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Chen CT, Liu TH, Shao YY, Liu KL, Liang PC, Lin ZZ. Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:12880. [PMID: 34884684 PMCID: PMC8657421 DOI: 10.3390/ijms222312880] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.
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Affiliation(s)
- Ching-Tso Chen
- Department of Oncology, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan;
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Kao-Lang Liu
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Cancer Center, Taipei 106328, Taiwan
| | - Po-Chin Liang
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan
| | - Zhong-Zhe Lin
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei 106328, Taiwan
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Yang W, Wang D, Huang L, Chen Y, Wen S, Hong Q, Kang D. Thalidomide Combined with Transcatheter Arterial Chemoembolization (TACE) for Intermediate or Advanced Hepatocellular Carcinoma: A Systematic Review and GRADE Approach. Asian Pac J Cancer Prev 2018; 19:2043-2055. [PMID: 30139041 PMCID: PMC6171403 DOI: 10.22034/apjcp.2018.19.8.2043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 06/29/2018] [Indexed: 02/08/2023] Open
Abstract
Objective:According to current guidelines, there is no clear second-line treatment for advanced liver cancer. In practice, clinicians have attempted to use thalidomide(TLD) combined with transcatheter arterial chemoembolization (TACE) for treating liver cancer. This study aims to assess the clinical efficacy and safety of TLD combined with TACE in patients with intermediate or advanced hepatocellular carcinoma. Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), database of ClinicalTrials.gov, CBM, CNKI, VIP and Wanfang database were searched for eligible studies. Criteria for inclusion in our meta-analysis included a study that patients diagnosed with intermediate or advanced HCC, the use of TACE plus TLD or its derivatives, and the availability of outcome data for survival. A meta-analysis was conducted to summarize the evidences of randomized controlled trials (RCTs). And finally, the GRADE approach was used to assess the quality of these evidences. Results: Twelve RCTs involving 894 Hepatocellular Carcinoma (HCC) patients were included. The meta-analysis results showed that TACE plus TLD was significantly superior than TACE alone in terms of 12-month survival rate (OR=2.55, 95% CI:1.78-3.64, P<0.01), 24-month survival rate (OR=2.95, 95% CI:1.96-4.44, P<0.01), 36-month survival rate (OR=2.95, 95% CI:1.41-6.19, P<0.004), progression-free survival (PFS) (MD=2.23, 95% CI:1.19-3.28 , P<0.001), objective response rate (OR=1.84, 95% CI:1.34-2.52, P<0.0001), and disease control rate (OR=2.68, 95% CI:1.80-3.99). Subgroup analysis demonstrated no differences across related outcomes. Sensitivity analyses showed no important differences in the estimates of effects. Quality of evidence for all outcomes was rated moderate to very low after applying GRADE approach. Conclusions: Current evidence seemed to support the suggestion that TACE plus TLD as the second line treatment for patients with intermediate or advanced HCC. However, this finding is not definitive due to the poor quality of included studies, more carefully designed and conducted RCTs are warranted to confirm above conclusions.
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Affiliation(s)
- Wenjie Yang
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, China.
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Lohitesh K, Chowdhury R, Mukherjee S. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. Cancer Cell Int 2018; 18:44. [PMID: 29568237 PMCID: PMC5859782 DOI: 10.1186/s12935-018-0538-7] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 03/12/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC. We have provided a comprehensive summary of the various strategies adopted by HCC cells, extending from apoptosis evasion, autophagy activation, drug expulsion to epigenetic transformation as modes of therapy resistance. The role of stem cells in imparting chemoresistance is also discussed. Furthermore, the review also focuses on how this knowledge might be exploited for the development of an effective, prospective therapy against HCC.
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Affiliation(s)
- K Lohitesh
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Rajdeep Chowdhury
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Sudeshna Mukherjee
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
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4
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Shao YY, Chen BB, Ou DL, Lin ZZ, Hsu CH, Wang MJ, Cheng AL, Hsu C. Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy. Aliment Pharmacol Ther 2017; 46:722-730. [PMID: 28815645 DOI: 10.1111/apt.14270] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/05/2017] [Accepted: 07/26/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Lenalidomide has immunomodulatory and anti-angiogenic effects and showed moderate anti-tumour efficacy in patients with. advanced hepatocellular carcinoma (HCC) AIM: To explore potential biomarkers of lenalidomide efficacy as second-line therapy for HCC. METHODS Eligible patients were diagnosed with advanced HCC, documented progression on sorafenib, and Child-Pugh class A liver function. Patients received 25 mg/day lenalidomide orally on days 1-21 every 4 weeks. The primary endpoint was 6 month progression-free survival rate. Early α-fetoprotein response was defined as a > 20% decline of α-fetoprotein levels from baseline within the first 4 weeks of treatment. Vascular response, evaluated using dynamic contrast-enhanced magnetic resonance imaging, was defined as a > 40% decline in Ktrans after 2 weeks of treatment. The percentage of peripheral blood lymphocyte subsets were also analysed. RESULTS Fifty-five patients were enrolled. The response rate was 13%, and the disease-control rate was 53%. The 6 month progression-free survival rate was 9.1%. The median progression-free and overall survival was 1.8 months and 8.9 months respectively. Early α-fetoprotein response was significantly associated with higher disease-control rate (76% vs 22%, P = .001) and longer progression-free survival (P = .020). Vascular response was not associated with any treatment outcomes. Patients with a high pre-treatment B cell percentage were more likely to have disease control (70% vs 36%, P = .010) and exhibited longer progression-free survival (P < .001) and overall survival (P = .042). CONCLUSIONS Lenalidomide exhibited moderate activity as second-line therapy for advanced HCC. Its immunomodulatory effects should be further explored (www.clinicaltrials.gov NCT01545804).
