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Sakr OS, Zaitoun MMA, Amer MS, Qubisi M, Elshafeey AH, Jordan O, Borchard G. Explosomes: A new modality for DEB-TACE local delivery of sorafenib: In vivo proof of sustained release. J Control Release 2023; 364:12-22. [PMID: 37816482 DOI: 10.1016/j.jconrel.2023.10.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/05/2023] [Accepted: 10/06/2023] [Indexed: 10/12/2023]
Abstract
The current medical practice in treating Hepatocellular carcinoma (HCC) using Drug Eluting Transarterial chemoembolization (DEB-TACE) technique is limited only to hydrophilic ionizable drugs, that can be attached ionically to the oppositely charged beads. This limitation has forced physicians to subscribe the more hydrophobic, first treatment option drugs, like sorafenib systemically via the oral route, thus flooding the patient system with a very powerful, non-specific, multiple-receptor tyrosine kinase inhibitor that is associated with notorious side effects. In this paper, a new modality is introduced, where highly charged, drug loaded liposomes are added to oppositely charged DEBs in a manner causing them to "explode" and the drug is eventually attached to the beads in the lipid patches covering their surfaces; therefore we call them "Explosomes". After fully describing the preparation process and in vitro characterization, this manuscript delves into an in vivo pharmacokinetic study over 50 New Zealand rabbits, where explosomal loading is challenged vs oral as well as current practice of emulsifying sorafenib in lipiodol. Over 14 days of follow up, and compared to other groups, explosomal loading of SRF on embolic beads proved to cause a slower release pattern with longer Tmax, lower Cmax and less washout to general circulation in healthy animals. This treatment modality opens a new untapped door for local sustained delivery of hydrophobic drugs in catheterized organs.
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Affiliation(s)
- Omar S Sakr
- Life Science Division, Nawah Scientific, Cairo, Egypt.
| | - Mohamed M A Zaitoun
- Diagnostic Radiology Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed S Amer
- Surgery, Anaesthesiology and Radiology Department, Faculty of Veterinary Medicine, Cairo University, Egypt
| | | | - Ahmed H Elshafeey
- Pharmaceutics Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Genuine Research Center, Heliopolis, Cairo, Egypt
| | - Olivier Jordan
- School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland
| | - Gerrit Borchard
- School of Pharmaceutical Sciences Geneva-Lausanne, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland
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2
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Lee TH, Devaki M, Formolo DA, Rosa JM, Cheng ASK, Yau SY. Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:5371. [PMID: 37047984 PMCID: PMC10094707 DOI: 10.3390/ijerph20075371] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 06/19/2023]
Abstract
Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: -9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: -29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.
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Affiliation(s)
- Thomas H. Lee
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
| | - Malegaddi Devaki
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
- Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
- Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong
| | - Douglas A. Formolo
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
- Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
- Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong
| | - Julia M. Rosa
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
- Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
- Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong
| | - Andy S. K. Cheng
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
| | - Suk-Yu Yau
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong; (T.H.L.); (M.D.); (D.A.F.); (J.M.R.)
- Mental Health Research Center (MHRC), Hong Kong Polytechnic University, Hung Hom, Hong Kong
- Research Institute for Smart Aging (RISA), Hong Kong Polytechnic University, Hung Hom, Hong Kong
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3
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Wen N, Cai Y, Li F, Ye H, Tang W, Song P, Cheng N. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines: 2022 update. Biosci Trends 2022; 16:20-30. [PMID: 35197399 DOI: 10.5582/bst.2022.01061] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This review is an updated version that summarizes comprehensive guidelines published from January 2001 to January 2022 worldwide with a focus on the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and the Japanese CiNii were systematically searched. A total of 22 characteristic guidelines for HCC management were ultimately included, including 1 international guideline, 11 guidelines from Asia, 5 from Europe, 4 from the America, and 1 from Australia. If guidelines were published in multiple versions, the most recent update was included, and surveillance, diagnosis, and treatment were compared. The composition of and recommendations in current guidelines on HCC varied, so these guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories: a "Size-based pathway" and a "Non-size-based pathway". The treatment criteria were summarized according to different treatment algorithms, and mainstream treatment options were reviewed. Findings from comparison of current guidelines might help target and concentrate efforts to improve the clinical management of HCC. However, further studies are needed to improve the management and outcomes of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions in the treatment of HCC in the future.
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Affiliation(s)
- Ningyuan Wen
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yulong Cai
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Fuyu Li
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hui Ye
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Wei Tang
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China.,International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Peipei Song
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nansheng Cheng
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Ezzat R, Eltabbakh M, El Kassas M. Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures. World J Gastrointest Oncol 2021; 13:1919-1938. [PMID: 35070033 PMCID: PMC8713321 DOI: 10.4251/wjgo.v13.i12.1919] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/17/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.
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Affiliation(s)
- Reem Ezzat
- Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Cairo, Egypt
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5
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Van Leeuwen MT, Luu S, Gurney H, Brown MR, Pearson SA, Webber K, Hunt L, Hong S, Delaney GP, Vajdic CM. Cardiovascular Toxicity of Targeted Therapies for Cancer: An Overview of Systematic Reviews. JNCI Cancer Spectr 2020; 4:pkaa076. [PMID: 33392444 PMCID: PMC7768929 DOI: 10.1093/jncics/pkaa076] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 07/01/2020] [Accepted: 08/18/2020] [Indexed: 12/16/2022] Open
Abstract
Background Several targeted therapies for cancer have been associated with cardiovascular toxicity. The evidence for this association has not been synthesized systematically nor has the quality of evidence been considered. We synthesized systematic review evidence of cardiovascular toxicity of individual targeted agents. Methods We searched MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for systematic reviews with meta-analyses of cardiovascular outcomes for individual agents published to May 2020. We selected reviews according to prespecified eligibility criteria (International Prospective Register of Systematic Reviews CRD42017080014). We classified evidence of cardiovascular toxicity as sufficient, probable, possible, or indeterminate for specific cardiovascular outcomes based on statistical significance, study quality, and size. Results From 113 systematic reviews, we found at least probable systematic review evidence of cardiovascular toxicity for 18 agents, including high- and all-grade hypertension for bevacizumab, ramucirumab, axitinib, cediranib, pazopanib, sorafenib, sunitinib, vandetanib, aflibercept, abiraterone, and enzalutamide, and all-grade hypertension for nintedanib; high- and all-grade arterial thromboembolism (includes cardiac and/or cerebral events) for bevacizumab and abiraterone, high-grade arterial thromboembolism for trastuzumab, and all-grade arterial thromboembolism for sorafenib and tamoxifen; high- and all-grade venous thromboembolism (VTE) for lenalidomide and thalidomide, high-grade VTE for cetuximab and panitumumab, and all-grade VTE for bevacizumab; high- and all-grade left ventricular ejection fraction decline or congestive heart failure for bevacizumab and trastuzumab, and all-grade left ventricular ejection fraction decline/congestive heart failure for pazopanib and sunitinib; and all-grade corrected QT interval prolongation for vandetanib. Conclusions Our review provides an accessible summary of the cardiovascular toxicity of targeted therapy to assist clinicians and patients when managing cardiovascular health.
