Cover Story

Obesity, Hepatitis C Epidemics Drive ‘Alarming’ Increase in Liver Cancer Incidence, Mortality

A SEER analysis published last summer revealed staggering statistics about liver cancer in the United States.

Incidence has increased steadily since the mid-1970s, and that trend is expected to continue until at least 2030, according to the report by Islami and colleagues, published in CA: A Cancer Journal for Clinicians.

Further, mortality rates for liver cancer — which doubled since the 1980s — are rising faster than for any other malignancy. About 80% of the estimated 40,710 Americans who will be diagnosed in 2017 will die from the disease within 5 years.

A sharp increase in incidence of hepatocellular carcinoma — the most common form of liver cancer — is driving the trend. HCC is the sixth most common malignancy in the country. Cases have tripled in the past 40 years, largely due to the obesity and hepatitis C epidemics. Fatty liver disease — a consequence of obesity — and hepatitis C virus both cause cirrhosis, the major risk factor for HCC.

“Hepatocellular carcinoma incidence and mortality is increasing at an alarming rate, and currently we do not have any effective treatment that can bring significant survival benefit to patients, especially those at an advanced stage,” Devanand Sarkar, MBBS, PhD, scientist and member of the cancer molecular genetics research program at Virginia Commonwealth University Massey Cancer Center and associate professor in the department of human and molecular genetics at VCU School of Medicine, told Healio Gastroenterology and Liver Disease. “We need to have more in-depth understanding of the molecular mechanism of HCC development that will facilitate design of effective targeted therapies.”

Surgical resection is the treatment of choice for early-stage HCC, and patients with localized disease are more than 10 times than those with distant-stage disease to survive 5 years (31% vs. 3%). However, due to vague symptoms, many cases are diagnosed in advanced stages.

Because the liver is often compromised in patients with HCC, nonsurgical treatment options are limited. The FDA has approved only two drugs for liver cancer, but they confer modest survival benefits.

Devanand Sarkar

Consequently, researchers have intensified their efforts to better understand tumor biology in hopes of identifying more effective, nontraditional therapies.

Healio Gastroenterology and Liver Disease spoke with surgical oncologists, epidemiologists and others about the challenges that have hindered therapeutic advances for HCC; the potential of immunotherapy for this malignancy; the value of a multidisciplinary team for ensuring optimal care; and how improved understanding of the disease’s genetic and genomic characteristics could lead to earlier detection and more effective treatment.

Prevalence and Risk Factors

The majority of liver cancer cases in the United States can be attributed to modifiable risk factors.

Metabolic disorders — which include nonalcoholic fatty liver disease, metabolic syndrome and diabetes — accounted for nearly one-third (32%) of all HCCs among Medicare recipients between 2000 and 2011. Other leading causes included chronic HCV infection (21%), excessive alcohol consumption (13%), tobacco use (9%) and chronic hepatitis B virus infection (4%).

Variations in risk factor prevalence accounted for most of the differences in liver cancer rates by sex, age, race/ethnicity and state, Islami and colleagues found.

For example, Hispanics in Texas — most of whom are of Mexican origin — demonstrated higher liver cancer death rates than Hispanics in Florida, most of whom are of Puerto Rican or Cuban origin. This difference could be due to increased prevalence of chronic HCV infection, excess body weight and nonalcoholic fatty liver disease among Mexican Americans.

Also, assimilation of foreign-born Asian and Hispanic populations into American culture may increase liver cancer risk, as obesity, alcohol consumption and smoking are more common in the United States than in parts of Latin America or Asia. Simultaneously, risk may also decrease across generations for some subgroups of Asian populations due to the lower HBV prevalence in the US compared to some Asian countries.

“Our findings reflect the underlying prevalence of different risk factors, which vary by state and demographics,” study researcher Kimberly D. Miller, MPH, epidemiologist in the department of surveillance and health services research at the American Cancer Society, told Healio Gastroenterology and Liver Disease.

The association between overweight or obesity and liver disease — and, in turn, HCC — has been well established.

A population-based cohort study of 1.2 million men — conducted by Hagström and colleagues, and published this year in Gut — showed high BMI in late adolescence predicted increased HCC risk.

Kimberly D. Miller

Compared with men who had adolescent BMI of 18.5 kg/m2 to 22.5 kg/m2, HCC risk increased for those who had adolescent BMI of 22.5 kg/m2 to 25 kg/m2 (HR = 1.28; 95% CI, 0.91-1.8), 25 kg/m2 to 30 kg/m2 (HR = 1.57; 95% CI, 1.01-2.45) or 30 kg/m2 or greater (HR = 3.59; 95% CI, 1.85-6.99).

A case-control study by Hassan and colleagues showed history of obesity during young adulthood increased risk for HCC among men (OR = 2.3; 95% CI, 1.2-4.4) and women (OR = 3.6; 95% CI, 1.5-8.9). Each additional BMI unit appeared associated with a 3.89-month decrease in age at HCC diagnosis (P < .001).

“There clearly is a rise in obesity in the last 10 to 20 years. This automatically increases risk for developing fatty liver disease or hepatic steatosis, which can then turn into fibrosis, cirrhosis and HCC,” David A. Iannitti, MD, chief of the division of hepatopancreaticobiliary surgery at Carolinas Medical Center and surgical oncologist at Levine Cancer Institute at Carolinas HealthCare System, told Healio Gastroenterology and Liver Disease. “This will be the most likely etiology for liver cancer moving forward. We can try to prevent it by controlling cholesterol, but also by keeping weight down to a healthy range.”

Impact of HCV

HCV also contributes to increased HCC incidence. The infection often causes cirrhosis, which leads to HCC.

Of every 100 people infected with HCV, 75 to 85 will develop chronic HCV, according to CDC data. Of those, 60 to 70 will develop chronic liver disease, 5 to 20 will develop cirrhosis, and 1 to 5 will die of cirrhosis or liver cancer.

