Sorafenib is the first systemic agent to be shown to improve survival in inoperable hepatocellular carcinoma patients who have good performance status along with mild liver dysfunction
Wen Wee Ma
Clinical and Research Fellow
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Primary liver cancer is the sixth most common cancer and the third most common cause of cancer deaths globally.(1) In 2002 about 626,000 new cases of primary liver cancer were diagnosed while almost the same number (598,000) died from the cancer. The disease is unevenly distributed geographically, with 82% of cases in developing countries such as China (55%) and countries in sub-Saharan Africa, eastern and southeastern Asia and Melanesia. In contrast, the incidence of the disease is relatively low in developed countries, such as countries in North and South America, Northern Europe and Oceania. However, the incidence of liver cancer seems to be increasing in developed countries, such as the USA, UK and Australia, and is partly attributed to the greater prevalence of hepatitis C virus infection.(2)
Hepatocellular carcinoma (HCC) accounted for 85–90% of primary liver cancer and affected more men than women.(3) Worldwide, hepatitis B and C infections were the major risk factors for liver cancer which both increased the risk about 20-fold.(4) Other risk factors included aflatoxin exposure, alcoholic liver disease, hereditary haemochromatosis, α-1 anti-trypsin deficiency, non-alcoholic steatohepatitis (fatty liver) and autoimmune hepatitis.(3) Chronic inflammation and cirrhosis seemed to be the common pathway to HCC development for most of these risk factors.(5,6)
Surgical resection and liver transplantation remained the main modalities for cure in HCC but only a small subset of patients would be eligible.(7) More than 80% of patients had advanced or unresectable HCC at diagnosis and half of those who underwent surgical resection relapsed in two years.(8,9) As such, many HCC patients were candidates for systemic anti-cancer therapy. However, the prognosis for HCC patients remained dismal despite advances in cancer therapy. A 1997 meta-analysis evaluating the results of 37 randomised controlled trials of systemic and regional chemotherapies in 2,804 HCC patients concluded that nonsurgical therapies were ineffective or minimally effective.(10) The development of systemic chemotherapy in HCC patients had been difficult since many of the patients were in advanced stage, with multiple comorbidities and poor hepatic reserve at diagnosis.(11) Moreover, most HCC patients were in developing countries where significant barriers to healthcare services and clinical trials exist.
The multinational Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was the first to show a significant survival benefit with a systemic anticancer drug in HCC.
This article will review the scientific rationale and the clinical studies leading to the successful development of sorafenib for treating unresectable HCC patients.
Cancer targets in hepatocellular carcinoma
Angiogenesis and cell signalling through the mitogen-activated protein kinase (MAPK) pathway play critical roles in the development of HCC and had been the focus of therapy development.(12–14) Angiogenesis refers to the formation of new blood vessels from existing vasculature, important for physiological processes but pathological in neoplasms such as HCC.(15) The process is controlled by a balance of pro- and antiangiogenic factors, with vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) being important mediators in tumour vasculatures. HCC is a highly vascular tumour and high level of serum VEGF was linked to tumour development and poor prognosis in HCC patients.(12) The MAPK pathway consists of a cascade of intracellular signalling proteins including Raf, MAP, MEK and Erk, and is important in cellular growth and proliferation. The pathway is abnormally activated in many cancers and inhibition of this reduced cell proliferation and induced cell death in HCC.(16)
Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers in preclinical models.(17) It has potent inhibitory effects against a number of cellular signalling proteins, including VEGFR-2 and Raf. The agent had significant clinical activity against renal cell carcinoma in a randomised multicentre phase III trial and was approved for use in this cancer in the USA in 2005.(18) In the preclinical HCC model, sorafenib inhibited MAPK pathway activation and angiogenesis, and was linked to tumour growth inhibition and cell death.(19) This provided the scientific rationale to test sorafenib as an anti-cancer drug for HCC in the clinic.