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Affiliation(s)
- Marina T Van Leeuwen
- Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Steven Luu
- Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Howard Gurney
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Martin R Brown
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Sallie-Anne Pearson
- Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Kate Webber
- Department of Oncology, Monash Health, Clayton, Victoria, Australia.,School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
| | - Lee Hunt
- Cancer Voices NSW, Milsons Point, New South Wales, Australia
| | - Soojung Hong
- Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia.,Division of Oncology-Haematology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Geoffrey P Delaney
- Liverpool Cancer Therapy Centre, Liverpool, New South Wales, Australia.,Collaboration for Cancer Outcomes Research and Evaluation, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Liverpool, New South Wales, Australia
| | - Claire M Vajdic
- Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia
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6
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Bazarbachi AH, Al Hamed R, Malard F, Mohty M, Bazarbachi A. Allogeneic transplant for FLT3- ITD mutated AML: a focus on FLT3 inhibitors before, during, and after transplant. Ther Adv Hematol 2019; 10:2040620719882666. [PMID: 31700594 PMCID: PMC6826920 DOI: 10.1177/2040620719882666] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/25/2019] [Indexed: 01/17/2023] Open
Abstract
FMS-like tyrosine kinase 3 (FLT3) mutations are one of the most frequently encountered genetic alterations in acute myeloid leukemia (AML), and are generally associated with unfavorable outcomes. Several tools are currently available to provide an accurate prognosis for patients with these mutations, including FLT3 mutation type (internal tandem duplication versus tyrosine kinase domain), mutation allelic ratio (high versus low), and concurrent nucleophosmin-1 (NPM1) mutation, to help decide on optimal treatment. Recent advances in targeted therapies have paved the way for modern treatment strategies, such as the development of FLT3 kinase inhibitors. These novel drugs can be incorporated into any treatment component, including induction and consolidation, the relapse/refractory setting, bridging for transplant, salvage post-transplant, and as prophylactic long-term post-transplant maintenance. Many challenges remain though, such as their intolerability with high-dose chemotherapy in frail patients; whether their optimal use involves watchful waiting for molecular or hematologic relapse compared with prophylactic use as maintenance; and the exact role and indication for allogeneic stem cell transplantation, which arguably remains the only curative option for these high-risk patients.
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Affiliation(s)
- Abdul Hamid Bazarbachi
- Department of Haematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Paris, France
- Sorbonne University, Paris, Île-de-France, France
| | - Rama Al Hamed
- Department of Haematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Paris, France
- Sorbonne University, Paris, Île-de-France, France
| | - Florent Malard
- Department of Haematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Paris, France
- Sorbonne University, Paris, Île-de-France, France
| | - Mohamad Mohty
- Department of Haematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Paris, France
- Sorbonne University, Paris, Île-de-France, France
| | - Ali Bazarbachi
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 113-6044, Beirut, Lebanon
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7
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Song P, Cai Y, Tang H, Li C, Huang J. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017. Biosci Trends 2018; 11:389-398. [PMID: 28904327 DOI: 10.5582/bst.2017.01202] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. In this review, we made a review on current guidelines published from January 2001 to June 2017 worldwide with a focus on the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and the Japanese CiNii were systematically searched. A total of 18 characteristic guidelines for HCC management were finally included, including 8 guidelines from Asia, 5 from Europe, and 5 from the United States of America (USA). If guidelines were published in multiple versions, the most recent update was included, and surveillance, diagnosis, and treatment were compared. The composition of and recommendations in current guidelines on HCC varied, so these guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories of a "Size-based pathway" and a "Non-size-based pathway." The treatment criteria were divided into 4 categories: i) Criteria based on the Barcelona Clinic Liver Cancer staging system; ii) Criteria based on the modified Union of International Cancer Control staging system; iii) Criteria based on the Child-Pugh class of liver function; and iv) Criteria based on tumor resectability. Findings from comparison of current guidelines might help target and concentrate efforts to improve the clinical management of HCC. However, further studies are needed to improve the management and outcomes of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions in the treatment of HCC in the future.
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Affiliation(s)
- Peipei Song
- Graduate School of Frontier Sciences, The University of Tokyo
| | - Yulong Cai
- Department of Bile Duct Surgery, West China Hospital, Sichuan University
| | - Haowen Tang
- Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital
| | - Chuan Li
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University
| | - Jiwei Huang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University
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8
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Lucà MG, Nani R, Schranz M, De Giorgio M, Iegri C, Agazzi R, Sala F, Virotta G, Sarti D, Conte G, Pinelli D, Nicora C, Colledan M, Sironi S, Fagiuoli S. Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib. Future Oncol 2018; 14:727-735. [DOI: 10.2217/fon-2017-0566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: The aim was to evaluate cost–effectiveness of yttrium-90 transarterial radioembolization (TARE) in comparison to sorafenib treatment. Patients & methods: A single-center, retrospective, observational study was performed, 166 patients with intermediate-/advanced-stage hepatocellular carcinoma were treated with sorafenib and 19 with TARE. The patients out of the sorafenib group matching the inclusion criteria for TARE, were reassigned to a subgroup SOR3. Results: Mean costs for SOR3 patients amounted to €27,992 per patient, instead for TARE treatment, mean expense per patient was €17,761 (p = 0.028). Overall survival was similar between the two groups, while midterm survival rates (p = 0.012) were significantly higher with TARE treatment. Conclusion: TARE causes significantly lower treatment costs than sorafenib with better outcome in midterm survival.
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Affiliation(s)
- Maria Grazia Lucà
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Roberto Nani
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Melanie Schranz
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Massimo De Giorgio
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Claudia Iegri
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Roberto Agazzi
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Francesco Sala
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Giorgio Virotta
- Nuclear Medicine, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Donatella Sarti
- Onco-Hematology Department, Azienda Ospedaliera Ospedali Riuniti Marche Nord, via Lombroso 1, 61122 Pesaro, Italy
| | - Grazia Conte
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Domenico Pinelli
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Carlo Nicora
- General Management, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Michele Colledan
- General Surgery 3 – Abdominal Transplantations, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Sandro Sironi
- Department of Radiology, University Milano Bicocca, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
| | - Stefano Fagiuoli
- Gastroenterology 1 – Hepatology & Transplantology, ASST Papa Giovanni XXIII, Piazza OMS – Organizzazione Mondiale della Sanità 1, 24127 Bergamo, Italy
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Hesketh RL, Zhu AX, Oklu R. Radiomics and circulating tumor cells: personalized care in hepatocellular carcinoma? Diagn Interv Radiol 2016; 21:78-84. [PMID: 25430530 DOI: 10.5152/dir.2014.14237] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Personalized care in oncology is expected to significantly improve morbidity and mortality, facilitated by our increasing understanding of the molecular mechanisms driving tumors and the ability to target those drivers. Hepatocellular carcinoma has a very high mortality to incidence ratio despite localized disease being curable, emphasizing the importance of early diagnosis. Radiomics, the use of imaging technology to extrapolate molecular tumor data, and the detection of circulating tumor cells (CTCs) are two new technologies that could be incorporated into the clinical setting with relative ease. Here we discuss the molecular mechanisms leading to the development of hepatocellular carcinoma focusing on the latest developments in liver magnetic resonance imaging, CTC, and radiomic technology and their potential to improve diagnosis, staging, and therapy.
