Treating Hepatocellular Carcinoma: A Fight Against the Odds

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death and accounts for more than 90% of primary liver cancers.¹ It is most frequently diagnosed at an advanced stage in patients with chronic liver injury and cirrhosis.² Despite dedicated research in the last few decades, significant advancements in the treatment of HCC have not been achieved,³ and HCC still belongs to the category of cancers with a very low 5-year survival rate of less than 20%.⁴

The main risk factors for HCC are chronic hepatitis B and C virus infections and obesity and metabolic syndrome.⁵ Alcoholic liver disease, steatohepatitis, alfatoxins, and hemochromatosis have also been recognized to contribute to HCC development.²

Treatment of HCC is hindered by a high rate of advanced stage diagnosis and lack of therapeutic options for advanced disease.¹ Approximately 40% of HCC cases are diagnosed at an advanced stage² when radical treatment approaches, including surgery and liver transplantation, are no longer available. Treatment of advanced HCC is especially challenging because of a high rate of drug resistance⁵ and underlying liver dysfunction that affects drug delivery and distribution.²

In an interview with Infectious Disease Advisor, Richard Burkhart, MD, assistant professor of surgery at Johns Hopkins Hospital, Baltimore, Maryland, and Amulya A. Nageswara Rao, associate professor of pediatrics and director of the Pediatric Brain Tumor Clinic at Mayo Clinic, Rochester, Minnesota, discussed the challenges associated with treating HCC.

Infectious Disease Advisor: Sorafenib is the current standard of care for treatment of advanced-stage HCC. How effective is this treatment in hindering the progression of HCC?

Richard A. Burkhart, MD: Sorafenib, as you mention, is the current standard of care for HCC. Unfortunately, for many patients there is very little to no benefit despite added toxicities and an impact on quality of life. Data supporting this notion have been widely published, including by the SHARP trial investigators, demonstrating that the median survival remains under 1 year despite a 3-month benefit for patients taking sorafenib vs placebo.⁶

Infectious Disease Advisor: Research has shown that certain patients with HHC derive a greater benefit from treatment with sorafenib. Have specific molecular markers been identified in tumors of these patients?

Dr Burkhart: With additional toxicity impacting life, and a limited benefit in the average patient, some researchers have endeavored to use molecular markers to identify patients in whom sorafenib might be of the most benefit. This research remains in its early stages, but, 1 day, may help to decide which patients should receive sorafenib and which patients should receive alternative therapies or be referred for clinical trials. Our manuscript reviews the state of the art in molecular characterization of HCC, including reviewing the proposed biomarkers for sorafenib responsiveness: WNT-pathway activation, SLC15A2 levels, or miR-122 levels.⁴

Infectious Disease Advisor: How far is the medical community from using molecular markers in assessing the therapeutic response in patients with HCC?

Dr Burkhart: At this point, the molecular characterization of tumors and correlation with responsiveness to systemic therapies has been conducted in a retrospective manner. In other words, we’ve attempted to find an association by looking at historical data and trying to find associations between good outcomes and treatments received. Although at this point it is the best we can do, the largest flaw in this research method is finding false results and associating 2 things that aren’t actually related. Because of this, the medical community remains years away from being able to routinely use molecular markers in therapeutic selection for patients diagnosed with HCC.

Infectious Disease Advisor: What are some of the challenges associated with this effort?

Dr Burkhart: To truly realize precision medicine in HCC, there are 2 challenges that remain. First, drug discovery efforts must continue in hopes that truly effective therapies for HCC can be found. Second, prospective data must be accrued to demonstrate that molecular characterization of each patient’s tumor can identify an optimal treat strategy. Until these 2 challenges are overcome, we will continue to treat HCC as a singular entity with therapies that remain limited in their effectiveness.

Infectious Disease Advisor: In which areas do you expect the main advancements to occur in the search for novel therapies for HCC?

Amulya Nageswara Rao, MD: Early-stage tumors and those tumors that can be completely resected surgically confer a better survival advantage. Our understanding of the complex molecular basis of HCC tumorigenesis has increased over the years, and this, coupled with the limited treatment options available for advanced HCC and unresectable tumors, has led to more emphasis on studies that use agents targeting the biological pathways involved (eg, EGFR, Ras/ERK, PI3K/mTOR, HGF/MET, Wnt, and apoptotic pathways). We do expect that the main advancements in the next few years will be in exploring targeted therapy options and immunotherapy-based options including the use of virotherapy, either as monotherapy or in combination, in an effort to target multiple pathways involved.

