Interim analysis of START: Study in asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial
Article first published online: 28 NOV 2012
Copyright © 2012 UICC
International Journal of Cancer
Volume 132, Issue 10, pages 2448–2458, 15 May 2013
How to Cite
Chung, Y.-H., Han, G., Yoon, J.-H., Yang, J., Wang, J., Shao, G.-L., Kim, B. I., Lee, T.-Y. and Chao, Y. (2013), Interim analysis of START: Study in asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int. J. Cancer, 132: 2448–2458. doi: 10.1002/ijc.27925
- Issue published online: 28 FEB 2013
- Article first published online: 28 NOV 2012
- Accepted manuscript online: 6 NOV 2012 01:16AM EST
- Manuscript Accepted: 20 SEP 2012
- Manuscript Received: 31 AUG 2012
- Bayer (South East Asia) Pte Ltd
- hepatocellular carcinoma;
- transarterial chemoembolization;
- combination therapy;
- Phase II
Transarterial chemoembolization (TACE) represents a first-line noncurative therapy for hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown to be effective and safe monotherapy in patients with advanced HCC and the current study reports the interim results of a prospective Phase II, open label, trial investigating the safety and efficacy of the combination of sorafenib and conventional TACE in patients from the Asia-Pacific region with intermediate HCC. Patients with histologically or clinically diagnosed HCC were treated with conventional TACE followed by sorafenib 4 to 7 days later. TACE was performed by selective transarterial chemotherapy in the vessels feeding the tumor with an emulsion of lipiodol (5–20 ml) and doxorubicin (30–60 mg) followed by embolization with absorbable particles (gel foam). TACE/sorafenib cycles were repeated every 6–8 weeks. Primary objectives were to evaluate the safety and tolerability, in addition to the efficacy of TACE combined with sorafenib for HCC. A total of 147 patients were included in the intention-to-treat analysis and received at least one dose of sorafenib. Gastrointestinal AEs were reported by 62.6% of patients while 57.8% reported skin AEs although most were mild to moderate. The mean number of cycles undertaken was 2.1 and 63.3% of patients achieved either partial response or stable disease. Clinically, the disease control rate was 91.2% while the overall response rate was calculated as 52.4%. Our study shows that concurrent sorafenib and TACE therapy is safe and effective with no unexpected side effects.
Hepatocellular carcinoma (HCC) is fifth most common cancer worldwide1 but has a very uneven geographic distribution. South-east Asian countries and tropical Africa show the highest incidence with peak rates of 150 per 100,000 in Taiwan2 and 28 per 100,000 in Singapore.3 Over 600,000 new cases of liver cancer are diagnosed globally each year,1 and the Asia-Pacific regions contribute more than 50% of these. The lowest rates are found in western countries, Australia, South America and India, with intermediate rates in Japan, the Middle East and Mediterranean countries1 but the incidence of HCC is increasing globally.
A number of treatment options for HCC are available depending primarily on the patients' suitability for surgical intervention. Resection of the tumor is the treatment of choice for HCC,4 nevertheless, it is necessary to demonstrate sufficient liver reserve by calculating the Child-Pugh Score as mortality rates for patients undergoing surgery correlate well with Child-Pugh status: Class A 10%, Class B 30% and 76–82% for those with Child class C cirrhosis.5, 6 Adjuvant chemotherapy and chemoembolization appear to have minimal benefit7, 8 while internal radiation with I-131–labeled lipiodol,9 adoptive immunotherapy with activated lymphocytes10 and interferon11, 12 may be beneficial but large studies are lacking. Liver transplantation results in 5-year survival rates of 70–75%, far greater than survival after resection or ablation.13, 14 However, the majority of HCC identified at initial presentation are unresectable. Tumors may be locally ablated using image-guided chemical (ethanol, acetic acid) and thermal (radiofrequency, cryoablation) techniques with radiofrequency ablation (RFA) being superior to ethanol ablation but typically demonstrating similar survival rates to resection.15, 16 Local ablation is not suitable for infiltrative lesions and in large tumors. Transarterial radioembolization with the use of the radioisotope yttrium-90 (Y-90) has also produced results similar to transarterial chemoembolization (TACE) in small numbers of patients.17, 18 Internal radioembolization might be more advantageous than TACE in Child-Pugh A patients with very large tumors where TACE does not provide very effective treatment.17, 18 Unfortunately, these trials excluded Child-Pugh B patients limiting conclusions of efficacy in the broader class of intermediate HCC. For large or multifocal tumors (intermediate stage B), TACE has become a cornerstone in the management of HCC in Asia where it is recommended as a first-line noncurative therapy.19 TACE works by concentrating chemotherapeutic agents at the tumor site while blocking the primary artery feeding the tumor.20, 21 A meta-analysis of seven randomized trials showed a significant benefit of TACE with cisplatin or doxorubicin, with improvement in 2-year survival.22
Unfortunately, TACE is associated with unsatisfactory long-term outcomes. One potential reason for this may be the increase in plasma vascular endothelial growth factor (VEGF) levels after TACE.23, 24 Disturbances in the tumor microenvironment following TACE result in increased hypoxia, leading to an upregulation in hypoxia inducible factor-1a, which in turn upregulates VEGF and platelet-derived growth factor receptor (PDGFR) and increases tumor angiogenesis.23–25 Increased angiogenesis may in turn result in tumor promoting effects and elevations in serum VEGF are a poor prognostic indicator in patients with HCC.26–28 Combining antiangiogenic-targeted agents with TACE to decrease post-TACE angiogenesis may improve the efficacy of TACE therapy as well as improving long-term outcomes.