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Affiliation(s)
- Y-Y Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - B-B Chen
- Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
| | - D-L Ou
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Z-Z Lin
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - C-H Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - M-J Wang
- Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - A-L Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - C Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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5
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Cao DD, Xu HL, Liu L, Zheng YF, Gao SF, Xu XM, Ge W. Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2017; 8:44976-44993. [PMID: 28402958 PMCID: PMC5546534 DOI: 10.18632/oncotarget.16689] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 03/16/2017] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Transcatheter arterial chemoembolization (TACE) and thalidomide have been used for treating primary hepatocellular carcinoma(HCC). This study aims to evaluate the clinical efficacy and safety of thalidomide and TACE in primary HCC. METHODS Randomized controlled trials(RCTs) about efficacy and safety of thalidomide combined with TACE for primary HCC were identified from the Cochrane Library, Pubmed, Embase, CNKI, and Wan Fang until August, 2016. The retrieved trials were reviewed and the data were extracted by two reviewers, independently. Combined analyses of survival rates, overall response rate(ORR), disease control rate(DCR), changes of KPS, parameters of cellular immunity and vascular endothelial growth factor(VEGF), and adverse events were performed using RevMan 5.3 software. RESULTS A total of 23 RCTs involving 1836 patients were included. The results showed that thalidomide plus TACE was significantly superior in increasing 6-month survival rate(OR=1.79, 95% CI:1.02-3.15, P=0.04), 1-year survival rate(OR=1.76, 95% CI:1.38-2.24, P<0.0001), 1.5-year survival rate(OR=4.72, 95% CI:2.64-8.43, P<0.001), 2-year survival rate(OR=1.78, 95% CI:1.37-2.30, P<0.001), ORR(OR=1.89, 95% CI:1.48-2.42, P<0.0001), DCR(OR=2.62, 95% CI:1.90-3.63, P<0.001), improvement in cellular immunity(MD=0.63, 95% CI:0.45-0.80, P<0.0001), and reduction of VEGF(MD=-119.71, 95% CI:-135.75-103.68, P<0.0001), when compared with TACE group. The incidences of gastrointestinal reactions, myelosuppression, and liver dysfunction were similar between combination group and TACE group(P>0.05). However, compared to TACE, the combination of thalidomide and TACE had a higher incidence of drug rash(OR=6.35, 95% CI:2.75-14.68, P<0.0001). CONCLUSION Our findings suggest that thalidomide combined with TACE shows better clinical efficacy and tolerable adverse events in patients with primary HCC when compared with TACE alone.
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Affiliation(s)
- De-Dong Cao
- Department of Oncology, RenMin Hospital of WuHan University, WuHan, Hubei, China
| | - Hui-Lin Xu
- Department of Oncology, The Fifth Hospital of WuHan, WuHan, Hubei, China
| | - Liang Liu
- Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Yong-Fa Zheng
- Department of Oncology, RenMin Hospital of WuHan University, WuHan, Hubei, China
| | - Si-Fa Gao
- Department of Oncology, RenMin Hospital of WuHan University, WuHan, Hubei, China
| | - Xi-Ming Xu
- Department of Oncology, RenMin Hospital of WuHan University, WuHan, Hubei, China
| | - Wei Ge
- Department of Oncology, RenMin Hospital of WuHan University, WuHan, Hubei, China
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Perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging predict outcomes of hepatocellular carcinoma receiving radiotherapy with or without thalidomide. Hepatol Int 2014; 9:258-68. [PMID: 25788178 DOI: 10.1007/s12072-014-9557-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 06/21/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND To correlate between signal parameters using dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) and outcomes of hepatocellular carcinoma (HCC) receiving radiotherapy with or without concomitant thalidomide. METHODS DCEMRI was performed in advanced HCC patients undergoing radiotherapy with or without concomitant thalidomide. Initial first-pass enhancement slopes (slope) and peak enhancement ratios (peak) were measured over an operator-defined region of interest over tumor and non-tumor liver parenchyma. The perfusion parameters were correlated with clinical outcomes. The study was registered with ClinicalTrials.gov. (identifier NCT00155272). RESULTS Forty-three patients were evaluable. There were 18 partial responses (PRs), 5 minimal responses (MRs), 17 stable diseases (SDs), and 3 progressive diseases (PDs). Baseline perfusion parameters as well as slope at 14 days of radiotherapy were higher in patients with PR or MR compared to SD or PD (0.81 ± 0.29 vs. 0.49 ± 0.34, p < 0.01; 0.39 ± 0.15 vs. 0.28 ± 0.16, p = 0.02; 0.97 ± 0.38 vs. 0.46 ± 0.26, p < 0.01; respectively). Multivariate analysis revealed perfusion parameters over liver parenchyma, but not over tumor, and independently predicted progression-free and overall survival (182 ± 33 vs. 105 ± 26 days, p = 0.01; 397 ± 111 vs. 233 ± 19 days, p = 0.001 respectively). For 22 patients receiving concomitant thalidomide, the perfusion parameters were not significantly different from those receiving radiotherapy alone. CONCLUSIONS Signal parameters of DCEMRI over tumor and liver parenchyma correlated with tumor response and survival, respectively, in HCC patients receiving radiotherapy.
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8
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Maxwell JE, Sherman SK, O'Dorisio TM, Howe JR. Medical management of metastatic medullary thyroid cancer. Cancer 2014; 120:3287-301. [PMID: 24942936 DOI: 10.1002/cncr.28858] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 05/02/2014] [Accepted: 05/07/2014] [Indexed: 12/21/2022]
Abstract
Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer that occurs in both heritable and sporadic forms. Discovery that mutations in the rearranged during transfection (RET) proto-oncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even those with familial disease still present with lymph node or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormone therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long-term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day.
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Affiliation(s)
- Jessica E Maxwell
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
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Chien CH, Chien RN. Thalidomide induces complete remission of advanced hepatocellular carcinoma. ADVANCES IN DIGESTIVE MEDICINE 2014. [DOI: 10.1016/j.aidm.2014.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Shaaban S, Negm A, Ibrahim EE, Elrazak AA. Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action. Oncol Rev 2014; 8:246. [PMID: 25992234 PMCID: PMC4419609 DOI: 10.4081/oncol.2014.246] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/06/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a dreaded malignancy that every year causes half a million deaths worldwide. Being an aggressive cancer, its incidence exceeds 700,000 new cases per year worldwide with a median survival of 6-8 months. Despite advances in prognosis and early detection, effective HCC chemoprevention or treatment strategies are still lacking, therefore its dismal survival rate remains largely unchanged. This review will characterize currently available chemotherapeutic drugs used in the treatment of HCC. The respective mode(s) of action, side effects and recommendations will be also described for each drug.
