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Periferakis A, Tsigas G, Periferakis AT, Tone CM, Hemes DA, Periferakis K, Troumpata L, Badarau IA, Scheau C, Caruntu A, Savulescu-Fiedler I, Caruntu C, Scheau AE. Agonists, Antagonists and Receptors of Somatostatin: Pathophysiological and Therapeutical Implications in Neoplasias. Curr Issues Mol Biol 2024; 46:9721-9759. [PMID: 39329930 PMCID: PMC11430067 DOI: 10.3390/cimb46090578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/28/2024] Open
Abstract
Somatostatin is a peptide that plays a variety of roles such as neurotransmitter and endocrine regulator; its actions as a cell regulator in various tissues of the human body are represented mainly by inhibitory effects, and it shows potent activity despite its physiological low concentrations. Somatostatin binds to specific receptors, called somatostatin receptors (SSTRs), which have different tissue distributions and associated signaling pathways. The expression of SSTRs can be altered in various conditions, including tumors; therefore, they can be used as biomarkers for cancer cell susceptibility to certain pharmacological agents and can provide prognostic information regarding disease evolution. Moreover, based on the affinity of somatostatin analogs for the different types of SSTRs, the therapeutic range includes conditions such as tumors, acromegaly, post-prandial hypotension, hyperinsulinism, and many more. On the other hand, a number of somatostatin antagonists may prove useful in certain medical settings, based on their differential affinity for SSTRs. The aim of this review is to present in detail the principal characteristics of all five SSTRs and to provide an overview of the associated therapeutic potential in neoplasias.
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Affiliation(s)
- Argyrios Periferakis
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
| | - Georgios Tsigas
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Aristodemos-Theodoros Periferakis
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Elkyda, Research & Education Centre of Charismatheia, 17675 Athens, Greece
| | - Carla Mihaela Tone
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Daria Alexandra Hemes
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Konstantinos Periferakis
- Akadimia of Ancient Greek and Traditional Chinese Medicine, 16675 Athens, Greece
- Pan-Hellenic Organization of Educational Programs, 17236 Athens, Greece
| | - Lamprini Troumpata
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ioana Anca Badarau
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Cristian Scheau
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Radiology and Medical Imaging, "Foisor" Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 030167 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, The "Carol Davila" Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, "Titu Maiorescu" University, 031593 Bucharest, Romania
| | - Ilinca Savulescu-Fiedler
- Department of Internal Medicine, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine and Cardiology, Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, The "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, "Prof. N.C. Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Andreea-Elena Scheau
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania
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Kasprzak A, Geltz A. The State-of-the-Art Mechanisms and Antitumor Effects of Somatostatin in Colorectal Cancer: A Review. Biomedicines 2024; 12:578. [PMID: 38540191 PMCID: PMC10968376 DOI: 10.3390/biomedicines12030578] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/02/2024] [Accepted: 03/03/2024] [Indexed: 01/03/2025] Open
Abstract
Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β-catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland;
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Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era? LIVERS 2022. [DOI: 10.3390/livers2040024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) have a very limited survival rate even after the recent inclusion of kinase inhibitors or immune checkpoint inhibitors in the therapeutic armamentarium. A significant problem with the current proposed therapies is the considerable cost of treatment that may be a serious obstacle in low- and middle-income countries. Implementation of somatostatin analogues (SSAs) has the potential to overcome this obstacle, but due to some negative studies their extensive evaluation came to a halt. However, experimental evidence, both in vitro and in vivo, has revealed various mechanisms of the anti-tumor effects of these analogues, including inhibition of cancer cell proliferation and angiogenesis and induction of apoptosis. Favorable indirect effects such as inhibition of liver inflammation and fibrosis and influence on macrophage-mediated innate immunity have also been noted and are presented in this review. Furthermore, the clinical application of SSAs is both presented and compared with clinical trials of kinase and immune checkpoint inhibitors (ICIs). No direct trials have been performed to compare survival in the same cohort of patients, but the cost of treatment with SSAs is a fraction compared to the other modalities and with significantly less serious side effects. As in immunotherapy, patients with viral HCC (excluding alcoholics), as well as Barcelona stage B or C and Child A patients, are the best candidates, since they usually have a survival prospect of at least 6 months, necessary for optimum results. Reasons for treatment failures are also discussed and further research is proposed.
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Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma. Anal Cell Pathol (Amst) 2021; 2021:1840069. [PMID: 34873567 PMCID: PMC8643256 DOI: 10.1155/2021/1840069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/12/2021] [Indexed: 11/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.
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Long Term Survival Analysis in a Cohort of 125 Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Using Small Drug Eluting Beads. Cardiovasc Intervent Radiol 2021; 45:54-61. [PMID: 34820694 DOI: 10.1007/s00270-021-02991-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 10/11/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Different types of drug-eluting beads have been proposed for hepatocellular carcinoma (HCC) treatment, but long-term results are not well known. We report safety, efficacy and long-term overall survival of HCC patients not amenable of curative therapies treated with transcatheter arterial chemoembolization (TACE) using drug-eluting beads sized 70-150 micron. MATERIALS AND METHODS This single-center retrospective study included 125 patients with Barcelona Clinic Liver Cancer stage A (80), B (45) and compensated cirrhosis. TACE was executed injecting drug-elutings microparticles loaded with 75 mg of Doxorubicine and was repeated in patients with partial response or stable disease after one month. Adverse events, response according to modified Response Evaluation Criteria in Solid Tumors and overall survival were assessed. RESULTS Chemoembolization with 70-150 micron beads revealed an objective response rate of 88% according to mRECIST criteria and complete response was 60%. After a median follow-up of 53.3 months, overall survival was 36.6 months. Data were censored at the date of liver transplantation in 35 patients. 33 on 125 patients (26,4%) experienced at least one adverse event. We recorded a total of 102 adverse events and 18 were of a high grade (G3-G4). 30 day mortality was 0%. CONCLUSION Chemoembolization with very small particles (70-150 µm) is an effective and safe treatment in unresectable HCC both as a primary therapy or as bridge to transplantation.