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10
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Serie de casos de pacientes con hepatocarcinoma tratados con sorafenib como terapia puente a quimioembolización y finalmente como paliativo. GACETA MEXICANA DE ONCOLOGÍA 2016. [DOI: 10.1016/j.gamo.2016.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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11
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Qi X, Zhao Y, Li H, Guo X, Han G. Management of hepatocellular carcinoma: an overview of major findings from meta-analyses. Oncotarget 2016; 7:34703-34751. [PMID: 27167195 PMCID: PMC5085185 DOI: 10.18632/oncotarget.9157] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 04/11/2016] [Indexed: 02/07/2023] Open
Abstract
This paper aims to systematically review the major findings from meta-analyses comparing different treatment options for hepatocellular carcinoma (HCC). A total of 153 relevant papers were searched via the PubMed, EMBASE, and Cochrane library databases. They were classified according to the mainstay treatment modalities (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial embolization or chemoembolization, sorafenib, and others). The primary outcome data, such as overall survival, diseases-free survival or recurrence-free survival, progression-free survival, and safety, were summarized. The recommendations and uncertainties regarding the treatment of HCC were also proposed.
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Affiliation(s)
- Xingshun Qi
- Department of Gastroenterology and Meta-analysis Study Interest Group, General Hospital of Shenyang Military Area, Shenyang, 110840 China
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
| | - Yan Zhao
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
- Department of Gastroenterology, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, 710000 China
| | - Hongyu Li
- Department of Gastroenterology and Meta-analysis Study Interest Group, General Hospital of Shenyang Military Area, Shenyang, 110840 China
| | - Xiaozhong Guo
- Department of Gastroenterology and Meta-analysis Study Interest Group, General Hospital of Shenyang Military Area, Shenyang, 110840 China
| | - Guohong Han
- Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
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Truong L, Tat J, Booy M, Le A, Marasigan JM, Yuan C, Zeng A, Panchal A, Sadler GR. The Asian Grocery Store-Based Cancer Education Program: Creating New Education Modules. JOURNAL OF CANCER EDUCATION : THE OFFICIAL JOURNAL OF THE AMERICAN ASSOCIATION FOR CANCER EDUCATION 2016; 31:292-300. [PMID: 25971431 PMCID: PMC4644696 DOI: 10.1007/s13187-015-0836-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Operating since 1994, the UCSD Moores Cancer Center's Asian Grocery Store-Based Cancer Education Program (the Program) is a proven and sustainable strategy for disseminating cancer and poison control information to Asian and Pacific Islander (API) communities. This paper describes the process taken to identify health topics that can be readily addressed within the Program's infrastructure and reports results of the pilot testing of the educational module that was developed by following that process. The development of each new module is guided by the Health Belief Model and the Tipping Point Model. The process starts with the selection of a health topic demonstrating pressing need and treatment options in the API community. Then, using the Pareto principle, reasonably modifiable risk factors are chosen to be addressed in the module. "Sticky messaging" for the modifiable risk factors is developed to package the health information as memorable and transmissible calls-to-action. Finally, grocery store outreaches were used to pilot test the new module to assess its effectiveness at facilitating health care information to API community members. By adhering to the steps described in this paper, the authors were able to: (1) select liver cancer as a pressing API health issue that could be positively impacted by the Program; (2) identify reasonably modifiable risk factors for the chosen health issue; (3) generate compelling call-to-action messages to decrease risk of exposure; and (4) demonstrate the cultural and linguistic alignment of the liver cancer control module. The development and testing of new health education modules follow a methodical process guided by scientific principles. Understanding and employing the elements of an existing evidence-based and sustainable health education program can increase the likelihood of success in addressing the health needs of the API community.
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Affiliation(s)
- Linh Truong
- University of California, San Diego, School of Medicine, 9500 Dr, Gilman, La Jolla, CA, 92093, USA
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - John Tat
- Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd, MB-07, La Jolla, CA, 92037-1000, USA
- Kellogg School of Science and Technology, The Scripps Research Institute, 10550 North Torrey Pines Rd, MB-07, La Jolla, CA, 92037-1000, USA
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Molly Booy
- Northeast Ohio Medical University, 4209 Ohio 44, Rootstown, OH, 44272, USA
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Annie Le
- Fielding School of Public Health, University of California, Los Angeles, 640 Charles E. Young Dr. S, Los Angeles, CA, 90024, USA
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Jeanne Marie Marasigan
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
- San Diego Mesa College, 7250 Mesa College Drive, San Diego, CA, 92111, USA
| | - Christine Yuan
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Athena Zeng
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Anand Panchal
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA
| | - Georgia Robins Sadler
- University of California, San Diego, School of Medicine, 9500 Dr, Gilman, La Jolla, CA, 92093, USA.
- UC San Diego Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive MC 0850, La Jolla, CA, 92093-0850, USA.
- Department of Surgery, University of California, San Diego, School of Medicine, 9500 Gilman Dr, La Jolla, CA, 92093-0850, USA.
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Parvinian A, Casadaban LC, Hauck ZZ, van Breemen RB, Gaba RC. Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model. Diagn Interv Radiol 2016; 21:235-40. [PMID: 25835078 DOI: 10.5152/dir.2014.14394] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE Use of oral sorafenib, an antiangiogenic chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by an unfavorable side effect profile. Transarterial chemoembolization (TACE) employs targeted intravascular drug administration, and has potential as a novel sorafenib delivery method to increase tumoral concentrations and reduce systemic levels. This study aimed to discern the pharmacokinetics of sorafenib TACE in a rabbit VX2 liver tumor model. METHODS A 3 mg/kg dose of sorafenib ethiodized oil emulsion was delivered via an arterial catheter to VX2 liver tumors in seven New Zealand white rabbits. Following TACE, serum sorafenib levels were measured at days 0, 1, 2, 3, 7, 10, and 14 until the time of sacrifice, after which rabbit livers were harvested for analysis of sorafenib concentrations within treated tumors and normal liver. Liquid chromatography tandem mass spectrometry was used for drug quantification. RESULTS Sorafenib uptake within liver tumor and nontumorous liver tissue peaked at mean 3.53 and 0.75 μg/mL, respectively, immediately post-procedure (5:1 tumor to normal tissue drug uptake ratio), before decreasing with a 10-18 hour half-life. Serum sorafenib levels peaked immediately after TACE at a mean value of 58.58 μg/mL before normalizing with a 5.2-hour half-life, suggesting early drug washout from liver into the systemic circulation. Hepatic lab parameters showed transient increase 24 hours post-TACE with subsequent resolution. CONCLUSION While targeted transarterial delivery of sorafenib ethiodized oil emulsion shows preferential tumor uptake compared to normal liver, systemic washout occurs with a short half-life, resulting in high circulating drug levels.
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Affiliation(s)
- Ahmad Parvinian
- Department of Radiology, University of Illinois College of Medicine, Chicago, Illinois, USA.
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Lou Y, Wang L, Qian Q, You J, Qiu W, Wang Q, Zhu K, Qiu Y. Preclinical pharmacokinetics and tissue distribution of a novel multikinase inhibitor BZG by validated UPLC-MS/MS assay. J Pharm Biomed Anal 2016; 121:107-113. [PMID: 26799978 DOI: 10.1016/j.jpba.2016.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 12/31/2015] [Accepted: 01/03/2016] [Indexed: 12/19/2022]
Abstract
A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of BZG in rat plasma and tissues. All biological samples were prepared by protein precipitation method using Imatinib as an internal standard (IS). The analyte and IS were separated on a C18 reverse phase analytical column with 4.5 min of analytical run, at flow rate of 0.3 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization (ESI) by multiple reactions monitoring (MRM) of the transitions at m/z 451.0→254.0 for BZG and m/z 494.3→394.1 for IS, respectively. The linearity of this method was found to be within the concentration range of 0.5-2500 ng/mL with a lower limit of quantification of 0.5 ng/mL. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The method was successfully applied to a pharmacokinetic and tissue distribution study of BZG in rats. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of BZG.