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Affiliation(s)
- Saad Shaaban
- Department of Chemistry, Mansoura University , Egypt
| | - Amr Negm
- Department of Biochemistry, Mansoura University , Egypt
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11
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Ranieri G, Marech I, Lorusso V, Goffredo V, Paradiso A, Ribatti D, Gadaleta CD. Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment. World J Gastroenterol 2014; 20:486-497. [PMID: 24574717 PMCID: PMC3923023 DOI: 10.3748/wjg.v20.i2.486] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer in the world. According to Barcelona Clinic Liver Cancer modified criteria, patients with early stage disease are candidate to radiofrequency ablation (RFA), while patients with intermediate stage HCC are usually treated by transarterial chemoembolization (TACE). TACE and RFA induce a transient devascularisation effect followed by strong neo-angiogenic stimulus. In fact, after these procedures, it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A, which might contribute to accelerated progression in patients with incomplete response. Several studies have demonstrated that MAP-kinase and AKT pathways, in addition to neo-angiogenesis, have an important role in the development of HCC. In advanced HCC, anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit. Actually, a number of clinical studies are ongoing testing these agents in combination with TACE or RFA. In this paper, we have reviewed the most recent preclinical and clinical results of such trials.
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Zacharoulis D, Hatzitheofilou C, Athanasiou E, Zacharoulis S. Antiangiogenic strategies in hepatocellular carcinoma: current status. Expert Rev Anticancer Ther 2014; 5:645-56. [PMID: 16111465 DOI: 10.1586/14737140.5.4.645] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.
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Shao YY, Cheng AL, Hsu CH. Clinical Activity of Metronomic Chemotherapy in Liver Cancers. METRONOMIC CHEMOTHERAPY 2014:189-202. [DOI: 10.1007/978-3-662-43604-2_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hung KC, Hsieh PM, Yang KL, Lin KJ, Chen YS, Hung CH. Effect of thalidomide on the expression of vascular endothelial growth factor in a rat model of liver regeneration. Oncol Lett 2012; 5:852-856. [PMID: 23426142 PMCID: PMC3576220 DOI: 10.3892/ol.2012.1089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 12/06/2012] [Indexed: 12/24/2022] Open
Abstract
Liver regeneration is an angiogenesis-associated phenomenon. The present study investigated the influence of thalidomide, an antiangiogenic agent, on vascular endothelial growth factor (VEGF) expression and liver regeneration after 70% partial hepatectomy (PH) in rats. PH was performed on 50 rats dosed with either thalidomide (100 mg/kg) or a vehicle (controls) by intragastric administration. Serial changes in hepatic microcirculation were evaluated by laser Doppler flowmetry. The VEGF expression in liver tissue was assessed by immunohistochemical study and western blot analysis. Following hepatectomy, the liver regeneration rate increased markedly and reached a peak at 96 h in the two groups. Thalidomide did not affect the overall restoration of liver mass, although a delay in cell proliferation was observed. Prior to PH, the liver microcirculation in rats treated with thalidomide for 2 days was comparatively less than that in their corresponding controls; however, no significant difference between the groups was detected at any time-point following PH. Western blotting showed that the expression of VEGF was upregulated by hepatectomy and the expression levels in the two groups were equal at all studied time-points. The immunohistochemical staining revealed a waved pattern of VEGF expression which advanced from the periportal to pericentral area in both groups, but a slower advancement was detected in thalidomide-treated rats. In conclusion, thalidomide exerted no significant effects on the expression of VEGF and did not impair the overall restoration of liver mass in a rat model of PH-induced liver regeneration, providing supportive evidence for its use as an adjunct treatment modality for liver cancers.
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Affiliation(s)
- Kuo-Chen Hung
- Institute of Biotechnology and Chemical Engineering, I-Shou University
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15
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Lin ZZ, Hsu C, Hu FC, Shao YY, Chang DY, Yang CH, Hong RL, Hsu CH, Cheng AL. Factors impacting prognosis prediction in BCLC stage C and Child-Pugh class A hepatocellular carcinoma patients in prospective clinical trials of systemic therapy. Oncologist 2012; 17:970-7. [PMID: 22673633 DOI: 10.1634/theoncologist.2011-0411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials. METHODS From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor-node-metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria. RESULTS The median overall survival time was 129 days (95% confidence interval, 111-147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival. CONCLUSIONS The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.
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Affiliation(s)
- Zhong-Zhe Lin
- Department of Oncology, National Taiwan University, Taipei, Taiwan
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Chen YY, Yen HH, Chou KC, Wu SS. Thalidomide-based multidisciplinary treatment for patients with advanced hepatocellular carcinoma: A retrospective analysis. World J Gastroenterol 2012; 18:466-71. [PMID: 22346253 PMCID: PMC3270502 DOI: 10.3748/wjg.v18.i5.466] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 05/27/2011] [Accepted: 06/03/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of thalidomide in combination with other therapies to treat patients with advanced hepatocellular carcinoma (HCC).
METHODS: We performed a retrospective analysis of all patients with HCC who were treated with thalidomide for at least two months. The medical records of patients with HCC who were treated at our institution between April 2003 and March 2008 were reviewed. Image studies performed before and after treatment, tumor response, overall survival, and the decrease in α-fetoprotein (AFP) levels were evaluated.
RESULTS: A total of 53 patients with HCC received either 100 or 200 mg/d of thalidomide. The patient population consisted of 9 women and 44 men with a median age of 61 years. Thirty patients (56.6%) were classified as Child-Pugh A, and 12 patients (22.6%) were classified as Child-Pugh B. Twenty-six patients had portal vein thrombosis (49.1%), and 25 patients had extrahepatic metastasis (47.1%). The median duration of thalidomide treatment was 6.0 mo. Six of the 53 patients achieved a confirmed response (11.3%), one achieved a complete response (1.9%) and 5 achieved a partial response (9.4%). The disease control rate (CR + PR + SD) was 28.3% (95% CI: 17.8-42.4), and the median overall survival rate was 10.5 mo. The 1- and 2-year survival rates were 45% and 20%, respectively. Only one complete response patient showed an improved overall survival rate of 66.8 mo. Sixteen patients (30.2%) showed more than a 50% decrease in their serum AFP levels from baseline, indicating a better response rate (31.3%), disease control rate (43.8%), and overall survival time (20.7 mo). The therapy was well tolerated, and no significant toxicities were observed.
CONCLUSION: Thalidomide was found to be safe for advanced HCC patients, demonstrating anti-tumor activity including response, survival, and AFP decreases of greater than 50% from baseline.