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Reynaert H, Colle I. Treatment of Advanced Hepatocellular Carcinoma with Somatostatin Analogues: A Review of the Literature. Int J Mol Sci 2019; 20:ijms20194811. [PMID: 31569719 PMCID: PMC6801667 DOI: 10.3390/ijms20194811] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have underlying cirrhosis, which complicates or even precludes treatment. Therefore, efficacious treatments without major side effects are welcomed. Initial results of treatment of advanced hepatocellular carcinoma with somatostatin analogues were promising, but subsequent trials have resulted in conflicting outcomes. This might be explained by different patient populations, differences in dosage and type of treatment and differences in somatostatin receptor expression in the tumor or surrounding tissue. It has been shown that the expression of somatostatin receptors in the tumor might be of importance to select patients who could benefit from treatment with somatostatin analogues. Moreover, somatostatin receptor expression in hepatocellular carcinoma has been shown to correlate with recurrence, prognosis, and survival. In this review, we will summarize the available data on treatment of primary liver cancer with somatostatin analogues and analyze the current knowledge of somatostatin receptor expression in hepatocellular carcinoma and its possible clinical impact.
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Affiliation(s)
- Hendrik Reynaert
- Department of Gastroenterology-hepatology UZBrussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
- Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabelle Colle
- Department of Gastroenterology-hepatology, ASZ Aalst, Merestraat 80, 9300 Aalst, Belgium.
- Department of Gastroenterology-hepatology, Ghent University, De Pintelaan, 9000 Ghent, Belgium.
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019; 20:1042-1113. [PMID: 31270974 PMCID: PMC6609431 DOI: 10.3348/kjr.2019.0140] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology, and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Gut Liver 2019; 13:227-299. [PMID: 31060120 PMCID: PMC6529163 DOI: 10.5009/gnl19024] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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Feun LG, Wangpaichitr M, Li YY, Kwon D, Richman SP, Hosein PJ, Savaraj N. Phase II trial of SOM230 (pasireotide LAR) in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma 2018; 5:9-15. [PMID: 29392123 PMCID: PMC5769585 DOI: 10.2147/jhc.s153672] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background A phase II trial of pasireotide was performed to assess its efficacy and safety in advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods Patients with advanced HCC and Child-Pugh score ≤7 received pasireotide LAR 60 mg intramuscularly every 28 days. Primary endpoint was disease control rate. Secondary endpoints were time to tumor progression, response rate, treatment-related adverse events, and overall survival. Serum insulin growth factor-1 was measured before and after pasireotide. Results Twenty patients were treated and evaluable. Eighteen patients (90%) had prior therapy; 16 patients (80%) had multiple therapies. Median age was 65, 75% had Barcelona Clinic Liver Cancer stage C, and 55% had metastatic disease. The main toxicity was hyperglycemia. Rare adverse effects included reversible grade 4 elevation in alanina transaminase/aspartate transaminase in one patient. The best response was stable disease in 9 patients (45%). Median time to tumor progression for the 20 patients was 3 months, and median survival was 9 months. Conclusion Pasireotide had limited clinical benefit as second-line or third-line treatment in patients with advanced or metastatic HCC. Low baseline insulin growth factor-1 level may be indicative when SOM230 treatment may be ineffective, and decreasing levels after treatment may be indicative of disease control.
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Affiliation(s)
- Lynn G Feun
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | | | - Ying-Ying Li
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Deukwoo Kwon
- Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Stephen P Richman
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Peter J Hosein
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Niramol Savaraj
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami.,Department of Surgery, Miami VA Healthcare System, Research Service
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Ray EM, Sanoff HK. Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions. J Hepatocell Carcinoma 2017; 4:131-138. [PMID: 29184856 PMCID: PMC5687453 DOI: 10.2147/jhc.s124366] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.
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Affiliation(s)
- Emily M Ray
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Hanna K Sanoff
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
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Subramanian S, Pandey U, Chaudhari P, Tyagi M, Gupta S, Singh G, Dash A, Samuel G, Venkatesh M. Preliminary evaluation of indigenous 90 Y-labelled microspheres for therapy of hepatocellular carcinoma. Indian J Med Res 2017; 143:S74-S81. [PMID: 27748281 PMCID: PMC5080932 DOI: 10.4103/0971-5916.191786] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background & objectives: Yttrium-90 (90Y)-based radioembolization has been employed to treat hepatocellular carcinoma (HCC) as commercial radioactive glass and polymeric resin microspheres. However, in India and other Asian countries, these preparations must be imported and are expensive, validating the need for development of indigenous alternatives. This work was aimed to develop an economically and logistically favourable indigenous alternative to imported radioembolizing agents for HCC therapy. Methods: The preparation of 90Y-labelled Biorex 70 microspheres was optimized and in vitro stability was assessed. Hepatic tumour model was generated in Sprague-Dawley rats by orthotopic implantation of N1S1 rat HCC cell line. In vivo localization and retention of the 90Y-labelled Biorex 70 microspheres was assessed for seven days, and impact on N1S1 tumour growth was studied by histological examination and biochemical assays. Results: Under optimal conditions, >95% 90Y-labelling yield of Biorex70 resin microspheres was obtained, and these showed excellent in vitro stability of labelling (>95%) at seven days. In animal studies, 90Y-labelled Biorex 70 microspheres were retained (87.72±1.56% retained in liver at 7 days). Rats administered with 90Y-labelled Biorex 70 microspheres exhibited lower tumour to liver weight ratio, reduced serum alpha-foetoprotein level and greater damage to tumour tissue as compared to controls. Interpretation & conclusions: 90Y-labelled Biorex 70 microspheres showed stable retention in the liver and therapeutic effect on tumour tissue, indicating the potential for further study towards clinical use.
