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Hepatobiliary

Commentary: Sorafenib Use in Patients with Advanced Hepatocellular Carcinoma and Underlying Child-Pugh B Cirrhosis—Evidence and Controversy

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Andrew X. Zhu, M.D., Ph.D., or Jeffrey W. Clark, M.D., Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, Lawrence House/POB 232, 55 Fruit Street, Boston, MA 02114, USA. Telephone: 617-643-3415; Fax: 617-724-3166; e-mail: ahezel{at}partners.org or jclark{at}partners.org

Received December 19, 2008; accepted for publication January 5, 2009; first published online in THE ONCOLOGIST Express on January 15, 2009.

Disclosures

Andrew X. Zhu: Consultant/advisory role: Bayer (sorafenib); Jeffrey W. Clark: None

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.

Sorafenib (Nexavar®; Bayer HealthCare Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) is a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis by targeting the serine–threonine kinases Raf-1 and B-Raf and the receptor tyrosine kinases of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 and platelet-derived growth factor receptor β [1, 2]. Encouraged by the strong rationale of its mechanism of action, promising preclinical data against hepatocellular carcinoma (HCC), and early evidence of antitumor activity from the phase II study [3], the international, phase III, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was subsequently conducted [4]. That study demonstrated a longer overall survival (OS) time and time to tumor progression (TTP). The median OS time was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio for the sorafenib group, 0.69; p < .001). The median TTP was 5.5 months in the sorafenib group and 2.8 months in the placebo group (p < .001). In another randomized phase III study conducted in Asia, sorafenib also demonstrated a longer OS time in patients with advanced HCC [5]. The OS time was 6.5 months in the sorafenib group versus 4.2 months in the placebo group (hazard ratio for the sorafenib group, 0.68; p = .014). These studies have led to the approval of sorafenib for the treatment of advanced HCC in the U.S. and many other countries around the world.

Most patients with HCC have underlying cirrhosis of various etiologies, including hepatitis B virus, hepatitis C virus, alcohol, nonalcoholic fatty liver disease, and hemochromatosis. Therefore, patients with HCC have competing causes of death from progressive HCC versus worsening underlying cirrhosis. The most commonly used instrument to assess cirrhosis is the Child-Turcotte-Pugh (CTP) score. A systematic review of 118 studies of patients with cirrhosis but no known HCC reported that Child-Pugh class A (CPA) patients have 1-year and 2-year actuarial survival rates of 95% and 90%, versus 80% and 70% in Child-Pugh class B (CPB) patients and 45% and 38% in Child-Pugh class C (CPC) patients, respectively [6]. Recognizing that death from cirrhosis could potentially mask treatment-related antitumor efficacy, both of the above phase III studies have elected to target patients with underlying CPA cirrhosis. In fact, patients with advanced HCC and underlying CPA cirrhosis who received sorafenib accounted for 95% and 97% of the patients in SHARP and the Asian study, respectively [4, 5]. Despite the specific population studied in the SHARP study, the U.S. Food and Drug Administration approved sorafenib for first-line use in advanced HCC in 2007 without specifying the underlying cirrhosis status. This has left the oncology community and many treating physicians with increased confusion: how should we use sorafenib in HCC patients with worsening underlying hepatic function? This question has profound clinical implications because the majority of patients with advanced HCC have underlying either CPB or CPC cirrhosis.

Given the guarded prognosis in patients with CPC cirrhosis and the associated significantly abnormal liver function tests, most physicians would be rightfully cautious before offering sorafenib to HCC patients with underlying CPC cirrhosis. Therefore, the confusion and controversy have really centered on the use of sorafenib in HCC patients with underlying CPB cirrhosis. Unfortunately, the clinical experience and published data on the efficacy and safety in CPB patients have been limited. The number of HCC patients treated with sorafenib with CPB cirrhosis is small and most studies are retrospective in nature. In the initial single-arm phase II sorafenib trial in HCC, 38 of the 137 patients enrolled (28%) had CPB cirrhosis. A preliminary analysis reported that the OS time was 14 weeks in CPB patients, compared with 41 weeks in CPA patients [7]. In addition, more hyperbilirubinemia, encephalopathy, and ascites developed in the CPB group than in the CPA group. Because of the single-arm nature of the study, it is difficult to assess whether these were a result of drug-induced toxicity or worsening underlying cirrhosis and HCC. Yau and colleagues have reported their experience using sorafenib in 58 poor-risk HCC patients [8]. Thirty patients had CPA cirrhosis and 15 of these had extensive portal vein thrombosis. In addition, another 15 patients had CPB/CPC cirrhosis. Thirty-four percent of patients had grade 3 or 4 toxicity. In this issue of The Oncologist, Pinter and colleagues report their experience using sorafenib in HCC patients with mild and advanced stages of cirrhosis [9]. Of the 59 patients treated, 26 patients had CPA cirrhosis and 23 had CPB cirrhosis. The median OS time in the CPA and CPB groups was 8.3 and 4.3 months, respectively. Notably, of the 10 patients with CPC cirrhosis, the median OS time was only 1.5 months, supporting the notion that patients with CPC cirrhosis are unlikely to benefit from sorafenib.