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Shao YY, Lin ZZ, Hsu C, Lee KD, Hsiao CH, Lu YS, Huang CC, Shen YC, Hsu CH, Cheng AL. Efficacy, safety, and potential biomarkers of thalidomide plus metronomic chemotherapy for advanced hepatocellular carcinoma. Oncology 2012; 82:59-66. [PMID: 22310088 DOI: 10.1159/000336126] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 12/29/2011] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Thalidomide has been shown to have antitumor activity in some patients with advanced hepatocellular carcinoma (HCC). We initiated a phase II study to determine the safety and efficacy of adding metronomic chemotherapy to thalidomide as first-line therapy. METHODS This open- labeled, single-arm, multicentered, investigator-initiated study enrolled patients with treatment-naïve advanced HCC not amenable to locoregional therapies. Treatment included oral thalidomide (100 mg twice daily) and tegafur/uracil [125 mg/m(2) (based on tegafur) twice daily]. Tumor assessment was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Pretreatment plasma levels of angiogenesis factors were correlated with patient outcomes. RESULTS Forty-three patients were included. Sixteen (37%) patients had a Cancer of the Liver Italian Program (CLIP) score of 4, and 31 (72%) patients had chronic hepatitis B virus infection. The objective response rate was 9%, and the disease stabilization rate was 33%. The median progression-free survival was 1.9 months (95% CI 1.7-2.1 months), and the median OS was 4.6 months (95% CI 2.3-6.9 months). Treatment was generally tolerable. High baseline plasma levels of interleukin (IL)-6 and IL-8 were adversely correlated with patient survivals. CONCLUSIONS The combination of thalidomide and tegafur/uracil was safe and demonstrated modest activity in patients with advanced HCC.
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Affiliation(s)
- Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan, ROC
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A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: A possible link between twelve autism risk factors and the autism ‘epidemic’. Med Hypotheses 2011; 76:653-60. [DOI: 10.1016/j.mehy.2011.01.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2010] [Revised: 11/09/2010] [Accepted: 01/13/2011] [Indexed: 11/17/2022]
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Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int 2011; 31:146-62. [PMID: 21073649 DOI: 10.1111/j.1478-3231.2010.02369.x] [Citation(s) in RCA: 220] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nowadays, liver cancer, cirrhosis and other liver-related diseases are the fifth most common cause of mortality in the UK. Furthermore, chronic liver diseases (CLDs) are one of the major causes of death, which are still increasing year-on-year. Therefore, knowledge about the pathophysiology of CLDs and its complications is of uttermost importance. The goal of this review is to clarify the role of angiogenesis in the disease progression of various liver diseases. Looking closer at the pathophysiology of portal hypertension (PH), fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), we find that angiogenesis is a recurring factor in the disease progression. In PH, several factors involved in its pathogenesis, such as hypoxia, oxidative stress, inflammation and shear stress are potential mediators for the angiogenic response. The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. In several stages of NASH, a link might be made between the disease progression and hepatic microvasculature changes. HCC is one of the most vascular solid tumours in which angiogenesis plays an important role in its development, progression and metastasis. The close relationship between the progression of CLDs and angiogenesis emphasises the need for anti-angiogenic therapy as a tool for blocking or slowing down the disease progression. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs and its complications.
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Affiliation(s)
- Stephanie Coulon
- Department of Hepatology and Gastroenterology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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Ch'ang HJ, Hsu C, Chen CH, Chang YH, Chang JS, Chen LT. Phase II study of concomitant thalidomide during radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011; 82:817-25. [PMID: 21277098 DOI: 10.1016/j.ijrobp.2010.10.067] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 09/06/2010] [Accepted: 10/23/2010] [Indexed: 01/11/2023]
Abstract
PURPOSE Thalidomide has been demonstrated to possess antitumor activity in patients with advanced hepatocellular carcinoma (HCC). The objective of the present study was to determine whether the combined treatment of thalidomide with radiotherapy (RT) is associated with acceptable toxicity and an improved clinical outcome in HCC patients. METHODS AND MATERIALS A total of 24 patients were enrolled to receive RT combined with thalidomide. A total dose of 50 Gy was delivered in 2-Gy fractions within 5 weeks. Thalidomide was administered 100 mg twice daily starting 3 days before RT until the development of unacceptable toxicity or disease progression. Blood samples were collected before, during, and after treatment to measure the levels of angiogenic factors and cytokines. The results of patients receiving the combined therapy were compared with those from 18 HCC patients receiving RT only. RESULTS No significant difference in the clinical parameters was noted between the two groups, except for the baseline interleukin-6 level, which was greater in the concomitant group (p = .05). The most common toxicities related to thalidomide use were skin rash (54.2%), somnolence (37.5%), and constipation (33.3%). No significant differences were seen in the response rate (55.6% vs. 58.3%, p = .48), median progression-free survival (182 ± 48.9 vs. 148 ± 6.2 days, p = .15), or median overall survival (258 ± 45.6 vs. 241 ± 38.6, p = .16) between those who received concomitant therapy and those who received RT alone. Thalidomide suppressed the serum basic fibroblast growth factor level significantly during RT (p = .03) and, to a lesser extent, the interleukin-6 and tumor necrosis factor-α levels. After adjusting for other potential prognostic factors in the multivariate analysis, only the baseline interleukin-6 level and stem cell-derived factor-1 during RT independently predicted the progression-free survival. A decreased serum stem cell-derived factor-1 level 1 month after RT completion was a significant predictor of the overall survival of HCC patients receiving RT. CONCLUSIONS Despite the acceptable toxicity, thalidomide provided no additional benefit for HCC patients undergoing RT.
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Affiliation(s)
- Hui-Ju Ch'ang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
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Nitta-Seko A, Nitta N, Sonoda A, Otani H, Tsuchiya K, Ohta S, Takahashi M, Murata K. Anti-tumour effects of transcatheter arterial embolisation administered in combination with thalidomide in a rabbit VX2 liver tumour model. Br J Radiol 2010; 84:179-83. [PMID: 20959369 DOI: 10.1259/bjr/53771502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Using a liver tumour model we investigated whether thalidomide enhances the anti-tumour effect of transcatheter arterial embolisation (TAE). METHOD First, the viability of VX2 tumour cells co-cultured with thalidomide in a 21% and 1% O(2) atmosphere was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Second, we randomly assigned 20 rabbits bearing VX2 liver tumours to 4 groups: Group 1 (thalidomide plus TAE), Group 2 (TAE only), Group 3 (thalidomide only) and Group 4 (control). Thalidomide was orally administered for 5 days. The anti-tumour effects were assessed by the tumour proliferation rate using MRI and by immunohistochemical analysis of the area of intratumoural vessels. Analysis of variance and Tukey's honestly significant difference test were used for statistical analysis. RESULTS The viability of cells grown under hypoxic and normal conditions was not significantly different, nor was there a difference among the four groups. The tumour size increased by 55.9±29.3% in Group 1, 250.6±73.3% in Group 2, 355.2±51.7% in Group 3 and 424.7±110.7% in Group 4; the difference between Group 1 and the other three groups was significant. The area of intratumour vessels in specimens was 0.22±0.28% in Group 1, 0.42±0.29% in Group 2, 1.44±1.00% in Group 3 and 6.00±2.17% in Group 4; the difference between Group 1 and the other groups was statistically significant, as was the difference between Groups 3 and 4. CONCLUSION Thalidomide used in combination with TAE enhanced anti-tumour effects in rabbits bearing VX2 liver tumours.
