Global Perspectives on Hepatocellular Carcinoma

Treating hepatocellular carcinoma (HCC), the most common form of liver cancer, is exceptionally challenging today. Even as new therapies are on the horizon that show some promise, delays in diagnosis can derail their potential effectiveness. Many people diagnosed with cancer also suffer from other diseases, or comorbidities, which can complicate treatment as well.

A group of international oncology experts convened by OncLive Peer Exchange^® met recently 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, M.D., 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, M.D., M.S. 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.

Less common causes are nonalcoholic steatohepatitis (NASH) and excessive alcohol consumption, both of which contribute to cirrhosis.

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 NASH-induced HCC in the United States stemming from the growing prevalence of diabetes and obesity.

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 Stivarga (regorafenib) as a second-line treatment for patients with HCC following prior Nexavar (sorafenib). Nexavar 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 Opdivo (nivolumab) for patients with HCC following prior Nexavar. The agency also has accepted a supplemental new drug application (sNDA) for Lenvima (lenvatinib), a VEGF inhibitor, as a frontline systemic treatment for patients with advanced HCC.

Screening/Surveillance for HCC

In another development, Cabometyx (cabozantinib), a multikinase inhibitor, improved median overall survival (OS) versus placebo in patients with advanced HCC who have previously received Nexavar in the phase 3 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.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.

“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. Arndt Vogel, M.D., Ph.D., said it may also be necessary to screen people with NASH, which can lead to HCC before cirrhosis occurs.

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 with HCC and liver cirrhosis, almost 25 percent did not learn they had cirrhosis until after HCC was diagnosed. 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. 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.

Jordi Bruix, M.D., questioned whether using biomarkers to screen patients would be helpful. “The endpoint of screening is to detect the disease at an early stage so that the patients may benefit from treatment and have an improved survival … detection through tumor markers, by default, is going to detect tumors that are more advanced,” he said. Bruix said patients with advanced, aggressive tumors are less likely to benefit from early detection and treatment.

Singal expressed the hope that creating a panel of biomarkers would make them more useful for detecting early-stage HCC. He agreed with Vogel that biomarkers are the future, but said improving outcomes depends on “find[ing] accurate biomarkers for detection at an early stage.”

Panel members discussed how the Liver Imaging Reporting and Data System allows HCC to be diagnosed without a biopsy, which could have important implications for identifying biomarkers for diagnosis and treatment. Finn questioned whether skipping biopsies in the era of precision medicine might not be “shooting ourselves in the foot.” The group’s consensus was that while moving away from biopsies likely had hampered efforts to understand HCC better, biopsies should nevertheless be performed only when needed to guide therapy decisions or as part of a clinical trial.

Staging

Although the tumor/node/metastasis (TNM) system is effective for determining the stage of most types of cancer, Bruix said, “The TNM has never been really good at predicting outcomes in patients with liver cancer because it just takes into account tumor burden and TNM, which is pathology based.” He said staging for HCC must also take into account liver function and health status.

Bruix was a member of the team that developed the Barcelona Clinic Liver Cancer (BCLC) staging system, which is the most commonly used system in Western countries. It relies on an assessment of hepatic function, the patient’s performance status, and tumor variables to stratify patients into 1 of 5 groups and to guide treatment.

Singal praised the BCLC staging system as balancing the need to account for disease complexity with the need for ease of use. At the same time, he cautioned oncologists that they “can’t just follow the arrows” of the algorithm to stratify patients for treatment.

Bruix agreed. “No single staging system that connects staging with treatment will substitute the need to have a thinking clinician,” he said.

Initial Treatment

The panel briefly discussed other staging systems, including the Hong Kong Liver Cancer Staging System and the ITA.LI.CA staging system, which is partly derived from the BCLC staging system. Singal said while he feels these staging systems and others have some utility for research, “they have less utility on a day-to-day basis.”In patients with HCC, the intersection between liver disease and the cancer must always guide treatment selection. Vogel said some patients who undergo resection have such advanced liver disease that they are ineligible for adjuvant therapy. He said, “When we [do] decide on a treatment, we always have to keep in mind that the treatment itself might harm the liver.” He said it is important to monitor patients’ liver function closely to detect any negative effects on liver function as quickly as possible.