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Affiliation(s)
- Yan Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China
| | - Li Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China
| | - Qinbin Qian
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
| | - Wenqi Qiu
- Wenzhou Medical University,Wenzhou 325035, PR China
| | - Qian Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China
| | - Kundan Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China
| | - Yunqing Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, PR China.
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15
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Survival in relation to hospital type after resection or sorafenib treatment for hepatocellular carcinoma in The Netherlands. Clin Res Hepatol Gastroenterol 2015; 39:725-35. [PMID: 25846519 DOI: 10.1016/j.clinre.2015.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 01/21/2015] [Accepted: 02/05/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE Despite an increase in recent years, hepatocellular carcinoma remains uncommon in the Netherlands. The aim of the current study is to explore potential effects of hospital type and volume on outcomes after resection or sorafenib in patients with hepatocellular carcinoma. METHODS Initial treatment and survival of patients with hepatocellular carcinoma diagnosed in the period 2005-2011 were based on data of the Netherlands Cancer Registration. Potential risk factors (including hospital type and volume) for 30-days postoperative and long-term mortality in patients who underwent resection and in patients treated with sorafenib were evaluated by uni- and multivariate analyses. RESULTS In the period 2005-2011, 2402 patients were diagnosed with hepatocellular carcinoma: 12% received resection and 9% sorafenib. Postoperative mortality was higher in non-university hospitals (13% versus 4%; P=0.01). Resection in non-university hospitals was associated with higher postoperative mortality (odds ratio 3.38, 95% confidence interval 1.37-10.68) and long-term mortality (hazard ratio 1.21, 95% confidence interval 1.04-1.40). Sorafenib treatment in non-university hospitals was also associated with higher long-term mortality (hazard ratio 1.39, 95% confidence interval 1.06-1.82). Hospital volume was not independent predictor for outcome. CONCLUSION In low incidence countries, outcome after resection or sorafenib for hepatocellular carcinoma may differ between various hospital types.
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Varshosaz J, Farzan M. Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma. World J Gastroenterol 2015; 21:12022-12041. [PMID: 26576089 PMCID: PMC4641122 DOI: 10.3748/wjg.v21.i42.12022] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 5th most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth factor receptor receptors, monoclonal antibodies, retinoic acid receptors, integrin receptors targeted by Arg-Gly-Asp peptide, folate, and transferrin receptors are the most widely studied cell surface receptors which are used for the site specific delivery of drugs and siRNA-based therapeutics in HCC and discussed in detail in this article.
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Hepatocellular carcinoma: can circulating tumor cells and radiogenomics deliver personalized care? Am J Clin Oncol 2015; 38:431-6. [PMID: 25238287 DOI: 10.1097/coc.0000000000000123] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The 'omics revolution is facilitating a personalized approach to improving outcome by refining diagnosis, staging, treatment, and monitoring of hepatocellular carcinoma. Furthermore, the promise of being able to target a range of specific tumor drivers at a molecular level offers exciting new therapy prospects for a disease that is notoriously difficult to treat. We provide a unique perspective combining our understanding of the molecular mechanisms of hepatocellular carcinoma development with the potential of circulating tumor cells and radiogenomics to change the drivers of decision-making used in current practice.
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18
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Jo JC, Choi EK, Shin JS, Moon JH, Hong SW, Lee HR, Kim SM, Jung SA, Lee DH, Jung SH, Lee SH, Kim JE, Kim KP, Hong YS, Suh YA, Jang SJ, Choi EK, Lee JS, Jin DH, Kim TW. Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity. Mol Cancer Ther 2015; 14:2613-22. [PMID: 26351320 DOI: 10.1158/1535-7163.mct-14-0780] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 08/24/2015] [Indexed: 12/18/2022]
Abstract
The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET.
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Affiliation(s)
- Jae-Cheol Jo
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Eun Kyoung Choi
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jae-Sik Shin
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jai-Hee Moon
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Woo Hong
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Ha-Reum Lee
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Life Sciences, Sookmyung Women's University, Seoul, Republic of Korea
| | - Seung-Mi Kim
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Soo-A Jung
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Dae-Hee Lee
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seang Hwan Jung
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sun-Hye Lee
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jeong Eun Kim
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Kyu-pyo Kim
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Yong Sang Hong
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Young-Ah Suh
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Se Jin Jang
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Eun Kyung Choi
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jung Shin Lee
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Dong-Hoon Jin
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
| | - Tae Won Kim
- Innovative Cancer Research, ASAN Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
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Hoffmann K, Ganten T, Gotthardtp D, Radeleff B, Settmacher U, Kollmar O, Nadalin S, Karapanagiotou-Schenkel I, von Kalle C, Jäger D, Büchler MW, Schemmer P. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial. BMC Cancer 2015; 15:392. [PMID: 25957784 PMCID: PMC4449604 DOI: 10.1186/s12885-015-1373-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 04/27/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. METHODS Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). RESULTS The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. CONCLUSION The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group. TRIAL REGISTRATION ISRCTN24081794.
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Affiliation(s)
- Katrin Hoffmann
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Tom Ganten
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Daniel Gotthardtp
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Boris Radeleff
- Department of Radiology, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Utz Settmacher
- Department of General-, Visceral- and Vascular-Surgery, University Hospital, Erlanger Allee 101, 07747, Jena, Germany.
| | - Otto Kollmar
- Department of General and Visceral Surgery, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
| | - Silvio Nadalin
- Department of Surgery, University Hospital, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany.
| | | | - Christof von Kalle
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Dirk Jäger
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Markus W Büchler
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Peter Schemmer
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
- Department of General- Visceral- and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany.
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20
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Fouladi F, Jehn LB, Metzelder SK, Hub F, Henkenius K, Burchert A, Brendel C, Stiewe T, Neubauer A. Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation. Leuk Lymphoma 2015; 56:2690-8. [PMID: 25665465 PMCID: PMC4732463 DOI: 10.3109/10428194.2014.1003055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Gain-of-function mutations in the RAS and FLT3 genes are frequently found in cells of acute myeloid leukemia (AML), leading to constitutive activation of signaling pathways that regulate fundamental cellular processes, and are therefore attractive targets for AML therapy. The multi-targeted kinase inhibitor sorafenib is efficacious in AML with FLT3-internal tandem duplication (ITD), but resistance to therapy is an important clinical problem. It is unclear whether AML lacking FLT3-ITD responds to sorafenib. Using AML cell lines, we have shown that a low concentration of sorafenib induces opposing effects depending on the oncogenic background. In FLT3-ITD positive cells sorafenib blocks Erk activity and cell proliferation, and triggers apoptosis. However, in cells lacking FLT3-ITD, sorafenib paradoxically activates Erk2, and stimulates cellular proliferation and metabolic activity. Thus, depending on the genetic context, sorafenib is a beneficial inhibitor or paradoxical activator of mitogenic signaling pathways in AML. These results harbor important consequences in planning clinical trials in AML.
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Affiliation(s)
- Fariba Fouladi
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Lutz B Jehn
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Stephan K Metzelder
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Florian Hub
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Katharina Henkenius
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Andreas Burchert
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Cornelia Brendel
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Thorsten Stiewe
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
| | - Andreas Neubauer
- a Klinik für Innere Medizin und Hämatologie, Onkologie, Immunologie, Philipps Universität Marburg und Universitätsklinikum Gießen und Marburg , Marburg , Germany
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Biological evaluation of a novel sorafenib analogue, t-CUPM. Cancer Chemother Pharmacol 2014; 75:161-71. [PMID: 25413440 DOI: 10.1007/s00280-014-2626-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 11/06/2014] [Indexed: 01/07/2023]
Abstract
Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.