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Affiliation(s)
- A Nitta-Seko
- Department of Radiology, Shiga University of Medical Science, Japan.
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22
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Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives. J Gastroenterol 2010; 45:794-807. [PMID: 20567987 DOI: 10.1007/s00535-010-0270-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2010] [Accepted: 05/30/2010] [Indexed: 02/06/2023]
Abstract
Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.
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Whang-Peng J, Cheng AL, Hsu C, Chen CM. Clinical Development and Future Direction for the Treatment of Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/s1878-3317(10)60016-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, Kudo M, Lee JM, Choi BI, Poon RTP, Shiina S, Cheng AL, Jia JD, Obi S, Han KH, Jafri W, Chow P, Lim SG, Chawla YK, Budihusodo U, Gani RA, Lesmana CR, Putranto TA, Liaw YF, Sarin SK. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010; 4:439-474. [PMID: 20827404 PMCID: PMC2900561 DOI: 10.1007/s12072-010-9165-7] [Citation(s) in RCA: 838] [Impact Index Per Article: 55.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 12/09/2009] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. METHODS The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. RESULTS Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.
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Affiliation(s)
- Masao Omata
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
| | - Laurentius A. Lesmana
- Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
| | - Pei-Jer Chen
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shi-Ming Lin
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Haruhiko Yoshida
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
| | - Masatoshi Kudo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Jeong Min Lee
- Abdominal Radiology Section, Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Byung Ihn Choi
- Abdominal Radiology Section, Department of Radiology, Seoul National University Hospital, Seoul, Korea
| | - Ronnie T. P. Poon
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Shuichiro Shiina
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
| | - Ann Lii Cheng
- Department of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 100050 Beijing, China
| | - Shuntaro Obi
- Division of Hepatology, Kyoundo Hospital, Tokyo, Japan
| | - Kwang Hyub Han
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Wasim Jafri
- Department of Medicine, The Aga Khan University Hospital, Karachi, Pakistan
| | - Pierce Chow
- Department of General Surgery, Singapore General Hospital, Singapore, Singapore
| | - Seng Gee Lim
- Department of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore
| | - Yogesh K. Chawla
- Departments of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Unggul Budihusodo
- Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Rino A. Gani
- Hepatology Division, Internal Medicine Department, RSUPN Cipto Mangunkusumo, Jakarta, Indonesia
| | - C. Rinaldi Lesmana
- Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | | | - Yun Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Shiv Kumar Sarin
- Department of Gastroenterology, G. B. Pant Hospital, University of Delhi, New Delhi, India
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Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, Kudo M, Lee JM, Choi BI, Poon RTP, Shiina S, Cheng AL, Jia JD, Obi S, Han KH, Jafri W, Chow P, Lim SG, Chawla YK, Budihusodo U, Gani RA, Lesmana CR, Putranto TA, Liaw YF, Sarin SK. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010. [PMID: 20827404 DOI: 10.1007/s12072-011-9165-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. METHODS The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. RESULTS Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.
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Quek R, Lim ST, Ong S. Hepatocellular carcinoma--Pathological complete response to oral capecitabine, megestrol and thalidomide. Acta Oncol 2009; 45:95-7. [PMID: 16464803 DOI: 10.1080/02841860500341140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for development of HCC are well defined and some steps of hepatocellular carcinogenesis have been elucidated. Despite these scientific advances and the implementation of measures for early detection of HCC in patients who are at risk of this disease, survival of patients has not improved greatly over the past three decades. This situation is partly due to the limited therapeutic options available. While surgery and percutaneous or transarterial interventions are effective for patients with limited or compensated underlying liver disease, more than 80% of patients present with multifocal HCC and/or advanced liver disease, or have comorbidities at the time of diagnosis. Treatment options for these patients have previously been limited to best supportive care. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In 2007, the multitargeted kinase inhibitor, sorafenib, was found to prolong survival significantly for patients with advanced HCC. This Review discusses the mechanisms of targeted therapies and clinical studies that have investigated these therapies in patients with HCC. Perspectives for future developments are also provided.
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Liu BR, Wang TT, Qian XP. Advance in molecular targeted therapy for primary hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2009; 17:993-997. [DOI: 10.11569/wcjd.v17.i10.993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
New approaches targeting molecular abnormalities specific to primary hepatocellular carcinoma (PHC) has offered a new method to improve patient outcome. The increasing knowledge in the molecular pathogenesis of PHC as well as the introduction of molecular targeted therapies in oncology has created an encouraging trend in the management of this malignancy. Early studies of targeted therapies for hepatocellular carcinoma, including targeting the EGFR pathway and inhibiting angiogenesis and multikinase inhibitors, have shown effective and great perspective. This review summarizes the basic knowledge of those key aspects of the molecular pathogenesis. Relevant preclinical and clinical information on novel compounds for PHC are also reviewed.
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Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol 2009; 44 Suppl 19:136-41. [PMID: 19148808 DOI: 10.1007/s00535-008-2252-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Accepted: 07/03/2008] [Indexed: 02/08/2023]
Abstract
A majority of patients with HCC present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. Systemic cytotoxic chemotherapy agents are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. Hepatocellular carcinomas are inherently chemotherapy-resistant tumors and are known to overexpress the multidrug resistance genes. Hepatocellular carcinoma is a very heterogeneous disease in terms of its etiology, molecular carcinogenic mechanisms, and biological behavior, which complicate our ability to identify rational molecular therapeutic "targets." Nearly every pathway involved in carcinogenesis is altered to some degree in HCC. Changes in hepatocyte growth factor expression, intracellular signaling, protease and matrix metalloproteinase expression, and oncogene expression are seen in HCC. The recent demonstration, in randomized clinical trials, of survival benefit for HCC patients treated with the oral agent sorafenib is encouraging progress in the development of molecularly targeted anticancer agents in HCC.
