Liver Cancer Rates Are Rising; So Is Optimism Around Its Treatment

In celebration of Medscape's 25th birthday, we are highlighting key breakthroughs that have defined the last quarter century of medicine, as chosen by experts in their respective fields.

Over the past 25 years, cirrhosis and its related complications have undergone a fascinating evolution in the United States. Historically, cirrhosis was driven by viral hepatitis, yet despite curative therapy for hepatitis C and improvements in hepatitis B management, deaths from cirrhosis are expected to triple by 2030. This projection is driven by increasing rates of alcoholic liver disease and nonalcoholic fatty liver disease.

Hepatocellular carcinoma (HCC) is a known consequence of cirrhosis. As the etiologies causing cirrhosis change, liver cancer risk and rates are also evolving. Mortality data from 2000 to 2015 confirm an increase in liver cancer death rates, though hepatitis C virus (HCV) infection now accounts for less than one quarter of these cases.

Comorbid disorders other than cirrhosis add to HCC risk. This was best demonstrated when following individuals with cirrhosis secondary to HCV who had achieved a cure. Male sex, black race, alcohol use, type 2 diabetes, obesity, iron overload, hepatitis B co-infection, and advancing age were associated with the risk of developing liver cancer despite viral eradication.

Even as we have been able to reduce the role of viral hepatitis in liver cancer incidence, the number of people who will be diagnosed with and die of liver cancer continues to rise.

Surveillance and Diagnosis

Screening has had little change in the past 25 years. Patients with cirrhosis and positive hepatitis B surface antigen continue to be identified at higher risk for HCC. Ultrasound is still believed to be the most cost-effective modality (with or without alpha-fetoprotein). And whereas both 6- and 12-month intervals were previously acceptable as surveillance intervals, current recommendations advocate for 6-month intervals. Yet despite over two decades of consistency, surveillance is implemented in less than half of at-risk individuals. This is unfortunate. Liver cancer diagnosed through surveillance is often found when curative options are available compared with it being diagnosed when patients are already symptomatic.

By comparison, diagnostics have changed significantly over the past 25 years. Traditionally, cancer requires tissue sampling to confirm malignancy. However, noninvasive diagnosis of HCC based on CT or MRI criteria is endorsed in guidelines from both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL). More recently, the LI-RADS (Liver Reporting and Data System) nomenclature proposed by the American College of Radiology was incorporated into guidelines because of its reliability in well-characterized lesions. LI-RADS has 94% sensitivity in patients with characteristic imaging.

With high-quality imaging, most patients can be treated for liver cancer without a tissue biopsy. The marginalization of biopsy could change, though, in which case we would transition back to histology if features on the biopsy could direct the efficacy of systemic therapy.

The role of serum tumor markers has been tumultuous. Their purpose in surveillance, diagnosis, and prognosis oscillates in the literature and guidelines. Although serum biomarkers currently have a limited role and are not part of the diagnostic criteria advocated by society guidelines, they still play a prominent role in some scoring systems. In addition, AASLD and EASL guidelines have been unable to remove the recommendation to obtain serum alpha-fetoprotein as part of a screening algorithm.

Nonetheless, the quest for serum biomarkers continues for both screening and diagnosis, because a blood test is believed to have less user variability (compared with ultrasound) and better access outside of tertiary care centers.

Prognosis and Treatment

Despite the curative options for HCC, the overall 5-year survival rate is only 18%, according to the Surveillance, Epidemiology and End Results database of patients diagnosed between 2009 and 2015. The survival rate is skewed by the incredibly poor prognosis for those whose disease is diagnosed at advanced stages. The 5-year survival rate is only 2% in patients with extrahepatic spread, but even in those with localized disease, the 5-year survival rate is just 33%.

At face value, liver cancer does appear to be a death sentence. However, it's important to remember that patients whose disease is diagnosed in the early stages, when curative therapies (eg, liver transplant, hepatic resection) can be considered, experience a 5-year survival rate that is well above 60%. Local-regional therapy and systemic chemotherapy also continue to prolong survival.

