR 2.0) if the comorbidities prevent further sequential locoregional or systemic treatments. The data in this study provide significant and useful prognosis information for physicians and provide valuable information to researchers involved in clinical practice and research by adding granularity to the evolutionary events of HCC patients with recurrence after percutaneous ablation.AbstractBackground: Ablation is a first-line treatment for Barcelona Clinic Liver Cancer (BCLC)-0/A hepatocellular carcinoma (HCC). However, there are scarce data about patients’ outcomes after recurrence. The present study evaluates the impact of patient and tumor characteristics at baseline and at recurrence on the Clinical Decision-Making process. Methods: We evaluated BCLC-0/A patients treated with percutaneous ablation from January 2010 to November 2018. Clinical and radiological data such as age, tumor location at ablation, pattern of recurrence/progression, and comorbidities during follow-up were registered. Tumor location was divided into ‘suboptimal’ vs. ‘optimal’ locations for ablation. The Clinical Decision-Making was based on tumor burden, liver dysfunction, or comorbidities. The statistical analysis included the time-to-recurrence/progression, censoring at time of death, date of last follow-up or liver transplantation, and time-to-event was estimated by the Kaplan–Meier method and Cox regression models to evaluate the risk of an event of death and change of treatment strategy. Results: A total of 225 patients [39.1% BCLC-0 and 60.9% BCLC-A] were included, 190 had unifocal HCC and 82.6% were ≤3 cm. The complete response rate and median overall survival were 96% and 60.7 months. The HCC nodules number (Hazard Ratio—HR 3.1), Child-Pugh (HR 2.4), and Albumin-Bilirubin score (HR 3.2) were associated with increased risk of death during follow-up. HCC in ‘suboptimal location’ presented a shorter time to recurrence. When comorbidities prevented further loco-regional or systemic treatment, the risk of death was significantly increased (HR 2.0,p= 0.0369) in comparison to those who received treatment. Conclusions: These results expose the impact of non-liver comorbidities when considering treatment for recurrence after ablation in the real-world setting and in research trials. Ultimately, we identified an orphan population for which effective interventions are needed.