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Yau T, Chan P, Epstein R, Poon RT. Evolution of systemic therapy of advanced hepatocellular carcinoma. World J Gastroenterol 2008; 14:6437-41. [PMID: 19030192 PMCID: PMC2773326 DOI: 10.3748/wjg.14.6437] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.
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Thalidomide in advanced hepatocellular carcinoma as antiangiogenic treatment approach: a phase I/II trial. Eur J Gastroenterol Hepatol 2008; 20:1012-9. [PMID: 18787470 DOI: 10.1097/meg.0b013e3283036740] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND The high vascularity of hepatocellular carcinoma (HCC) seems to be a potential therapeutic target. We evaluated the efficacy, toxicity, and histologic response to thalidomide in advanced HCC in a single center phase I/II pilot trial. METHODS Between September 2000 and August 2004 patients with HCC uneligible for any established therapy were enrolled in the study. The initial thalidomide dosage of 100 mg/day was escalated in 100 mg steps weekly up to 300 mg/day based on tolerability. Discontinuation and dose reduction were based on toxicity. Tumor biopsies were scheduled to assess tumor microvessel density and serum levels of angiogenic factors, vascular endothelial growth factor, basic fibroblast growth factor, and endostatin were determined. RESULTS Twenty-eight patients with histologically proven HCC were entered into this study. The median maximum-tolerated dose of thalidomide was 300 mg/day. Most common toxicities were fatigue (75%), dizziness (64%), nausea (43%), and constipation (39%). Two patients had stable disease for 2.6 and 5.4 months, the remaining 26 patients had disease progression. The median overall survival was 5.1 months. Well preserved liver function was associated with longer overall survival on univariate analysis (P=0.0279). The serum concentrations of vascular endothelial growth factor and endostatin increased significantly (P=0.039 and P=0.024, respectively) after 3 months of thalidomide treatment. No clear differences were observed between the serum basic fibroblast growth factor concentrations at study entry and after 3 months (P=0.983). Microvessel density did not decrease significantly during thalidomide therapy (P=0.109). CONCLUSION Thalidomide is moderately tolerated and minimally effective in large HCC.
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RANGARAJU RR, ANIL K, VENNIYOOR A, SINGH H, RANJAN S, KAPUR B. Unusual responses to thalidomide in refractory solid tumors. Asia Pac J Clin Oncol 2008. [DOI: 10.1111/j.1743-7563.2008.00154.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Han CJ. Recent developments in systemic chemotherapy for hepatocellular carcinoma. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:4-11. [DOI: 10.3350/kjhep.2008.14.1.4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Chul Ju Han
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
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Pang RWC, Poon RTP. From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now. Oncology 2007; 72 Suppl 1:30-44. [PMID: 18087180 DOI: 10.1159/000111705] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.
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Affiliation(s)
- Roberta W C Pang
- Department of Medicine, Centre for Cancer Research, the University of Hong Kong, Hong Kong, SAR, China
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Cancer of the Liver and Bile Ducts. Oncology 2007. [DOI: 10.1007/0-387-31056-8_44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Demeria D, Birchall I, Bain VG. Dramatic reduction in tumour size in hepatocellular carcinoma patients on thalidomide therapy. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 21:517-8. [PMID: 17703252 PMCID: PMC2657977 DOI: 10.1155/2007/128792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Denny Demeria
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta
| | - Iain Birchall
- Department of Diagnostic Imaging, University of Alberta, Edmonton, Alberta
| | - Vincent G Bain
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta
- Correspondence: Dr Vincent G Bain, University of Alberta Liver Unit, 1–55 Zeidler Ledcor Center, 130 University Campus, Edmonton, Alberta T6G 2X8. Telephone 780-492-8128, fax 780-492-8130, e-mail
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Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007; 17:663-70. [PMID: 17696837 DOI: 10.1089/thy.2006.0289] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND There are no known effective therapies for distantly metastatic, rapidly progressive thyroid carcinomas unresponsive to radioiodine. OBJECTIVE Since thyroid carcinomas are hypervascular and thalidomide is antiangiogenic, we assessed thalidomide's tumoristatic effects and toxicity in a phase II trial. DESIGN Thirty-six patients with follicular, papillary, insular, or medullary thyroid carcinomas and distant, radioiodine-unresponsive metastases (volumes increasing >or= 30% per year before entry) were accrued between July 2001 and December 2002. Daily thalidomide started at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Toxicities and responses were assessed at 8-week intervals with tumor volume assessments. MAIN OUTCOMES Twenty-eight of 36 patients were evaluable, 5 with partial responses (PR: 18%; 95% confidence interval [95% CI]: 6-37%) and 9 patients with stable disease (SD: 32%; 95% CI: 12-42%) for overall 50% response (95% CI: 31-69%). Median PR duration was 4 months (range: 2-6 months), and SD duration was 6 months (range: 2-14 months). Median survival was 23.5 months for responders (PR + SD) and 11 months for nonresponders. Most frequent toxicity was fatigue (69% grade 1-2, 8% grade 3-4). Four patients had grade 3-4 infections (without neutropenia), one had pericardial effusion, and one had pulmonary embolus. CONCLUSIONS Thalidomide confers therapeutic benefit in subsets of thyroid cancer patients with rapidly progressive, distantly metastatic disease.
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Affiliation(s)
- Kenneth B Ain
- Thyroid Cancer Research Laboratory, Veterans Affairs Medical Center, Lexington, Kentucky, USA.
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Chuah B, Lim R, Boyer M, Ong AB, Wong SW, Kong HL, Millward M, Clarke S, Goh BC. Multi-centre phase II trial of Thalidomide in the treatment of unresectable hepatocellular carcinoma. Acta Oncol 2007; 46:234-8. [PMID: 17453375 DOI: 10.1080/02841860600702076] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumour, which overexpresses vascular endothelial growth factor. Thalidomide is an antiangiogenic agent with activity in refractory multiple myeloma. The purpose of this multi-centre phase II study was to evaluate the efficacy and toxicity of thalidomide in patients with advanced HCC. From February 2000 to November 2001, 37 patients with histologically proven, bi-dimensionally measurable advanced, unresectable HCC were enrolled. The starting dose of Thalidomide was 100 mg per day and escalated weekly by 100 mg to a maximum dose of 800 mg/day according to individual patient tolerance. Radiological tumour response and treatment related toxicities were prospectively assessed. Thirty-seven patients were evaluable for toxicity and 24 patients were evaluable for response. The median Thalidomide dose was 400 mg/day. There was no complete response (CR). One patient had a radiological partial response (PR) (3%; 95% confidence interval [95% CI], 0% to 8%) and six (16%) patients had stable disease for more than 6 months. Somnolence and fatigue were the most common side effects, occurring in 84% and 73% of patients respectively. Thalidomide monotherapy is tolerable and associated with modest antitumour activity in advanced HCC.
