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Hepatobiliary

Sorafenib in Unresectable Hepatocellular Carcinoma from Mild to Advanced Stage Liver Cirrhosis

Departments of ^aGastroenterology and Hepatology, ^fOncology, and ^gRadiology, AKH & Medizinische Universität Wien, Wien, Austria; ^bDepartment of Gastroenterology and Hepatology, LKH & Medizinische Universität Innsbruck, Innsbruck, Austria; ^cFourth Medical Department, KH Elisabethinen Linz, Linz, Austria; ^dKaiser Franz Josef-Spital, Third Medical Department, Centre for Oncology and Hematology, CEADDP, Applied Cancer Research, Institution for Translational Research Vienna (ACR-ITR VIEnna), and Ludwig Boltzmann-Institute for Applied Cancer Research (LBI-ACR VIEnna), Vienna, Austria; ^eDepartment of Oncology and Hematology, Wilhelminenspital Wien, Wien, Austria

Key Words. Hepatocellular carcinoma • Liver cirrhosis • Sorafenib • Multikinase inhibitors

Correspondence: Markus Peck-Radosavljevic, M.D., AKH & Medizinische Universität Wien, Klinik Innere Medizin III, Abteilung Gastroenterologie & Hepatologie, Währinger Gürtel 18-20, A-1090 Wien, Austria. Telephone: 43-1-40400-6589; Fax: 43-1-40400-4735; e-mail: markus.peck{at}meduniwien.ac.at

Received August 25, 2008; accepted for publication December 22, 2008; first published online in THE ONCOLOGIST Express on January 14, 2009.

Disclosures

Matthias Pinter: None; Wolfgang Sieghart: None; Ivo Graziadei: None; Wolfgang Vogel: None; Andreas Maieron: None; Robert Königsberg: None; Adalbert Weissmann: None; Gabriela Kornek: None; Christina Plank: None; Markus Peck-Radosavljevic: Consultant/advisory role: BayerSchering Pharma; Honoraria: BayerSchering Pharma; Research funding/ contracted research: BayerSchering Pharma

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers.

	ABSTRACT

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Background. Few data are available on the safety and efficacy of sorafenib in patients with multifocal hepatocellular carcinoma (HCC) and advanced liver cirrhosis.

Methods. Between May 2006 and December 2007, we treated 59 patients (Child-Pugh class A/B/C, 26/23/10) with unresectable HCC with sorafenib (daily target dose, 400 mg twice daily). Data were collected retrospectively. Survival curves were calculated via the Kaplan–Meier method.

Results. One patient (Child-Pugh class B) had a partial response, 14 patients (Child-Pugh class A/B/C, 5/7/2) had stable disease, and 32 patients (Child-Pugh class A/B/C, 15/11/6) had progressive disease; 12 patients were not evaluable because they had no follow-up radiologic evaluation. In the intention-to-treat group, the median time to progression and overall survival (OS) time were 2.8 months (range, 1.4–6.5 months) and 6.5 months (range, 0.4–17.4 months), respectively. Well-preserved liver function and lower Barcelona Clinic Liver Cancer stage were associated with a longer OS time on univariate analysis. There were four severe gastrointestinal bleedings (grade 4–5; Child-Pugh class B/C, 2/2). Most drug-related side effects were low grade and manageable irrespective of liver function.

Conclusions. Sorafenib is effective and safe in patients with multifocal HCC and Child-Pugh class A cirrhosis. Survival in Child-Pugh class B patients is significantly less than in Child-Pugh class A patients, warranting a prospective randomized trial with a placebo group. Child-Pugh class C patients have a limited life expectancy despite sorafenib treatment because of their severe underlying disease and derive little benefit from sorafenib treatment.

	INTRODUCTION

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Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and has a very poor prognosis in advanced stages with a median survival time of 6–9 months [1, 2]. In the Western hemisphere, HCC mostly develops in patients with liver cirrhosis, which is most commonly caused by hepatitis C virus (HCV) infection, hepatitis B virus infection, or chronic alcoholism [3, 4]. The HCC incidence has increased over the last years, largely because of chronic HCV infection–related liver cirrhosis [5].

Therapeutic options are stage dependent. Potential curative therapies such as surgical resection, liver transplantation, and percutaneous techniques (ethanol injection, radiofrequency ablation) can be performed successfully in early-stage patients. Asymptomatic patients with well-preserved liver function may benefit from arterial chemoembolization [6–8]. However, as cancer-related symptoms often emerge late after a long-standing asymptomatic period, HCC is often diagnosed at an advanced stage of disease [9]. For the longest time, no effective treatment was available for these patients [8].

