Understanding the causes of recurrent HCC after liver resection and radiofrequency ablation

Introduction Surgical resection and radiofrequency ablation are preferred options for early-stage disease, with 5-year recurrence rates as high as 70% when patients are treated according to guidelines. With increasing availability of therapeutic options, including but not limited to, immune-checkpoint inhibitors (ICI), tyrosine kinase inhibitors, antiangiogenics, and adoptive cell therapies, understanding the causes of recurrence and identifying its predictors should be priorities in the hepatocellular carcinoma (HCC) research agenda.Areas covered Current knowledge of HCC predictors of recurrence is reviewed, and recent insights about its underlying mechanisms are presented. In addition, results from recent clinical trials investigating treatment combinations are critically appraised.Expert opinion HCC recurrence is either due to progressive growth of microscopic residual disease, or to de novo cancer development in the context of a diseased liver, each occurring in an early (<2years) vs. late (≥2 years) fashion. Collectively, morphological, proteomic, and transcriptomic data suggest vascular invasion and angiogenesis as key drivers of HCC recurrence. Agents aimed at blocking either of these two hallmarks should be prioritized at the moment of early-stage HCC clinical trial design. Emerging results from clinical trials testing ICI in early-stage HCC underscore the importance of defining the best treatment sequence and the most appropriate combination strategies. Lastly, as different responses to systemic therapies are increasingly defined according to the HCC etiology, patient enrolment into clinical trials should take into account the biological characteristics of their inherent disease.