Infectious Disease Advisor: Can you identify any promising therapies for HCC that are currently being, or have been recently, tested?

Dr Rao: There have been preclinical as well as clinical studies that show great promise. These studies have primarily been conducted in adults with HCC. In addition to studies on sorafenib, early-phase immunotherapy-based studies have shown promise and the possibility of future trials using such agents. Pexa-Vec is an oncolytic and immunotherapeutic vaccinial virus that, when infused into HCC tumors, may have clinical activity. Preclinical data suggests that the addition of Pexa-Vec may sensitize the tumors to the antiangiogenic effects of sorafenib. A phase 3  comparing vaccinia virus-based immunotherapy plus sorafenib vs sorafenib alone is currently ongoing. Immunotherapy with checkpoint inhibitors is also showing a lot of promise. More recently, FDA has approved regorafenib, an oral multikinase inhibitor, as a second-line treatment for patients with HCC who have previously received sorafenib. This was based on the findings of a published phase 3 RESORCE study, a randomized, double-blinded, placebo-controlled trial that has shown survival benefit with regorafenib in patients who have progressed on sorafenib.⁷

Infectious Disease Advisor: Which knowledge gaps need to be filled before new effective treatments for HCC can be developed?

Dr Rao: The biology of HCC is very complex. In addition, several conditions are known to be associated with HCC, such as viral hepatitis and metabolic disorders. Although significant progress has been made in identifying several genomic alterations over the last few years, advanced HCC continues to remain a very difficult-to-treat disease. Systemic therapy options are limited. Knowledge of molecular pathways has opened the doors; however, many of these genomic alterations remain hard to target. So far, agents such as sorafenib and regorafenib, and certain immunotherapy-based options, have shown clinical efficacy, but we still have a long way to go in improving survival and long-term outcomes. To develop effective treatments, we may have to start looking at a more individualized treatment plan for each patient. In other words, future studies looking at matching therapeutic agents to particular alterations noted in individual tumors, perhaps in combination with immunotherapy, may help advance the care and management of this disease. Also, given the complexity, a multimodal approach that brings together oncologists, transplant surgeons, gastroenterologists, and infectious disease specialists, given the strong association with viral hepatitis, will also help advance the science further.

Infectious Disease Advisor: How is the approach to treating pediatric HCC different/similar to the approach to treating HCC in the adult population?

Dr Rao: HCC in children is rare and the underlying biology is often different in children with HCC compared to adults. Moreover, children often do not have an underlying liver abnormality or cirrhosis (30% of pediatric patients compared with 70%-90% of adult patients have underlying cirrhosis). Although there are guidelines for the treatment of adult HCC, no such guidelines exist for children. Up to 80% of pediatric patients with HCC present with primarily nonresectable tumors. Other modalities such as chemotherapy, transarterial chemoembolization, and molecular targeted therapy are often used to increase surgical resectability. Studies have suggested that orthotopic liver transplantation may offer a significant survival advantage and better long-term disease control. However, the Milan criteria developed for the adult population, requiring liver transplantation in HCC with cirrhotic livers, may be too restrictive for the pediatric population. Pediatric literature, including our own case reports, show that liver transplantation may provide a better long-term disease-free survival even in children not meeting the Milan criteria.^3,8

References

1. Grazie ML, Biagini MR, Tarocchi M, et al. Chemotherapy for hepatocellular carcinoma: The the present and the future. World J Hepatol. 2017;9:907-920.
2. Cidon EU. Systemic treatment of hepatocellular carcinoma: past, present and future. World J Hepatol. 2017;9:797-807.
3. Kohorst MA, Warand DM, Matsumoto JM, et al. Management of pediatric hepatocellular carcinoma: a multimodal approach [published online June 20, 2017]. Pediatr Transplant. doi: 10.1111/petr.13007
4. Burkhart RA, Ronnekleiv-Kelly SM, Pawlik TM, et al. Personalized therapy in hepatocellular carcinoma: Molecular markers of prognosis and therapeutic response. Surgical Oncology. 2017;26:138-145.
5. Galun D, Srdic-Rajic T, Bogdanovic A, et al. Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies. J Hepatocell Carcinoma. 2017;11:93-103.
6. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.
7. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.
8. Pham TA, Gallo AM, Concepcion W, et al. Effect of liver transplant on long-term disease-free survival in children with hepatoblastoma and hepatocellular cancers. JAMA Surg. 2015;150(12):1150-1158.