Curative Treatment: Liver Transplant

One of the steepest learning curves over the past 25 years has been in how we approach patients transplanted for liver cancer.

Before appropriate selection criteria were developed, the 5-year survival rate after transplant for liver cancer was only 30%. This changed with the 1996 landmark publication outlining the Milan criteria. With careful selection, the 5-year survival rate was > 70% in those who met the criteria, with recurrence rates of only 10%.

Despite excellent outcomes, measures to provide patients with cancer access to transplant continue to be challenged. In 2002, the Milan criteria were formally incorporated into the pathway that provided exception points to patients with cancer who are awaiting liver transplant, effectively allowing them to compete for organs in a system that ranked priority by the degree of liver failure. With the first adjustments, patients with cancer were transplanted at rates higher than those dying of other complications of liver disease, leading to revisions. The most recent correction in 2019 grants Model for End-Stage Liver Disease (MELD) exceptions only after 6 months after listing, and then with a score based on the medical MELD for that region minus 3 points. Expanded criteria and downstaging (treating a patient who presents outside of the Milan criteria until they meet them) continue to push the balance between risk and benefit.

Noncurative Treatments

Unfortunately, most patients with HCC are not eligible for curative options or must remain within the Milan criteria while they wait for access to liver transplantation. This obstacle has led to innovative research into treatments focused on this population. Treatment can be divided into systemic chemotherapy and local-regional therapy.

Systemic chemotherapy. The past two decades have been marked by the arrival of several key therapeutics for HCC.

Our first systemic chemotherapy, sorafenib, was approved for inoperable liver cancer in 2007. Although an important breakthrough, the agent extended survival by only 2.8 months over placebo. Sorafenib remained unchallenged as a first-line therapy until the approval of lenvatinib in 2018.

Several second-line agents have recently become available. Regorafenib and nivolumab were approved in 2017, followed by pembrolizumab in 2018 and cabozantinib in 2019. Regorafenib and cabozantinib are indicated in patients who tolerated sorafenib but experienced tumor progression, whereas immunotherapy can be used in those with both progression and intolerance.

Although these agents expanded our treatment choices, combination therapy is now the standard of care. Nivolumab with ipilimumab was approved in March 2020 as a second-line therapy. Atezolizumab with bevacizumab, a breakthrough first-line option for those who have not previously received systemic therapy, arrived in May 2020. For the first time, a treatment improved overall survival and progression-free survival compared with sorafenib.

This recent explosion of treatment options is exciting for both physicians and patients, even as it makes treatment decisions more challenging.

Local-regional therapy. Over the past two decades, local-regional therapy has evolved as a treatment for HCC.

Ablative therapy has been standard management for decades. Radiofrequency ablation can achieve a complete response rate of approximately 97% in lesions ≤ 2 cm, but efficacy is limited by size and location. Ablative options have expanded to include alcohol, microwave, and cryotherapy but still have similar limitations to radiofrequency ablation.

Embolization is more appropriate for extensive tumor burden. Although not considered curative, these techniques do prolong survival. Transarterial chemoembolization (TACE) has been an established therapy for decades. Recent improvements include drug-eluting beads (DEB-TACE), which release chemotherapy over time, and improve tolerability but not efficacy. Transarterial radioembolization (TARE) has overtaken TACE because it can be used in patients with portal vein thrombosis with fewer adverse effects. TARE may also have better 2- and 3-year survival rates. Combining local-regional therapy with systemic chemotherapy is also attractive but largely lacks supporting data.

Remaining Optimistic

Now driven by alcoholic liver disease and nonalcoholic fatty liver disease, it seems inevitable that the incidence and prevalence of primary liver cancer will continue to rise over the next decades. However, with improved surveillance to identify lesions at a time when curative options are available, along with the avalanche of systemic chemotherapy options for those who lack surgical alternatives, I am confident that the death rates from liver cancer will decline.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the AASLD and the IDSA, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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