An estimated 2.7 million to 3.9 million people in the United States have chronic HCV, and most do not know it.

“We are seeing the incidence of liver cancer increasing mainly because of the impact of the HCV epidemic among baby boomers, or individuals born between 1945 and 1965,” Miller said.

Baby boomers are five times more likely to have HCV than other adults. In fact, three of four adults with HCV were born during those 2 decades.

This could be due to several practices — such as use of contaminated blood products, injection drug use or blood transfusions — between the 1960s and 1980s, before the virus was discovered and infection control procedures were in place.

“The problem is the damage caused by hepatitis C when it peaked in the 1980s and 1990s. In terms of research data, we won’t see all the damage and cancer caused by it until 2020,” Jimmy J. Hwang, MD, section chief of gastrointestinal medical oncology at Levine Cancer Institute at Carolinas HealthCare System, said in an interview. “It will be interesting to see if the new drugs for hepatitis C will alter that frequency in the future.”

The overall cancer death rate decreased by 1.5% each year from 2003 to 2012.

However, the death rate for liver cancer increased by nearly 3% per year since 2000, more than that of any other malignancy during that time, according to the American Cancer Society. HCV- and liver cancer-associated deaths were highest among those born from 1945 to 1965.

Jimmy J. Hwang

In 2012, the CDC recommended one-time HCV screening for baby boomers. The following year, the U.S. Preventive Services Task Force issued a similar recommendation.

“We know the biggest cause of HCC is related to cirrhosis that develops from hepatitis C,” Mary Dillhoff, MD, surgical oncologist at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, told Healio Gastroenterology and Liver Disease. “If we effectively screen for hepatitis C, we can treat them with the new drugs to prevent them from ever getting cirrhosis, the biggest risk factor for developing HCC.”

Still — despite the opportunity to prevent cancer — uptake of HCV screening has been slow due to several factors, including lack of awareness and questions about cost-effectiveness.

“In a new national survey, only 14% of baby boomers have received one-time testing,” Miller said.

Without more screening, liver cancer incidence will continue to increase due to undiagnosed HCV.

“Many baby boomers who were infected with HCV have gone 30 or 40 years without knowing, and a number are now presenting with cancer,” Sarkar said. “The current prediction is the incidence will rise through 2030 to 2050, so we need to do something about that right now.”

Beyond better screening promotion, a substantial number of liver cancer deaths could be averted through prevention strategies designed to curtail alcohol and IV drug use, and encourage exercise and maintenance of healthy weight.

“The challenge for clinicians is that there is a lot of information but limited resources and time,” Miller said. “If clinicians received more guidance and support on how to deliver these interventions, it would address this substantial gap.”

Direct-acting antivirals — a relatively new treatment class for hepatitis C — present a huge opportunity to decrease the incidence of cirrhosis from HCV and, in turn, risk for HCC, Iannitti said.

“There are good treatments for hepatitis C, but there is a latency period,” he said. “If we can catch the virus early and treat patients with drugs like ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) — which has a 99% clearance rate — then you would expect to see a decrease in the incidence of hepatitis C in the next 10 to 20 years. Therefore, you would expect the incidence of HCC related to hepatitis C to also go down.”

‘A Perfect Storm’

Between 85% and 95% of patients with HCC have cirrhosis.

Consequently, surveillance of individuals with cirrhosis is crucial for early detection of cancer. The American Association for the Study of Liver Disease recommends transabdominal ultrasound every 6 months.

The recommendations — developed by Heimbach and colleagues, and published this year in Hepatology — cited data from a randomized study that showed routine surveillance reduced HCC mortality by 37% among hepatitis B virus carriers, although there are no randomized trial data from patients with cirrhosis from HCV.

Observational data show individuals with HCC who underwent surveillance were more likely than those with no prior surveillance to present with early-stage HCC (OR = 2.11; 95% CI, 1.88-2.33) and survive at least 3 years (50.8% vs. 27.9%; OR = 1.9; 95% CI, 1.67-2.17)

Other forms of surveillance for high-risk patients include evaluating alpha-fetoprotein (AFP), AFP-L3 and des-gamma-carboxy-prothrombin serum biomarkers.

The association’s recommendations included study data that showed use of ultrasound alone (OR = 2.04; 95% CI, 1.55-2.68) or with AFP (OR = 2.16; 95% CI, 1.8-2.6) increased detection of early-stage HCC compared with no surveillance, but no studies have directly compared the addition of AFP to ultrasound.

Despite the association between cirrhosis and HCC, patients often do not adhere to routine surveillance.

“Getting patients to undergo surveillance is very difficult and remains one of the biggest challenges for clinicians, because a lot of this is preventable,” Dillhoff said. “Getting a patient to come for an ultrasound every 6 months is difficult. However, if we diagnose them earlier, we would have many more treatment options at our disposal.”

Stigma may be partially to blame.

“There is a lot of research ... in terms of stigma and how HCV affects cure-seeking behavior among people at risk for chronic liver disease and cancer,” Miller said. “It’s not just a stigma with the cancer, but the risk factors themselves. It is a little bit of a perfect storm.”

Unlike for other malignancies, no clear diagnostic tool exists for HCC.

“We already have built-in early diagnosis parameters for other cancers that are large in number. For breast cancer, we have mammograms. For colorectal cancer, we have routine colonoscopy,” Sarkar said. “We still don’t have anything like that in the case of the liver, and this is another reason why we are not detecting it.”

That challenge is compounded by how liver disease essentially overlaps with the cancer.

“Liver cancer is difficult to treat because it is not diagnosed early enough,” Sarkar said. “Symptoms can be vague so it goes unnoticed by the patient, allowing the tumor to progress and form over months. By the time it is diagnosed, the cancer has already become extensively aggressive.”

Underlying liver disease is a significant problem for patients with HCC because it, too, can be fatal.

“That’s why some patients are better for transplant, because not only are we treating their cancer, but also their liver disease,” Dillhoff said.