Drug therapy for HCC is made more difficult by the underlying cirrhosis that is so commonly present, which makes clearance of those drugs with significant hepatic metabolism or conjugation more difficult, and therefore the issue of how to dose these agents in individuals with different degrees of hepatic dysfunction challenging. Sorafenib is a prime example of this in that metabolism occurs primarily in the liver. It is both oxidatively metabolized by cytochrome P-450 (CYP)3A4 as well as glucuronidated by uridine diphosphate-glucuronosyl-transferase (UGT)1A9 [10]. It is primarily excreted in feces as the parent compound, although approximately 19% is excreted as metabolites in glucuronidated form in the urine. The parent compound is the primary form found in plasma. At least eight metabolites have been identified, with the most prevalent of these being a pyridine N-oxide that accounts for 9%–16% of the circulating forms. This compound has in vitro activity similar to that of the parent compound. The fact that CYP3A4 is involved in the metabolism of a wide spectrum of drugs raises the issue of potential drug interaction concerns for sorafenib, although studies to date have suggested that combinations with other drugs, including ones metabolized at least in part by CYP3A4, may be feasible [11, 12]. This may be important in attempts to combine sorafenib with other agents, although it will have to be carefully evaluated on a case-by-case basis. Finally, because sorafenib is glucuronidated by UGT, it can lead to further elevations in bilirubin, especially in patients with underlying hepatic dysfunction [13]. Given these and other considerations, as discussed above, the two phase III sorafenib HCC trials included primarily patients with CPA cirrhosis [4, 5].

With this as a background, what is known about the metabolism of sorafenib in patients with different degrees of hepatic dysfunction? The data come primarily from two sources. The first is a study that evaluated metabolism in patients with hepatic and/or renal dysfunction [13]. The second are studies that have included patients with CPA or CPB cirrhosis (no study has included a sufficient number of patients with CPC cirrhosis to provide any meaningful information, although given the findings of the previously mentioned study, it is likely that significant toxicity would be seen in the absence of starting at a significantly reduced dose) [3, 14]. The first study established that full-dose sorafenib could be given to individuals with bilirubin levels up to 1.5x the upper limit of normal, but that a lower starting dose was advised above that. Studies with the use of sorafenib in patients with CPB cirrhosis have shown no significant difference in toxicities as compared with patients with CPA cirrhosis other than those reflecting the degree of hepatic dysfunction (hyperbilirubinemia, encephalopathy, and ascites) [7]. This correlates with overall similar to slightly higher plasma drug levels in those with CPB cirrhosis and no statistically significant difference in the pharmacokinetics (PK) of sorafenib between these two groups in any of the studies to date [3, 14]. Because the CTP score includes a number of factors besides bilirubin, PK studies based on bilirubin levels and on CTP scores are not directly comparable. However, in combination, they do provide some guidance for the potential use of sorafenib in patients with HCC and CPB scores. For patients with only slightly elevated bilirubin levels, CPB cirrhosis with a CTP score of 7, and an excellent performance status, the results from these studies would argue that standard dosing from the beginning with dose modifications as per current guidelines would be appropriate. Extra precaution should be taken in the initial dosing of those individuals whose score is primarily driven by elevated bilirubin rather than other components of the CTP score. The dose could then be further modified based on tolerance.

In summary, the published data and clinical experience thus far do not provide definitive conclusions about the use of sorafenib in HCC patients with CPB cirrhosis but they do provide some guidance. While using this information to help make decisions, it is important that clinicians should also continue to use caution and best judgment when treating patients with CPB cirrhosis with sorafenib until more definitive data become available. Despite the hesitancy of the oncology community and pharmaceutical sponsors to include patients with CPB cirrhosis in HCC clinical trials, the experience of sorafenib use in CPB patients underscores the importance of prospectively testing novel agents in HCC patients with different degrees of hepatic dysfunction.

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