Sorafenib is a potent multikinase inhibitor with antiangiogenic and antiproliferative properties that targets the Raf/MEK/ERK pathway,29 as well as VEGFR-1/2/3, PDGFR-β, the stem cell factor receptor (KIT), fms-like tyrosine kinase receptor-3 (Flt-3) and RET (REarragned during Transfection), a proto-oncogene which encodes a tyrosine kinase receptor.30 Two large randomized Phase III studies, the Sorafenib Health Assessment Randomized Protocol (SHARP)31 and Sorafenib Asia-Pacific (AP)32 trials, have confirmed sorafenib efficacy in patients with HCC across different geographical regions with a wide range of HCC etiologies. Median survival and time to radiologic progression were 3 months longer for patients treated with sorafenib than for those who received placebo.31 Currently, sorafenib is the first and only systemic agent to be approved for the treatment of HCC and to have demonstrated an overall survival (OS) benefit in advanced HCC.31 Here, we report the results of an interim analysis of a prospective Phase II, open label, trial that investigated the safety and efficacy of the combination of sorafenib and conventional TACE in patients from the Asia-Pacific region with intermediate HCC.
Patients and Methods
Prior informed consent was obtained for all patients ≥18 years of age prospectively treated in our study with a life expectancy of at least 12 weeks. Protocols were approved by the following 31 Institutional Review Boards (IRBs): China (Sun Yat-sen University Cancer Center IRB, Guangdong General Hospital IRB, The First Affiliate Hospital Sun Yat-Sen University IRB, Tongji Medical College, Huazhong Science and Technology University IRB, People's Liberation Army General Hospital IRB, Beijing Cancer Hospital IRB, Shengjing Hospital of China Medical University IRB, Ethics Committee of Shanghai Zhong Shan Hospital National Unit of Clinical Study of Drugs, IRB of Southeast University Zhongda Hospital, Shanghai Changhai Hospital Ethics Committee, Zhejiang Cancer hospital Ethics Committee Xijing Hospital, Fourth Military Medical University of People's Liberation Army IRB), Korea (Asan Medical Center IRB, Samsung Medical Center IRB, Seoul National University Hospital IRB, Seoul St. Mary's Hospital The Catholic University of Korea IRB, Kangbuk Samsung Hospital IRB), Malaysia (Medical Research & Ethics Committee, Ministry of Health Malaysia), Singapore (NHG Domain-Specific Review Board, Parkway Independent Ethics Committee), Taiwan (IRB Taipei Veterans General Hospital, Mackay Memorial Hospital IRB, IRB of the Taichung Veterans General Hospital, Chang Gung Medical Foundation IRB, IRB National Cheng Kung University Hospital, IRB of Kaohsiung Veterans General Hospital, IRB of Tri-Service General Hospital, National Defense Medical Center, IRB E-Da Hospital) and Thailand (IRB, Royal Thai Army Medical Department, The Ethics Committee, Faculty of Medicine, Prince of Songkla University).