However, eligibility criteria for transplantation among those with HCC are stringent: one tumor 5 cm in diameter or smaller among those with single tumors, or no more than three tumors — each 3 cm in diameter or less — for those with multiple tumors.

“At my institution, we try to keep patients within those numbers to keep them on the transplant list,” Dillhoff said. “In order to do that, we might apply locoregional therapies to the liver, such as ablation.”

Other locoregional therapy options include transarterial chemoembolization — also called TACE, an image-guided, nonsurgical procedure that treats malignant lesions — and yttrium-90 resin microspheres (SIR-Spheres, Sirtex Medical Limited), which are microscopic resin beads that travel through the bloodstream to deliver radiation to the tumor.

“We use a combination of these strategies depending on the patients and tumors to keep them within transplant criteria,” Dillhoff said.

Staging, Prognosis

The various causes of HCC make it a very heterogenous disease.

This heterogeneity has prevented researchers from developing a solid understanding of disease and tumor biology. This, in turn, has made it difficult to develop an effective staging system.

The most common staging system — or treatment algorithm — for HCC is the Barcelona Clinic Liver Cancer classification. However, heterogeneity of the disease limits the staging system’s practicality in the clinical setting.

“We just haven’t had a good functional staging system for HCC, and this has been a problem from a clinician’s point of view,” Iannitti said. “We also don’t use the staging systems generally in the day-to-day treatment of patients.”

Staging systems have not changed or been updated in recent years, Hwang added.

“There are a half-dozen different staging systems that people worldwide look at — Barcelona Clinic Liver Cancer classification is the most publicized and used — but they all have their limitations,” he said.

Researchers also seek molecular biomarkers to determine a patient’s prognosis.

In a study published in Scientific Reports, Chen and colleagues evaluated DUOX1, GLS2 and FBP1 gene expression in 72 samples from patients with HCC who underwent tumor resection. Researchers hoped to better understand the relationship between expression of these genes and prognosis, as well as to predict the risk for recurrence and mortality.

The three markers were overexpressed among patients who survived after surgery (P < .001 for all markers) and patients who did not experience recurrence after surgery (DUOX1, P = .026; GLS2 and FBP1, P = .001).

A classifier comprised of all three markers had 93.1% power to predict OS and 86.1% power to predict DFS.

Researchers also have sought to identify biological factors that contribute to progression of liver disease to HCC that could be early markers of the disease and potential treatment targets.

In a study published in The Journal of Clinical Investigation, Yoo and colleagues found that astrocyte elevated gene-1 (AEG-1) played a role in HCC pathogenesis. Although researchers observed low AEG-1 expression in the normal human liver, expression increased with cancer stage and grade in 90% of HCC samples.

A study by Srivastava and colleagues, published in Hepatology, showed AEG-1 may affect metabolism and cell division through interacting with another gene, c-Myc. Mice with overexpressed AEG-1 and c-Myc developed spontaneous liver cancer with lung metastases.

Sarkar, a researcher on both studies, and his colleagues continue to explore various molecular mechanisms associated with AEG-1 and other genes to determine their role in the development of liver cancer.

“We hope to target AEG-1 to block inflammation and additional fat in the liver and, at the same time, we can inhibit tumor cells,” Sarkar said. “This could be a very good approach of targeting liver cancer or can be combined with other traditional approaches like chemotherapies.”

Therapeutic Approaches

The many factors that contribute to HCC’s heterogeneity also affect treatment.

Options include radical hepatectomy, liver transplantation, locoregional therapies and systemic therapies; however, not all of these are options for every patient.

“There are so many variables when it comes to this patient population, and this is why it can be so difficult to treat,” Iannitti said.

Patients with HCC who do not have underlying chronic liver disease or cirrhosis have more options. However, this group accounts for only a small percentage of patients.

“Less than 10% of patients with liver cancer in the United States do not have cirrhosis or liver disease,” Iannitti said. “Because 80% to 90% of people with HCC also have cirrhosis, their degree of cirrhosis will dictate what you can and can’t do in terms of treatment.”

Those without liver disease or cirrhosis may be able to undergo resection to remove the tumor.

“We think of doing resection in patients who have good liver function and solitary tumors, but the question is, how big is the tumor?” Hwang said. “That is when things get gray, because these patients generally have two diseases at once, if not more.”

If a patient cannot undergo surgery due to cirrhosis or portal hypertension, many therapeutic approaches used for other malignancies are not an option. If drugs are not properly metabolized by the liver, they may be less effective or more toxic.

“For a lot of drugs to work, they need to be metabolized by the liver,” Sakar said. “If this doesn’t happen, then the drug won’t work. Liver cancer is inherently resistant to standard therapies and radiotherapies.”

For this reason, patients who cannot undergo surgery are not automatically referred for chemotherapy or other systemic therapies, like often is the case for other cancers.

“If surgery isn’t an option, then transplant is an important option to treat both the liver disease and cancer; however, there are transplant guidelines to consider,” Hwang said. “Locoregional therapy like chemoembolization, radioembolization and ablation also are options.”

Options still may exist for patients with cirrhosis, Iannitti said. Those with Model of End-stage Liver Disease scores of 8 to 9 will have more options than patients with scores of 20, who have limited treatments available.

“Not only are there tumor factors to consider, such as size and nodal status, but you have to consider the degree of cirrhosis, liver dysfunction and portal hypertension,” Iannitti said. “You have to deal with these two sets of variables and that can be a bit challenging.”

Whether to begin a patient on TACE, Y-90 radiation or ablation is at the discretion of the institution and disciplinary team.

A trial is underway at Ohio State to evaluate the efficacy of radiation before TACE, Dillhoff said.

“It is institution dependent as to which regional therapies are used first when a patient can’t undergo surgery,” she added. “At our institution, the most commonly used locoregional therapy is TACE first. Then, for patients who don’t respond or have tumors that keep growing, we turn to Y-90 or ablation.”

Due to compromised liver function, nontraditional therapies may ultimately be more relevant for the disease, Sakar said.

