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

ABSTRACTIntroduction Surgical resection and radiofrequency ablation are preferred options for early-stage disease. With the increasing availability of therapeutic options 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 their underlying mechanisms are presented. In addition, results from recent clinical trials investigating treatment combinations are critically appraisedExpert opinion HCC recurrence is either due to the progressive growth of microscopic residual disease or to de novo cancer development in the context of a diseased liver, each occurring in an early (<2 years) 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.Finally,as different responses to systemic therapies are increasingly defined according to the HCC etiology, patient enrollment into clinical trials should take into account the biological characteristics of their inherent disease.KEYWORDS: Hepatocellular carcinomarecurrenceradiofrequency ablationsurgeryLenvatinibAtezolizumabBevacizumabTACE Article highlights HCC 5-year recurrence rates after radiofrequency ablation and/or surgical resection can be as high as 70–80%, depending on the patient's disease stage, tumor extent, and treatment center. So dismal a prognosis justifies treatment scale-up in the neoadjuvant, perioperative, or adjuvant setting.Predictors of recurrence can be classified as tumor- or host-related. Among tumor-related factors, vascular invasion, size, and number of lesions have long-established predictive capacity. Emerging predictors include recently defined histopathological patterns, including the macrotrabecular-massive HCC phenotype and the vessels encapsulating tumor clusters (VETC) pattern. Circulating biomarkers with potential prognostic validity include fibronectin and miRNAs.Among host-related predictors of recurrence, cirrhosis has the highest prognostic validity. Adequate administration of antivirals in the case of HBV/HCV infection, as well as optimal management of metabolic comorbidities, is key to achieve better outcomes.HCC etiology is emerging as a major determinant of response to systemic treatment and shall be considered at the moment of patient inclusion in clinical trials.The most recent data indicate possible benefits from immune checkpoint inhibitors and antiangiogenic combinations in early-stage disease.Systemic treatment sequence (e.g. adjuvant vs. neoadjuvant), number of therapeutic cycles, and synergistic therapeutic combinations with locoregional treatments are the most relevant themes open to discussion at the moment of clinical trial design in HCC.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe paper received no funding.