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Affiliation(s)
- Suresh Subramanian
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Usha Pandey
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Pradip Chaudhari
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Monica Tyagi
- Advanced Centre for Treatment, Research & Education in Cancer, Navi Mumbai, India
| | - Sanjay Gupta
- Advanced Centre for Treatment, Research & Education in Cancer, Navi Mumbai, India
| | - Geetanjali Singh
- Advanced Centre for Treatment, Research & Education in Cancer, Navi Mumbai, India
| | - Ashutosh Dash
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Grace Samuel
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India
| | - Meera Venkatesh
- Isotope Production & Applications Division, Bhabha Atomic Research Centre, Mumbai, India; Division of Physical & Chemical Sciences, Department of Nuclear Sciences & Applications, International Atomic Energy Agency, 1400 Vienna, Austria,
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Zhang A, Yin C, Wang Z, Zhang Y, Zhao Y, Li A, Sun H, Lin D, Li N. Development and application of a fluorescence protein microarray for detecting serum alpha-fetoprotein in patients with hepatocellular carcinoma. J Int Med Res 2016; 44:1414-1423. [PMID: 27885040 PMCID: PMC5536749 DOI: 10.1177/0300060516672370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Objective To develop a simple, effective, time-saving and low-cost fluorescence protein microarray method for detecting serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC). Method Non-contact piezoelectric print techniques were applied to fluorescence protein microarray to reduce the cost of prey antibody. Serum samples from patients with HCC and healthy control subjects were collected and evaluated for the presence of AFP using a novel fluorescence protein microarray. To validate the fluorescence protein microarray, serum samples were tested for AFP using an enzyme-linked immunosorbent assay (ELISA). Results A total of 110 serum samples from patients with HCC (n = 65) and healthy control subjects (n = 45) were analysed. When the AFP cut-off value was set at 20 ng/ml, the fluorescence protein microarray had a sensitivity of 91.67% and a specificity of 93.24% for detecting serum AFP. Serum AFP quantified via fluorescence protein microarray had a similar diagnostic performance compared with ELISA in distinguishing patients with HCC from healthy control subjects (area under receiver operating characteristic curve: 0.906 for fluorescence protein microarray; 0.880 for ELISA). Conclusion A fluorescence protein microarray method was developed for detecting serum AFP in patients with HCC.
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Affiliation(s)
- Aiying Zhang
- 1 Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Chengzeng Yin
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Zhenshun Wang
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Yonghong Zhang
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Yuanshun Zhao
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Ang Li
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Huanqin Sun
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Dongdong Lin
- 2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Ning Li
- 1 Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China.,2 Department of General Surgery, Beijing You'an Hospital, Capital Medical University, Beijing, China
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Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, Sastre J, Martí-Bonmati L, Llovet JM, Bilbao JI, Sangro B, Pardo F, Ayuso C, Bru C, Tabernero J, Bruix J. [Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH]. Med Clin (Barc) 2016; 146:511.e1-511.e22. [PMID: 26971984 DOI: 10.1016/j.medcli.2016.01.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/22/2016] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociación Española para el Estudio del Hígado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Española de Trasplante Hepático, Sociedad Española de Radiología Médica, Sociedad Española de Radiología Vascular e Intervencionista y Sociedad Española de Oncología Médica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (www.cancer.gov) and the strength of recommendation is based on the GRADE system.
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Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, España
| | - Marta Burrel
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Jaime Feliu
- Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Sociedad Española de Oncología Médica, Madrid, España
| | - Javier Briceño
- Unidad de Trasplante Hepático, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Javier Sastre
- Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, España
| | - Luis Martí-Bonmati
- Departamento de Radiología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Josep María Llovet
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, Estados Unidos
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España; Unidad de Hepatología, Departamento de Medicina Interna, Clínica Universidad de Navarra, Pamplona, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Carmen Ayuso
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Concepció Bru
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Radiodiagnóstico, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebrón, Barcelona, Universidad Autónoma de Barcelona, Barcelona, España
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España.
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14
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Ghatalia P, Morgan CJ, Sonpavde G. Meta-analysis of regression of advanced solid tumors in patients receiving placebo or no anti-cancer therapy in prospective trials. Crit Rev Oncol Hematol 2015; 98:122-36. [PMID: 26597016 DOI: 10.1016/j.critrevonc.2015.10.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 10/05/2015] [Accepted: 10/28/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND A meta-analysis of prospective trials systematically investigated regression of advanced solid tumors in patients receiving placebo or no anticancer therapy to inform on spontaneous regressions. PATIENT AND METHODS Arms of randomized controlled trials (RCTs) of metastatic solid tumors receiving placebo or no anti-cancer therapy were used. Statistical analyses were conducted to calculate the overall response rate (ORR) and to detect differentials based on histology, progression at baseline and prior therapies. RESULTS A total of 7676 patients were evaluable from 61 RCTs evaluating 18 solid tumors. The ORR was 1.95% (95% CI: 1.52-2.48%). There was no significant effect of histology (p=0.110), baseline progressive disease (p>0.20) or the line of therapy (p>0.20) on ORR. CONCLUSIONS Spontaneous regressions are seen across all advanced solid tumors. Some malignancies demonstrated higher rates of spontaneous regressions and may be relatively immunotherapy responsive.