Transplant Eligibility

The Milan criteria are used to identify patients with HCC who are suitable for liver transplant and have a low risk of recurrence. Singal said this would include patients with “1 tumor less than 5 cm or 2 to 3 tumors less than 3 cm each, [with] no vascular invasion or extrahepatic disease.” He said cancer recurrence after transplant would be expected in approximately 10 percent of patients meeting these criteria.

Some groups in the United States have proposed more generous eligibility guidelines than the Milan criteria for liver transplants in patients with HCC, but Singal said the recommendations are associated with higher recurrence rates. He mentioned that studies using the Toronto criteria, which applies AFP levels and histologic data to exclude patients with more aggressive histology, have observed similar recurrence rates in patients who meet Milan tumor size criteria and patients who do not. Because most people with HCC do not undergo biopsy and thus do not have histologic data, Singal said the Toronto criteria have limited usefulness in clinical practice.

Vogel said that in Germany, people with HCC who do not meet Milan criteria cannot get a liver transplant even if their tumors respond well to locoregional therapy. Singal said he expects that “a shift away from a static one-time measurement to how the tumor changes over time” will eventually be used to identify the best candidates for transplant.

Locoregional Therapy

Resection is an option for patients with early-stage HCC who are good surgical candidates. Richard H. Marshall, M.D., said that while resection has long been the gold standard, especially for smaller tumors, recent studies have observed that “radiofrequency ablation [RFA] can have similar outcomes and similar overall survival compared with surgery in [patients with] tumors that are 2 cm and 3 cm or smaller.”

Percutaneous microwave ablation (MWA) is a newer technique for local ablation therapy in HCC, and Marshall said some trials have observed lower recurrence rates with MWA. “Some [recurrence rates] are on the order of 20 percent for RFA versus 10 percent for MWA, so I think we will see an expanded role for MWA in the future,” he said.

Transcatheter arterial chemoembolization (TACE) is another option for HCC. Bruix said TACE is his first choice for select patients with a large tumor burden because it improves survival. “The patients have to be compensated, with minimal symptoms and no vascular invasion,” he said.

Marshall said data, primarily from retrospective studies, suggest that combining TACE with RFA is better than using either therapy alone. He said his center uses the combination regimen when feasible for patients with tumors 5 cm or smaller but that there is debate on “how to sequence these therapies—whether to do them both at the same time or to do one prior to the other.”

Radioembolization or selective internal radiation therapy (SIRT) is another emerging option for HCC. With SIRT, small radioactive particles are delivered directly to the tumor. Marshall said the duration of OS in clinical trials is similar with TACE and SIRT but that SIRT is typically better tolerated. Recently, investigators presented results from a phase 3 trial that compared systemic therapy with Nexavar versus SIRT, but although SIRT appeared to be tolerated better, it failed to meet the primary endpoint for OS and was not superior to Nexavar. Bruix said that even though SIRT has shown antitumor activity, the data do not support its use as a viable alternative to Nexavar.

Finn asked the panel, “How do we know when locoregional therapy is no longer working and it’s time to transition to systemic treatment?”

“If you surveyed 100 different hepatologists or interventional radiologists, you would probably get about 50 different answers,” Singal responded. He said he transitions patients to systemic therapy if they do not respond to 2 rounds of TACE or continue to have disease progression.

Vogel said the more difficult decision is how to proceed if a patient has stable disease after local therapy. “Progressive disease is clearly a failure of TACE, but I also think that stable disease is an indication of TACE failure,” he said.

“Whenever I see something that I would define as a treatment failure or new disease or expanding disease, I always have to ask why … before I decide what is the next step in the treatment of this patient,” Marshall said. He and Vogel agreed with Singal that after 2 TACE procedures fail, it is usually time to move on to systemic therapy. Marshall said patients who do not respond to 2 TACE procedures probably have “bad tumor biology.”

Conclusions

Hepatocellular carcinoma is a growing problem globally. Many people do not receive a diagnosis until their cancer is advanced and their hepatic function is compromised. Screening patients at high risk is essential for early detection and treatment, but stronger biomarkers for early disease are needed. Resection and transplant are potentially curative and remain the gold standard for eligible patients. However, new locoregional and systemic therapies are emerging that may improve survival outcomes for patients who are ineligible for curative approaches or who experience recurrence.