Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide (1). This Fast Fact provides an overview of staging and treatment options for generalist and palliative care clinicians who are often asked to navigate complicated decision making in HCC patients.

HCC Staging:

*Barcelona Clinic Liver Cancer; bEastern Cooperative Oncology Group Performance Status​

Prognosis and Quality of Life (QoL):  Only 10-15% of HCC patients have curative options at the time of diagnosis (2). This clinical factor plus the high prevalence of cirrhosis as a comorbidity contributes to a 5-year survival rate of only 10% (3).  BCLC staging is an important prognostic factor. Whereas, the one-year survival rate is 77-83% with treatment (33% without treatment) when HCC is localized to the liver; the one-year survival of metastatic disease is only 15% (3). HCC patients often suffer from pain, jaundice, anorexia, and depression as well as ascites, fatigue and edema from coexisting cirrhosis (4). This debilitating symptom burden leads to a diminished health-related quality of life (QoL) (4).   

Localized, Arterially Directed Therapy:  While normal liver tissue is perfused by the hepatic artery and portal vein, HCC is almost exclusively supplied by the hepatic artery (5). This has led to the development of arterially directed techniques to block hepatic tumor perfusion via the localized delivery of chemotherapy or radiotherapy. These procedures are performed and clinically monitored by specialized interventional radiologists. They are reserved for patients with unresectable HCC who have preserved liver function, an ECOG PS of 0-2, and no evidence of extra-hepatic disease (6). Relative contraindications include infection, leukopenia, renal insufficiency, decompensated heart failure, hepatic encephalopathy, and biliary obstruction. The goal of this therapy is to improve QoL, prolong survival, and in some cases, downstage the tumor in hopes of making the mass surgically resectable

Commonly Used Localized, Arterially Directed Therapies

• Conventional Transarterial Chemoembolization (cTACE): cTACE uses a combination of cytotoxic chemotherapy (typically cisplatin and doxorubicin) and an oily embolic material called lipiodol. This substance is injected into the hepatic arteries directly supplying the liver mass (7).
• Drug Eluting Bead Transarterial Chemoembolization (DEB-TACE): DEB-TACE differs from cTACE by using drug eluting microspheres instead of lipiodol to locally administer chemotherapy which are associated with increased tumor retention and less systemic toxicity (8).
• Radioembolization with Yttrium-90 (Y-90): Microspheres made of glass or resin are tagged with a radioactive material, most commonly Y-90, and delivered to the malignant liver mass via tumor feeding arteries to induce tumor cell death (9).

Treatment Effect on Symptoms and Quality of Life:   Studies have demonstrated survival benefits as well as improvements in patient-reported outcomes including QoL, pain, function, and emotional well-being with cTACE, DEB-TACE, and Y-90 in patients with BCLC B or C disease (10-12). Compared to cTACE, Y-90 was associated with less nervousness, less side effects, less hospitalizations, and an improved QoL (12).  However, Y-90 is more expensive with an approximate cost of $31,000 to $48,000 comparted to $17,000 for cTACE (13). In many centers, cTACE is more commonly utilized, but controversy remains regarding the optimal localized, arterially directed therapy. ​

Treatment Complications:  Postembolization syndrome characterized by a resolving, 3-day course of pain, nausea, and vomiting can occur with cTACE and DEB-TACE. A short course of IV opioids, corticosteroids, 5HT3 receptor antagonists, and/or ketorolac in a hospital setting have been described as an effective way to manage this syndrome (14). In more rare circumstances, chemoembolization can lead to vascular injury, hepatic failure, abscess formation, tumor rupture, ulcer formation, and biliary duct injury (15). Y-90 is not associated with postembolization syndrome and severe complications appear to be rarer. As a result, hospitalization is often unnecessary (6,16).

Progression After Localized Therapy:  Many with advanced HCC are faced with the complicated decision of whether to pursue systemic targeted therapy, most usually oral sorafenib. Although sorafenib is associated with a significant improvement in median survival (10.7 months vs 7.9 months with placebo) for patients with BCLC Stage C (17,18), several trade-offs need to be considered.  These trade-offs include a substantial risk for diarrhea, nausea, liver dysfunction, and cytopenia. It is also associated with increased health care costs and clinic visits which can be barriers for hospice initiation. Hence, QoL, not just prognostic, concerns need to be elicited before deciding about sorafenib. For HCC patients with life prolonging goals who progress through sorafenib therapy, the FDA approved the use of nivolumab based on phase 1 and 2 data showing a 18.2% response rate (19).

References

1. El-Serag, H.B., Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology, 2012. 142(6): p. 1264-1273 e1.
2. Rougier, P., et al., Hepatocellular carcinoma (HCC): an update. Semin Oncol, 2007. 34(2 Suppl 1): p. S12-20.
3. Altekruse, S.F., K.A. McGlynn, and M.E. Reichman, Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol, 2009. 27(9): p. 1485-91.
4. Heffernan, N., et al., Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol, 2002. 20(9): p. 2229-39.
5. Crissien, A.M. and C. Frenette, Current management of hepatocellular carcinoma. Gastroenterol Hepatol (N Y), 2014. 10(3): p. 153-61.
6. Minocha J, Salem R, Lewandowski R.  Transarterial chemoembolization and yittrium-90 for liver cancer and other lesions.  Clin Liver Dis 2014;18:877-890.
7. Ensminger, W., Hepatic arterial chemotherapy for primary and metastatic liver cancers. Cancer Chemother Pharmacol, 1989. 23 Suppl: p. S68-73.
8. Vogl, T.J., et al., Liver, gastrointestinal, and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: results from the PRECISION V randomized trial. Am J Roentgenol, 2011. 197(4): p. W562-70.
9. Salem, R., et al., Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology, 2010. 138(1): p. 52-64.
10. Wible, B.C., et al., Longitudinal quality of life assessment of patients with hepatocellular carcinoma after primary transarterial chemoembolization. J Vasc Interv Radiol, 2010. 21(7): p. 1024-30.
11. Xing, M., et al., Preservation of quality of life with doxorubicin drug-eluting bead transarterial chemoembolization for unresectable hepatocellular carcinoma: Longitudinal prospective study. J Gastroenterol Hepatol, 2015. 30(7): p. 1167-74.
12. Salem, R., et al., Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol, 2013. 11(10): p. 1358-1365 e1.
13. Rostambeigi, N., et al., Cost effectiveness of radioembolization compared with conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Vasc Interv Radiol, 2014. 25(7): p. 1075-84.
14. Blackburn H, West S. Management of postembolization syndrome following hepatic transarterial chemoembolization for primary or metastatic liver cancer. Cancer Nurse 2016; 39(5):E1-18.
15. Xia, J., et al., Study of severe and rare complications of transarterial chemoembolization (TACE) for liver cancer. Eur J Radiol, 2006. 59(3): p. 407-12.
16. Riaz, A., et al., Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J Vasc Interv Radiol, 2009. 20(9): p. 1121-30; quiz 1131.
17. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double- blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34.
18. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
19. Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.J Clin Oncol. 2017;35 (suppl; abstr 4013).

Conflicts of Interest:  None

Author Affiliations:  Medical College of Wisconsin

Version History:  Originally edited by Sean Marks MD; first electronically published in December 2017.