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Affiliation(s)
- Pooja Ghatalia
- Department of Internal Medicine, University of Alabama at Birmingham (UAB), AL, United States
| | - Charity J Morgan
- Department of Biostatistics, UAB School of Medicine, United States
| | - Guru Sonpavde
- Department of Internal Medicine, Section of Medical Oncology, UAB Medical Center, United States.
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15
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2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015; 9:267-317. [PMID: 25918260 PMCID: PMC4413964 DOI: 10.5009/gnl14460] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/09/2015] [Indexed: 12/23/2022] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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16
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Abdel-Hamid NM, Mohafez OM, Nazmy MH, Farhan A, Thabet K. The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma. Environ Health Prev Med 2015; 20:195-203. [PMID: 25726025 PMCID: PMC4434234 DOI: 10.1007/s12199-015-0451-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 02/09/2015] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES To investigate the effect of Lawsonia inermis total methanolic extract (LIE) and octreotide (OC) on hepatocellular carcinoma (HCC) progression, depending on somatostatin receptor 2 (SSTR-2) and Alfa fetoprotein (AFP) perturbations. METHODS Sixty albino mice, divided into five groups (12/each); all except control were injected with single diethyl nitrosamine (DENA) dose of 90 mg/kg body weight, intraperitoneally (IP). DENA group was killed at the last day of week 18. LIE group was given 200 mg/100 ml drinking water from first day of DENA injection until end of week 18. OC group received OC (0.1 mg/kg body weight, twice daily by subcutaneous injection, SC from the first day of week 17 till end of week 18. LIE + OC was given medications till the last day of week 18. Serum AFP, liver tissue SSTR-2 mRNA, its protein expression, reduced glutathione (GSH) and malondialdehyde (MDA) were analyzed. RESULTS A significant increase in plasma AFP and hepatic mRNA, associated to liver tissue neoplastic changes, SSTR-2 expression and MDA with decreased hepatic GSH were observed in DENA group. These changes were significantly improved by LIE and/or OC. CONCLUSIONS LIE and/or OC treatment has effective chemopreventive action due to their ability to alleviate oxidative stress, desensitizing cellular growth receptor to SST.
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Affiliation(s)
- N M Abdel-Hamid
- Biochemistry Department, Colleges of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt,
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17
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2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma. Korean J Radiol 2015; 16:465-522. [PMID: 25995680 PMCID: PMC4435981 DOI: 10.3348/kjr.2015.16.3.465] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/02/2015] [Indexed: 02/07/2023] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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18
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Sanoff HK, Kim R, Ivanova A, Alistar A, McRee AJ, O'Neil BH. Everolimus and pasireotide for advanced and metastatic hepatocellular carcinoma. Invest New Drugs 2015; 33:505-9. [PMID: 25613083 DOI: 10.1007/s10637-015-0209-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/13/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC. METHODS Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80% power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival. RESULTS After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88%) had BCLC stage C cancer, and 11 (46%) metastatic disease. Median TTP was 3.5 months (95% CI 2-5.8) and median survival 6.7 months (95% CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25%). There were no grade 4 treatment-emergent events. CONCLUSION Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.
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Affiliation(s)
- Hanna K Sanoff
- Division of Hematology and Oncology, University of North Carolina at Chapel Hill, 170 Manning Drive, CB 7305, Chapel Hill, NC, 27599, USA,
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Pivonello C, De Martino MC, Negri M, Cuomo G, Cariati F, Izzo F, Colao A, Pivonello R. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets. Infect Agent Cancer 2014; 9:27. [PMID: 25225571 PMCID: PMC4164328 DOI: 10.1186/1750-9378-9-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 06/23/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.
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Affiliation(s)
- Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | | | - Federica Cariati
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Francesco Izzo
- National Cancer Institute G Pascale Foundation, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
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20
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Gandhi S, Khubchandani S, Iyer R. Quality of life and hepatocellular carcinoma. J Gastrointest Oncol 2014; 5:296-317. [PMID: 25083303 DOI: 10.3978/j.issn.2078-6891.2014.046] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 06/25/2014] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths. Potentially curative therapies like surgery, transplant and ablation are not an option for most patients as they are often diagnosed when the disease is advanced. Liver directed therapy and oral targeted therapies are used in these patients to prolong life and palliate symptoms of the cancer and associated liver failure. Overall survival remains poor and hence health-related quality of life (HRQoL) is of paramount importance in these patients. As novel therapies are developed to improve outcomes, a comprehensive knowledge of available tools to assess impact on QoL is needed. Hence we reviewed all the studies in HCC patients published within the last 13 years from 2001-2013 which assessed HRQoL as a primary or secondary endpoint. A total of 45 studies and 4 meta-analysis were identified. Commonly used tools were European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (15 studies) and the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) (14 studies). Of the 45 publications which incorporated HRQoL as end-point only 24 were clinical trials, 17/24 (71%) assessed systemic therapies while 7/24 (29%) assessed liver-directed therapies. Majority of the publications (trials + retrospective reviews) that had HRQoL as an endpoint in HCC patients were studies evaluating liver-directed therapies (23/45 or >50%). We discuss the measures included in the tools, their interpretation, and summarize existing QoL data that will help design future HCC trials.
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Affiliation(s)
- Shipra Gandhi
- 1 Department of Internal Medicine, University at Buffalo, NY, USA ; 2 Department of Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Sapna Khubchandani
- 1 Department of Internal Medicine, University at Buffalo, NY, USA ; 2 Department of Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Renuka Iyer
- 1 Department of Internal Medicine, University at Buffalo, NY, USA ; 2 Department of Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
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21
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Germano D, Daniele B. Systemic therapy of hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2014; 20:3087-3099. [PMID: 24696596 PMCID: PMC3964381 DOI: 10.3748/wjg.v20.i12.3087] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/31/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations:resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient’s treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.