“Virus-based therapies and nanoparticle-based small interfering RNA [siRNA] therapies are showing meaningful objective responses in HCC patients,” he added. “We are targeting AEG-1 using hepatocyte-specific nanoparticle-delivered siRNA which is showing very promising results in preclinical studies both in nonalcoholic steatohepatitis and in HCC.”

‘Dismal’ Survival Benefit

There are only three approved drugs for HCC.

Sorafenib (Nexavar, Bayer HealthCare), a tyrosine kinase inhibitor, is approved for first-line therapy. Regorafenib (Stivarga, Bayer HealthCare) — a multikinase inhibitor that received FDA approval in April — is indicated for patients previously treated with sorafenib. Nivolumab (Opdivo, Bristol-Myers Squibb) is an anti-PD-1 antibody approved in September to treat patients who previously failed sorafenib.

Otherwise, initial enthusiasm for drugs under investigation for HCC historically has ended in disappointment.

Results of the phase 3 EVOLVE-1 trial showed daily treatment with the mTOR inhibitor everolimus (Afinitor, Novartis) failed to extend survival compared with placebo for patients with advanced HCC (7.6 months vs. 7.3 months; HR = 1.5; 95% CI, 0.86-1.27).

In the phase 3 REACH trial, researchers reported no significant difference in median OS between patients with HCC treated with ramucirumab (Cyramza, Eli Lilly) — a fully human monoclonal antibody — and those who received placebo (9.2 months vs. 7.6 months; HR = 0.87; 95% CI, 0.72-1.05).

“We’ve seen a lot of clinical trials open and close, and we are enthusiastic every time with no luck,” Iannitti said. “But we’re still trying, and that is the bottom line.”

Jeff Evans, MD, FRCP, director of Institute of Cancer Sciences at University of Glasgow, and colleagues are comparing the use of the tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai) with sorafenib for the first-line treatment of HCC.

Results from the REFLECT clinical trial, presented at this year’s ASCO Annual Meeting, showed lenvatinib was noninferior to sorafenib (median OS, 13.6 months vs. 12.3 months; HR = 0.92; 95% CI, 0.79-1.06).

Eisai has submitted a supplemental new drug application to the FDA for approval of lenvatinib as a frontline therapy for HCC.

“For a decade, there has been no advance in the first-line systemic treatment of [unresectable] HCC in Europe, so [these data support] a potential new option for liver cancer patients that offers greater choice,” Evans said in a press release.

Still, the survival advantages offered by the two approved drugs for HCC — sorafenib and regorafenib — are modest, and new approaches are needed.

A randomized, double-blind study by Bruix and colleagues — the data from which supported regorafenib’s approval — included patients with HCC who progressed during sorafenib treatment. Researchers randomly assigned patients 2:1 to best supportive care plus either once-daily regorafenib or placebo.

Results showed regorafenib conferred statistically significant — but still small — benefits with regard to median OS (10.6 months vs. 7.8 months; HR = 0.62; 95% CI, 0.5-0.78) and median PFS (3.1 months vs. 1.5 months; HR = 0.46; 95% CI, 0.37-0.56).

“These drugs are approved because they do offer some survival benefit,” Hwang said. “However, the benefit is dismal, so everyone is waiting on the answer to immunotherapies.”

Results of the CheckMate 040 trial, presented in April at The International Liver Congress, showed patients ineligible for surgery treated with nivolumab achieved median OS of 16.7 months.

“Unfortunately, we do not have any miraculous systemic agents out there at this point,” Dillhoff said. “Immunotherapies, such as nivolumab and ipilimumab [Yervoy, Bristol-Myers Squibb] — which are being investigated in trials now — will hopefully be one of the biggest changes in our future.”

Multidisciplinary Approach

The individualization necessary to treat each patient — in addition to the potential addition of immune-oncology agents and other therapies to the treatment armamentarium — will require a multidisciplinary approach for HCC.

“Most surgeons aren’t comfortable operating on a patient with cirrhosis or portal hypertension or administering ablation therapies,” Iannitti said. “More education is needed for surgeons and I ideally would like to see more multidisciplinary, thoughtful, comprehensive care management plans.”

A multidisciplinary team is “critical” for any patient with cancer, Dillhoff said.

“We all know our specialty so well, so it takes a real team to work fluidly together to decide the timing of therapies and when we should use each one,” she said. “There are a lot of options for our patients, from transplant and locoregional therapies to radiation and chemotherapy. Therefore, it is important for our patients to go to institutions where teams meet on a regular basis and discuss options.”

However, access to multidisciplinary care is not consistent.

“There is substantial progress in localized disease,” Miller said. “There are actually curative treatments available. The issue is that there are substantial disparities in who receives these treatments.”

“One of the things we found in our study was that who is diagnosed at what stage of disease was relatively similar among the different ethnic and racial groups,” she added. “However, we saw overall disparities in survival, and we suspect part of that is driven by inequalities and access to care.”

Hwang agreed.

“The access to the right personnel is a big challenge and a bigger concern in underserved areas where there may not be a surgeon, interventional radiologist or hepatologist available,” he said.

Cost of direct-acting antivirals for HCV also should be considered, Miller said.

“These treatments are much better than what we used to have, but they are also ... expensive,” she said. “A lot of the people who need them most are medically underinsured. This is a huge issue, and I think it will become a very important point in the future.”

The difficulties researchers and clinicians face in liver cancer management require broader understanding of the challenges in this disease, as well as more funding than is currently allocated, Sarkar said.

“Apart from the NIH ... funding for research and trials for liver cancer is virtually nonexistent unless it’s a foundation or individual raising money,” he said. “We need to overcome this lack of community awareness and help people understand how important it is that we better understand this cancer.” – by Melinda Stevens

Disclosures: Hwang reports consultant roles with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly and Genentech/Roche; and speakers bureau roles with Amgen, Celgene and Genentech/Roche. Dillhoff, Iannitti, Miller and Sarkar report no relevant financial disclosures.

