ABSTRACT: The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib(Drug information on sorafenib) (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The US Food and Drug Administration (FDA) authorized use of sorafenib for “unresectable HCC,” an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.
Hepatocellular carcinoma (HCC) in the United States accounts for approximately 23,000 new cases annually. The incidence of HCC continues to increase, partly as a result of the unsolved problem of hepatitis C and deficient screening in high-risk patients. Globally, HCC is the fifth most common cancer worldwide and the third most common cause of cancer mortality. The only potentially curative options for patients with HCC are liver resection, radiofrequency ablation (RFA), and liver transplantation (LT). Patients who are fortunate enough to undergo LT have a 4-year survival rate of 85% if the tumors are within the Milan criteria. Recurrence rates in this patient population range from about 8% to 12%. However, among patients undergoing hepatic resection in whom the procarcinogenic liver is not replaced, the disease recurrence rate can exceed 70% at 5 years. Other noncurative options include local therapies such as transarterial chemoembolization (TACE), radioembolization, RFA, and systemic therapy. Advanced HCC carries a very poor prognosis, and use of cytotoxic agents has provided only marginal benefit.[6,7]
In 2007, sorafenib was approved in United States and Europe for ad- vanced HCC based on results from the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial. Sorafenib is an oral multikinase inhibitor that blocks tumor cell proliferation by targeting multiple pathways including the Raf/mitogen-activated protein kinase/extracellular signal–regulated kinase (Raf/MEK/ERK) signaling pathway, along with tyrosine kinases (TKs), VEGF receptor 2 (VEGFR-2), VEGFR-3, and the platelet-derived growth factor receptor β (PDGFR-β) pathway. In the landmark SHARP trial, 602 patients with advanced HCC were randomized to either sorafenib at 400 mg twice a day or to placebo. The final result showed that sorafenib had overall survival (OS) and time to tumor progression (TTP) benefits in patients with advanced HCC, compared with placebo. Median OS was 10.7 months in the sorafenib group and 7.9 months in the placebo group. In Asia, a similar phase III trial was being conducted simultaneously. This trial also showed a similar magnitude of benefit in the sorafenib arm compared with the placebo arm.[8,10] Based on these two phase III trials, sorafenib became the first molecularly targeted therapy to show an OS benefit, establishing it as the first new standard treatment for advanced HCC.
The new data are now being met with cautious optimism, but there are several unanswered questions. The US Food and Drug Administration (FDA) authorized use of sorafenib for patients with “unresectable hepatocellular carcinoma,” a very vague and broad indication. In Europe, the indication is even broader, as sorafenib is indicated for “hepatocellular carcinoma.” Therefore, the exact indication for sorafenib in advanced HCC is confusing and gives rise to many uncertainties, including use of sorafenib in patients with decompensated liver disease, use in conjunction with local therapy, or use in a transplant setting.
Most of the patients enrolled in these large phase III trials had well-compensated liver function (Child-Pugh A cirrhosis); therefore the utility of sorafenib in Child-Pugh class B or C cirrhotic patients remains unknown. Also unclear is the potential role of sorafenib in combination with locoregional therapies, as well as its potential use in liver-transplant settings. The safety and feasibility of the implementation of sorafenib as a pretransplant neoadjuvant agent, or as an adjuvant therapy for posttransplant HCC recurrence, are uncertain. These practical questions have to be addressed as we deal with a complex disease in which an oncologic state evolves from conditions of liver dysfunction or immunosuppression. In this review article we will discuss the current data on, and future role of, sorafenib in the treatment of HCC beyond Child-Pugh A cirrhosis, in conjunction with local therapy, and in a transplant setting. The role of sorafenib in combination with other targeted therapies or other promising agents in the treatment of advanced HCC is beyond the scope of this article and will not be discussed.
Sorafenib in Child-Pugh B or C Cirrhosis
The safety and efficacy of sorafenib have been proven in patients with Child-Pugh A cirrhosis based on the aforementioned two large phase III trials. Little is known about the safety and efficacy of sorafenib in patients with Child-Pugh class B or C cirrhosis. Nevertheless, since there are no other effective treatments for cirrhotic patients with advanced disease, many single institutions have used sorafenib in these patients.
Prior to the SHARP study, a phase II trial by Abou-Alfa et al analyzed use of sorafenib in both Child-Pugh A and B cirrhotic patients.[11,12] In this trial, out of 137 patients, 38 had Child-Pugh B cirrhosis and 99 had Child-Pugh A cirrhosis. In the analysis of the study, toxicity profiles for Child-Pugh A and B cirrhosis, drug discontinuation rates, and dose reduction rates were similar in both groups. Nevertheless, overall outcome was much worse in the Child-Pugh B group, with an overall survival (OS) outcome of 3.5 months and time to tumor progression (TTP) of 3.3 months. Another large retrospective study from the Western Hemisphere, by Pinter et al, included 23 patients with Child-Pugh B cirrhosis and 10 with Child-Pugh-C cirrhosis. Results revealed an OS of 4.3 months and a TTP of 2.9 months in the Child-Pugh B group, similar to findings from the phase II trial by Abou-Alfa et al. In the Child-Pugh C group, however, OS was only 1.5 months, and the authors concluded that sorafenib should not be used in patients with advanced-stage cirrhosis.
