Research ArticleVandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study
Introduction
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with approximately 80% of cases arising in Asia and Africa [1]. HCC is typically a hypervascular tumor. The extensive tumor vasculature forms the basis of HCC imaging diagnosis [2], [3]. The inhibition of tumor angiogenesis is a promising approach for systemic therapy of patients with advanced HCC. Sorafenib, a multi-target kinase inhibitor that targets both RAF and vascular endothelial growth factor receptor (VEGFR) kinases, improves overall survival of advanced HCC patients in both Western and Asian populations [4], [5]. Most of the other agents under development for HCC treatment, such as sunitinib, brivanib, and linifanib, also target tumor angiogenesis as their major anti-tumor mechanism [6].
The epidermal growth factor receptor (EGFR) is involved in liver regeneration and hepatocarcinogenesis [7], [8]. The EGFR inhibitor erlotinib has modest anti-tumor effects in patients with advanced HCC [9]. Additionally, EGFR inhibitors may indirectly inhibit tumor angiogenesis [10]. Combination of erlotinib and the anti-VEGF antibody bevacizumab produced an objective response rate of 25% in 40 patients with advanced HCC [11]. Therefore, simultaneous inhibition of both pathways may provide greater benefits than targeting either pathway alone.
Vandetanib targets both VEGFR and EGFR signaling pathways [12]. Vandetanib can also inhibit the REarranged during Transfection (RET) receptor tyrosine kinase. RET is associated with the development of certain types of thyroid cancer; however, the significance of RET signalling in HCC is not clear [13], [14], [15]. Phase I dose-escalation studies performed in Western and Japanese patients showed that vandetanib was generally well tolerated at daily doses up to 300 mg [16], [17]. Vandetanib can significantly prolong progression-free survival (PFS) of patients with advanced medullary thyroid cancer [18] and is not inferior to erlotinib as a second-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) [19]. Vandetanib plus docetaxel can significantly prolong PFS, compared with docetaxel alone, in patients with advanced NSCLC after progression following first-line chemotherapy [20].
In this randomized, placebo-controlled phase II study, the efficacy and safety of vandetanib in patients with advanced HCC was examined. The primary objective was to evaluate the tumor stabilization rate of vandetanib. Secondary objectives were to evaluate the safety of vandetanib in patients with advanced HCC and to explore the correlation between treatment responses and biomarkers, including circulating angiogenic factors and vascular response measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
Section snippets
Patients
Eligible patients had locally advanced or metastatic inoperable HCC with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.0, and no treatment with curative intent was available. The diagnosis of HCC could be histological or clinical. Clinical diagnosis required chronic viral hepatitis and/or cirrhosis, presence of hepatic tumor(s) with typical vascular patterns of HCC, and persistent elevation of serum α-fetoprotein (AFP) level ⩾400 ng/ml. The
Patients
Between July 2007 and November 2008, 67 patients were randomized (Fig. 1). Twenty-nine patients entered the secondary phase to receive treatment with open-label V300 (13 initially randomized to V100 and 16 initially randomized to placebo). At data cut-off (30 June 2009), 63 patients had progressed and 54 had died. Two patients (one from each of the V100 and placebo groups) were continuing to receive treatment in the randomized phase and no patient was receiving treatment in the open-label
Discussion
Anti-angiogenic agents usually exert cytostatic rather than cytotoxic effects in established tumors. Therefore, a randomized phase II trial design with time-to-event end points is recommended to better detect treatment efficacy [22]. This study was designed before the proof of efficacy of sorafenib for advanced HCC, therefore a placebo was used as control. A non-significant positive trend was observed for both PFS and OS after vandetanib treatment; however, it is possible that due to dose
Conflict of interest
Dr. Ann-Lii Cheng is a consultant for Sanofi-Aventis Inc.; Pfizer, Bayer Schering Pharma; Bristol-Myers Squibb (Taiwan) Ltd.; Boehringer Ingelheim Taiwan Limited; Novartis Inc. Dr. Chiun Hsu is a member of the speaker’s bureau of Bayer-Schering Pharma. Dr. Robin Meng is an employee of AstraZeneca. Other authors have nothing relevant to this manuscript to disclose.
Financial support
This study, including medical writing support provided by Zoë van Helmond of Mudskipper Bioscience, was sponsored by AstraZeneca.
Authors’ contributions
Chiun Hsu: design of the clinical trial, conduct of the clinical trial, data analysis and interpretation, writing of the manuscript, approval of the manuscript.
Tsai-Sheng Yang, Teh-Ia Huo, Ruey-Kuen Hsieh, Wei-Shou Hwang, Tsai-Yuan Hsieh, Wen-Tsung Huang, Yee Chao: design of the clinical trial, conduct of the clinical trial, approval of the manuscript.