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22
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Abdel-Rahman O, Lamarca A, Valle JW, Hubner RA. Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations. Endocr Relat Cancer 2014; 21:R485-93. [PMID: 25336571 DOI: 10.1530/erc-14-0389] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Angela Lamarca
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Juan W Valle
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Richard A Hubner
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
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23
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Bharadwaj M, Roy G, Dutta K, Misbah M, Husain M, Hussain S. Tackling hepatitis B virus-associated hepatocellular carcinoma--the future is now. Cancer Metastasis Rev 2013; 32:229-68. [PMID: 23114844 DOI: 10.1007/s10555-012-9412-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in many developing countries including India. Among the various etiological factors being implicated in the cause of HCC, the most important cause, however, is hepatitis B virus (HBV) infection. Among all HBV genes, HBx is the most critical carcinogenic component, the molecular mechanisms of which have not been completely elucidated. Despite its clinical significance, there exists a very elemental understanding of the molecular, cellular, and environmental mechanisms that drive disease pathogenesis in HCC infected with HBV. Furthermore, there are only limited therapeutic options, the clinical benefits of which are insignificant. Therefore, the quest for novel and effective therapeutic regimen against HBV-related HCC is of paramount importance. This review attempts to epitomize the current state of knowledge of this most common and dreaded liver neoplasm, highlighting the putative treatment avenues and therapeutic research strategies that need to be implemented with immediate effect for tackling HBV-related HCC that has plagued the medical and scientific fraternity for decades. Additionally, this review proposes a novel "five-point" management algorithm for HBV-related HCC apart from portraying the unmet needs, principal challenges, and scientific perspectives that are relevant to controlling this accelerating global health crisis.
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Affiliation(s)
- Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, Institute of Cytology & Preventive Oncology (ICMR), Noida, India.
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24
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Liu Y, Jiang L, Mu Y. Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment. Oncol Lett 2013; 6:821-828. [PMID: 24137418 PMCID: PMC3789087 DOI: 10.3892/ol.2013.1435] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 06/21/2013] [Indexed: 01/29/2023] Open
Abstract
Liver resections for hepatocellular carcinoma (HCC) in cirrhotic livers are associated with early recurrence and poor survival. Somatostatin analogues (SSAs) have been reported to inhibit cell proliferation by interacting with specific somatostatin receptors (SSTRs) 2 and 5. The present study investigated whether SSTR expression in HCC was associated with the clinical outcome following octreotide long-acting release (LAR) treatment. Paired tumor and cirrhotic liver samples were obtained following a liver resection from 99 patients with stage I-II HCC and HBV-related cirrhosis. The expression of SSTR2 and 5 was assessed using quantitative (q)PCR and immunohistochemistry. The patients were classified into two groups, the high expression (n=47) and low expression (n=52) groups, based on the gene expression levels. The clinicopathological data and survival results of the two groups were compared. When compared with the surrounding cirrhotic tissue, the SSTR2 and 5 mRNA levels were significantly decreased in the HCC tissue. There were no significant differences between the groups with respect to the baseline characteristics. The tumor recurrence rate was significantly lower in the high expression group compared with that of the low expression group (63.83% vs. 82.69%; P=0.033). The 1-, 3- and 5-year disease-free and overall survival rates of the high expression group were 97, 89 and 71% and 98, 89 and 74%, respectively. The survival time of the members of the high expression group was longer compared with that of the low expression group. The multivariate analysis revealed that the TNM-7 stage and SSTR2 expression were independent prognostic factors for survival. In conclusion, SSTR mRNA expression correlated with survival in patients with early-stage hepatitis B virus (HBV)-related HCC who were treated with octreotide LAR following surgery. The inhibitory effects of SSAs on tumor growth may be mediated by SSTR expression.
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Affiliation(s)
- Yao Liu
- Department of Pediatric Surgery, National Center for Cardiovascular Disease and Fuwei Hospital, Chinese Acadamy of Medical Sciences, Peking Union Medical College, Beijing 100037, P.R. China
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25
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Maida M, Cabibbo G, Brancatelli G, Genco C, Alessi N, Genova C, Romano P, Raineri M, Giarratano A, Midiri M, Cammà C. Assessment of treatment response in hepatocellular carcinoma: a review of the literature. Future Oncol 2013; 9:845-854. [PMID: 23718305 DOI: 10.2217/fon.13.33] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high incidence all over the world. Even if the primary end point of treatment of HCC is survival, radiological response could be a surrogate end point of survival, and could have a key role in clinical management. Since 1950 several radiological response criteria have been applied; however, it was not until 2000 that specific criteria for HCC were introduced by the European Association for the Study of the Liver (EASL), and these were then standardized in 2010 with the development of the modified Response Evaluation Criteria for Solid Tumors (mRECIST) for HCC. The purpose of this brief review is to compare data in literature regarding the application and the performance of mRECIST in clinical practice, and to discuss unclear and open issues.