Two of the largest Asian experiences in patients with Child-Pugh B cirrhosis are described in studies from Korea, where hepatitis B is the number one risk factor for HCC. Lee et al reported on 29 patients with Child-Pugh B cirrhosis who received sorafenib and exhibited an OS of 3.7 months. Another series included 23 patients with Child-Pugh B cirrhosis; TTP was 2 months but OS was not reported. Results of other small series that included patients with Child-Pugh B cirrhosis are listed in Table 1.
In terms of drug-related toxicity profiles, most of these retrospective analyses did not distinguish between Child-Pugh A and B cirrhosis. Four of the studies did attempt to make a distinction, however, and the toxicities are outlined in Table 2.
There are data showing no statistically significant difference in the pharmacokinetics (PK) of sorafenib in Child-Pugh A versus Child-Pugh B patients. A phase I trial conducted in Japan also showed no substantial differences in the incidence of adverse events or clinically relevant differences in PK between the Child-Pugh A and B groups. Overall, toxicity profiles for Child-Pugh B patients seem to be similar to or slightly worse than those for Child-Pugh A patients (see Table 2). However, toxicity reflecting worsening hepatic dysfunction, such as hyperbilirubinemia, encephalopathy, and ascites, appears to be to be greater in Child-Pugh B patients. Notably worsening bilirubin levels were reported in 40% of Child-Pugh B patients, compared with 18% of Child-Pugh A patients. Nevertheless, because direct bilirubin levels were not reported, it is unclear if the rise in total bilirubin was related to sorafenib as a result of decreased bilirubin glucuronidation; this can increase indirect bilirubin or cause pre-existing hepatic dysfunction to worsen, which usually increases direct bilirubin levels. Interestingly, it seems that patients with hepatitis B may have a higher chance of developing liver toxicity from treatment with sorafenib. A phase II trial by Yao et al did not break down all of the toxicity findings by Child-Pugh class, but it did report a 73% rate of grade 3 or 4 liver toxicity among patients with Child-Pugh B or C cirrhosis. Even though this finding was not statically significant compared with the high rate of liver toxicity seen in Child-Pugh A patients, it does raise an eyebrow. One of the hypotheses that may explain this result is that administration of targeted therapy can lead to reactivation of the underlying hepatitis B infection and, consequently, can worsen liver function.[18,19]
Efficacy of sorafenib in Child-Pugh B patients in the small series reported in the medical literature seems to be very modest, with OS ranging from 2–5 months. Difficulty in evaluating survival in Child-Pugh B patients has to do with the coexistence of HCC and advanced-stage liver disease. Patients who have Child-Pugh B cirrhosis without HCC have a 1-year survival rate of about 80%. Therefore, deaths from cirrhosis could potentially mask treatment-related antitumor efficacy. The potential for a clinically meaningful gain in OS with use of sorafenib in Child-Pugh B patients can only be evaluated in a prospective, randomized, placebo-controlled trial. However, placebo-controlled trials in Child-Pugh B patients will be very difficult in an era in which drug regulatory agencies allow sorafenib to be used to treat patients with HCC and any degree of liver failure.
These retrospective analyses, therefore, give us important insights into use of sorafenib in Child-Pugh B patients, despite their obvious limitations. It is hoped that, as more institutions publish their experiences with incorporating sorafenib into the treatment of patients with advanced cirrhosis, we will gain further knowledge about its efficacy and toxicity profiles in a variety of patient settings.
In the future, instead of lumping all Child-Pugh B cirrhosis patients together in the outcomes analysis, we should consider categorizing them into subgroups. For example, Child-Pugh B patients with a Child-Pugh score of 7 may have a better outcome with sorafenib than those with a score of 8 or 9. Unfortunately, HCC patients who are classified as having Child-Pugh C disease will most likely not benefit from any therapeutic options except for LT secondary to liver cirrhosis. Quality of life also should be part of the assessment, given that OS in most patients with HCC and Child-Pugh C disease is measured in months.
GIDEON (Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib) is an ongoing global, prospective, noninterventional study of patients with unresectable HCC and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. The purpose of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially in patients with Child-Pugh B disease, or in conjunction with local therapy, a treatment option for which data are limited. The plan is to accrue more than 3,000 patients, and the findings are likely to provide us with valuable information about certain HCC patient subgroups.
Meanwhile, until more definitive data become available, it is imperative that clinicians employ caution and their best judgment when using sorafenib in patients with Child-Pugh B cirrhosis. As expected, patients with Child-Pugh C cirrhosis had a very poor outcome despite being on sorafenib, with median survival times between 2 and 3 months.[13,22] The poor outcome is most likely related to underlying liver cirrhosis, so it is highly unlikely that sorafenib or any other therapy will provide those patients with clinically meaningful benefits. Biomarker development or new information about tumor characteristics that identify subgroups of patients who may respond to sorafenib independent of Child-Pugh stage may be helpful in the future.