2012-06-01 15:50:52 UTC

The Hepatologist’s Role in Prescribing Therapy for HCC

June 1, 2012

NAME

Marcus-Alexander Wörns, MD

Head of Hepatobiliary Oncology, Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

NAME

Peter R. Galle, MD, PhD

 

Director, Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

 

 

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and represents today the leading cause of death amongst cirrhotic patients. After years of therapeutic nihilism due to the inefficacy of conventional cytotoxic chemotherapy, the multi-targeted tyrosine kinase inhibitor (TKI) sorafenib (Nexavar®, Bayer Pharmaceuticals Corporation) was the first agent to demonstrate a significant improvement in the overall survival of patients with advanced HCC. Although the approval of sorafenib represented a milestone and proved that molecular targeted therapy can be effective, it was just the first step towards an improved systemic therapy in this dismal disease.

HCC arises in more than 80 percent of cases in a cirrhotic liver, complicating or limiting the treatment of HCC. This burden, addressed by the Barcelona Clinic Liver Cancer algorithm, is in sharp contrast to most other malignancies. Concomitant liver insufficiency, treatment of underlying liver disease (e.g., viral hepatitis) and complications of portal hypertension require all-encompassing care by a multidisciplinary team best guided by oncology-oriented hepatologists. It is of paramount importance that the treatment of patients with HCC is accompanied from the beginning by an experienced hepatologist because apart from the tumor burden, all treatment options — and particularly the decision to prescribe sorafenib — mainly depend on patients’ performance status and liver function. Most patients with HCC are treated by transarterial approaches such as chemoembolization (TACE) or radioemolization (SIRT) during the course of their disease. However, it is crucial to choose the best time point to discontinue these approaches because an impairment of liver function caused by repeated transarterial treatment may limit patients’ future benefit from targeted therapy. These arrangements with interventional radiologists are even more important in the emerging field of combined treatment approaches (TACE with targeted therapy).

After initiation of sorafenib therapy, the impact of the sorafenib therapy on the underlying liver disease and vice versa has to be considered permanently. From our opinion, these assessments are best delivered by hepatologists, and exclusive treatment by other professionals (e.g., oncologists) will be not optimal for these patients.

From our own experience,1 maintained liver function (Child-Pugh class A) is a basic requirement for successful sorafenib treatment in patients with HCC. It has become evident that patients with advanced liver cirrhosis (Child-Pugh class B/C) on sorafenib therapy have a shorter treatment period, a higher rate of liver-related toxicities and only modest clinical benefit with respect to overall survival (two to five months). Therefore, we postulate that Child-Pugh class B patients should only be treated with extreme caution on an individual basis after careful education. Child-Pugh class C patients, in whom survival is not dictated by their cancer as much as by their cirrhosis, are unlikely to benefit from sorafenib or any other investigational drug, and should be treated with best supportive care.

In this context, it is important to note that we demonstrated that sorafenib in combination with the mTOR inhibitor sirolimus may be administered to patients with HCC recurrence after liver transplantation without any deterioration of liver graft function and promising overall survival.2 These results underscore the importance of maintained liver function in patients with HCC undergoing sorafenib treatment.

The target dose of 400 mg sorafenib twice daily may be administered in most patients; however, it is also possible to start at a reduced dose (200 mg twice daily) and titrate to target dose after the patient has proven to tolerate the drug. For the prevention and treatment of most common and predictable toxicities (diarrhea and skin reactions), all patients should receive prescriptions for loperamide and urea-containing ointments. Clinical visits should be performed every two to four weeks on an outpatient basis. Prevention and treatment of sorafenib-related toxicity is important to prevent discontinuation of sorafenib therapy, particularly because it was recently shown that diarrhea or skin reactions may be surrogate parameters for response and better survival.

Almost all patients present with radiological progression within a few months on sorafenib treatment, particularly considering the Response Evaluation Criteria in Solid Tumors (RECIST). Evaluation of tumor response according to RECIST probably cannot capture the subtle effects of sorafenib to prevent tumor progression, and the discontinuation of sorafenib treatment after the first radiological progression would eventually deny these patients the opportunity of improved survival. No second-line therapy is established, and only few data exist on the sequential treatment approach with another TKI (e.g., sunitinib, brivanib) after progression on sorafenib.

We treat patients with ongoing sorafenib in case of concomitant clinical benefit if there is no possibility of inclusion in a second-line trial. Treatment is discontinued only in case of clear radiological progression in tumor volume without signs of tumor necrosis or in case of new lesions (modified RECIST). Establishment of modified RECIST, together with the identification of biomarkers predicting the response to targeted therapy, is urgently needed in clinical practice. Alpha-fetoprotein (AFP) measurement is broadly applicable; in case of elevated AFP, we and others have demonstrated that serial AFP measurement may provide additional information in monitoring response to sorafenib.

Taken together, assessment of liver function and interpretation of treatment response are crucial for a meaningful and successful targeted therapy in HCC. Therefore, we postulate that hepatologists should take primary care of these patients.

No pathognomonic molecular mechanism (oncogene addiction) in hepatocarcinogenesis exists. Molecular alterations may differ depending on etiology, activity and duration of the underlying liver injury, hereby influencing response to therapy. However, we showed that complete response to sorafenib may be possible in a small subgroup of patients with advanced HCC, strongly dependent on one or more of the targets inhibited by sorafenib.

It will be necessary in the future to classify HCC patients into subclasses according to their gene expression signatures.3 The identification of the molecular key drivers and the assessment of their relevance as potential targets will be the main future challenge. It is hoped that this approach will lead to more personalized medicine, in the end allowing treatment of those benefiting most and excluding those who do not. However, this goal can only be reached on a high-quality multidisciplinary background with the availability of advanced bioinformatics.

Dr. Wörns has provided lectures under the sponsorship of Bayer HealthCare and Bristol Myers Squibb. He is also on the advisory board for Bayer HealthCare and Lilly (including consulting fees).

Dr. Galle has provided lectures under the sponsorship of Bayer and Bristol-Myers Squibb. He is also on the executive board of the International Liver Cancer Association, and coeditor of the European Association for the Study of the Liver’s journal, Journal of Hepatology.

References

1. Wörns MA, Weinmann A, Pfingst K, Schulte-Sasse C, Messow CM, Schulze-Bergkamen H, Teufel A, Schuchmann M, Kanzler S, Düber C, Otto G, Galle PR. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol 2009 May-Jun;43(5):489-95.

2. Weinmann A, Niederle IM, Koch S, Hoppe-Lotichius M, Heise M, Düber C, Schuchmann M, Otto G, Galle PR, Wörns MA. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis 2012 Jan 18. [Epub ahead of print].

3. Marquardt JU, Galle PR, Teufel A. Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. J Hepatol 2012 Jan;56(1):267-75.

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