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Affiliation(s)
- Marcello Maida
- Section of Gastroenterology, DIBIMIS, University of Palermo, Piazza delle Cliniche 2, Palermo, Italy
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Dubey N, Varshney R, Shukla J, Ganeshpurkar A, Hazari PP, Bandopadhaya GP, Mishra AK, Trivedi P. Synthesis and evaluation of biodegradable PCL/PEG nanoparticles for neuroendocrine tumor targeted delivery of somatostatin analog. Drug Deliv 2012; 19:132-42. [PMID: 22428685 DOI: 10.3109/10717544.2012.657718] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Neuroendocrine tumors often present a diagnostic and therapeutic challenge. We have aimed to synthesize and develop biodegradable nanoparticles of somatostatin analogue, octreotide for targeted therapy of human neuroendocrine pancreatic tumor. METHODS Direct solid phase peptide synthesis of octreotide was done. Octreotide loaded PCL/PEG nanoparticles were prepared by solvent evaporation method and characterized for transmission electron microscopy, differential scanning calorimetery (DSC), Zeta potential measurement studies. The nanoparticles were evaluated in vitro for release studies and peptide content. For biological evaluations, receptor binding & cytotoxicity studies were done on BON-1 neuroendocrine tumor cell line. Biodistribution of radiolabeled peptide and nanoparticles, tumor regression studies were performed on tumor-bearing mouse models. RESULTS We have synthesized and purified octreotide with the purity of 99.96% in our laboratory. PEG/PCL nanoparticles with an average diameter of 130-195 nm having peptide loading efficiency of 66-84% with a negative surface charge were obtained with the formulation procedure. Octreotide nanoparticles have a negative action on the proliferation of BON-1 cells. In vivo biodistribution studies exhibited major accumulation of octreotide nanoparticles in tumor as compared to plain octreotide. Octreotide nanoparticles inhibited tumor growth more efficiently than free octreotide. CONCLUSIONS Thus, it was concluded that the PCL/PEG nanoformulation of octreotide showed high tumor uptake due to the enhanced permeation and retention (EPR) effect and then peptide ligand imparts targetability to the sst2 receptor and there by showing increase tumor growth inhibition. Selective entry of nanoparticles to the tumor also give the reduce side effects both in vivo and in vitro.
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Affiliation(s)
- Nazneen Dubey
- School of Pharmaceutical Sciences, Drug Discovery Lab, Rajiv Gandhi Technological University, Bhopal, India
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Monden M, Sakon M, Sakata Y, Ueda Y, Hashimura E. 5-fluorouracil arterial infusion + interferon therapy for highly advanced hepatocellular carcinoma: A multicenter, randomized, phase II study. Hepatol Res 2012; 42:150-65. [PMID: 22044786 DOI: 10.1111/j.1872-034x.2011.00905.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM The efficacy and safety of 5-fluorouracil arterial infusion + interferon therapy (FAIT) was evaluated in patients with hepatocellular carcinoma (HCC) with a high degree of vascular invasion associated with poor prognosis, using best salvage therapy (BST) as a reference group. METHODS Sixty-nine patients with advanced HCC with a high degree of vascular invasion (Vp3, Vp4, Vv3) were randomly assigned to a FAIT group or a BST group. The FAIT group received interferon-α and 5-fluorouracil combination therapy; the BST group received either combination therapy of cisplatin and 5-fluorouracil (low-dose FP therapy) or cisplatin for arterial infusion. RESULTS Thirty patients in the FAIT group and 31 patients in the BST group were included in the efficacy analysis. The response rate (primary endpoint) was 26.7% (eight out of 30 patients) for the FAIT group and 25.8% (eight out of 31) for the BST group. The number of occurrences of adverse events of grade 3 or higher was 115 in 30 patients in the FAIT group and 113 in 29 patients in the BST group. None of the deaths were related to the study therapy. CONCLUSIONS FAIT exerts modest antitumor effects and poses no particular safety concerns. FAIT may be a strategy of choice worth trying for advanced HCC with high degree of vascular invasion, which is associated with poor prognosis.
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Affiliation(s)
- Morito Monden
- Osaka University, Suita, Osaka Nishinomiya Municipal Central Hospital, Nishinomiya, Hyogo Misawa City Hospital, Misawa, Aomori Otsuka Pharmaceutical Co., Ltd., Osaka, Osaka, Japan
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Ji XQ, Ruan XJ, Chen H, Chen G, Li SY, Yu B. Somatostatin analogues in advanced hepatocellular carcinoma: an updated systematic review and meta-analysis of randomized controlled trials. Med Sci Monit 2011; 17:RA169-176. [PMID: 21804474 PMCID: PMC3539608 DOI: 10.12659/msm.881892] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background The role of somatostatin analogues in advanced hepatocellular carcinoma (HCC) remains controversial. The aim of this study was to examine the effect of octreotide on the survival of patients with advanced HCC. Material/Methods Electronic databases including Medline, Embase, Cochrane controlled trials register, Web of Science and PubMed (updated to Dec 2010) and manual bibliographical searches were conducted. A meta-analysis of all randomized controlled trials (RCTs) comparing octreotide versus placebo or no treatment was performed. Results Eleven RCTs including 802 patients were assessed and 9 were included in the meta-analysis. Meta-analysis showed that the 6-mo and 12-mo survival rates in the octreotide group were significantly higher than those of the control group (6-mo: RR 1.41, 95%CI 1.12–1.77, P=0.003; 12-mo: RR 2.66, 95%CI 1.30–5.44, P=0.008). When including the studies using no treatment as control, with high quality, being performed in China, including >50 patients and with follow-up >2 years, the sensitivity analyses tended to confirm the primary meta-analysis. Whereas, when including the studies using placebo as control or being performed in western countries, the difference was not significant. Conclusions This meta-analysis demonstrates that octreotide could improve the survival of patients with advanced HCC, but possibly not in western countries. The role of detecting SSTR expression in the administration of octreotide in advanced HCC needs further investigation.
