Early discovery of liver disease improves chances to cure liver cancer
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Liver cancer — the fastest-growing cause of cancer death in the U.S. — has been notoriously difficult to treat.
Based on an estimated 41,000 deaths, liver and intrahepatic bile duct cancer is poised to become the third most common cause of cancer-related death by 2040, surpassing colorectal cancer, according to results of a cross-sectional study published in April in JAMA Network Open.
Source: David Bernstein, MD.
“It’s really a striking, sobering figure,” Robin K. (Katie) Kelley, MD, professor of clinical medicine and chair of the data and safety monitoring committee in the division of hematology and oncology at UCSF Helen Diller Family Comprehensive Cancer Center, told Healio Gastroenterology. “Year upon year we have increasing referrals for patients with hepatobiliary cancers, specifically hepatocellular carcinoma, but also intrahepatic cholangiocarcinoma. We are seeing more patients coming to us from community practices, as well as internal referrals.”
Healio Gastroenterology spoke with experts on the front lines of hepatobiliary cancer care about collaborative treatment between hepatologists and oncologists, the importance of screening, research about the expanding treatment landscape, evolving studies of drug combinations and biomarkers, and the push to answer remaining questions that may drive the next breakthrough for the treatment of HCC.
Global Burden
Accounting for an estimated 30,200 deaths in 2018, liver cancer is the most rapidly growing cause of cancer death in the U.S., according to data from American Cancer Society.
In a study published in Cancer, Ma and colleagues showed that the overall liver cancer death rate per 100,000 people increased between 2000 and 2015 from 7.5 to 11.2 among men and from 2.8 to 3.8 among women.
A steady increase in global liver cancer incidence represents another worrisome trend.
In another study published in Cancer, Liu and colleagues observed a growing number of primary liver cancer cases in most developed countries, especially among older age groups. From 1990 to 2017, the number of cases worldwide increased from 216,561 to 359,770 among those aged 30 years to 59 years and from 241,189 to 578,344 among those aged 60 years and older.
Despite the availability of hepatitis B vaccination and effective treatments for hepatitis C virus — two liver diseases that are the leading causes of liver cancer — Liu and colleagues found that the rise in cases appears to be driven in part by growing incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Those two obesity-associated diseases are likely to drive continued increases in liver cancer cases over the next 3 to 5 decades without greater preventive efforts, according to the researchers.
“We already recognized that obesity and diabetes increased liver cancer rates as well as extrahepatic cancer rates,” Nancy S. Reau, MD, FAASLD, AGAF, the Richard B. Capps Chair of Hepatology at Rush University in Chicago, Illinois, told Healio Gastroenterology. “Alcohol increases that rate, as well as some ethnicities, being male, aging, and then when you stick obesity, diabetes, nonalcoholic fatty liver disease and alcohol-related liver disease, you’re really inviting a person to have very pro-cancer risk. Now, we still have a fair amount of cancer that comes from cirrhosis related to hepatitis C that’s been cured. But most of our liver cancer patients now are transitioning to alcohol-related liver disease or a combination of both.”
David Bernstein, MD, chief of hepatology, Northwell Health, told Healio Gastroenterology that any condition that may lead to cirrhosis may increase the risk for primary liver cancer, including hepatitis B and fatty liver.
“If someone has fatty liver, specifically, the only way to prevent cancer from developing would be to treat the fatty liver, which at this stage is diet, exercise, weight loss, and prevent the development of significant fibrosis or cirrhosis,” Bernstein said. “The key to patients who have cirrhosis is to have them screened. We screen people every 6 months with imaging, usually either an ultrasound or MRI with a blood test, which would be a tumor marker, alpha-fetoprotein. Because if we catch tumors when they’re small, they’re more likely to be able to be treated by reception or liver directed therapy. When we get them when they’re quite large or when they’ve metastasized somewhere, including the vessels that feed the liver, then they’re more likely to need the oncologists and various types of chemotherapy. We can’t prevent cancer from occurring in patients with cirrhosis, but we can find them earlier and then all of our treatments are more successful.”
“As Western countries have a greater degree of obesity, in theory you will see more fatty liver disease as a result,” Jimmy J. Hwang, MD, chief of gastrointestinal medical oncology at Levine Cancer Institute at Atrium Health, said in an interview. “We are at the point where liver cancer related to hepatitis B is starting to drop off, and hepatitis C is being detected when blood is screened prior to transfusion. The fact that the numbers have still gone up is a reflection of alcohol use — and we’ll see if the pandemic will affect that in the future — and nonalcoholic fatty liver disease.”
Liver cancer fundamentally represents two diseases in one, Kelley said.
“The vast majority of patients have underlying liver disease, as well as the cancer,” she said. “Choice of therapy and management of toxicity really require that we address both aspects of their disease and that their comorbidity may be due, even differentially, more to the liver disease than the cancer in some cases.”