Sorafenib is a multikinase inhibitor that has already been approved for the treatment of metastatic renal cancer. Sorafenib targets the Raf/mitogen-activated protein kinase/extracellular signal–related kinase (ERK) kinase/ERK signaling pathway as well as other tyrosine kinases like vascular endothelial growth factor receptor, platelet-derived growth factor receptor β, KIT, FLT-3, or REarranged during Transfection, which are important for tumor cell proliferation and angiogenesis. Encouraging preclinical results in several human tumors, including HCC [10], led to a large, open-label, nonrandomized, phase II trial in patients with HCC. In that phase II trial with 137 advanced HCC patients, the investigators reported modest efficacy and manageable toxicity, qualifying sorafenib for a large, randomized, placebo-controlled, multicenter trial for this indication [11]. The phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial finally demonstrated a significant survival benefit (placebo, 7.9 months; sorafenib, 10.7 months) and good tolerance in patients with HCC, making sorafenib the new reference standard for systemic therapy of patients with advanced HCC [12]. However, this phase III trial was restricted to patients with well-preserved liver function (Child-Pugh class A). Thus, little is known about the safety and efficacy of sorafenib in patients with multifocal HCC and Child-Pugh class B cirrhosis. For Child-Pugh class C patients, only symptomatic treatment is suggested [8]. Nevertheless, we have treated some patients with HCC and Child-Pugh class C cirrhosis with sorafenib because no data are available on the first effective drug therapy for HCC in this group of patients.

	MATERIALS AND METHODS

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Patients
Between May 2006 and December 2007, 59 patients with advanced HCC without an option for any standard therapy were treated with sorafenib at five experienced institutions in Austria. HCC was diagnosed either by histology or by the combination of characteristic radiographic findings and elevated -fetoprotein serum levels according to the European Association for the Study of the Liver criteria [13]. Relevant data from the patients' clinical records, including history, laboratory results, radiological findings, histological results, and survival data, as well as the dosage and adverse events of sorafenib therapy, were collected retrospectively.

Sorafenib Treatment
An initial sorafenib dose of 400 mg was administered orally twice daily. Discontinuation and dose reduction were based on tolerance. Side effects of sorafenib were determined via the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0.

Assessment of Tumor Response
Based on the computed tomography/magnetic resonance tomography (MRT) scans of the liver performed at baseline and every 2–4 months, tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) [14]. Patients who died before their first radiographic control were judged as having progressive disease (PD).

Statistics
Patients' basal characteristics were analyzed by descriptive statistical methods. The overall survival (OS) time was defined as the time from sorafenib initiation to the date of death or the patient's last follow-up. The survival curves were calculated via the Kaplan–Meier method. Univariate survival curves were compared using the log-rank test. A p-value < .05 was considered statistically significant. All analyses were performed using the statistical software package SPSS (version 15.0; SPSS Inc., Chicago, IL).

	RESULTS

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Patient Characteristics
There were 46 male patients (78%) and 13 female patients (22%) with a mean age of 64 years (range, 27–85). The predominant etiology of cirrhosis was alcohol (n = 22; 37%). Twenty-six (44%) patients had Child-Pugh class A, 23 (39%) patients had Child-Pugh class B, and 10 (17%) patients had Child-Pugh class C liver cirrhosis. Forty-six (78%) individuals had portal vein thrombosis (PVT) or extrahepatic metastases. The Eastern Cooperative Oncology Group performance status scores were 0 (n = 31; 53%), 1 (n = 26; 44%), and 3 (n = 2; 3%). Tumor stage was classified according to the Barcelona Clinic Liver Cancer (BCLC) staging classification [7] and also according to the tumor–node–metastasis stage [15]. Thirty-one (53%) patients had been treated prior to sorafenib therapy with surgical, locoregional, or pharmacologic therapies (Table 1).

Response and Efficacy According to Severity of Underlying Liver Disease (Child-Pugh Class)
Efficacy results according to Child-Pugh class are given in Table 2. Five of the 26 Child-Pugh class A patients (19%) had SD, with a median TTP of 2.2 months (range, 1.4–6.5 months). Of the 23 Child-Pugh class B patients, one (4%) had a PR and seven (30%) had SD; the median TTP was 2.9 months (range, 1.6–6.0 months). Two of the 10 (20%) Child-Pugh class C patients had SD for 2.8 months and 5.2 months; the median TTP in Child-Pugh class C patients was 4.0 months. TTP was not statistically different among patients with different severities of liver disease (log-rank p = .866).

View larger version (30K): [in this window] [in a new window]   Figure 1. Overall survival (Kaplan–Meier) curves for 59 patients treated with sorafenib. (A): Kaplan–Meier survival curves for Child-Pugh class A (n = 26), class B (n = 23), and class C (n = 10) patients; log-rank p = .0001. (B): Kaplan–Meier survival curves for Barcelona Clinic Liver Cancer (BCLC) stage B–C (n = 43) and stage D (n = 16) patients; log-rank p = .0001.