A SEER analysis published last summer revealed staggering statistics about liver cancer in the United States.

Incidence has increased steadily since the mid-1970s, and that trend is expected to continue until at least 2030, according to the report by Islami and colleagues, published in CA: A Cancer Journal for Clinicians.

Further, mortality rates for liver cancer — which doubled since the 1980s — are rising faster than for any other malignancy. About 80% of the estimated 40,710 Americans who will be diagnosed in 2017 will die from the disease within 5 years.

A sharp increase in incidence of hepatocellular carcinoma — the most common form of liver cancer — is driving the trend. HCC is the sixth most common malignancy in the country. Cases have tripled in the past 40 years, largely due to the obesity and hepatitis C epidemics. Fatty liver disease — a consequence of obesity — and hepatitis C virus both cause cirrhosis, the major risk factor for HCC.

“Hepatocellular carcinoma incidence and mortality is increasing at an alarming rate, and currently we do not have any effective treatment that can bring significant survival benefit to patients, especially those at an advanced stage,” Devanand Sarkar, MBBS, PhD, scientist and member of the cancer molecular genetics research program at Virginia Commonwealth University Massey Cancer Center and associate professor in the department of human and molecular genetics at VCU School of Medicine, told Healio Gastroenterology and Liver Disease. “We need to have more in-depth understanding of the molecular mechanism of HCC development that will facilitate design of effective targeted therapies.”

Surgical resection is the treatment of choice for early-stage HCC, and patients with localized disease are more than 10 times than those with distant-stage disease to survive 5 years (31% vs. 3%). However, due to vague symptoms, many cases are diagnosed in advanced stages.

Because the liver is often compromised in patients with HCC, nonsurgical treatment options are limited. The FDA has approved only two drugs for liver cancer, but they confer modest survival benefits.

Devanand Sarkar

Consequently, researchers have intensified their efforts to better understand tumor biology in hopes of identifying more effective, nontraditional therapies.

Healio Gastroenterology and Liver Disease spoke with surgical oncologists, epidemiologists and others about the challenges that have hindered therapeutic advances for HCC; the potential of immunotherapy for this malignancy; the value of a multidisciplinary team for ensuring optimal care; and how improved understanding of the disease’s genetic and genomic characteristics could lead to earlier detection and more effective treatment.

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Prevalence and Risk Factors

The majority of liver cancer cases in the United States can be attributed to modifiable risk factors.

Metabolic disorders — which include nonalcoholic fatty liver disease, metabolic syndrome and diabetes — accounted for nearly one-third (32%) of all HCCs among Medicare recipients between 2000 and 2011. Other leading causes included chronic HCV infection (21%), excessive alcohol consumption (13%), tobacco use (9%) and chronic hepatitis B virus infection (4%).

Variations in risk factor prevalence accounted for most of the differences in liver cancer rates by sex, age, race/ethnicity and state, Islami and colleagues found.

For example, Hispanics in Texas — most of whom are of Mexican origin — demonstrated higher liver cancer death rates than Hispanics in Florida, most of whom are of Puerto Rican or Cuban origin. This difference could be due to increased prevalence of chronic HCV infection, excess body weight and nonalcoholic fatty liver disease among Mexican Americans.

Also, assimilation of foreign-born Asian and Hispanic populations into American culture may increase liver cancer risk, as obesity, alcohol consumption and smoking are more common in the United States than in parts of Latin America or Asia. Simultaneously, risk may also decrease across generations for some subgroups of Asian populations due to the lower HBV prevalence in the US compared to some Asian countries.

“Our findings reflect the underlying prevalence of different risk factors, which vary by state and demographics,” study researcher Kimberly D. Miller, MPH, epidemiologist in the department of surveillance and health services research at the American Cancer Society, told Healio Gastroenterology and Liver Disease.

The association between overweight or obesity and liver disease — and, in turn, HCC — has been well established.

A population-based cohort study of 1.2 million men — conducted by Hagström and colleagues, and published this year in Gut — showed high BMI in late adolescence predicted increased HCC risk.

Kimberly D. Miller

Compared with men who had adolescent BMI of 18.5 kg/m2 to 22.5 kg/m2, HCC risk increased for those who had adolescent BMI of 22.5 kg/m2 to 25 kg/m2 (HR = 1.28; 95% CI, 0.91-1.8), 25 kg/m2 to 30 kg/m2 (HR = 1.57; 95% CI, 1.01-2.45) or 30 kg/m2 or greater (HR = 3.59; 95% CI, 1.85-6.99).

A case-control study by Hassan and colleagues showed history of obesity during young adulthood increased risk for HCC among men (OR = 2.3; 95% CI, 1.2-4.4) and women (OR = 3.6; 95% CI, 1.5-8.9). Each additional BMI unit appeared associated with a 3.89-month decrease in age at HCC diagnosis (P < .001).

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“There clearly is a rise in obesity in the last 10 to 20 years. This automatically increases risk for developing fatty liver disease or hepatic steatosis, which can then turn into fibrosis, cirrhosis and HCC,” David A. Iannitti, MD, chief of the division of hepatopancreaticobiliary surgery at Carolinas Medical Center and surgical oncologist at Levine Cancer Institute at Carolinas HealthCare System, told Healio Gastroenterology and Liver Disease. “This will be the most likely etiology for liver cancer moving forward. We can try to prevent it by controlling cholesterol, but also by keeping weight down to a healthy range.”

Impact of HCV

HCV also contributes to increased HCC incidence. The infection often causes cirrhosis, which leads to HCC.

Of every 100 people infected with HCV, 75 to 85 will develop chronic HCV, according to CDC data. Of those, 60 to 70 will develop chronic liver disease, 5 to 20 will develop cirrhosis, and 1 to 5 will die of cirrhosis or liver cancer.

An estimated 2.7 million to 3.9 million people in the United States have chronic HCV, and most do not know it.