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Enguita-Germán M, Fortes P. Targeting the insulin-like growth factor pathway in hepatocellular carcinoma. World J Hepatol 2014; 6:716-737. [PMID: 25349643 PMCID: PMC4209417 DOI: 10.4254/wjh.v6.i10.716] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/14/2014] [Accepted: 08/31/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.
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Wu J, Song L, Zhao DY, Guo B, Liu J. Chemotherapy for transarterial chemoembolization in patients with unresectable hepatocellular carcinoma. World J Gastroenterol 2014; 20:10960-10968. [PMID: 25152600 PMCID: PMC4138477 DOI: 10.3748/wjg.v20.i31.10960] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/08/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the efficacy of different chemotherapeutic agents during conventional transarterial chemoembolization (cTACE) in the treatment of unresectable hepatocellular carcinoma (HCC).
METHODS: A retrospective review was undertaken of patients with unresectable HCC undergoing cTACE from May 2003 to November 2011. A total of 107 patients were treated with at least one cTACE session. Irinotecan (CPT-11) was used as a chemotherapeutic agent in 24 patients, gemcitabine (GEM) in 24 and doxorubicin in 59.
RESULTS: The time to progression and overall survival rates were significantly superior in patients treated with CPT-11 compared with the GEM or doxorubicin treated groups (11.4, 8.2, 9.5 mo, P = 0.02 and 21.7, 12.7, 14.5 mo, P = 0.004, respectively). Subgroup analysis showed that for intermediate-stage HCC, CPT-11 resulted in a significantly longer time to progression and overall survival compared with the GEM or doxorubicin treated groups (P = 0.022; P = 0.003, respectively). There were no significant differences in adverse events among the three groups (P > 0.05).
CONCLUSION: For patients treated with cTACE, the chemotherapeutic agent CPT-11 was significantly associated with improved overall survival and delayed tumor progression compared with GEM or doxorubicin. There were no significant differences in clinical adverse events between the three agents. CPT-11 thus appears to be a promising agent when combined with cTACE for the treatment of HCC.
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Peng HS, Liao MB, Zhang MY, Xie Y, Xu L, Zhang YJ, Zheng XFS, Wang HY, Chen YF. Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells. PLoS One 2014; 9:e100814. [PMID: 24956259 PMCID: PMC4067386 DOI: 10.1371/journal.pone.0100814] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 05/29/2014] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO) therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC) but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS Hepatoma cell lines (BEL-7402 and SK-Hep1) were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation) in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression in hepatoma cells.
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Affiliation(s)
- Hai-Shan Peng
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ming-Bin Liao
- Hyperbaric Oxygen Therapy Center, Affiliated Guangzhou First People's Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yin Xie
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Li Xu
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yao-Jun Zhang
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - X. F. Steven Zheng
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- * E-mail: (YFC); (HYW)
| | - Yi-Fei Chen
- Hyperbaric Oxygen Therapy Center, Affiliated Guangzhou First People's Hospital of Guangzhou Medical University, Guangzhou, China
- * E-mail: (YFC); (HYW)
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Transarterial chemoembolization (TACE) plus sorafenib versus TACE for intermediate or advanced stage hepatocellular carcinoma: a meta-analysis. PLoS One 2014; 9:e100305. [PMID: 24945380 PMCID: PMC4063775 DOI: 10.1371/journal.pone.0100305] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 05/24/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Sorafenib is used in patients with intermediate or advanced stage hepatocellular carcinoma (HCC) before or after of transarterial chemoembolization (TACE). However, the survival outcomes of TACE combined with sorafenib versus TACE alone remain controversial. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC. METHODS Pubmed and Embase databases were systematically reviewed for studies published up to November 2013, that compared TACE alone or in combination with sorafenib. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), time to progression (TTP), objective response rate (ORR), and progression free survival (PFS) using random-effects or fixed-effects model, depending on the heterogeneity between the included studies. RESULTS Six studies published from 2011 to 2013, with a total of 1254 patients, were included in this meta-analysis. The pooled results showed that TACE combined with sorafenib significantly improved OS (HR = 0.65; 95% CI: 0.47-0.89, P = 0.007), TTP (HR = 0.68; 95% CI: 0.52-0.87, P = 0.003), ORR (HR = 1.06; 95% CI: 1.01-1.12, P = 0.021), but did not affect PFS (HR = 0.84; 95% CI: 0.62-1.14, P = 0.267). The incidence of grade III/IV adverse reaction was higher in the TACE plus sorafenib group than in the TACE group. CONCLUSIONS The meta-analysis confirmed that the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC, can improve the OS, TTP, and ORR. This combination therapy was also associated with a significantly increased risk of adverse reactions.
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Plasmid transfer of plasminogen K1-5 reduces subcutaneous hepatoma growth by affecting inflammatory factors. BIOMED RESEARCH INTERNATIONAL 2014; 2014:656527. [PMID: 24895598 PMCID: PMC4034484 DOI: 10.1155/2014/656527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 04/09/2014] [Accepted: 04/10/2014] [Indexed: 11/18/2022]
Abstract
There is evidence that plasminogen K1-5 (PlgK1-5) directly affects tumour cells and inflammation. Therefore, we analysed if PlgK1-5 has immediate effects on hepatoma cells and inflammatory factors in vitro and in vivo. In vitro, effects of plasmid encoding PlgK1-5 (pK1-5) on Hepa129, Hepa1-6, and HuH7 cell viability, apoptosis, and proliferation as well as VEGF and TNF-alpha expression and STAT3-phosphorylation were investigated. In vivo, tumour growth, proliferation, vessel density, and effects on vascular endothelial growth factor (VEGF) and tumour necrosis factor alpha (TNF-alpha) expression were examined following treatment with pK1-5. In vivo, pK1-5 halved cell viability; cell death was increased by up to 15% compared to the corresponding controls. Proliferation was not affected. VEGF, TNF-alpha, and STAT3-phosphorylation were affected following treatment with pK1-5. In vivo, ten days after treatment initiation, pK1-5 reduced subcutaneous tumour growth by 32% and mitosis by up to 77% compared to the controls. Vessel density was reduced by 50%. TNF-alpha levels in tumour and liver tissue were increased, whereas VEGF levels in tumours and livers were reduced after pK1-5 treatment. Taken together, plasmid gene transfer of PlgK1-5 inhibits hepatoma (cell) growth not only by reducing vessel density but also by inducing apoptosis, inhibiting proliferation, and triggering inflammation.
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Zhang Q, Bai XL, Chen W, Ma T, Liu H, Zhang Y, Hu XJ, Liang TB. Postoperative adjuvant transarterial (chemo)embolisation after liver resection for hepatocellular carcinoma. Cochrane Database Syst Rev 2013. [DOI: 10.1002/14651858.cd010897] [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: 04/09/2025]
Affiliation(s)
- Qi Zhang
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Xue Li Bai
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Wei Chen
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Tao Ma
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Hao Liu
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Yun Zhang
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
| | - Xiao Jun Hu
- Zhejiang University; Center for Medical Information; 388 Yuhangtang Road Hangzhou China
| | - Ting Bo Liang
- the Second Affiliated Hospital, School of Medicine, Zhejiang University; Department of Hepatobiliary and Pancreatic Surgery; 88 Jiefang Road Hangzhou Zhejiang Province China 310009
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Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Berdel WE. Sorafenib in Combination With Intensive Chemotherapy in Elderly Patients With Acute Myeloid Leukemia: Results From a Randomized, Placebo-Controlled Trial. J Clin Oncol 2013; 31:3110-8. [DOI: 10.1200/jco.2012.46.4990] [Citation(s) in RCA: 258] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. Results Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. Conclusion In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.
