Recent Advances in Therapy for Advanced Hepatocellular Carcinoma

Hepatocellular Carcinoma: Magnitude of the Problem

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, which represents the fifth most common cancer worldwide.^[1] Indeed, primary liver cancer is the third most common cause of death from cancer and results in more than 600,000 global deaths per year. Risk factors for HCC include chronic viral hepatitis, alcoholic cirrhosis, and nonalcoholic steatohepatitis. Moreover, HCC cases are often identified in the setting of cirrhosis, except in patients from areas with endemic hepatitis B virus infection.^[2]

Both the incidence and mortality from HCC are increasing in Western nations.^[3,4] In the United States, an estimated 11,500 new cases of HCC occur each year. Data from the National Cancer Institute Surveillance Epidemiology and End Results registry demonstrated that the age-adjusted US incidence of HCC doubled between 1985 and 1998.^[4] Accordingly, healthcare expenditures for HCC have also increased significantly, with hospital charges for HCC-related treatments doubling over a 12-year period of time from 1988-2000 to exceed $500 million.^[5] Additional epidemiologic factors such as aging and obesity will likely further contribute to the increasing prevalence of HCC.^[6]

Treatment

Sorafenib
Until recently, there had been no proven medical therapy for advanced HCC. Sorafenib, a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis, and increases the rate of apoptosis in a wide range of tumor models, offers the first hope of such a therapy (Capsule Summary).^[7] This agent acts by inhibiting the serine-threonine kinases Raf-1 and B-Raf, the receptor tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3, and platelet-derived growth factor receptor β, all of which are implicated in the molecular pathogenesis of HCC.^[7,8]

The Sorafenib Hepatocarcinoma Assessment Randomized Protocol (SHARP) study, a phase III study conducted in a population of HCC patients with relatively preserved liver function (Child-Pugh class A cirrhosis), showed a significant 3-month survival gain with sorafenib vs placebo. The drug was shown to retard tumor progression, which led to enhanced survival. Based on these results, the US Food and Drug Administration approved sorafenib for the treatment of advanced HCC in November 2007. Currently, the pharmacy price of sorafenib is approximately $5400 per month in the United States.

The overall incidence of treatment-related adverse events in the SHARP study was higher in the sorafenib arm vs the placebo arm (80% vs 52%, respectively) and included diarrhea, weight loss, hand-foot skin reactions, alopecia, and anorexia.^[7] Interestingly, hypertension was reported to occur in 2% of patients in the placebo arm—a rate that is considerably lower than that seen in trials of patients with other types of cancer, suggesting that it is a reflection of systemic vasodilation associated with cirrhosis. A study by Hilgard and colleagues^[9] recently presented at the 2008 American Association for the Study of Liver Diseases (AASLD) meeting in San Francisco, California, concluded that adverse events with the same dosing of sorafenib as in the SHARP study (400 mg twice daily) were frequent (86%) but usually were effectively managed without dose reduction. The one exception was hand-foot skin reactions, which occurred in one third of patients and was the only adverse event that regularly led to dose reductions. In the majority of cases, hand-foot skin reactions were treated with local panthenol and urea ointment or hempseed oil ointment. Also at the 2008 AASLD meeting, Zimmerman and colleagues^[10] reported their experience with sorafenib in a population enriched for Child-Pugh class B; many of these patients had also been resected or received local-ablative therapy. Larger studies are required to determine whether sorafenib delays or prevents disease recurrence after surgery or in patients undergoing local-ablative therapy and whether these patients require more frequent dose reductions of the drug.

Local Ablative Therapies
Partial hepatectomy is considered the gold standard of treatment because it aims to “cure” patients with resectable HCC and is associated with < 5% risk of mortality, but it is often contraindicated because of compromised liver function.^[11] As a result, there has been widespread application of local ablative therapies, including radio-frequency ablation, transarterial chemoembolization, and percutaneous ethanol injection.^[12] At the 2008 AASLD meeting, results of radioembolization with Yttrium-90 glass microspheres for advanced HCC (large tumor burden, multifocal distribution, portal vein thrombosis) were presented.^[13] Transarterial application of Yttrium-90 glass microspheres provides treatment for patients who are not candidates for other locoregional therapy in a lobar fashion without causing liver toxicity. On average, each patient received 1.4 treatments, and at 6 months, approximately 50% of the patients had stable disease, 25% had partial tumor response, and 23% had progressive disease. Remarkably, the survival rates in this cohort of patients with advanced HCC were 98% at 1 month, 81% at 6 months, and 53% at 1 year with a mean overall survival of 657 days.