“We are seeing the incidence of liver cancer increasing mainly because of the impact of the HCV epidemic among baby boomers, or individuals born between 1945 and 1965,” Miller said.

Baby boomers are five times more likely to have HCV than other adults. In fact, three of four adults with HCV were born during those 2 decades.

This could be due to several practices — such as use of contaminated blood products, injection drug use or blood transfusions — between the 1960s and 1980s, before the virus was discovered and infection control procedures were in place.

“The problem is the damage caused by hepatitis C when it peaked in the 1980s and 1990s. In terms of research data, we won’t see all the damage and cancer caused by it until 2020,” Jimmy J. Hwang, MD, section chief of gastrointestinal medical oncology at Levine Cancer Institute at Carolinas HealthCare System, said in an interview. “It will be interesting to see if the new drugs for hepatitis C will alter that frequency in the future.”

The overall cancer death rate decreased by 1.5% each year from 2003 to 2012.

However, the death rate for liver cancer increased by nearly 3% per year since 2000, more than that of any other malignancy during that time, according to the American Cancer Society. HCV- and liver cancer-associated deaths were highest among those born from 1945 to 1965.

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Jimmy J. Hwang

In 2012, the CDC recommended one-time HCV screening for baby boomers. The following year, the U.S. Preventive Services Task Force issued a similar recommendation.

“We know the biggest cause of HCC is related to cirrhosis that develops from hepatitis C,” Mary Dillhoff, MD, surgical oncologist at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, told Healio Gastroenterology and Liver Disease. “If we effectively screen for hepatitis C, we can treat them with the new drugs to prevent them from ever getting cirrhosis, the biggest risk factor for developing HCC.”

Still — despite the opportunity to prevent cancer — uptake of HCV screening has been slow due to several factors, including lack of awareness and questions about cost-effectiveness.

“In a new national survey, only 14% of baby boomers have received one-time testing,” Miller said.

Without more screening, liver cancer incidence will continue to increase due to undiagnosed HCV.

“Many baby boomers who were infected with HCV have gone 30 or 40 years without knowing, and a number are now presenting with cancer,” Sarkar said. “The current prediction is the incidence will rise through 2030 to 2050, so we need to do something about that right now.”

Beyond better screening promotion, a substantial number of liver cancer deaths could be averted through prevention strategies designed to curtail alcohol and IV drug use, and encourage exercise and maintenance of healthy weight.

“The challenge for clinicians is that there is a lot of information but limited resources and time,” Miller said. “If clinicians received more guidance and support on how to deliver these interventions, it would address this substantial gap.”

Direct-acting antivirals — a relatively new treatment class for hepatitis C — present a huge opportunity to decrease the incidence of cirrhosis from HCV and, in turn, risk for HCC, Iannitti said.

“There are good treatments for hepatitis C, but there is a latency period,” he said. “If we can catch the virus early and treat patients with drugs like ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) — which has a 99% clearance rate — then you would expect to see a decrease in the incidence of hepatitis C in the next 10 to 20 years. Therefore, you would expect the incidence of HCC related to hepatitis C to also go down.”

‘A Perfect Storm’

Between 85% and 95% of patients with HCC have cirrhosis.

Consequently, surveillance of individuals with cirrhosis is crucial for early detection of cancer. The American Association for the Study of Liver Disease recommends transabdominal ultrasound every 6 months.

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The recommendations — developed by Heimbach and colleagues, and published this year in Hepatology — cited data from a randomized study that showed routine surveillance reduced HCC mortality by 37% among hepatitis B virus carriers, although there are no randomized trial data from patients with cirrhosis from HCV.

Observational data show individuals with HCC who underwent surveillance were more likely than those with no prior surveillance to present with early-stage HCC (OR = 2.11; 95% CI, 1.88-2.33) and survive at least 3 years (50.8% vs. 27.9%; OR = 1.9; 95% CI, 1.67-2.17)

Other forms of surveillance for high-risk patients include evaluating alpha-fetoprotein (AFP), AFP-L3 and des-gamma-carboxy-prothrombin serum biomarkers.

The association’s recommendations included study data that showed use of ultrasound alone (OR = 2.04; 95% CI, 1.55-2.68) or with AFP (OR = 2.16; 95% CI, 1.8-2.6) increased detection of early-stage HCC compared with no surveillance, but no studies have directly compared the addition of AFP to ultrasound.

Despite the association between cirrhosis and HCC, patients often do not adhere to routine surveillance.

“Getting patients to undergo surveillance is very difficult and remains one of the biggest challenges for clinicians, because a lot of this is preventable,” Dillhoff said. “Getting a patient to come for an ultrasound every 6 months is difficult. However, if we diagnose them earlier, we would have many more treatment options at our disposal.”

Stigma may be partially to blame.

“There is a lot of research ... in terms of stigma and how HCV affects cure-seeking behavior among people at risk for chronic liver disease and cancer,” Miller said. “It’s not just a stigma with the cancer, but the risk factors themselves. It is a little bit of a perfect storm.”

Unlike for other malignancies, no clear diagnostic tool exists for HCC.

“We already have built-in early diagnosis parameters for other cancers that are large in number. For breast cancer, we have mammograms. For colorectal cancer, we have routine colonoscopy,” Sarkar said. “We still don’t have anything like that in the case of the liver, and this is another reason why we are not detecting it.”

That challenge is compounded by how liver disease essentially overlaps with the cancer.

“Liver cancer is difficult to treat because it is not diagnosed early enough,” Sarkar said. “Symptoms can be vague so it goes unnoticed by the patient, allowing the tumor to progress and form over months. By the time it is diagnosed, the cancer has already become extensively aggressive.”

Underlying liver disease is a significant problem for patients with HCC because it, too, can be fatal.

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“That’s why some patients are better for transplant, because not only are we treating their cancer, but also their liver disease,” Dillhoff said.

However, eligibility criteria for transplantation among those with HCC are stringent: one tumor 5 cm in diameter or smaller among those with single tumors, or no more than three tumors — each 3 cm in diameter or less — for those with multiple tumors.