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Affiliation(s)
- Xi-Qing Ji
- Department of General Surgery, The Military General Hospital of Beijing PLA, Beijing, China
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29
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Georgiadou M, Notas G, Xidakis C, Drygiannakis I, Sfakianaki O, Klironomos S, Valatas V, Kouroumalis E. TNF receptors in Kupffer cells. J Recept Signal Transduct Res 2011; 31:291-8. [DOI: 10.3109/10799893.2011.586354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Perumalswami PV, Schiano TD. The management of hospitalized patients with cirrhosis: the Mount Sinai experience and a guide for hospitalists. Dig Dis Sci 2011; 56:1266-81. [PMID: 21416246 DOI: 10.1007/s10620-011-1619-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 02/05/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cirrhosis and chronic liver disease carry appreciable morbidity and mortality. Cirrhotic patients frequently require hospitalization and their care is both extremely complex and labor-intensive. AIM We seek to provide a review for gastroenterologists, hepatologists, internists, and hospitalists on the approach to care in patients hospitalized for complications related to end-stage liver disease. METHODS The Mount Sinai Medical Center's inpatient liver service has developed an integrated team approach for cirrhotic patients and throughout the years has educated fellows-in-training and medical house staff on both the treatment principles and "pearls" in managing the hospitalized cirrhotic patient. We reviewed the literature and provide recommendations on the management of complications of end-stage liver disease. Additionally, we provide a review of the protocols used at our institution in the care for cirrhotic patients. RESULTS Major complications of advanced liver disease include infection, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, portal hypertension, variceal hemorrhage, hepatorenal syndrome, and hepatocellular carcinoma. Management of these complications involves selecting the appropriate diagnostic studies and prompt administration of therapy. CONCLUSIONS There are many complications of cirrhosis. Management of these complications can be complex and are targeted at stabilizing the patient's clinical condition. Liver transplantation remains the only definitive treatment.
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Affiliation(s)
- Ponni V Perumalswami
- Division of Liver Diseases, The Mount Sinai Medical Center, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1104, New York, NY 10029, USA
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Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G, Kouroumalis EA. Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells. World J Gastroenterol 2011; 17:313-21. [PMID: 21253389 PMCID: PMC3022290 DOI: 10.3748/wjg.v17.i3.313] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2010] [Revised: 09/25/2010] [Accepted: 10/02/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of octreotide on cellular proliferation and apoptosis of human hepatoma (HepG2) cells.
METHODS: We studied cellular proliferation, apoptosis and the possible internal caspase-mediated apoptosis pathway involved, after treatment of HepG2 carcinoma cells with octreotide in comparison with the apoptosis caused by tumor necrosis factor-α (TNF-α). Activities of caspase-3, caspase-9, caspase-8 and caspase-2 were studied, while apoptosis was investigated through detection of DNA fragmentation and through identification of apoptotic cells with the annexin-V/propidium iodide flow cytometric method.
RESULTS: After an initial increase in HepG2 cellular proliferation, a significant inhibition was observed with 10-8 mol/L octreotide, while TNF-α dose-dependently decreased proliferation. Early and late apoptosis was significantly increased with both substances. Octreotide significantly increased caspase-3, caspase-8 and caspase-2 activity. TNF-α significantly increased only caspase-2. Cellular proliferation was decreased after treatment with octreotide or TNF-α alone but, in contrast to TNF-α, octreotide decreased proliferation only at concentrations of 10-8 mol/L, while lower concentrations increased proliferation.
CONCLUSION: Our findings are suggestive of caspase-mediated signaling pathways of octreotide antitumor activity in HepG2 cells, and indicate that measurements of serum octreotide levels may be important, at least in clinical trials, to verify optimal therapeutic drug concentrations.
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Palmer D, Johnson PJ. Cytotoxic Chemotherapy and Endocrine Therapy for Hepatocellular Carcinoma. HEPATOCELLULAR CARCINOMA: 2011:337-353. [DOI: 10.1007/978-1-60327-522-4_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Hepatocellular carcinoma (HCC) is a major health problem. It is currently the third cause of cancer-related death, it is highly prevalent in the Asia-Pacific region and Africa, and is increasing in Western countries. The natural history of HCC is very heterogeneous and prediction of survival in individual patients is not satisfactory because of the wide spectrum of the disease. During the past decade, major advances have been achieved in prevention, through better surveillance of patients at risk, and in therapy through better surgical and ablative therapies and multimodal treatment approaches. Moreover, the increasing knowledge of molecular hepatocarcinogenesis provides the opportunity for targeted therapies. In this setting, the impact of sorafenib on advanced-stage HCC is a landmark finding in the treatment of liver cancer. The role of sorafenib administration as adjuvant therapy after curative treatment is being evaluated in clinical studies. Future research should lead to a molecular classification of the disease and a more personalized treatment approach.
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Affiliation(s)
- Giuseppe Cabibbo
- Sezione di Gastroenterologia, Di.Bi.Mi.S., University of Palermo, Italy
- Dipartimento di Biopatologia e Metodologie Biomediche, University of Palermo, Italy
| | - Michela Antonucci
- Department of Oncology, Division of General and Oncological Surgery, University of Palermo, Italy
| | - Chiara Genco
- Sezione di Gastroenterologia, Di.Bi.Mi.S., University of Palermo, Italy
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Abstract
Many patients are diagnosed with hepatocellular carcinoma (HCC) at an advanced or terminal stage. Due to hepatic decompensation, they have missed the best opportunity for treatment. Of all HCC staging systems, the Barcelona Clinic Liver Cancer (BCLC) staging classification is the only one that can satisfy the aspects of tumor progression, liver function and performance scale. Patients at each stage of BCLC are provided with different therapies. Interventional therapies for advanced HCC include transcatheter arterial chemoembolization (TACE), transcatheter arterial embolization (TAE) and hepatic arterial infusion chemotherapy (HIAC). HIAC may be a choice for patients with poor liver function and portal vein thrombosis (PVT). While systematic therapy for advanced HCC is not recommended and there are still disputes over the efficacy of biotherapies, molecular targeted therapy may become a first-line treatment for advanced HCC.