Patients were screened using the following inclusion criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; Child-Pugh Score ≤7 (Child A or B); Barcelona Clinic Liver Cancer (BCLC) staging classification B (intermediate stage), that is, multinodular asymptomatic tumors, without extra-hepatic spread (but second branch invasion of the unilateral lobe is allowed). Patients must have histologically diagnosed HCC, or clinically diagnosed HCC for patients with difficulty in obtaining histological samples. Patients were accepted if positive for chronic hepatitis B (CHB) or C and/or evidence of liver cirrhosis, the presence of hepatic tumor(s) with image findings [sonography, computerized tomography (CT) scan, or magnetic resonance imaging (MRI) scan] compatible with HCC, and no evidence of other gastrointestinal tumors with a persistent elevation of serum α-fetoprotein (AFP) level ≥ 400 ng/ml without any evidence of an existing AFP-secreting germ cell tumor. All patients had a solitary hepatic tumor >3 cm but ≤10 cm in diameter or multifocal disease as evidenced by CT or MRI scanning. The patient must not be a candidate for surgical resection or ablation of the tumor. The target lesion must not have been previously treated with local therapy. Patients who had received previous local therapy treatments (radiofrequency ablation (RFA, percutaneous ethanol injection, cryoablation, surgery, resection) to nontarget lesions were eligible. Local therapy must have been completed at least 4 weeks before baseline scan. Laboratory criteria for inclusion were: Hb ≥ 9g/l; absolute neutrophil count (ANC) >1,000/mm3; platelet count ≥60 × 109/L; adequate clotting function: international normalized ratio <1.5; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <5 × upper limit of normal (ULN); serum creatinine <1.5 × ULN and bilirubin <3mg/dl.
Patients were excluded if they had: the presence of extra-hepatic metastasis; predominantly infiltrative lesions; diffuse tumor morphology with extensive lesions involving both lobes; vascular complications including hepatic artery thrombosis, or partial or complete thrombosis of the main portal vein, or tumor invasion of portal branch of contralateral lobe, or hepatic vein tumor thrombus or significant arterioportal shunt not amenable to shunt blockage. Patients with advanced liver disease (ascites, hepatic encephalopathy) or clinically significant gastrointestinal bleeding within the 30 days before study entry were also excluded. Patients could not have received prior treatment for HCC target lesions, nor had previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors. However, any cancer curatively treated >3 years before entry was permitted. Patients were also excluded if they had a history of cardiac disease including: congestive heart failure > New York Heart Association Class 2; active coronary artery disease or cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, or if they had hypertension defined as systolic blood pressure greater than 150 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management. Patients with serious nonhealing wounds (including wounds healing by secondary intention), acute or nonhealing ulcers or bone fractures within 3 months, patients with any active clinically serious infections [>Grade 2 National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0]33 or those receiving therapeutic anticoagulation with coumarin, heparins or heparinoids were also excluded. Finally, pregnant or lactating women, patients with HIV infection or AIDS-related illness or serious acute or chronic illness (based on medical history), patients with an impairment of swallowing that would preclude administration of sorafenib or hypersensitivity to intravenous contrast agents were also excluded.
TACE was performed by selective transarterial chemotherapy in the vessels feeding the tumor with an emulsion of lipiodol (5–20 ml) and doxorubicin (30–60mg) followed by embolization with absorbable particles (Gel foam). Patients started receiving sorafenib 400 mg bid on Day 4 (to Day 7) after the 1st TACE (Day 1) were interrupted after the evening dose on Day 4 before each next TACE and restarted on sorafenib on Day 4 (to Day 7) after each subsequent TACE. Four to 6 weeks after the first TACE, a multislice spiral CT of the abdomen and a determination of the AFP was performed to assess the need of a consecutive TACE. TACE cycles were repeated every 6–8 weeks on demand, up to a maximum of six TACE cycles. When no vital tumor tissue is seen on the CT, TACE was discontinued but the patient remained on sorafenib 400 mg bid if tolerated and underwent CT and AFP determination at 3 month intervals. If the CT revealed new lesions, the patient was evaluated for feasibility of a new TACE treatment.
Criteria for delaying or deferring TACE treatment
Before each TACE, the enrolment criteria relating to PS, portal vein patency, hepatic, clotting and renal function must be met including: white blood cells <2 × 109/L, ANC <1 × 109/L and platelets <50 × 109/L. If these conditions were not met, a weekly check for above conditions was performed. Treatment was delayed until such time as these conditions were met. A delay of more than 3 weeks resulted in stopping TACE treatment. For patients no longer eligible for TACE, the dose of sorafenib remained at 400 mg bid if tolerated and the patient underwent CT and AFP determination at 3 month intervals.