Liver Transplantation
Liver transplantation is the most definitive treatment of HCC and 26% of patients receiving a liver allograft between 2002 and 2007 had HCC.^[14] Improvements in the outcome of liver transplantation for HCC in the past decade are almost entirely attributable to better patient selection rather than improved surgery or adjuvant therapy.^[2] The Milan criteria (1 lesion ≤ 5 cm, or 2-3 lesions ≤ 3 cm each) have remained the gold standard,^[15] achieving a survival comparable to that of other recipients with benign liver disease. With the growing success of liver transplantation for HCC, the Milan criteria, based on pretransplantation radiologic tumor number and size, have been criticized for being excessively restrictive, excluding many patients who would have otherwise done well with low risk of recurrence after liver transplantation.^[2] Various expanded criteria have been proposed to extend the limits of tumor size and number while preserving patient survival.^[16-18] An attractive strategy to improve the results of liver transplantation for expanded criteria HCC is the use of locoregional therapy to downstage patients to Milan criteria.^[19] Barakat and colleagues^[20] presented their experience with this approach at the 2008 AASLD meeting. Patients with advanced stages of HCC exceeding Milan or proposed University of California, San Francisco (UCSF) criteria (1 lesion ≤ 6.5 cm, 2-3 lesions ≤ 4.5 cm each with total tumor diameter ≤ 8 cm)^[17] received locoregional therapy (transarterial chemoembolization, selective arterial radiotherapy using Y90 microspheres, and radio-frequency ablation). Downstaging was successful in 56% of patients and, in an intent-to-treat analysis, the median survival in these patients was significantly better than those patients who failed the downstaging process (33 vs 7 months, respectively). Encapsulated tumors (vs infiltrative tumors) were independently associated with the likelihood of successful downstaging. The survival rate after liver transplantation was 93.0% and 78.5% at 1 and 2 years, respectively.

Future Prospects

For the first time, medical therapies for the treatment of advanced HCC are generating some effective results. Additional studies are required to define the patient subsets that would benefit most from the combination of molecularly targeted agents with conventional chemotherapeutic approaches and whether these agents can further expand the criteria for patients undergoing liver transplantation.

 

 

References

 

1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557-2576.

 

2. Varela M, Sanchez W, Bruix J, Gores GJ. Hepatocellular carcinoma in the setting of liver transplantation. Liver Transpl. 2006;12:1028-1036.

 

3. Fattovich GT, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35-S50.

 

4. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745-750.

5. Kim WR, Gores GJ, Benson JT, Therneau TM, Melton LJ 3rd. Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology. 2005;129:486-493.

6. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MH. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 2003;348:1625-1638.

7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.

8. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109.

 

9. Hilgard P, Ertle JM, Penndorf V, Haag S, Gerken G. Significance and management of adverse events associated with systemic therapy with sorafenib in patients with advanced hepatocellular carcinoma. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 1472.

 

10. Zimmermann L, Csepregi A. Sorafenib therapy for advanced hepatocellular carcinoma: single-center experience on 43 patients. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 436.

 

11. Liang HH, Chen MS, Peng ZW, et al. Percutaneous radiofrequency ablation versus repeat hepatectomy for recurrent hepatocellular carcinoma: a retrospective study. Ann Surg Oncol. 2008;15:3484-3493.

 

12. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2008;Sept 22:[Epub ahead of print].

 

13. Barakat O, Wood RP, Ozaki CF, et al. Aggressive loco-regional therapy and liver transplantation in patients with advanced hepatocellular carcinoma beyond the Milan and UCSF criteria. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 1469.

 

14. Ioannou GN, Perkins JD, Carithers Jr RL. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology. 2008;134:1342-1351.

 

15. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693-699.

 

16. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394-1403.

 

17. Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant. 2008;8:1982-1989.

 

18. Soejima Y, Taketomi A, Yoshizumi T, et al. Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma. Transplantation. 2007;83:893-899.

 

19. Lo C. Downstaging of hepatocellular carcinoma before transplantation: an advance in therapy or just another selection criterion. Am J Transplant. 2008;8:2485-2486.

 

20. Hilgard P. Antoch G, Ertle JM, et al. Radioembolization with Yttrium-90 glass microspheres for advanced hepatocellular carcinoma: results from a European pilot phase II study. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases; October 31 - November 4, 2008; San Francisco, California. Abstract 1444.

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