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Affiliation(s)
- Benjamin Chuah
- Cancer Therapeutics Research Group, Department of Hematology-Oncology, National University Hospital, Singapore
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40
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WANG TE, LIM KH, HUANG MJ. Combined thalidomide and interferon-? for chronic hepatitis C-related hepatocellular carcinoma. Asia Pac J Clin Oncol 2007. [DOI: 10.1111/j.1743-7563.2006.00082.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Ho MC, Lin JJ, Chen CN, Chen CC, Lee H, Yang CY, Ni YH, Chang KJ, Hsu HC, Hsieh FJ, Lee PH. A gene expression profile for vascular invasion can predict the recurrence after resection of hepatocellular carcinoma: a microarray approach. Ann Surg Oncol 2007; 13:1474-84. [PMID: 17009164 DOI: 10.1245/s10434-006-9057-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recurrence after hepatocellular carcinoma (HCC) resection is the major obstacle to improved survival. The presence of vascular invasion (VI) in pathology specimens is a well-known unfavorable prognostic factor for HCC recurrence. Though some VI-related genes have been reported, their association with recurrence-free survival is not known. We hypothesized that a gene expression profile for VI can predict the recurrence of HCC after liver resection. METHODS Eighteen patients receiving complete HCC resection were included as a "training group". Genome-wide gene expression profile was obtained for each tumor using a microarray technique. Datasets were subjected to clustering analysis supervised by the presence or absence of VI to obtain 14 discriminative genes. We then applied those genes to execute pattern recognition using the k-Nearest Neighbor (KNN) classification method, and the best model for this VI gene signature to predict recurrence-free survival in the training group was obtained. The resulting model was then tested in an independent "test group" of 35 patients. RESULTS A 14-gene profile was extracted which could accurately separate ten patients with VI and eight patients without VI in the "training group". In the "test group", significant difference in disease-free survival was found between patients predicted to have and not to have recurrence (P = .02823). In patients with stage_I disease, this model can also predict outcomes (P = .000205). CONCLUSIONS Using the 14-gene expression profile extracted from microarrays based on the presence of VI can effectively predict recurrence after HCC resection. This approach might facilitate "personalized medicine" for HCC patients after surgical resection.
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Affiliation(s)
- Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan
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Han SH, Park SH, Kim JH, Lee JJ, Kwon SY, Kwon OS, Kim SS, Kim JH, Kim KK, Park YH, Lee JN, Nam E, Bang SM, Cho EK, Shin DB, Lee JH. Thalidomide for treating metastatic hepatocellular carcinoma: a pilot study. Korean J Intern Med 2006; 21:225-9. [PMID: 17249503 PMCID: PMC3891026 DOI: 10.3904/kjim.2006.21.4.225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Thalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy. METHODS Eight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals. RESULTS The median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient. CONCLUSIONS The results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.
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Affiliation(s)
- Sang Hoon Han
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Se Hoon Park
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Jung Ho Kim
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Jong Jun Lee
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - So Young Kwon
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Sun Suk Kim
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Keon Kug Kim
- Department of General Surgery, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Yeon Ho Park
- Department of General Surgery, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Jeong Nam Lee
- Department of General Surgery, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Eunmi Nam
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Soo-Mee Bang
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Eun Kyung Cho
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Dong Bok Shin
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
| | - Jae Hoon Lee
- Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Korea
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Chen SC, Tsai HJ, Jan CM, Wang YH, Chen LT. Low dose of thalidomide can be effective in advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2006; 21:1868-9. [PMID: 17074035 DOI: 10.1111/j.1440-1746.2006.04303.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Abstract
AIM: To evaluate which patients with hepatocellular carcinoma (HCC) are most likely to respond to thalidomide treatment.
METHODS: From July 2002 to July 2004, patients with HCC who received thalidomide treatment, were enrolled. We extracted relevant data from the patients’ medical records, including history and type of hepatitis, comorbidity, serum α-fetoprotein (α-FP) level, volumetric changes in tumor, length of survival, and the dose, duration, side effects of thalidomide treatment. The tumor response was evaluated. On the basis of these data, the patients were divided into two groups: those with either partial response or stable disease (PR + SD group) and those with progressive disease (PD group).
RESULTS: Two of 42 (5%) patients had a partial tumor response after treatment with thalidomide, 200 mg/d, and 9 (21%) had stable disease. Patients in the PR + SD group all had cirrhosis. Comparing patients with and without cirrhosis, the former were more likely to respond to thalidomide therapy (PR + SD: 100% vs PD: 64.5%, P = 0.041 < 0.05). Thalidomide was significantly more likely to be effective in tumors smaller than 5 cm (PR + SD: 63.6% vs PD: 25.8%, P = 0.034 < 0.05). Compared with patients with progressive disease (PD), patients in the PR + SD group had a higher total dose of thalidomide (13 669.4 ± 8446.0 mg vs 22 022.7 ± 11 461.4 mg, P = 0.023 < 0.05) and a longer survival (181.0 ± 107.1 d vs 304.4 ± 167.1 d, P = 0.047 < 0.05). Patients with comorbid disease had a significantly greater incidence of adverse reactions than those without (93.8% vs 60.0%, P = 0.021 < 0.05). The average number of adverse reactions in each person with a comorbid condition was twice as high as in those without other diseases (2.2 ± 1.3 vs 1.1 ± 1.2; P = 0.022 < 0.05).
CONCLUSION: Thalidomide therapy is most likely to be effective in patients with early stage small HCC, especially in those with other underlying diseases. A low dose (200 mg/d) of thalidomide is recommended to continue the treatment long enough to make it more effective.
