Purpose-To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.This article is dedicated to the memory of Dr. Scott Wadler, physician, scientist, mentor, friend, and founder of the New York Phase II Consortium. Employment or Leadership NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptPatients and Methods-Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay.Results-The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma.Conclusion-We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.

<b><i>Background:</i></b> Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. First-line sorafenib has been the standard of care for a decade, but the treatment landscape is expanding. This review provides a practical overview of current and future systemic treatment options for advanced HCC and their place in clinical practice. <b><i>Summary:</i></b> First-line sorafenib and lenvatinib have shown to improve the survival of patients with advanced HCC. In the second line, regorafenib provides benefit for patients who previously tolerated sorafenib. Anti-PD1 antibodies, nivolumab and pembrolizumab, recently became available for second-line use in the US. Ramucirumab (for patients with α-fetoprotein [AFP] levels ≥400) and cabozantinib present potential future second-line treatment options. Combinations of systemic and locoregional treatment, such as radiofrequency ablation or selective internal radiotherapy, require further research. Precision medicine has not yet been translated into clinical practice, as the most common driver mutations (<i>TERT</i> promoter, <i>CTNNB1</i>, <i>TP53</i>, and <i>ARID1A</i> mutations) have not yet been shown to be suitable therapeutic targets. However, our growing understanding of signaling pathways and efforts in drug development are expected to pave the way for precision medicine in HCC in the future. Evaluating the place for the current and novel systemic treatment options in clinical practice can be challenging due to the diverse toxicity profiles of the treatment options and characteristics of the patient population. Sorafenib data elucidate the effect patient characteristics (such as the performance score, Child-Pugh class, AFP, etiology of the underlying disease, and level of macrovascular invasion and extrahepatic spread) may have on outcomes in advanced stages. <b><i>Key Messages:</i></b> Lenvatinib is expected to join sorafenib as a preferred first-line treatment in advanced HCC. In the second line, the treatment of choice, regorafenib, is soon expected to be accompanied by cabozantinib and ramucirumab in patients with AFP ≥400 ng/mL, whereas nivolumab and pembrolizumab present second-line alternatives in the US.

CR = complete response, EASL ¼ European Association for the Study of the Liver, HCC = hepatocellular carcinoma, MAA = macroaggregated albumin, mRECIST = modified Response Evaluation Criteria In Solid Tumors, PET = positron emission tomography, PFS = progression-free survival, PD = progressive disease, PR = partial response, RECIST = Response Evaluation Criteria In Solid Tumors, SD = stable disease, TTP = time to progression, WHO = World Health Organization Transcatheter liver-directed intraarterial therapies-such as embolization, chemoembolization, and radioembolization-represent fundamental interventional oncology procedures that have gained international acceptance for the treatment of primary and secondary hepatic malignancies. The growing use of these interventions mandates objective and formalized criteria for the consistent reporting of research outcomes to optimize accurate communication in the field and to facilitate valid comparison of technologies and results across clinical studies. Accordingly, a panel of experts was convened in 2007 and again in 2009 to develop standard terminology for transcatheter therapy (1,2). The evolution and advancement of the field of transcatheter therapy for hepatic malignancy since that time has seen the introduction of new delivery vehicles (3,4), expanded use of novel targeting technologies (5), and development of improved response assessment criteria (6), all of which must be incorporated into updated Research Reporting Standards to ensure that standard definitions, terms, principles, and benchmarks properly align with current interventional oncologic clinical practice. Thus, the present independent review, revision, and ratification of the previous report by the Society of Interventional Radiology (SIR) Interventional Oncology Service Line and Technology Assessment Committee (1,2) represents a continuation of the collaborative initiative to consolidate and unite all investigators and clinicians practicing interventional oncology by providing a common language to describe transcatheter therapies and outcomes. CLASSIFICATION OF THERAPIES Image-Guided Transcatheter Tumor Therapy The term "image-guided transcatheter tumor therapy" is defined as the intravascular delivery of therapeutic agents via selective catheter placement with imaging guidance for the treatment of malignancy. Currently, various devices-such as embolic or drug-eluting particles, chemotherapeutic medications, or radioactive materials-are injected via tumor-feeding vessels with intent to achieve cytoreduction through focused delivery and deposition of high concentrations of therapeutic agent as well as ischemic devascularization (7-14). Therapeutic material may eventually include biologically active agents, chemical mediators of cell function and/or the tumor microenvironment, viral vectors, genetic material, nanoparticles, or other agents not yet developed or described. The term "transcatheter" aims to distinguish these therapies from other treatments that are applied orally or via a systemic intravenous ...