Table 3 shows the adverse events of sorafenib according to Child-Pugh class. GI bleeding, nausea, emesis, and epistaxis were observed only in Child-Pugh class B and class C patients and not in Child-Pugh class A patients. Four of the 26 Child-Pugh class A patients (15%), six of the 23 Child-Pugh class B patients (26%), and two of 10 Child-Pugh class C patients (20%) experienced grade 3–4 toxicities; one Child-Pugh class C patient died as a result of GI bleeding (10%; grade 5). There was no trend toward greater toxicity with more advanced liver dysfunction, but hand–foot skin reaction was more frequent in Child-Pugh class A patients than more advanced liver disease.

	DISCUSSION

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The multikinase inhibitor sorafenib demonstrated a significant survival benefit and good tolerance in patients with HCC in a phase III randomized controlled trial (SHARP) [12]. However, this phase III trial was restricted to patients with well-preserved liver function (Child Pugh class A). We analyzed the safety and efficacy of sorafenib in patients with unresectable HCC in the Austrian extended access program of sorafenib, including >50% of patients with advanced-stage liver cirrhosis (Child-Pugh class B and also class C). Nevertheless, the retrospective nature of our study was a limiting factor, which should be considered if outcome results are compared with the referenced prospective trials [11, 12, 16].

In our ITT group, the OS time was 6.5 months. A subgroup analysis with respect to Child-Pugh class revealed a strong dependency of patient survival on the severity of the underlying cirrhosis (Table 4). For Child-Pugh class A patients, we can only report the median time of follow-up (8.3 months) up until now, but not OS, because 17 of the 26 patients (65%) were still alive at the end of follow-up. The real OS time of Child-Pugh class A patients in this study is at least 8.3 months, and most likely even longer. We are expecting a similar median OS time to that in the sorafenib group of the SHARP trial (10.7 months) [12], or even better. Hence, we confirmed the favorable efficacy of sorafenib in Child-Pugh class A patients with advanced HCC in a "real-life" patient population outside a prospective clinical trial.

Also with sorafenib treatment, patient survival is strongly dependent on the severity of liver disease. Not unexpectedly, it was significantly worse in Child-Pugh class B and class C patients in our analysis. We observed an OS duration of 4.3 months for Child-Pugh class B patients, which is lower than the OS time reported in all Child-Pugh class A patients so far. It could be questioned whether tumor-related factors or the severity of underlying liver cirrhosis were responsible for this poor outcome. The lower rate of extrahepatic metastases in Child-Pugh class B patients (48%) than in Child-Pugh class A patients (58%) does not point to an influence of extrahepatic involvement on the inferior outcome of the Child-Pugh class B patients in our observation. In contrast, 52% of the Child-Pugh class B patients but only 39% of the Child-Pugh class A patients had PVT. Thus, portal vein involvement could, at least partly, be responsible for the poor survival of the Child-Pugh class B patients. TTP was not worse in Child-Pugh class B or class C patients than in Child-Pugh class A patients, indicating that the antitumor activity of sorafenib is preserved in advanced cirrhosis and not dependent on the severity of liver disease. Whether the potential gain in OS in Child-Pugh class B patients results in a clinically meaningful survival benefit can only be evaluated in a prospective, randomized, placebo-controlled trial of sorafenib in Child-Pugh class B patients with advanced HCC.

This is the very first study reporting the efficacy of sorafenib in Child-Pugh class C patients. The median survival time for Child-Pugh class C patients (alive, 1 of 10) was only 1.5 months. These patients have a limited life expectancy despite treatment because of their severe underlying disease. Thus, sorafenib treatment does not seem to provide a clinically meaningful benefit in Child-Pugh class C patients and patients should instead be treated with best supportive care, as suggested by all current guidelines [8].

Side effects in this cohort of patients were, overall, low grade and manageable. Diarrhea (n = 21; 36%) was the most troublesome side effect, similar to the phase II study [11, 16] and the phase III randomized, controlled trial [12]. GI bleeding, nausea, emesis, and epistaxis were observed only in Child-Pugh class B and class C patients and not in Child-Pugh class A patients. The risk for high-grade toxicities could be increased in individuals with advanced liver dysfunction (Table 3). The lower discontinuation rate in Child-Pugh class C patients (20%) than in Child-Pugh class A patients (42%) and class B patients (43%) could be a result of the very short median survival time of the Child-Pugh class C patients (1.5 months). Notably, hand–foot skin reactions were more common in patients with well-preserved liver function (Child-Pugh class A patients) than in patients with more advanced disease stages. The rate of hand–foot skin reaction in Child-Pugh class A patients was similar to the rate in renal cancer patients [18]. This suggests that sorafenib metabolism by the normal liver might play a role in this toxicity, which would explain the surprisingly low rate of hand–foot skin reaction in more advanced liver disease patients.