Hepatologists, Oncologists Working Together
Bernstein said hepatologists normally diagnose and recommend initial treatments for primary liver cancer and then collaborate with other physicians including oncologists to determine the best therapy. He noted hepatologists first figure out if the cancer can be removed or if the patient needs to be evaluated for a liver transplant. If so, hepatologists work with surgeons who specialize in the liver.
“We work closely then with the transplant surgeons,” Bernstein said. “After they’ve been seen by the transplant team, the patient will also be evaluated by a multidisciplinary team, which includes interventional radiologists and oncologists, in addition to the hepatologist and surgeon. The interventional radiologists can do what is called liver directed therapy, either embolization or ablation. In a patient then who is not a candidate for resection, not a candidate for transplantation, not a candidate for liver directed therapy, but with multiple lesions or very large lesions, we get the oncologists involved.”
Reau said hepatologists and oncologists need to work together. She said a hepatologist’s main approach to liver cancer is to determine if they can use a curative therapy such as resection and local regional treatment.
“We’ve recognized now that there are curative options,” Reau said. “When we approach a patient, that’s really our focus well before we think, ‘Oh, none of these things are appropriate. I now need some help with this.’”
Reau said oncologists may also focus on systemic therapy and forget there are curative opportunities, even for those that start outside of criteria. They may treat patients with systemic chemotherapy until the disease progresses, not realizing that these treatments could have been downsized for a potentially curative alternative like transplantation.
She said that a multidisciplinary approach, including hepatologists, needs to be involved early in the liver cancer treatment process. She also said that the opposite is true — the focus may be so driven toward curative treatment that there is the risk for not beginning systemic chemotherapy early enough. Repeated local regional interventions could compromise hepatic function and the window for systemic chemotherapy options can close.
“Systemic chemotherapies are much more effective in early cancer than they are in patients who have very advanced cancer,” Reau said. “Regardless of how we work together, identifying the earliest time point when we should work together is going to be really important.”
Importance of Screenings
Reau said hepatologists have some of the best liver cancer screening rates. She noted most of the patients screened are either those with cirrhosis or hepatitis B.
“Our guidelines have not identified a group of non-cirrhotic patients with either alcohol use disorder or with fatty liver disease who should be screened, unless they have cirrhosis,” Reau said. “We can argue whether that’s a good idea or a bad idea, but liver specialists tend to do a good job with liver cancer screening of patients with cirrhosis.”
Reau said cancer discovered during screening tends to be “easier to control cancer.”
“It really is a strong message that screening is important. Possibly even more important than screening patients with advanced disease for liver cancer is screening for the presence of cirrhosis,” Reau said. “A lot of patients who have risk for liver disease have no staging, have no knowledge that they’re at risk for liver cancer or that they have an existing liver disease. You have to screen patients at risk for liver disease for liver disease, and then those who are found to have more advanced disease need to be screened for malignancy.”
She said patients need to understand their cancer risk does not go away after 5 years, and they need to do screening with ultrasound and blood work about twice a year for a lifetime. Furthermore, risk increases with age.
“[Age] is always working against you,” Reau said. “How you keep patients engaged and understanding why you’re doing what you’re doing is imperative.”
Bernstein noted the only tumor marker available is alpha-fetoprotein and imaging. He said it is key for all patients with advanced fibrosis and cirrhosis to be screened. Once a patient is diagnosed, then some type of therapy can be initiated.
Breakthroughs
Fifteen years ago, there was no treatment for liver cancer that prolonged overall survival.
“We gave chemotherapy to patients with advanced disease, really for no reason other than we wanted to do something for them,” Richard S. Finn, MD, professor of medicine in the division of hematology/oncology at David Geffen School of Medicine at University of California, Los Angeles, and Jonsson Comprehensive Cancer Center, told Healio Gastroenerology.
The breakthrough clinicians needed arrived in 2007, when Josep M. Llovet, MD, founder and director of the liver cancer program and professor of medicine at Mount Sinai School of Medicine, presented results of the SHARP trial at the ASCO Annual Meeting.
In the phase 3, double-blind, randomized trial that included 602 patients with advanced disease, those who received sorafenib had a 44% increase in OS compared with those assigned placebo (median OS, 10.7 months vs. 7.9 months; HR = 0.69; 95% CI, 0.55-0.87).
“It was the first time we had a systemic therapy for HCC,” Llovet told Healio Gastroenterology. “People were standing up and clapping. It was very, very nice.”
These data ushered in a period of intense clinical development in liver cancer research, according to Finn.
“[The SHARP trial] showed that sorafenib improved survival by a median of about 3 months,” he said. “Tumors didn’t necessarily shrink, but it improved survival, which is ultimately the most important thing. It set the stage for progress. The results showed you can develop a drug for liver cancer, that you can be successful in a well-designed study.”