“At my institution, we try to keep patients within those numbers to keep them on the transplant list,” Dillhoff said. “In order to do that, we might apply locoregional therapies to the liver, such as ablation.”

Other locoregional therapy options include transarterial chemoembolization — also called TACE, an image-guided, nonsurgical procedure that treats malignant lesions — and yttrium-90 resin microspheres (SIR-Spheres, Sirtex Medical Limited), which are microscopic resin beads that travel through the bloodstream to deliver radiation to the tumor.

“We use a combination of these strategies depending on the patients and tumors to keep them within transplant criteria,” Dillhoff said.

Staging, Prognosis

The various causes of HCC make it a very heterogenous disease.

This heterogeneity has prevented researchers from developing a solid understanding of disease and tumor biology. This, in turn, has made it difficult to develop an effective staging system.

The most common staging system — or treatment algorithm — for HCC is the Barcelona Clinic Liver Cancer classification. However, heterogeneity of the disease limits the staging system’s practicality in the clinical setting.

“We just haven’t had a good functional staging system for HCC, and this has been a problem from a clinician’s point of view,” Iannitti said. “We also don’t use the staging systems generally in the day-to-day treatment of patients.”

Staging systems have not changed or been updated in recent years, Hwang added.

“There are a half-dozen different staging systems that people worldwide look at — Barcelona Clinic Liver Cancer classification is the most publicized and used — but they all have their limitations,” he said.

Researchers also seek molecular biomarkers to determine a patient’s prognosis.

In a study published in Scientific Reports, Chen and colleagues evaluated DUOX1, GLS2 and FBP1 gene expression in 72 samples from patients with HCC who underwent tumor resection. Researchers hoped to better understand the relationship between expression of these genes and prognosis, as well as to predict the risk for recurrence and mortality.

The three markers were overexpressed among patients who survived after surgery (P < .001 for all markers) and patients who did not experience recurrence after surgery (DUOX1, P = .026; GLS2 and FBP1, P = .001).

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A classifier comprised of all three markers had 93.1% power to predict OS and 86.1% power to predict DFS.

Researchers also have sought to identify biological factors that contribute to progression of liver disease to HCC that could be early markers of the disease and potential treatment targets.

In a study published in The Journal of Clinical Investigation, Yoo and colleagues found that astrocyte elevated gene-1 (AEG-1) played a role in HCC pathogenesis. Although researchers observed low AEG-1 expression in the normal human liver, expression increased with cancer stage and grade in 90% of HCC samples.

A study by Srivastava and colleagues, published in Hepatology, showed AEG-1 may affect metabolism and cell division through interacting with another gene, c-Myc. Mice with overexpressed AEG-1 and c-Myc developed spontaneous liver cancer with lung metastases.

Sarkar, a researcher on both studies, and his colleagues continue to explore various molecular mechanisms associated with AEG-1 and other genes to determine their role in the development of liver cancer.

“We hope to target AEG-1 to block inflammation and additional fat in the liver and, at the same time, we can inhibit tumor cells,” Sarkar said. “This could be a very good approach of targeting liver cancer or can be combined with other traditional approaches like chemotherapies.”

Therapeutic Approaches

The many factors that contribute to HCC’s heterogeneity also affect treatment.

Options include radical hepatectomy, liver transplantation, locoregional therapies and systemic therapies; however, not all of these are options for every patient.

“There are so many variables when it comes to this patient population, and this is why it can be so difficult to treat,” Iannitti said.

Patients with HCC who do not have underlying chronic liver disease or cirrhosis have more options. However, this group accounts for only a small percentage of patients.

“Less than 10% of patients with liver cancer in the United States do not have cirrhosis or liver disease,” Iannitti said. “Because 80% to 90% of people with HCC also have cirrhosis, their degree of cirrhosis will dictate what you can and can’t do in terms of treatment.”

Those without liver disease or cirrhosis may be able to undergo resection to remove the tumor.

“We think of doing resection in patients who have good liver function and solitary tumors, but the question is, how big is the tumor?” Hwang said. “That is when things get gray, because these patients generally have two diseases at once, if not more.”

If a patient cannot undergo surgery due to cirrhosis or portal hypertension, many therapeutic approaches used for other malignancies are not an option. If drugs are not properly metabolized by the liver, they may be less effective or more toxic.

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“For a lot of drugs to work, they need to be metabolized by the liver,” Sakar said. “If this doesn’t happen, then the drug won’t work. Liver cancer is inherently resistant to standard therapies and radiotherapies.”

For this reason, patients who cannot undergo surgery are not automatically referred for chemotherapy or other systemic therapies, like often is the case for other cancers.

“If surgery isn’t an option, then transplant is an important option to treat both the liver disease and cancer; however, there are transplant guidelines to consider,” Hwang said. “Locoregional therapy like chemoembolization, radioembolization and ablation also are options.”

Options still may exist for patients with cirrhosis, Iannitti said. Those with Model of End-stage Liver Disease scores of 8 to 9 will have more options than patients with scores of 20, who have limited treatments available.

“Not only are there tumor factors to consider, such as size and nodal status, but you have to consider the degree of cirrhosis, liver dysfunction and portal hypertension,” Iannitti said. “You have to deal with these two sets of variables and that can be a bit challenging.”

Whether to begin a patient on TACE, Y-90 radiation or ablation is at the discretion of the institution and disciplinary team.

A trial is underway at Ohio State to evaluate the efficacy of radiation before TACE, Dillhoff said.

“It is institution dependent as to which regional therapies are used first when a patient can’t undergo surgery,” she added. “At our institution, the most commonly used locoregional therapy is TACE first. Then, for patients who don’t respond or have tumors that keep growing, we turn to Y-90 or ablation.”

Due to compromised liver function, nontraditional therapies may ultimately be more relevant for the disease, Sakar said.

