Richard Finn, MD
Although new therapies are being rapidly introduced in the hepatocellular carcinoma (HCC) field after years of clinical trial disappointments, clinicians face many challenges when treating patients with this malignancy, including delays in diagnosis and comorbidities.OncLive
convened a group of international oncology experts to provide a global perspective on HCC. The panel discussed screening and staging issues, treatment of advanced HCC, and results of recent clinical trials. At the start of the discussion, moderator Richard S. Finn, MD, noted that HCC encompasses a “diverse group of malignancies with a global impact.”
“Hepatocellular carcinoma is the fifth most common [cancer] worldwide,” said panelist Amit Singal, MD, MS. He said the highest rates of HCC are in East Asia and Africa, where the primary driver is hepatitis B virus (HBV). Rates of HCC are lower in the United States and Europe, where hepatitis C virus (HCV) causes most cases.1 Less common causes are nonalcoholic steatohepatitis (NASH) and excessive alcohol consumption, both of which contribute to cirrhosis.1
Singal said he expects the advent of curative direct-acting antiviral agents (DAAs) for HCV to change the future of HCC in the United States and Europe, leading to lower rates and a shift in HCC etiology toward metabolic causes of cirrhosis. Data already show an increase in the incidence of NASHinduced HCC in the United States stemming from the growing prevalence of diabetes and obesity.2
Surgical resection or transplant remain the only cure for HCC. Finn said although HCC survival outcomes have started to improve, many patients have cirrhosis and other comorbidities that complicate management. As with most cancers, early diagnosis and intervention can significantly improve survival.
In the United States, excitement has been building among HCC specialists since April, when the FDA approved regorafenib (Stivarga) as a secondline treatment for patients with HCC following prior sorafenib (Nexavar). Sorafenib was the only approved systemic therapy in HCC for a decade as a series of late-stage clinical trials failed to produce additional therapies.
In September, the FDA granted an accelerated approval to nivolumab (Opdivo) for patients with HCC following prior sorafenib after the phase I/II CheckMate 040 trial demonstrated a 14.3% overall response rate per RECIST v1.1 criteria for patients who had previously been treated with sorafenib.3
The agency also has accepted a supplemental new drug application (sNDA) for lenvatinib (Lenvima), a VEGF inhibitor, as a frontline systemic treatment for patients with advanced HCC.
In another development, cabozantinib (Cabometyx), a multikinase inhibitor, improved median overall survival (OS) versus placebo in patients with advanced HCC who have previously received sorafenib in the phase III CELESTIAL trial, meeting the primary endpoint. Based on these results, Exelixis, the company developing the drug, plans to submit an sNDA to the FDA in the first quarter of 2018.
Screening/Surveillance for HCC
Current guidelines do not advise routine screening for HCC in the general population. However, international and US guidelines for HCC do recommend routine screening in individuals at higher risk of developing HCC.1,2
“These are probably patients who have known cirrhosis or known hepatitis,” Finn said. Carriers of HBV have an increased risk of HCC even in the absence of cirrhosis, as do patients with HCV who have a family history of HCC or bridging fibrosis.1
Arndt Vogel, MD, PhD, said it may also be necessary to screen people with NASH, which can lead to HCC before cirrhosis occurs.2
Vogel said a major challenge to implementing HCC screening for high-risk populations is that many people with chronic liver disease do not know they have it. “If people have HCV or HBV without any symptoms of advanced liver disease, they might not even know they have liver disease,” he explained. In a retrospective study of US veterans (N = 1201) with HCC and liver cirrhosis, almost 25% did not learn they had cirrhosis until after HCC was diagnosed.4 Vogel said the lack of awareness is particularly tragic for individuals with HCV, who could potentially be cured with a DAA before acquiring HCC.
Ultrasonography is the standard for surveilling high-risk individuals for HCC.1
Vogel said ultrasonography screening “is a good tool to detect liver nodules…[but] in patients who have obesity and have a fatty liver, detecting nodules is far more difficult.” He said measuring serum levels of alpha-fetoprotein (AFP) is another option, but recommended against relying solely on AFP testing due to its low sensitivity. Emerging biomarkers include AFP-L3 and des-gamma-carboxy prothrombin. Vogel said in the future, algorithms may combine multiple biomarkers with gender, age, and other risk factors to identify individuals who should undergo screening with ultrasonography or magnetic resonance imaging.