Still, the progress that followed moved slowly at first.
“We had 10 years of additional drugs being tested and all trials were negative. We were shocked,” Llovet said. “Some were negative because the drug was powerful but toxic, like sunitinib [Sutent, Pfizer], and others were not powerful enough.”
The next breakthrough occurred in April 2017.
Stivarga (regorafenib, Bayer) — a kinase inhibitor that works by blocking several enzymes that promote cancer growth — became the first FDA-approved treatment for advanced liver cancer since sorafenib. Sixteen months later, based on data from the phase 3 REFLECT trial, Lenvima (lenvatinib, Eisai) received FDA approval, becoming the first front-line therapy approved for unresectable HCC in a decade. Within a year, FDA approved two more multi-kinase inhibitors, Cabometyx (cabozantinib, Exelixis) and Cyramza (ramucirumab, Eli Lilly).
Three additional treatments received accelerated approval — the anti-PD-1 antibodies Opdivo (nivolumab, Bristol Myers Squibb) and Keytruda (pembrolizumab, Merck), and nivolumab plus the anti-CTLA-4 antibody Yervoy (ipilimumab, Bristol Myers Squibb) — although these approvals have been the subject of an FDA review.
After a decade-long drought, the tidal wave of drugs approved for HCC from 2017 to 2020 opened the window to a myriad of opportunities for advancing research and improving outcomes.
“We’ve learned some things from what we did during those negative studies in regard to trial design and the natural history of liver cancer,” Finn said. “It took time and trial and error to develop these more active drugs.”
Finn led the phase 3 IMbrave150 trial, which compared the PD-L1 inhibitor Tecentriq (atezolizumab, Genentech/Roche) plus the VEGF inhibitor Avastin (bevacizumab, Genentech/Roche) with sorafenib among patients with unresectable HCC. Results of the trial, published in May in The New England Journal of Medicine, are considered the next milepost in research and led to FDA approval of the combination for this patient population.
An updated analysis presented in January after median follow-up of 15.6 months showed the combination reduced the risk for death by 34% (median OS, 19.2 months vs. 13.4 months; HR = 0.66; 95% CI, 0.52-0.85).
“It’s the dawn of a new era of combinations, a true breakthrough,” Llovet said. “The first HR reported [from IMbrave150] was 0.58, which is outstanding. With longer follow-up there was some regression to the HR, to 0.66, which is still outstanding. The objective response rate of approximately 30% is very, very good.”
Challenges Remain
The latest approvals for HCC have presented oncologists with many treatment options for their patients. Choosing the right treatments from this ever-changing landscape has been challenging, especially in later treatment settings.
“We don’t yet have level I evidence or clinical trial data to guide our decisions after first-line therapy,” Kelley said. “Most of us right now are very much eagerly awaiting meta-analyses and future clinical trials to give us the kind of prospective evidence we need. In the meantime, we’re treating patients on a patient-to-patient basis and looking at a variety of factors, including risk factors and comorbidity profile.”
European Association for the Study of the Liver recently published a position paper in the Journal of Hepatology providing clinical practice guidelines for systemic treatment of HCC. Jordi Bruix, MD, PhD, professor of medicine at the University of Barcelona, director of the Barcelona Clinic Liver Cancer Group within the Liver Unit at the Hospital Clinic of Barcelona, Spain, and colleagues said atezolizumab-bevacizumab is the preferred option for patients when systemic therapy is appropriate. They said physicians should switch from first to second line therapy after they consider progression at imaging but also liver function, general condition and pattern of progression.
“Current guidelines recommend chemoembolization for patients with liver-only disease who are free of cancer symptoms and in whom liver function is preserved,” Bruix and colleagues noted. “The same criteria should be met when considering new chemoembolization sessions. If this is not the case, patients have reached the untreatable progression stage and systemic therapy should be considered.”
Therapy selection is particularly challenging due to the lack of established biomarkers in HCC. Only one treatment, ramucirumab, has a biomarker known to predict treatment outcomes, and that treatment is indicated only for patients with a serum alpha-fetoprotein level of 400 ng/mL or greater. The other multi-kinase inhibitors available have been shown to benefit patients across serum alpha-fetoprotein levels, but active research is exploring the possibility of using circulating tumor DNA or PD-L1 levels as biomarkers.
“Alpha-fetoprotein is a biomarker in this sense, but it’s not an ideal biomarker, such as when there is a driver mutation that a drug blocks,” Llovet said. “Right now, there is a huge effort to define biomarkers for predicting response to checkpoint inhibitors.”
It also is important to differentiate whether treatment benefits differ according to disease etiology, Hwang said.