Criteria for delaying or deferring sorafenib treatment
Liver function tests were performed for patients after TACE. If ALT or AST > 5 × ULN, sorafenib was withheld and documented. The patient was then reviewed weekly and commenced on sorafenib, within the week, when ALT and AST < 5 × ULN on follow-up liver function tests. Patients were treated with sorafenib for a period of 24 months maximum or until evidence of tumor progression (except for progression treatable by TACE) or the appearance of unacceptable toxicities related to the study drug.
START was designed with the primary objectives to evaluate the safety and tolerability, in addition to the efficacy of TACE combined with sorafenib for HCC. Secondary objectives included: progression-free survival (PFS), time to progression (TTP), number of TACE cycles, response rate and stable disease rate of sorafenib in HCC.
One hundred sixty-five patients, 31–78 years of age (average 56.4 ×10.4 years), were enrolled in the study, of which, 85.5% were males (Table 1). Most patients (82.1%) were ECOG Score 0 with the remainder Score 1. The majority of patients were BCLC stage B (A‒17.3%, B‒80.9% and C‒1.9% of 162 scored), Child-Pugh Class A (91.6% A, 7.7% B, 0.7% unknown of 143 staged) and 140 patients were staged as TNM Stage I–IIIA (I-36.4%, II-36.4% and IIIA-27.1%). CHB was the most common etiology ascribed to patients HCC (81.9%) followed by chronic hepatitis C (6.9%) and CHB combined with alcohol use (4.4%).
One hundred forty-seven patients receiving at least one dose of sorafenib were included in the intention-to-treat analysis and most patients (89.4%) had not received prior surgical treatment for HCC or had not received locoregional treatments for HCC (88.7%). For the 27 patients treated previously, 40.7% had prior surgery, 33.3% had prior TACE, 18.5% prior RFA and 7.4% other treatments. The average daily dose of sorafenib received throughout the study was 743.51 ± 107.20 mg. First patient first visit occurred on February 25, 2009 and this analysis was conducted in Q4, 2011.
Nonlaboratory Adverse Events
Gastrointestinal and skin adverse events were the most common adverse events (AEs) reported using the NCI CTCAE reported by 62.6 and 57.8% of patients, respectively (Table 2 lists all nonlaboratory AEs reported by 2% or more of patients). Most AEs were mild to moderate with only one patient reporting a Grade 5 AE for gastrointestinal disorders (chronic gastrointestinal bleeding) and two patients reporting Grade 5 AEs for malignant hepatic neoplasms (Table 2). Single patients each reported Grade 4 AEs for pain at the administration site and dyspnoea events (Table 2). The only specific nonlaboratory Grade 3 AEs reported by 2% of patients or more were skin reaction (4.1%) and palmar-plantar erythrodysesthesia syndrome (2.7%). However, abdominal pain, dyspepsia, dysphagia, upper gastrointestinal hemorrhage, fatigue, irritability, pain in extremities, altered state of consciousness, dizziness, cough, erythema, erythema multiforme, rash and skin exfoliation were all reported as Grade 3 AEs by single patients (data not shown). Similarly, diarrhoea, vomiting and blister were each reported by two patients (data not shown). A Grade 3 post embolization syndrome event was reported in one patient.
Laboratory data indicated the most common Grade 3 AEs were increases in ALT and AST for 6.8 and 4.1% of patients, respectively, and decreases in neutrophil counts (4.1%), platelet counts (3.4%) and white blood cell counts (3.4%; Table 3). A Grade 4 change in ALT was reported in one patient, Grade 4 increases in AST were found in 1.4% of patients and two patients (1.4%) reported Grade 5 AEs for hepatic failure (Table 3). No Grade 4 or 5 AEs were deemed to be related to sorafenib but again, gastrointestinal and skin adverse events were the most common AEs reported (Table 4).
The mean number of TACE cycles received was 2.1 with 39.5, 34, 11.6, 7.5 and 6.1% of patients receiving 1–5 cycles, respectively. Only 1.4% of patients required a sixth or seventh cycle (0.7% each). The best radiological evaluation using modified RECIST guidelines34 indicated 27.9% of patients achieved complete response, 24.5% achieved partial response and 38.8% had stable disease with the overall response rate calculated as 52.4%. The disease control rate was 91.2% and progression of disease (PD) was calculated as 8.8% at the time of analysis. The combination of TACE and sorafenib therapy achieved a median PFS of 270 days (Figure 1a), a TTP of 280 days (Figure 1b) and an OS probability of >90% over the same time period (Figure 2).