The most severe complication in our study was GI bleeding (n = 4; 7%). We observed one episode of melaena (Child-Pugh class B, BCLC stage D), one variceal bleed (Child-Pugh class C, BCLC stage D), one bleeding of unknown origin (Child-Pugh class C, BCLC stage D), and one gastric ulcer bleeding (Child-Pugh class B, BCLC stage B). One patient (variceal bleeding) had to discontinue sorafenib treatment and another patient (bleeding of unknown origin) died as a result of the GI bleed. No direct causal relationship to sorafenib treatment could be established in any case. GI bleeding is a common complication of chronic liver disease and bleedings are a known side effect of multikinase inhibitors [19], but the rate of bleeding was not greater than that seen with placebo in the prospective phase III trials reported so far. Still, caution is warranted before starting sorafenib therapy in patients with advanced liver dysfunction. Prophylactic endoscopic evaluation with prophylactic variceal band ligation in patients with high-risk varices could be considered in this group of patients.

	CONCLUSION

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Sorafenib is effective and safe in patients with multifocal HCC and Child-Pugh class A cirrhosis, as shown by several large prospective trials [12, 20]. The efficacy and safety of sorafenib in Child-Pugh class B patients require further evaluation in a prospective, placebo-controlled trial. Child-Pugh class C patients have a limited life expectancy because of their severe underlying disease, which cannot be substantially improved by sorafenib treatment.

	AUTHOR CONTRIBUTIONS

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Conception/design: Markus Peck-Radosavljevic

Provision of study materials: Markus Peck-Radosavljevic, Ivo Graziadei, Wolfgang Vogel, Andreas Maieron, Robert Königsberg, Adalbert Weissmann, Christina Plank

Collection/assembly of data: Markus Peck-Radosavljevic, Ivo Graziadei, Wolfgang Vogel, Andreas Maieron, Robert Königsberg, Adalbert Weissmann, Christina Plank, Matthias Pinter, Gabriela Kornek, Wolfgang Sieghart

Data analysis: Markus Peck-Radosavljevic, Wolfgang Sieghart, Matthias Pinter

Manuscript writing: Markus Peck-Radosavljevic, Wolfgang Sieghart, Matthias Pinter

Final approval of manuscript: Markus Peck-Radosavljevic

	REFERENCES

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1. Parkin DM, Bray F, Ferlay J et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153–156.[CrossRef][Medline]
2. Yoo HY, Patt CH, Geschwind JF et al. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003;21:4329–4335.[Abstract/Free Full Text]
3. Bruix J, Barrera JM, Calvet X et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004–1006.[CrossRef][Medline]
4. Shiratori Y, Shiina S, Imamura M et al. Characteristic difference of hepatocellular carcinoma between hepatitis B- and C- viral infection in Japan. Hepatology 1995;22:1027–1033.[CrossRef][Medline]
5. El-Serag HB, Davila JA, Petersen NJ et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: An update. Ann Intern Med 2003;139:817–823.[Abstract/Free Full Text]
6. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 2005;40:225–235.[CrossRef][Medline]
7. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329–338.[Medline]
8. Llovet JM, Fuster J, Bruix J. Barcelona-Clínic Liver Cancer Group. The Barcelona approach: Diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10(suppl 1):S115–S120.[CrossRef][Medline]
9. Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: Two ends of the therapeutic spectrum. Lancet Oncol 2004;5:409–418.[CrossRef][Medline]
10. Liu L, Cao Y, Chen C et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006;66:11851–11858.[Abstract/Free Full Text]
11. Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24:4293–4300.[Abstract/Free Full Text]
12. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390.[Abstract/Free Full Text]
13. Bruix J, Sherman M, Llovet JM et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–430.[CrossRef][Medline]
14. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.[Abstract/Free Full Text]
15. Sobin L, Wittekind C, eds. TNM Classification of Malignant Tumours. Sixth Edition. New York: Wiley-Liss, 2002:81-83.
16. Abou-Alfa GK, Amadori D, Santoro A et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? the 2008 Gastrointestinal Cancers Symposium; January 25–27, 2008; Orlando, Florida. Presented at.
17. Benjamin RS, Choi H, Macapinlac HA et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007;25:1760–1764.[Abstract/Free Full Text]
18. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–134.[Abstract/Free Full Text]
19. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007;7:475–485.[CrossRef][Medline]
20. Cheng A, Kang Y, Chen Z et al. Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma. J Clin Oncol 2008;26;(20) (suppl):4509a.

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