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Affiliation(s)
- Hsueh-Erh Chiou
- Pharmacy Department, Mackay Memorial Hospital, Taipei 10449, Taiwan, China
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Lin CC, Hsu C, Hsu CH, Hsu WL, Cheng AL, Yang CH. Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial. Invest New Drugs 2006; 25:77-84. [PMID: 16937079 DOI: 10.1007/s10637-006-9004-9] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2006] [Accepted: 07/21/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND Arsenic trioxide induces growth inhibition and apoptosis in human hepatocellular carcinoma (HCC) cell lines. A phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with HCC. METHODS Inclusion criteria included advanced HCC patients to whom no standard palliative treatment can be offered, good organ function and liver function reserve. Patients received arsenic trioxide 0.16-0.24 mg/kg per day for 5-6 days per week for 3-4 weeks, followed by one-week rest. Tumor response was assessed every 2 cycles. Primary endpoint was the percentage of patients with 6-month disease stabilization. RESULTS Twenty-nine patients (median age, 59) with locally advanced or metastatic HCC received a total of 61 cycles (median, 2; range, 1-6). One patient had partial response. Three patients had disease stabilization for at least six months. The 6-month tumor stabilization rate was 14% (95% CI, 1-27). The median overall survival was 4.8 months (95% CI, 1.4-8.2) and one-year survival was 30%. CONCLUSION Single-agent arsenic trioxide using this dose schedule is not active against advanced HCC.
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Affiliation(s)
- Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100 Taiwan
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Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006; 32:437-44. [PMID: 16870349 DOI: 10.1016/j.ctrv.2006.06.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2006] [Revised: 06/01/2006] [Accepted: 06/02/2006] [Indexed: 12/16/2022]
Abstract
Experimental and clinical data indicate that in human hepatocellular carcinoma (HCC) tumor progression is associated with angiogenesis and that an increase in microvascular density is associated with a poor prognosis. This review summarizes the literature concerning the relationship between angiogenesis and progression in HCC. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumor progression. Accordingly, anti-angiogenic tumor therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block HCC progression are reviewed.
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Affiliation(s)
- Domenico Ribatti
- Department of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11 Policlinico, 70124 Bari, Italy.
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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.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
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Lee CC, Wu YH, Chung SH, Chen WJ. Acute tumor lysis syndrome after thalidomide therapy in advanced hepatocellular carcinoma. Oncologist 2006; 11:87-8; author reply 89. [PMID: 16401719 DOI: 10.1634/theoncologist.11-1-87] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Hsu WC, Chan SC, Ting LL, Chung NN, Wang PM, Ying KS, Shin JS, Chao CJ, Lin GD. Results of three-dimensional conformal radiotherapy and thalidomide for advanced hepatocellular carcinoma. Jpn J Clin Oncol 2006; 36:93-9. [PMID: 16517834 DOI: 10.1093/jjco/hyi242] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE To evaluate the effectiveness of three-dimensional conformal radiotherapy and thalidomide in the treatment of advanced hepatocellular carcinoma. METHODS Between 1999 and 2003, 121 patients (mean age, 54.4 +/- 12.4 years; range, 20-81 years) with advanced hepatocellular carcinoma received three-dimensional conformal radiotherapy and thalidomide. Radiation was delivered in 1.5 Gy fractions twice daily for 5 days a week, for a total dose of 45-75 Gy. Mean treatment volume was 429.52 +/- 408.50 cm(3) (range, 26.89-2284.82 cm(3)). Thalidomide was given concomitantly: 200 mg/day in 109 patients, 300 mg/day in 8 patients and 400 mg/day in 4 patients. Treatment responses, survival rates and factors affecting survival were analyzed. RESULTS Treatment responses were observed in 61% of the patients. Liver cirrhosis (P = 0.001) and tumor size (P = 0.001) significantly affected the tumor responses. Overall survival at 6, 12 and 24 months was 84.8, 60.0 and 44.6%, respectively. On univariate analysis, liver cirrhosis (P = 0.003), Karnofsky performance status (P = 0.007), tumor size (P < 0.001), portal vein tumor thrombosis (P < 0.001) and alpha-fetoprotein level (P = 0.003) were shown to significantly affect survival. On multivariate analysis, only thrombosis (P = 0.039) and alpha-fetoprotein level (P = 0.006) were shown to be factors affecting survival. CONCLUSIONS Three-dimensional conformal radiotherapy with thalidomide seems to be effective in the treatment of advanced hepatocellular carcinoma.
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Affiliation(s)
- Wei-Chung Hsu
- Department of Radiation Oncology, Cheng-Ching General Hospital, Taichung, Taiwan
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Bertolotto M, Pozzato G, Crocè LS, Nascimben F, Gasparini C, Cova MA, Tiribelli C. Blood flow changes in hepatocellular carcinoma after the administration of thalidomide assessed by reperfusion kinetics during microbubble infusion: preliminary results. Invest Radiol 2006; 41:15-21. [PMID: 16355035 DOI: 10.1097/01.rli.0000188363.93670.45] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES We sought to investigate whether thalidomide is able to produce tumor vascular changes in patients with untreatable hepatocellular carcinoma (HCC) that can be detected using microbubble contrast agents. MATERIALS AND METHODS Eleven consecutive patients with untreatable HCC underwent contrast-enhanced ultrasound before and during thalidomide administration. Real-time destruction reperfusion kinetics was obtained from a representative HCC nodule and from the surrounding liver parenchyma during SonoVue infusion (Bracco, Milan, Italy) at a constant rate of 0.10 mL/s by using a syringe pump and modelized according to the mathematical function SI = A(1 - exp(-betat)) where the plateau signal intensity A reflects the percent blood volume, the time constant beta reflects the average speed of blood, and their product A*beta reflects the nutrient blood flow. RESULTS Size of the representative nodule reduced significantly 3 to 6 months after the start of thalidomide treatment. Before thalidomide administration A, beta, and A*beta of the index lesion were 44 +/- 60 LIU, 0.31 +/- 0.40 seconds and 8.1 +/- 11.8 LIU/s, respectively). A and A*beta reduced significantly after 15 days (26 +/- 50 LIU and 2.9 +/- 4.8 LIU/s, P < 0.01), 3 months (12 +/- 18 LIU, and 4.3 +/- 7.7 LIU/s, P < 0.01), and 6 months (13 +/- 23 LIU and 2.4 +/- 3.7 LIU/s, P < 0.05) of treatment. No statistically significant changes of the exponential time constant beta were observed, nor changes of A, beta and A*beta in the liver parenchyma. CONCLUSIONS Contrast-enhanced ultrasound can be used effectively to evaluate changes in perfusion parameters of HCC nodules during thalidomide administration.
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