In this Phase II, open label trial, we evaluated the safety and efficacy of the combination of sorafenib and conventional TACE in patients with intermediate HCC. As previously documented in a smaller US trial,35 we observed many patients experiencing AEs with combination therapy and these were mostly related to drug treatment (Table 4). Importantly, these were not unexpected side effects, and combination therapy did not appear to lead to worse AEs than observed with either TACE or sorafenib therapy alone. Despite the higher incidence of AEs with TACE prior to sorafenib reported previously,36 the AE profile and incidence observed in the current study was similar to the SHARP31 and Asia-Pacific32 sorafenib-only trials, in addition to two recent small TACE plus sorafenib combination therapy trials.35, 37 However, a recent European study evaluating the combination of TACE and sorafenib was stopped prematurely because of safety concerns.38 Importantly, we note that the European study incorporated a continuous rather than an interrupted sorafenib schedule with higher doses of doxorubicin which may have resulted in a greater number and severity of AEs. Further support for this treatment intensity effect is reflected by the AE profile in the current study being slightly better than that reported for the recently reported COTSUN trial.39 The COTSUN study also used an interrupted sorafenib plus TACE protocol and included a 3 day break before recommencing sorafenib after TACE as per the protocol for the current study. However, before each TACE cycle, the COTSUN study only incorporated a 1 day break between sorafenib cessation and subsequent TACE cycles, compared to the current study which incorporated a 3-day sorafenib break before TACE. AEs in the current study were mostly mild to moderate with skin and gastrointestinal AEs the most commonly reported. The incidence of serious AEs was minimal. The average daily dose of sorafenib observed in the current study (743 mg) was comparable with the earlier SHARP (797 mg)31and Sorafenib AP (795 mg)32 trials. The current study confirms earlier reports that the combination of sorafenib and TACE was well tolerated and safe, with the caveat that an interrupted sorafenib schedule may result in a better safety profile than continuous sorafenib treatment protocols.
In addition to encouraging safety and tolerability results, our study also reveals promising efficacy results with almost 50% of patients achieving partial or complete responses after the first TACE cycle and almost 50% achieving a partial response or stable disease up to 2 years after the first TACE cycle. More than 80% of patients in our study were BCLC B demonstrating combination TACE plus sorafenib produces clinically meaningful results in patients with intermediate HCC.
In terms of secondary endpoints, the combination of TACE and sorafenib therapy achieved a median TTP of 9.3 months (280 days), considerably longer than that observed in a recent study (5.4 months) in Japanese and Korean patients.36 There were, however, a number of differences between the previous study and the data reported here, including a lower average daily dose of sorafenib (386 mg), differences in assessment criteria and the concurrent but interrupted use of sorafenib in the current study compared to sequential TACE followed by sorafenib in the previous study complicating direct comparisons between them. The timing of sorafenib relative to TACE is an important difference as the Kudo et al.36 study essentially evaluated sorafenib as an adjuvant to TACE, with a delayed start of sorafenib by more than 9 weeks in over 50% of patients. A recent study incorporating a sequential TACE plus sorafenib protocol but with earlier sorafenib administration reported a significantly longer TTP in patients with intermediate-stage hepatitis C virus (HCV)-related HCC treated with sorafenib compared to placebo.40 Additionally, patients in the Kudo et al.36 study receiving sorafenib were confirmed responders to TACE treatment while the current START population involves a concurrent combination of TACE with sorafenib with unknown TACE responsivity.
Interestingly, the Kudo et al.36 study noted better outcomes in Korean patients compared to Japanese patients. The authors speculate that this may be due to several possibilities: a longer median treatment duration (31 vs. 16 weeks) in Korean patients, the older age of Japanese patients, a higher percentage of Japanese patients had P3 lesions on enrolment and a greater percentage of Japanese patients had HCV infections while Korean patients had predominantly hepatitis B virus (HBV). We note that over 80% of patients in the current study had HBV infection compared to less than 20% of patients in the sorafenib only SHARP trial. Subgroup analysis of these groups of patients may provide additional insights into selecting optimal target populations for combination TACE plus sorafenib therapy but conclusions are not possible at this time. It is hoped that the results of the global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib (GIDEON) study,41, 42 a large observational evaluation of the safety and efficacy of sorafenib in different subgroups will provide additional data to address these observations.