Chih-Wei Yu: analysis and interpretation of the dynamic contrast-enhanced magnetic resonance imaging data.
Robin Meng: support for design and
Acknowledgements
The authors thank the following co-investigators for their help in trial conduct and patient care:
Zhong-Zhe Lin, Chih-Hung Hsu, Chih-Hsin Yang, Yen-Shen Lu, Ruey-Long Hong, Kun-Huei Yeh, Ying-Chun Shen, Yu-Lin Lin, Sung-Hsin Kuo, Jo-Pai Chen, Ta-Chen Huang: Department of Oncology, National Taiwan University Hospital, Taipei; Jen-Shi Chen: Division of Hematology and Oncology, Chang-Gung Memorial Hospital Linkou, Linkou; Tsu-Yi Chao: Division of Hematology and Oncology, Tri-Service General
References (32)
- et al.
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial
Lancet Oncol
(2009) Growth factors in liver development, regeneration and carcinogenesis
Prog Growth Factor Res
(1991)- et al.
Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumours
Ann Oncol
(2005) - et al.
A Phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumours
J Thorac Oncol
(2006) - et al.
Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial
Lancet Oncol
(2010) - et al.
Absence of epidermal growth factor receptor exon 18–21 mutation in hepatocellular carcinoma
Cancer Lett
(2005) - et al.
Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma
Cancer Lett
(2006) - et al.
International trends and patterns of primary liver cancer
Int J Cancer
(2001) - et al.
Management of hepatocellular carcinoma: an update
Hepatology
(2011) - et al.
Asian pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma
Hepatol Int
(2010)
Sorafenib in advanced hepatocellular carcinoma
N Engl J Med
Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives
J Gastroenterol
Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma
Liver
Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer
J Clin Oncol
The role of the EGFR signaling in tumour microenvironment
J Cell Physiol
Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma
J Clin Oncol
Cited by (81)
Phase 0 Study of Vandetanib-Eluting Radiopaque Embolics as a Preoperative Embolization Treatment in Patients with Resectable Liver Malignancies
2022, Journal of Vascular and Interventional RadiologyCitation Excerpt :Following BTG-002814 TACE, there was no marked change in any perfusion CT parameter assessed. Previous perfusion studies (7,20–22) have also shown mixed results in response to TACE and oral vandetanib, suggesting that the antiangiogenic effects of vandetanib are not detectable using currently available perfusion imaging or within the time period evaluated in these trials. This study evaluated potential biomarkers of response to BTG-002814 for patient selection in subsequent larger studies.
Chemotherapy for hepatocellular carcinoma—an updated review
2022, Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma: Volume 3: Translational and Clinical OutcomesMERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system
2020, Pharmacology and TherapeuticsDiarrhea with epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of randomized controlled trials
2019, Critical Reviews in Oncology/HematologyCitation Excerpt :When examining by agent, vandetanib was investigated in 6 trials (Arnold et al., 2007; Lee et al., 2012a; Ahn et al., 2013; Hsu et al., 2012; Wells et al., 2012; Leboulleux et al., 2012), gefitinib in 6 trials (Thatcher et al., 2005; Zhang et al., 2012; Goss et al., 2009; Dutton et al., 2014; Gaafar et al., 2011; Goss et al., 2013a), erlotinib in 4 trials (Cappuzzo et al., 2010; Kelly et al., 2015; Lee et al., 2012b; Shepherd and Rodrigues Pereira, 2005), afatinib in 1 trial (Miller et al., 2012), dacomitinib in 1 trial (Ellis et al., 2014), lapatinib in 6 trials (Harrington et al., 2015; Powles et al., 2017; Decensi et al., 2011; Del Campo et al., 2011; Harrington et al., 2013; Goss et al., 2013b). The most common underlying malignancies represented were small-cell lung cancer (SCLC) (Arnold et al., 2007), NSCLC (Lee et al., 2012a; Ahn et al., 2013; Thatcher et al., 2005; Zhang et al., 2012; Goss et al., 2009; Gaafar et al., 2011; Ellis et al., 2014), hepatocellular carcinoma (HCC) (Hsu et al., 2012), thyroid cancer (Wells et al., 2012; Leboulleux et al., 2012), oesophageal cancer (Dutton et al., 2014), squamous cell carcinoma (SCC) (Harrington et al., 2015; Del Campo et al., 2011; Harrington et al., 2013), bladder cancer (Powles et al., 2017), and breast cancer (Decensi et al., 2011; Goss et al., 2013b). The methods of randomization were reported in 19 studies.