Use of Sorafenib in Advanced HCC Patients with Child-Pugh Class B Liver Dysfunction

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Early pivotal trials demonstrating the efficacy of sorafenib for patients with advanced hepatocellular cancer included primarily those with minimal liver dysfunction (Child-Pugh [CP] class A). The current Phase 2 study examined sorafenib treatment in both CP class A and B patients. Those with CP class B liver dysfunction were shown to tolerate sorafenib but treatment outcomes remained less satisfactory than for CP class A patients.

Source: Pressiani T, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: A prospective feasibility analysis. Ann Oncol 2013;24:406-411.

Hepatocellular cancer (HCC) is among the most common cancers worldwide and is becoming more prevalent in western countries.1 In 50% or more of cases, the disease presents at an advanced stage for which systemic therapies have been of limited demonstrable value. Sorafenib, a small molecule multikinase inhibitor,2 was the first systemic agent to prolong survival in patients with advanced HCC, as demonstrated in two Phase 3 trials,3,4 and now represents the standard systemic treatment for such patients.5-7 In patients with advanced HCC but with only modest pre-existing liver injury (Child Pugh [CP] class A) sorafenib has shown survival benefits.3,4 However, the question remains of whether sorafenib can be administered safely and with similar efficacy for advanced HCC patients with more advanced liver dysfunction (CP class B).

To address this, Pressiani and colleagues conducted an open-label, multicenter, Phase 2 trial throughout Italy. This was a dual-phase trial; the first phase was designed to prospectively investigate the feasibility of sorafenib treatment in patients with poorer (CP class B) compared with better (CP class A) liver function.

During the first phase, all patients received continuous oral treatment with sorafenib 400 mg twice daily until radiological progression (as defined by RECIST), symptomatic progression or deterioration of PS, unacceptable toxic effects, or patient withdrawal. Treatment interruptions and dose reductions were permitted for drug-related adverse events (AEs). The second phase of the trial (reported at ASCO 2012 Gastrointestinal Cancers Symposium8) was initiated on radiological disease progression. Patients were randomized to sorafenib dose escalation (600 mg twice daily) or best supportive care.

For this study, a consecutive, prospective series of 300 patients with CP class A or B HCC were enrolled to determine safety of treatment and assess survival in the context of liver function (CP class A or B). Patients received oral sorafenib 800 mg daily.

Overall progression-free survival (PFS), time to progression (TTP), and overall survival (OS) were 3.9, 4.1, and 9.1 months, respectively. For patients with CP class A vs B status, PFS was 4.3 vs 2.1 months, TTP was 4.2 vs 3.8 months, and OS was 10.0 vs 3.8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar.

Commentary

It is well established that for patients with advanced HCC, preexisting liver dysfunction (CP class B) predicts poorer outcomes,9 and it remained to be determined whether systemic treatment with sorafenib would be tolerable and or effective in this situation. Although instructive, the current descriptive analysis was not specifically designed to compare outcomes in patients according to CP class. However, a good number of CP class B patients were treated and the data would suggest the drug can be administered safely and on the same schedule as for those with less compromised liver function. The overall value of sorafenib for CP class B HCC patients in terms of TTP, PFS, and OS remains to be established.

References

1. Parkin DM, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.

2. Simpson D, Keating GM. Sorafenib: In hepatocellular carcinoma. Drugs 2008;68:251-258.

3. Cheng AL, 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.

4. Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.

5. Alves RC, et al. Advanced hepatocellular carcinoma. Review of targeted molecular drugs. Ann Hepatol 2011;10:21-27.

6. Keating GM, Santoro A. Sorafenib: A review of its use in advanced hepatocellular carcinoma. Drugs 2009;69:223-240.

7. Peck-Radosavljevic M, et al. Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2010;22:391-398.

8. Pressiani T, et al. Phase II randomized trial on dose-escalated sorafenib (S) versus best supportive care (BSC) in patients with advanced hepatocellular carcinoma (HCC) with disease progression on prior S treatment. J Clin Oncol 2012;29(Suppl):Abstract 4115.

9. Tandon P, Garcia-Tsao G. Prognostic indicators in hepatocellular carcinoma: A systematic review of 72 studies. Liver Int 2009;29:502-510.