The diagnosis and treatment of hepatocellular carcinoma (HCC) constitute a complex and challenging clinical paradigm. The complexity relates to the multitude of treatment options available, including surgical approaches, locoregional therapies, and emerging systemic treatments. In addition, the presence of underlying liver disease, which usually is advanced and includes cirrhosis, further and uniquely complicates the therapeutic approach. In recent years, considerable evidence-based data have been generated to help provide a framework to govern therapeutic decisions. In particular, the Barcelona Clinic Liver Cancer (BCLC) staging system has linked treatment options to stages of HCC disease, severity of liver disease using the Child-Pugh score, and performance status.[1]
A major milestone was achieved with the approval of sorafenib(Drug information on sorafenib) (Nexavar) for treatment of patients with HCC.[2,3] Most patients in the clinical trials that led to its approval had Child-Pugh A cirrhosis and BCLC stage C disease (cancer with macrovascular invasion, and/or lymph node metastases, and/or extrahepatic spread). Despite the narrow, albeit extremely appropriate inclusion criteria for these trials, sorafenib package labeling used by the United States and European regulatory agencies was vague. In the context of this vague labeling indication for sorafenib, Kim et al expertly review in this issue of ONCOLOGY the clinical issues and considerations regarding when and how to use sorafenib for patients with HCC.[4] The major pragmatic questions are: Can or should sorafenib be extended to patients with liver disease that is at a more advanced stage? Should sorafenib be used in an adjuvant or neoadjuvant manner or in conjunction with locoregional therapies? Can sorafenib be used more effectively in multidrug regimens?
Can or should sorafenib be used in patients with Child-Pugh B or C cirrhosis?
The pharmacokinetics of sorafenib are similar in Child-Pugh A and B cirrhotic patients, and thus, from a purely pharmacologic perspective, the dose need not be altered in patients with Child-Pugh B versus Child-Pugh A cirrhosis.[5] Drug-related toxicity and hepatic decompensation, however, especially as reflected by hyperbilirubinemia, may occur more frequently in Child-Pugh B patients receiving sorafenib compared with Child-Pugh A patients. Also, the survival benefit with sorafenib in Child-Pugh B patients is not well established, due to limited information. There appears to be no survival benefit from sorafenib in patients with Child-Pugh C cirrhosis, however, because of the high mortality rate from their underlying liver disease. Also, as Kim et al indicate, patients with less severe Child-Pugh B cirrhosis, that is, a Child-Pugh B score of 7 points, are often much better compensated than patients with Child-Pugh B scores of 8 or 9 points. Therefore, sorafenib perhaps can be used judiciously in patients with less-advanced Child-Pugh B cirrhosis, but not in Child-Pugh C cirrhosis.
Can or should use of sorafenib be expanded to adjuvant and neoadjuvant inductions, and in scombination with local/regional therapies?
This question is explored in depth by Kim et al. As described in detail, numerous studies are ongoing to examine these expanded indications for the use of sorafenib. These studies are well designed, and it is hoped that they will yield definitive answers. Until the trial results are available, use of sorafenib for these indications is not encouraged and is difficult to defend, given its cost and toxicity. An indication that will not be addressed by current trials is the use of sorafenib pre– and post–liver transplantation. Use of sorafenib for recurrent HCC following liver transplantation is logical, and given the absence of cirrhosis may, in fact, be better tolerated than in the pretransplant setting. Potential drug-drug interactions will need to be carefully examined, however. The use of sorafenib for patients who are waiting for a liver transplant is more complex. If sorafenib is ultimately found to be effective in conjunction with locoregional therapies, then many transplant centers may opt to use it for this patient population, to decrease disease progression–related dropout from the waitlist. Transplant centers may also use the drug in conjunction with locoregional therapies to help downstage highly selected patients currently not eligible for liver transplantation. In the transplant arena, new information regarding the use of sorafenib will be limited, largely case-based, and often center-specific.
Can sorafenib be used more effectively in combination drug therapy?
Sorafenib is only modestly effective, extending overall survival by approximately 3 months in Child-Pugh A cirrhosis, BCLC stage C HCC. Clearly, better therapy is urgently needed. A logical drug therapy combination based on preclinical data was sorafenib plus an mTOR (mammalian target of rapamycin) inhibitor such as rapamycin (sirolimus, Rapamune), temsirolimus (Torisel), or everolimus (Afinitor).[6] However, one trial comparing sorafenib alone versus sorafenib plus everolimus was stopped prematurely by the data monitoring committee because of excess toxicity in the combination arm (Jordi Bruix, MD, Barcelona Clinic Liver Cancer Group, personal communication). Yet there are other strategies for combination therapy. Sorafenib significantly reduces cellular expression of myeloid cell leukemia sequence 1 (Mcl-1), a potent antiapoptotic protein, rendering cells sensitive to proapoptotic therapies.[7,8] In this context, trials are underway to examine the efficiency/toxicity of different TRAIL (tumor necrosis factor–related apoptosis-inducing ligand, a proapoptotic death ligand) agonists plus sorafenib in patients with HCC. Also, given the encouraging results of a trial employing epidermal growth factor receptor (EGFR) inhibitors in HCC,[9] a large ongoing trial is investigating outcomes of treating HCC patients with sorafenib versus sorafenib plus the EGFR inhibitor erlotinib (Tarceva). We encourage more studies examining combination therapy with sorafenib. The current strategy by industry is often to identify the “best in class” of agents for HCC, largely receptor tyrosine kinase inhibitors. It is likely, however, that combination approaches will ultimately yield the best results. More effective therapy is still required, and we must continue to strive to identify better treatment options for our patients with HCC.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
