Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?

Abstract

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC. The Oncologist

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

“…Objective tumor response rate to single-agent cytotoxic therapies is usually less than 10%, and no survival benefit has been observed [372][373][374][375][376]. An earlier randomized trial comparing doxorubicin, 60-75 mg/m 2 every 3 weeks, with no treatment indicated a borderline improvement in overall survival (10.6 vs. 7.5 weeks) for patients who received doxorubicin [377].…”

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

“…Up to 70% of patients with hepatocellular carcinoma have been suffering from limited treatment options because of late diagnosis and/or advanced stage of the disease when, however, surgical treatments including liver transplantation and hepatectomy as well as regional therapy are not feasible. Currently, there is no proven effective conventional systemic chemotherapy for patients with advanced hepatocellular carcinoma because of the inherent chemoresistant nature of hepatocellular carcinoma and with intolerable cytotoxicity, resulting in the dismal prognosis of these patients (2)(3)(4). Hepatocellular carcinoma is a heterogeneous disease in terms of etiology, molecular, and carcinogenic mechanisms as well as biologic behaviors, which can collectively contribute to diverse mechanisms of chemoresistance among patients with hepatocellular carcinoma (5).…”

Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

“…1 Systemic therapy with cytotoxic agents provides only marginal benefit. 2,3 The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood after intensive research in recent years. 4,5 Among these advances, several important intracellular signaling pathways such as the Ras/Raf/Mek/ ErK and PI3K/Akt/mTOR pathways have been implicated.…”