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Affiliation(s)
- Hubert Serve
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Utz Krug
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Ruth Wagner
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - M. Cristina Sauerland
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Achim Heinecke
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Uta Brunnberg
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Markus Schaich
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Oliver Ottmann
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Justus Duyster
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Hannes Wandt
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Thomas Fischer
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Aristoteles Giagounidis
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Andreas Neubauer
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Albrecht Reichle
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Walter Aulitzky
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Richard Noppeney
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Igor Blau
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Volker Kunzmann
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Reingard Stuhlmann
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Alwin Krämer
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Karl-Anton Kreuzer
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Christian Brandts
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Björn Steffen
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Christian Thiede
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Carsten Müller-Tidow
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Gerhard Ehninger
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
| | - Wolfgang E. Berdel
- Hubert Serve, Uta Brunnberg, Oliver Ottmann, Christian Brandts, Björn Steffen, Goethe-University, Frankfurt; Utz Krug, Ruth Wagner, Carsten Müller-Tidow, and Wolfgang E. Berdel, University Hospital; Ruth Wagner, M. Cristina Sauerland, Achim Heinecke, University of Muenster, Muenster; Markus Schaich, Christian Thiede, and Gerhard Ehninger, University Hospital, Dresden; Justus Duyster, Technische Universität München, München; Hannes Wandt, Klinikum Nürnberg, Nürnberg; Thomas Fischer, University Hospital,
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Cha J, Seong J, Lee IJ, Kim JW, Han KH. Feasibility of sorafenib combined with local radiotherapy in advanced hepatocellular carcinoma. Yonsei Med J 2013; 54:1178-85. [PMID: 23918567 PMCID: PMC3743177 DOI: 10.3349/ymj.2013.54.5.1178] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Sorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy. MATERIALS AND METHODS From July 2007 to July 2011, 31 patients were treated with a daily dose of 800 mg of sorafenib and radiotherapy. Among them, 13 patients who received radiotherapy on the bone metastasis were excluded. Thirteen patients received 30-54 Gy of radiotherapy on the primary tumor (primary group) and 5 patients received 30-58.4 Gy on the measurable metastatic lesions (measurable metastasis group). Tumor responses at 1 month after the completion of radiotherapy and overall survival were evaluated. RESULTS The in-field response rate was 100% in the primary group and 60% in the measurable metastasis group. A decrease of more than 80% in the tumor marker α-fetoprotein was observed in 7 patients in the primary group (54%). Toxicities of grades 3-4 were hand-foot syndrome in 3 (17%) patients, duodenal bleeding in 1 (6%) patient, thrombocytopenia in 3 (17%) patients and elevation of aspartate transaminase in 1 (6%) patient. The median overall survival was 7.8 months (95% confidence interval, 3.0-12.6). CONCLUSION The combined treatment of sorafenib and radiotherapy was feasible and induced substantial tumor responses in the target lesions. The results of this study emphasize the importance of individualized approach in the management of advanced hepatocellular carcinoma and encourage the initiation of a controlled clinical trial.
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Affiliation(s)
- Jihye Cha
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Won Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Yonsei Liver Cancer Special Clinic, Yonsei University Health System, Seoul, Korea
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Muhammad A, Dhamija M, Vidyarthi G, Amodeo D, Boyd W, Miladinovic B, Kumar A. Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma. World J Hepatol 2013; 5:364-371. [PMID: 23898369 PMCID: PMC3724964 DOI: 10.4254/wjh.v5.i7.364] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 06/02/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the overall survival (OS) and progression-free survival (PFS) with associated adverse events (AE) in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) + sorafenib vs TACE alone.
METHODS: In this retrospective cohort study we collected data on all consecutive patients with a diagnosis of unresectable HCC between 2007 and 2011 who had been treated with TACE + sorafenib or TACE alone. We hypothesized that the combination therapy is superior to TACE alone in improving the survival in these patients. Data extracted included patient’s demographics, etiology of liver disease, histology of HCC, stage of liver disease with respect to model of end stage liver disease score and Child-Turcotte-Pugh (CTP) classification and Barcelona Clinic Liver Cancer (BCLC) staging for HCC. Computed tomography scan findings, alpha fetoprotein levels, number of treatments and related AE were also recorded and analyzed.
RESULTS: Of the 43 patients who met inclusion criteria, 13 were treated with TACE + sorafenib and 30 with TACE alone. There was no significant difference in median survival: 20.6 mo (95%CI: 13.4-38.4) for the TACE + sorafenib and 18.3 mo (95%CI: 11.8-32.9) for the TACE alone (P = 0.72). There were also no statistically significant differences between groups in OS (HR = 0.82, 95%CI: 0.38-1.77; P = 0.61), PFS (HR = 0.93, 95%CI: 0.45-1.89; P = 0.83), and treatment-related toxicities (P = 0.554). CTP classification and BCLC staging for HCC were statistically significant (P = 0.001, P = 0.04 respectively) in predicting the survival in patients with HCC. The common AE observed were abdominal pain, nausea, vomiting and mild elevation of liver enzymes.
CONCLUSION: Combination therapy with TACE + sorafenib is safe and equally effective as TACE alone in patients with unresectable HCC. CTP classification and BCLC staging were the significant predictors of survival. Future trials with large number of patients are needed to further validate this observation.
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Gaba RC, Yap FY, Martinez EM, Li Y, Guzman G, Parvinian A, van Breemen RB, Kumar N. Transarterial sorafenib chemoembolization: preliminary study of technical feasibility in a rabbit model. J Vasc Interv Radiol 2013; 24:744-50. [PMID: 23510657 DOI: 10.1016/j.jvir.2013.01.488] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 01/13/2013] [Accepted: 01/14/2013] [Indexed: 12/28/2022] Open
Abstract
PURPOSE To test the feasibility of targeted intraarterial administration of the tyrosine kinase inhibitor chemotherapeutic agent sorafenib to inhibit embolotherapy-induced tumor angiogenesis and reduce systemic drug side effects. MATERIALS AND METHODS The left hepatic lobes of five New Zealand White rabbits (mean weight, 2.7 kg±0.2) were treated with chemoembolization with sorafenib and ethiodized oil emulsion, followed by immediate euthanasia. Postprocedure noncontrast computed tomography (CT) was used to evaluate intrahepatic chemotherapy mixture distribution. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was then used to directly measure sorafenib concentration in the treated liver tissue. Histopathologic assessment of treated left lobes was performed to identify any immediate toxic effects of the sorafenib solution. RESULTS Lobar sorafenib chemoembolization was successfully performed in all cases via the left hepatic artery. Sorafenib and ethiodized oil (mean, 6.4 mg±3.8 and 0.95 mL±0.7, respectively) were injected, and CT confirmed targeted left hepatic lobe sorafenib emulsion delivery in all cases. Corresponding LC-MS/MS analysis yielded a mean sorafenib concentration of 94.2 μg/mL±48.3 in treated left lobe samples (n = 5), significantly greater than typical therapeutic drug levels (2-10 μg/mL) achieved with oral sorafenib systemic therapy. Histopathologic assessment showed only mild or moderate nonspecific ballooning degeneration in zone 3 hepatocytes, without tissue necrosis. CONCLUSIONS Targeted transarterial sorafenib delivery is feasible and results in higher tissue drug levels than reported for systemic sorafenib therapy, without immediate histopathologic tissue toxicity. Future studies should aim to determine the utility of sorafenib chemoembolization in reducing hypoxia-induced vasculogenesis in liver tumors.