Although the current study reports similar AEs to those reported in recent sorafenib only trials,31, 32 the lack of a comparator arm complicates the determination of drug-related AEs versus complications related to the natural PD. Additional GIDEON study data from patients in real clinical settings across different disease subclasses and stages may also provide clarity in this regard.42
Despite a number of clinical trials in progress, there is a paucity of available data regarding the effect of combination of sorafenib with TACE. Given the trend in Asia of repeated TACE procedures, the potential interactions of this combination will need to be addressed in detail. Studies in mice and rats have demonstrated the sorafenib-induced stabilization of tumor growth in human carcinoma xenografts in mice43 and experimental prostate carcinomas in rats44 is associated with a decrease in vascularity.43 Preliminary confirmation of this effect was observed in a recent Phase II trial which demonstrated a reduction in tumor vessel density and intratumoral interstitial fluid pressure in two sarcoma patients with stable disease following sorafenib treatment.45 Whether this reduction in vascularity following sorafenib therapy results in any clinically meaningful change in the application and effectiveness of subsequent cycles of TACE remains to be seen.
Importantly, the current study reveals that not only is the combination of sorafenib and conventional TACE well tolerated in predominantly BCLC stage B HCC patients, when combined with observations from recent trials,39, 40 it provides tangible benefits in terms of response to disease and TTP. Additional data will come from the sorafenib or placebo in combination with TACE for intermediate stage HCC (SPACE) trial46 which is evaluating sorafenib treatment in addition to TACE with doxycycline eluting beads,47 and the TACTICS trial (ClinicalTrials.gov NCT01217034) in Japan in which an interrupted TACE plus sorafenib protocol is combined with dose reductions of sorafenib to evaluate potential improvements in safety and toxicity. It is hoped that these ongoing trials will contribute to the determination of optimal therapy combinations and timing which will be crucial in improving outcomes with intermediate HCC.
The authors thank the following coinvestigators for their help in trial conduct and patient care: Jianyong Yang: The First Affiliate Hospital Sun Yat-Sen University, Guangzhou, China; Maoqiang Wang: People Liberation Army General Hospital, Beijing, China; Zhaoyu Liu: Second Affiliated Hospital of China Medical University, Shenyang, China; Gaojun Teng: Nanjing Zhongda Hospital, Southeast University, Nanjing, China; Gansheng Feng: Union Hospital, Tongji Medical College, Huazhong University of Science And Technology, Wuhan, China; Renjie Yang: University School of Oncology, Beijing Cancer Hospital & Institute, Department of Interventional Therapy, Beijing, China; Ligong Lu: Guangdong General Hospital, Guangzhou, China; Peihong Wu: Sun Yat-Sen University Cancer Center, Guangzhou, China; Sihyun Bae: The Catholic University Of Korea, Seoul, Korea; Kwang Chul Ko: Samsung Medical Center, Seoul, Korea; Krishnan Raman: Selayang Hospital, Selayang, Malaysia; Chan Chung Yip: Tan Tock Seng Hospital, Singapore; Hsieh Wen Son: International Cancer Specialists, Singapore; Chen-Chun Lin: Chang-Gung Memorial Hospital and Chang Gung University, Linkou, Taiwan; Chiung-Yu Chen: National Cheng Kung University Hospital, Tainan, Taiwan; Tsang-En Wang: Mackay Memorial Hospital, Taipei, Taiwan; Gin-Ho Lo: E-Da Hospital, Kaohsiung, Taiwan; Heng-Cheng Chu: Tri-Service General Hospital, Taipei, Taiwan; Hsien Chung Yu: Veterans General Hospital, Kaohsiung, Taiwan; Kasan Seetalarom: Phramongkutklao Hospital, Bangkok, Thailand; Teerha Piratvisuth: Prince of Songkla University, Hat-Yai, Thailand. The authors would also like to acknowledge Bruce Mungall BSc, PhD from UBM Medica Pte Ltd Singapore for providing editorial and writing support.
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- 42NCT 00812175. Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of Its Treatment With Sorafenib (GIDEON). Available from http://www.clinicaltrials.gov/ct2/show/NCT00812175 (accessed 21 November, 2012).
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- 47NCT00855218. A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC). Available from http://www.clinicaltrials.gov/ct2/show/NCT00855218 (accessed 21 November, 2012).