“Virus-based therapies and nanoparticle-based small interfering RNA [siRNA] therapies are showing meaningful objective responses in HCC patients,” he added. “We are targeting AEG-1 using hepatocyte-specific nanoparticle-delivered siRNA which is showing very promising results in preclinical studies both in nonalcoholic steatohepatitis and in HCC.”

‘Dismal’ Survival Benefit

There are only three approved drugs for HCC.

Sorafenib (Nexavar, Bayer HealthCare), a tyrosine kinase inhibitor, is approved for first-line therapy. Regorafenib (Stivarga, Bayer HealthCare) — a multikinase inhibitor that received FDA approval in April — is indicated for patients previously treated with sorafenib. Nivolumab (Opdivo, Bristol-Myers Squibb) is an anti-PD-1 antibody approved in September to treat patients who previously failed sorafenib.

Otherwise, initial enthusiasm for drugs under investigation for HCC historically has ended in disappointment.

Results of the phase 3 EVOLVE-1 trial showed daily treatment with the mTOR inhibitor everolimus (Afinitor, Novartis) failed to extend survival compared with placebo for patients with advanced HCC (7.6 months vs. 7.3 months; HR = 1.5; 95% CI, 0.86-1.27).

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In the phase 3 REACH trial, researchers reported no significant difference in median OS between patients with HCC treated with ramucirumab (Cyramza, Eli Lilly) — a fully human monoclonal antibody — and those who received placebo (9.2 months vs. 7.6 months; HR = 0.87; 95% CI, 0.72-1.05).

“We’ve seen a lot of clinical trials open and close, and we are enthusiastic every time with no luck,” Iannitti said. “But we’re still trying, and that is the bottom line.”

Jeff Evans, MD, FRCP, director of Institute of Cancer Sciences at University of Glasgow, and colleagues are comparing the use of the tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai) with sorafenib for the first-line treatment of HCC.

Results from the REFLECT clinical trial, presented at this year’s ASCO Annual Meeting, showed lenvatinib was noninferior to sorafenib (median OS, 13.6 months vs. 12.3 months; HR = 0.92; 95% CI, 0.79-1.06).

Eisai has submitted a supplemental new drug application to the FDA for approval of lenvatinib as a frontline therapy for HCC.

“For a decade, there has been no advance in the first-line systemic treatment of [unresectable] HCC in Europe, so [these data support] a potential new option for liver cancer patients that offers greater choice,” Evans said in a press release.

Still, the survival advantages offered by the two approved drugs for HCC — sorafenib and regorafenib — are modest, and new approaches are needed.

A randomized, double-blind study by Bruix and colleagues — the data from which supported regorafenib’s approval — included patients with HCC who progressed during sorafenib treatment. Researchers randomly assigned patients 2:1 to best supportive care plus either once-daily regorafenib or placebo.

Results showed regorafenib conferred statistically significant — but still small — benefits with regard to median OS (10.6 months vs. 7.8 months; HR = 0.62; 95% CI, 0.5-0.78) and median PFS (3.1 months vs. 1.5 months; HR = 0.46; 95% CI, 0.37-0.56).

“These drugs are approved because they do offer some survival benefit,” Hwang said. “However, the benefit is dismal, so everyone is waiting on the answer to immunotherapies.”

Results of the CheckMate 040 trial, presented in April at The International Liver Congress, showed patients ineligible for surgery treated with nivolumab achieved median OS of 16.7 months.

“Unfortunately, we do not have any miraculous systemic agents out there at this point,” Dillhoff said. “Immunotherapies, such as nivolumab and ipilimumab [Yervoy, Bristol-Myers Squibb] — which are being investigated in trials now — will hopefully be one of the biggest changes in our future.”

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Multidisciplinary Approach

The individualization necessary to treat each patient — in addition to the potential addition of immune-oncology agents and other therapies to the treatment armamentarium — will require a multidisciplinary approach for HCC.

“Most surgeons aren’t comfortable operating on a patient with cirrhosis or portal hypertension or administering ablation therapies,” Iannitti said. “More education is needed for surgeons and I ideally would like to see more multidisciplinary, thoughtful, comprehensive care management plans.”

A multidisciplinary team is “critical” for any patient with cancer, Dillhoff said.

“We all know our specialty so well, so it takes a real team to work fluidly together to decide the timing of therapies and when we should use each one,” she said. “There are a lot of options for our patients, from transplant and locoregional therapies to radiation and chemotherapy. Therefore, it is important for our patients to go to institutions where teams meet on a regular basis and discuss options.”

However, access to multidisciplinary care is not consistent.

“There is substantial progress in localized disease,” Miller said. “There are actually curative treatments available. The issue is that there are substantial disparities in who receives these treatments.”

“One of the things we found in our study was that who is diagnosed at what stage of disease was relatively similar among the different ethnic and racial groups,” she added. “However, we saw overall disparities in survival, and we suspect part of that is driven by inequalities and access to care.”

Hwang agreed.

“The access to the right personnel is a big challenge and a bigger concern in underserved areas where there may not be a surgeon, interventional radiologist or hepatologist available,” he said.

Cost of direct-acting antivirals for HCV also should be considered, Miller said.

“These treatments are much better than what we used to have, but they are also ... expensive,” she said. “A lot of the people who need them most are medically underinsured. This is a huge issue, and I think it will become a very important point in the future.”

The difficulties researchers and clinicians face in liver cancer management require broader understanding of the challenges in this disease, as well as more funding than is currently allocated, Sarkar said.

“Apart from the NIH ... funding for research and trials for liver cancer is virtually nonexistent unless it’s a foundation or individual raising money,” he said. “We need to overcome this lack of community awareness and help people understand how important it is that we better understand this cancer.” – by Melinda Stevens

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Disclosures: Hwang reports consultant roles with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly and Genentech/Roche; and speakers bureau roles with Amgen, Celgene and Genentech/Roche. Dillhoff, Iannitti, Miller and Sarkar report no relevant financial disclosures.