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Affiliation(s)
- Ron C Gaba
- Department of Radiology and Interventional Radiology Section, University of Illinois Hospital and Health Sciences System, Chicago IL 60612, USA.
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Cheng JW, Lv Y. New progress of non-surgical treatments for hepatocellular carcinoma. Med Oncol 2013; 30:381. [PMID: 23292867 DOI: 10.1007/s12032-012-0381-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 12/11/2012] [Indexed: 02/07/2023]
Abstract
Many non-surgical treatments of hepatocellular carcinoma (HCC) have significantly improved in the last few decades and have shown survival benefits for selected patients with HCC. Today ablation can improve survival in individuals diagnosed in early HCC and even offer a curative treatment in selected candidates. Patients with intermediate-stage HCC benefit from transarterial chemoembolization (TACE). Drug-eluting bead transarterial chemoembolization (DEB-TACE) has shown a better combined ischemic and cytotoxic effect locally and less system toxicity when compared with conventional TACE. Those diagnosed at advanced stage benefit from sorafenib. In addition to TACE and sorafenib which could improve survival for selected patients, three-dimensional conformal radiotherapy treatment (3-DCRT), selection internal radiation therapy and systemic chemotherapy have also shown anti-tumor activity in the treatment of advanced HCC, but their survival benefit have not been proven. The limited effects of single therapy suggested that the combination would enhance the overall treatment effect. Other potential non-surgical therapies like gene therapy and immunotherapy are still in testing phases, except for some small-scale clinical trials which have been reported to show some beneficial effect. Here, we review the current non-surgical treatments in HCC and the new advances in this field.
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Affiliation(s)
- Ji-Wen Cheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an 710061, People's Republic of China.
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Hung CS, Liu HH, Huang MT, Cheng CW, Kuo LJ, Ho YS, Wu CH, Chen CM, Wei PL, Chang YJ. Knockdown survivin expression reduces the efficacy of curcumin treatment in hepatocellular carcinoma cells. Ann Surg Oncol 2012; 19:3547-3555. [PMID: 22711176 DOI: 10.1245/s10434-012-2393-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Indexed: 01/04/2025]
Abstract
BACKGROUND Survivin is a potential therapeutic target for cancer. Increased survivin expression promotes cell survival and therapeutic resistance. However, there is little information regarding whether the expression level of survivin affects curcumin treatment in hepatocellular carcinoma (HCC). METHODS Survivin expression was suppressed in HCC cells using a short interfering RNA (siRNA) technique. The anticancer effects of curcumin were examined using a biosensor system, MTT assay, TUNEL assay, and cell cycle analysis. RESULTS Curcumin resistance developed in cells with suppressed survivin, in contrast to the parental cells, as determined by survival assays. Cell cycle analysis and TUNEL assays revealed that the apoptotic cell population was increased in the scrambled-siRNA cells treated with curcumin compared with the survivin-siRNA cells. Suppression of survivin expression resulted in curcumin resistance via the modulation of Bcl-2 and Bax expression. CONCLUSIONS We conclude that the expression levels of survivin may mediate the therapeutic efficacy of curcumin in HCC cells.
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Affiliation(s)
- Chin-Sheng Hung
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Zhang X, Yang XR, Huang XW, Wang WM, Shi RY, Xu Y, Wang Z, Qiu SJ, Fan J, Zhou J. Sorafenib in treatment of patients with advanced hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int 2012; 11:458-466. [PMID: 23060390 DOI: 10.1016/s1499-3872(12)60209-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups. DATA SOURCES A computer-based systematic search from January 2005 to June 2011 with "sorafenib" and "advanced hepatocellular carcinoma" as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0). RESULTS Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation. CONCLUSIONS Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.
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Affiliation(s)
- Xin Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Shanghai Key Laboratory for Organ Transplantation, Shanghai 200032, China
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Zugazagoitia J, Manzano A, Sastre J, Ladero JM, Puente J, Díaz-Rubio E. Sorafenib for non-selected patient population with advanced hepatocellular carcinoma: efficacy and safety data according to liver function. Clin Transl Oncol 2012; 15:146-53. [PMID: 22875650 DOI: 10.1007/s12094-012-0902-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 04/19/2012] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Sorafenib is the standard treatment of patients with advanced hepatocellular carcinoma, regardless of the liver functional reserve. We present a single institutional series of Child-Pugh A and Child-Pugh B patients treated with sorafenib with the aim to establish the efficacy and safety of sorafenib in patients of daily clinical conditions and to compare these results between Child-Pugh A and Child-Pugh B patients. MATERIALS AND METHODS A total of 51 patients were treated with sorafenib 400 mg/12 h until disease progression or unacceptable toxicity. RESULTS The median progression-free survival and overall survival for the overall population were 3.5 and 8.2 months, respectively, with a 1-year survival rate of 27 %. Overall survival was significantly longer for patients Child-Pugh A compared with those with Child-Pugh B liver function (8.7 vs. 4.7 months, respectively). The most common adverse events were fatigue (62.7 %), diarrhea (58 %), hypertension (31.3 %), and hand-foot syndrome (31.3 %), and in most cases grade 1 or 2 according to the NCI-CTC 3.0. Grade 4 liver-related events occurred mainly in Child-Pugh B patients with decompensated cirrhosis at the time of sorafenib initiation (54.5 % of that group). DISCUSSION The benefit of sorafenib in Child-Pugh B patients, if exist, may be limited by frequent liver-related events, especially in decompensated patients, and then, toxicity and impact in quality of life should be carefully monitored.
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Affiliation(s)
- Jon Zugazagoitia
- Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), c/Martin Lagos s/n, 28040, Madrid, Spain
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Ueda H, Fukuchi H, Tanaka C. Toxicity and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma (Review). Oncol Lett 2011; 3:259-263. [PMID: 22740891 DOI: 10.3892/ol.2011.469] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 09/29/2011] [Indexed: 12/22/2022] Open
Abstract
The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly for patients with portal vein tumor thrombosis. Chemotherapy is one of the most significant treatment options for patients with advanced HCC not indicated for hepatic resection, percutaneous ablation and transcatheter arterial chemoembolization. Systemic chemotherapy does not play a central role in the treatment of HCC due to the issue of low sensitivity for chemotherapeutic agents and the difficulties in administering a sufficient dose due to chronic liver dysfunction. Therefore, patients with advanced HCC are usually treated with hepatic arterial infusion chemotherapy (HAIC), which is increasingly used as an approach to advanced HCC in Japan. HAIC provides moderate therapeutic efficacy and survival benefit with substantially tolerable toxicity profiles in patients with advanced HCC.
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Affiliation(s)
- Hiroki Ueda
- Department of Chemotherapy, Wakayama Medical University Oncology Center, Wakayama City, Wakayama 641-8509, Japan
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Lee JM, Trevisani F, Vilgrain V, Wald C. Imaging diagnosis and staging of hepatocellular carcinoma. Liver Transpl 2011; 17 Suppl 2:S34-43. [PMID: 21739567 DOI: 10.1002/lt.22369] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Jeong Min Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.
