From the AGA Journals

AGA Clinical Practice Guidelines: Systemic HCC therapy



New recommendations from the American Gastroenterological Association focus on choice of systemic therapy in hepatocellular carcinoma (HCC) patients. The guideline authors point out that prognosis and treatment decisions are both heavily dependent on a combination of the severity of underlying disease and biological characteristics of the tumor.

The document includes options for patients who are ineligible for locoregional therapy or resection, patients with metastatic disease and preserved liver function, patients with poor liver function, and patients receiving adjuvant therapy following surgery or locoregional therapy (LRT).

Grace L. Su, MD, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor; Veterans Affairs Ann Arbor Healthcare System

Dr. Grace L. Su

Intermediate or advanced tumor stage is common among HCC patients, and curative options such as surgery and ablation are generally limited to early-stage disease. LRTs – including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and systemic therapy – may be employed against advanced or metastatic HCC, according to the authors, led by Grace L. Su, MD, of the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor, and the Veterans Affairs Ann Arbor Healthcare System.

In 2007, the Food and Drug Administration approved the multikinase inhibitor sorafenib as the first systemic therapy for HCC. The new guideline comes in the wake of new systemic therapeutic options that have arrived in the years since, including molecularly targeted therapy and immunotherapy. The authors of the guidance, published in Gastroenterology, include advice on both first- and second-line therapies.

Certainty of evidence for the recommendations ranges from low to very low, indicating limited or very little confidence in the effect estimated, and the true effect is likely to be considerably different than predicted by best current estimates. Accordingly, the recommendations are conditional, and decisions should be made with the values and preferences of the individual patient in mind.

In patients with preserved liver function who are ineligible for LRT or resection, or who have metastatic disease, the authors suggest that first-line treatment should be the combination of atezolizumab and bevacizumab rather than sorafenib. Bevacizumab comes with a bleeding risk, so patients should first be evaluated endoscopically and treated for esophageal varices. For patients who are ineligible for bevacizumab, alternatives are lenvatinib or sorafenib. Patients who are more concerned about disease progression than adverse events may want to consider lenvatinib rather than sorafenib, while those concerned about blood pressure control and who are less concerned about adverse skin reactions may choose sorafenib.

Options for second-line therapy after sorafenib include cabozantinib (mortality reduction, 2.2 months) and pembrolizumab (mortality reduction, 3.3 months). Patients with alpha-fetoprotein levels higher than 400 ng/mL may be candidates for treatment with ramucirumab (mortality reduction, 1.2 months). Another option is regorafenib (mortality reduction, 2.8 months). Patients who are more concerned about adverse effects than a potential survival benefit with any of these therapies may reasonably choose no systemic therapy.

For HCC patients with poor liver function, who are not eligible for LRT or resection, or with metastatic disease, the guidelines recommend against routine use of sorafenib.

In the setting of adjuvant therapy following curative surgical resection, curative local ablation, or TACE LRT, the guidelines recommend against the use of sorafenib. The authors also recommended against the use of bevacizumab following TACE LRT.

The authors noted that there is no high-quality comparative evidence in the second-line setting for atezolizumab plus bevacizumab, sorafenib, or lenvatinib. There is a dearth of evidence and few biomarkers to guide personalization of therapies, which places the emphasis on patient preferences, risks, and benefits.

The authors disclosed no conflicts.

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