“Is there a difference for patients with nonalcoholic fatty liver disease vs. patients who have hepatitis C vs. patients who have alcoholic liver disease?” he said. “My feeling is there certainly may be. If we can do better in predicting who is going to benefit from a treatment, we can spare those who won’t from both side effects and cost.”
The fact that clinical trial data do not necessarily reflect a large segment of the patient population also clouds treatment decisions, according to Hwang. He said one-third of all patients with HCC do not have optimal liver function and thus are not accounted for in recent and ongoing studies.
Also concerning to researchers and clinicians is liver cancer’s link to historically underrepresented groups and patients facing socioeconomic disparities, which has led to a stigma surrounding HCC.
“[HCC] afflicts people with poverty. It is a disease that discriminates by race and ethnicity. It seeks those with substance abuse,” Kelley said. “One of the challenges in treating patients is not just the tumor and underlying liver disease, but often patients don’t have adequate insurance to get their treatments. That’s something that we need to face head-on — as oncologists, as medical professionals, as a society — to try to decouple our health care and disease with some of these underlying structural disparities.”
To better serve these patients and give them the best chance at achieving optimal outcomes will take a team effort, Finn said.
“We need to be very supportive of the interactions between industry and academia, because that is really what’s helping drive a lot of this progress,” Finn said. “At the end of the day, the goal for everybody is to help patients live longer. That is not a one-person effort. There has to be collaboration among all the players — including government, insurance companies, academia, clinicians and industry — to get new drugs out, make them available and to help keep moving things forward.”
The Next Big Break
The explosion in research and drug approvals in HCC has set new expectations, goals and benchmarks for trials moving forward.
“We have to continue to move the bar higher,” Finn said. “We have a median OS with atezolizumab-bevacizumab of 19 months, so our next challenge is getting to 24 months.”
Although pending phase 3 trials may be positive because they used sorafenib or lenvatinib as the control therapy, the results seen with atezolizumab-bevacizumab are now the reference for improvement, Finn said.
“Will the magnitude of benefit [of these new combinations] be similar to what we saw with IMbrave150?” he said. “It’s possible that will be the case, and then we’ll be choosing between various front-line regimens based on efficacy, safety and tolerability.”
Fine-tuning these combinations to boost the immune system is the next step toward achieving a cure, Llovet said.
“We need one out-of-the-box approach to cure liver cancer at advanced stages,” he said. “There’s still a lot to do in achieving a cure. There’s an additional layer of complexity there.”
Another potential breakthrough in terms of disease management would be the use of liquid biopsy to detect liver cancer tumors at earlier stages, Llovet said.
“If we detect tumors at their earliest, at less than 2 cm, the likelihood of complete response, meaning cure, is 90%,” he said. “It would be outstanding if we could discover key blood biomarkers to define tumors, even when they’re that tiny.”
Despite all the progress in the treatment of liver cancer, when discussing the next big breakthrough, many of the experts with whom Healio Gastroenterology spoke returned to the fact that, for 80% of patients, liver cancer starts with liver disease.
“We need to raise awareness of chronic liver disease,” Finn said. “There is great underappreciation for the importance of screening for patients who have chronic liver disease and cirrhosis specifically; although subspecialty societies recommend it, the U.S. Preventive Services Task Force has no recommendation on screening for liver cancer.
“When patients are found at advanced stages, we now have better treatments, and they can be treated,” he added. “But finding disease early is the difference between treatment and cure.”
- References:
- Bruix J, et al. J Hepatol. 2021;doi:10.1016/j.jhep.2021.07.004.
- Finn RS, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.00808.
- Finn RS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1915745.
- Finn RS, et al. Abstract CT009. Presented at: American Association for Cancer Research Annual Meeting; April 10-15, 2021 (virtual meeting).
- Finn RS, et al. Abstract 267. Presented at: Gastrointestinal Cancers Symposium; Jan. 15-17, 2021 (virtual meeting).
- Kelley RK, et al. Abstract 4508. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
- Llovet JM, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; May 31-June 5, 2007.
- Llovet JM, et al. Nat Rev Dis Primers. 2021;doi:10.1038/s41572-020-00240-3.
- Liu Z, et al. Cancer. 2020;doi:10.1002/cncr.32789.
- Ma J, et al. Cancer. 2019;doi:10.1002/cncr.32023.
- Rahib L, et al. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2021.4708.
- For more information:
- David Bernstein, MD, can be reached at: dernste@northwell.edu.
- Richard S. Finn, MD, can be reached at: rfinn@mednet.ucla.edu.
- Jimmy J. Hwang, MD, can be reach at: jimmy.hwang@atriumhealth.org.
- Robin K. (Katie) Kelley, MD, can be reached at: katie.kelley@ucsf.edu.
- Josep M. Llovet, MD, can be reached at: josep.llovet@mssm.edu.
- Nancy S. Reau, MD, FAASLD, AGAF, can be reached at: nancy_reau@rush.edu.
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