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Abstract
Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post-treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy.
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Chang YJ, Tai CJ, Kuo LJ, Wei PL, Liang HH, Liu TZ, Wang W, Tai CJ, Ho YS, Wu CH, Huang MT. Glucose-regulated protein 78 (GRP78) mediated the efficacy to curcumin treatment on hepatocellular carcinoma. Ann Surg Oncol 2011; 18:2395-2403. [PMID: 21347788 DOI: 10.1245/s10434-011-1597-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2010] [Indexed: 01/04/2025]
Abstract
BACKGROUND Glucose-regulated protein 78 (GRP78) plays an important role in the therapeutic treatment and progression of cancer. However, little is known about the effect of GRP78 expression to curcumin in hepatocellular carcinoma (HCC). MATERIALS AND METHODS In this study, we generated GRP78 knockdown cells (GRP78KD) by a short interfering RNA (siRNA) technique. The antiproliferation effects of curcumin were determined by MTT assay, TUNEL assay, and cell cycle determination. RESULTS We found that GRP78KD cells were more resistant to curcumin treatment compared with the parental cells in MTT assay. The apoptosis cell population was increased in scrambled-siRNA cells treated with curcumin compared with GRP78KD cells in cell cycle distribution and TUNEL assays. Finally, we found that knocking down GRP78 causes resistance to curcumin treatment through the suppression of caspase-3 and caspase-8 expression levels. CONCLUSIONS We conclude that the expression level of GRP78 may contribute to the therapeutic effect of curcumin on HCC cells.
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Affiliation(s)
- Yu-Jia Chang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Keld RR, Ang YS. Targeting key signalling pathways in oesophageal adenocarcinoma: A reality for personalised medicine? World J Gastroenterol 2011; 17:2781-90. [PMID: 21734785 PMCID: PMC3120937 DOI: 10.3748/wjg.v17.i23.2781] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Revised: 07/20/2010] [Accepted: 07/27/2010] [Indexed: 02/06/2023] Open
Abstract
Cancer treatments are rapidly changing. Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy. Outcomes for both regimes are generally poor as a result of tumor recurrence. We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways. There are many trials underway with the aim of improving survival in oesophageal cancer. Currently, phase 2 and 3 trials are focused on MAP kinase inhibition, either through inhibition of growth factor receptors or signal transducer proteins. In order to avoid tumor resistance, it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas. This may be achievable in the future with the advent of gene signatures and a combinatorial approach.
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Cucchetti A, Cescon M, Ercolani G, Morelli MC, Del Gaudio M, Zanello M, Pinna AD. Comparison between observed survival after resection of transplantable hepatocellular carcinoma and predicted survival after listing through a Markov model simulation. Transpl Int 2011; 24:787-96. [PMID: 21615549 DOI: 10.1111/j.1432-2277.2011.01276.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
There is still some debate on whether hepatic resection or liver transplantation should be the initial treatment for hepatocellular carcinoma (HCC) in compensated cirrhosis. Clinical data and observed survivals of 150 transplantable patients (within Milan criteria) resected for HCC were reviewed and their predicted survival after listing for liver transplantation was calculated using a Markov model simulation. Differences between observed and predicted survival estimates were explored by standardized differences (d). The mean observed survival within 5 years after surgery was 45.35 months, and the predicted survival after listing was 49.18 months (d = 0.265). The largest gain in life-expectancy with liver transplantation would be obtained in patients with Model for End-stage Liver Disease (MELD) score >9 (d = 0.403); conversely, observed and predicted survivals were similar in HCV+ patients (d = -0.002) and in patients with MELD ≤9 (d = -0.057). For T1 tumors, the observed mean estimate of survival after hepatic resection was higher than that predicted by the simulation (d = -0.606). In conclusion, in HCV patients and in those with very well compensated cirrhosis, hepatic resection could lead to results similar to those of transplantation strategy for HCC within Milan criteria; HCC T1 patients are probably best served by resection as first-line therapy rather than listing for transplantation.
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Affiliation(s)
- Alessandro Cucchetti
- Liver and Multiorgan Transplant Unit, Department of General Surgery of the S.Orsola Hospital, University of Bologna, Bologna, Italy.
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Theodoropoulos J, Brooks A. Inconsistency in the Management of Patients with Hepatocellular Carcinoma: The Need for a Strict Protocol. Am Surg 2011. [DOI: 10.1177/000313481107700223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
As more therapies become available for the treatment of hepatocellular carcinoma (HCC), the management of patients with HCC is more complex, and the indications for the various therapeutic modalities are less clear. Although all of the treatment options have shown a certain efficacy in well-selected patient groups, their everyday use, especially in nonspecialized centers, is not always appropriate. We report our experience with 81 individuals who were diagnosed and treated in our institution between 2001 and 2007. Only patients who received transplants had good long-term outcomes, and we noted significant inconsistencies in the management of patients with similar stages of disease and degrees of cirrhosis. Despite recent progress, HCC still carries an overall dismal prognosis, making the optimization of the therapeutic plan mandatory to improve outcomes. We believe that a unified protocol, as well as the early involvement of the hepatology and transplant teams, can help physicians optimize the care of these patients.
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Affiliation(s)
- John Theodoropoulos
- Hahnemann University Hospital, Philadelphia, Pennsylvania and the Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Ari Brooks
- Hahnemann University Hospital, Philadelphia, Pennsylvania and the Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
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Nery F, Graca L, Ribeiro M, Guimaraes H, Miranda HP. Sorafenib Improves Survival in Metastatic Hepatocellular Carcinoma: A Case Report. World J Oncol 2010; 1:213-217. [PMID: 29147210 PMCID: PMC5649801 DOI: 10.4021/wjon240w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2010] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a very common cancer. Curative treatments and local ones are well validated. Sorafenib, a multi-kinase receptor inhibitor was introduced in 2007 for advanced HCC in patients with preserved liver function. HCC is known to be resistant to systemic chemotherapy, and there are no validated therapies improving survival for metastatic disease. Herein, we report a case of a 45 years old woman with chronic hepatitis B infection submitted to a right hepatectomy in May 2001 for an hepatic tumor with more than 10 cm wide, confirmed as a HCC moderately differentiated. Three years later, a solitary pulmonary metastasis was documented and a metastectomy was done. In February 2009, the patient started on sorafenib 400 mg twice daily due to an inferior mediastinal metastasis with a vena cava thrombus associated. Computed tomography (CT) scan done 13 months after revealed a consistently mass reduction in more than 50% and a clinically well patient without important collateral effects. HCC is a highly vascularized tumor and sorafenib is known to inhibit both tumor angiogenesis and tumor cell survival. It is already approved for the treatment of advanced and metastatic renal cell cancer. In our case, the combination of two well done surgical procedures and the posterior use of sorafenib when a metastasis was found in an inaccessible surgical place with macroscopic vascular invasion, led to a long survival without important side effects.
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Affiliation(s)
- Filipe Nery
- Internal Medicine Department, Centro Hospitalar do Porto – Hospital Santo Antonio, Portugal
| | - Luis Graca
- Surgical Department, Centro Hospitalar do Porto – Hospital Santo Antonio, Portugal
| | - Manuel Ribeiro
- Radiology Department, Centro Hospitalar do Porto – Hospital Santo Antonio, Portugal
| | - Henrique Guimaraes
- Radiology Department, Centro Hospitalar do Porto – Hospital Santo Antonio, Portugal
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