Clinical development of sorafenib in HCC
The recommended dosing schedule for sorafenib was 400 mg twice a day orally on a continuous basis. In the dose-finding study, sorafenib was tested on escalating dose levels from 50 mg to 800 mg with varying schedules in patients with advanced refractory solid tumours.(20) Dose levels above the 400 mg twice-daily continuous schedule resulted in unacceptable (grade 3 and above) side-effects, including diarrhoea, fatigue and skin rashes. Pharmacodynamic studies showed that the MAPK pathway in peripheral mononuclear cells was successfully inhibited at dose level 200 mg and above. One HCC patient achieved partial response, signalling likely efficacy in this cancer.
In a later single-arm “proof-of-concept” phase II trial, sorafenib demonstrated encouraging anti-cancer activity in advanced HCC patients.(21) The trial enrolled 137 patients with Child-Pugh (CP) score A or B, and 34% achieved stable disease for at least 16 weeks, 8% with partial or minor responses, with median overall survival 9.2 months. Common side-effects included fatigue and dermatological and gastrointestinal reactions. Grade 3 or 4 side-effects were hand–foot syndrome, fatigue and diarrhoea.
The SHARP trial was a multicentre phase III trial that randomised 602 patients with previously untreated advanced HCC with good performance status (ECOG Performance Status 0 to 2) and CP score A to receive sorafenib 400 mg twice daily or placebo.(22) The study was stopped early when an independent data monitoring committee determined that the overall survival endpoint was met in favor of the sorafenib arm. The sorafenib arm achieved a superior median survival (10.7 vs 7.9 months) and time to progression (5.5 vs 2.8 months) compared to the placebo arm. The improvement in overall survival in the sorafenib arm compared to the placebo arm was modest with hazard ratio 0.69 (95% confidence interval: 0.55–0.87, p < 0.05). However, the quality-of-life measures were not significantly different between both arms. The most frequent grade 3 or 4 toxicities attributed to sorafenib included diarrhoea and hand–foot syndrome. The authors concluded that sorafenib was well tolerated and improved survival significantly, thus should be used as the first-line therapy in this group of patients.
The role of sorafenib in combination with conventional cytotoxic agents was investigated in a phase II randomised, double-blind study. The unplanned preliminary analysis was presented at the 2007 European Cancer Conference (ECCO-14) in September 2007.(23) The study randomised 96 untreated advanced HCC patients with ECOG PS 0–2 and CP score A to receive doxorubicin plus sorafenib or placebo. An unplanned analysis was performed at the request of the external data monitoring committee in view of the results from the SHARP trial. When compared to the doxorubicin/placebo arm, the doxorubicin/sorafenib arm achieved a superior time to progression (8.5 vs 2.8 months) and survival (14.0 vs 5.6 months). The study was unblinded and the remaining patients on the control arm were crossed over to the sorafenib-containing arm.
Hepatocellular carcinoma remains a difficult-to-treat cancer with limited treatment options. Sorafenib is the first anticancer agent to show significant survival benefit in patients with advanced disease and received FDA approval for use in patients with inoperable HCC in November 2007.(24) The usual dose of sorafenib is 400 mg twice a day orally to be taken on an empty stomach.(25) The most common side-effects include fatigue, rash, skin desquamation, hand–foot syndrome, alopecia, diarrhoea, anorexia, nausea and abdominal pain.
The successful development of sorafenib in HCC therapy heralds a refreshing optimism to the field. However, many issues regarding the role of sorafenib in the management of HCC remain unanswered. The large randomised trial demonstrated that sorafenib benefited patients with mild liver dysfunction (CP score A), who were ambulatory and at least able to carry out work of a light or sedentary nature, such as light housework and office work (ECOG PS 0 or 1). The benefit of sorafenib in patients with more severe liver dysfunction (CP score B and C) and worse performance status was unclear. Most patients in the trials were of European descent, thus limiting the generalisability of the results to patients of other ethnicities. The new therapy is also costly and can be a significant financial burden to patients and healthcare systems with limited resources. Though the combination of sorafenib with doxorubicin is superior to doxorubicin alone, the role of conventional cytotoxics in sorafenib-containing regimens is unclear since the addition of cytotoxics may potentially be detrimental to the survival of patients with poor liver reserves. Sorafenib will undoubtly become the benchmark against which future advanced HCC therapies will be compared, and will increasingly be prescribed to patients with advanced HCC. ■
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