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Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010; 51:1274-83. [PMID: 20112254 DOI: 10.1002/hep.23485] [Citation(s) in RCA: 339] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Knowing the spontaneous outcome of hepatocellular carcinoma (HCC) is important for designing randomized controlled trials (RCTs) of new therapeutic approaches; however, survival of patients in the absence of treatment is highly variable, and prognostic factors influencing outcomes are incompletely defined. The aims of this meta-analysis were to estimate the 1-year and 2-year survival rates of untreated HCC patients enrolled in RCTs of palliative treatments, and to identify prognostic factors. RCTs evaluating therapies for HCC with placebo or no-treatment arms were identified on MEDLINE through April 2009. Data were combined in a random effect model. Primary outcomes were 1-year and 2-year survival. Thirty studies met the inclusion criteria. The pooled estimates of the survival rates were 17.5% at 1 year (95% confidence interval [95%CI], 11%-27%; range, 0%-75%) and 7.3% at 2 years (95%CI, 3.9%-13%; range, 0%-50%). Heterogeneity among studies was highly significant (P < 0.0001) both for 1-year and 2-year survival, and persisted when RCTs were stratified according to all patient and study features. Through meta-regression, impaired performance status, Child-Pugh B-C class, and presence of portal vein thrombosis were all independently associated with shorter survival. Ascites was strongly linked to a worse outcome in intermediate/advanced Barcelona Clinic Liver Cancer stages. CONCLUSION This meta-analysis confirms the heterogeneity of behavior of untreated HCC and provides a sound basis for stratifying patients with HCC according to expected survival in future trials of new anti-cancer agents.
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Affiliation(s)
- Giuseppe Cabibbo
- Cattedra di Gastroenterologia, DIBIMIS, University of Palermo, Italy
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Forner A, Rodríguez De Lope C, Reig M, Bruix J. [Treatment of advanced hepatocellular carcinoma]. GASTROENTEROLOGIA Y HEPATOLOGIA 2010; 33:461-8. [PMID: 20227796 DOI: 10.1016/j.gastrohep.2009.12.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Accepted: 12/12/2009] [Indexed: 12/28/2022]
Abstract
In the last few years, much progress has been made in the diagnosis and treatment of hepatocellular carcinoma (HCC). Due to these advances, HCC is no longer regarded as a disease with an extremely poor prognosis and has become the focus of some of the most active basic and clinical research in recent years. The most important advance is possibly the demonstration that sorafenib, a multikinase inhibitor with antiproliferative and antiangiogenic properties, is an effective treatment, able to increase survival in patients with advanced-stage HCC. This increased survival has demonstrated that these drugs, which act selectively on the molecular pathways involved in tumoral progression, can be effective in the treatment of HCC and has opened the door to the evaluation of these molecular agents, alone or in combination, in HCC. The present article provides a review of the treatment of advanced-stage HCC, with special emphasis on the distinct agents that are currently under evaluation.
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Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (BCLC), Servicio de Hepatología, ICMDM, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España.
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Liu J, Mittendorf T, von der Schulenburg JM. A structured review and guide through studies on health-related quality of life in kidney cancer, hepatocellular carcinoma, and leukemia. Cancer Invest 2010; 28:312-22. [PMID: 19863345 DOI: 10.3109/07357900903287022] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Aim of this paper is to review and describe Health-Related Quality of Life (HRQoL) measures applied in kidney cancer, hepatocellular carcinoma, and leukemia patients under drug therapy. A comprehensive search in PubMed was conducted to identify studies assessing quality of life (QoL) in these indications. In total 32 studies, including four studies through reference list checking and 21 different HRQoL instruments, were identified. Six generic, five disease-specific, and 10 domain-specific instruments were identified. In conclusion no overall standards in HRQoL measurement could be observed in the respective indications.
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Affiliation(s)
- Jia Liu
- Center for Health Economics, Leibniz University Hannover, Hannover, Germany
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Bornschein J, Drozdov I, Malfertheiner P. Octreotide LAR: safety and tolerability issues. Expert Opin Drug Saf 2010; 8:755-68. [PMID: 19998528 DOI: 10.1517/14740330903379525] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Somatostatin analogues are the cornerstone in therapy of acromegaly and functioning neuroendocrine tumors. Long-acting retard formulations have improved patient survival and contributed considerably to quality of life. The first such compound was octreotide LAR ('long-acting release'), characterized by high affinity to somatostatin receptor subtypes 2 and 5, which has to be injected intramuscularly every 4 weeks. OBJECTIVE The aim was to screen all octreotide LAR-related literature and assess the compound's profile for safety and tolerability. METHODS An extensive literature search has been performed using the MEDLINE database to retrieve data from clinical studies evaluating the efficacy and tolerability of octreotide LAR. RESULTS/CONCLUSION Octreotide LAR is well tolerated; however, diarrhea and gallstone formation were identified as the main adverse events. Impairment of glucose homeostasis was a regular phenomenon, but its occurrence was unpredictable. General side effects such as headache, abdominal discomfort or fatigue were also reported. According to incidental case reports, administration during pregnancy appears to be safe for both mother and child; however, definitive evidence is missing. In addition, octreotide LAR has been evaluated for further indications including treatment of solid tumor entities, due to its antiproliferative effect. Currently, several compounds (lanreotide, SOM230) with a broader receptor spectrum are under evaluation and may improve treatment efficacy and lower incidence of side effects.
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Affiliation(s)
- Jan Bornschein
- Otto-von-Guericke University of Magdeburg, Department of Gastroenterology, Hepatology and Infectious Diseases, Germany
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40
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Giacomin A, Sergio A, Vanin V, Tartaro P, Paccagnella D, Mazzucco M, Farinati F. Megestrol and embryonic extracts in the treatment of advanced hepatocellular carcinoma: A prospective randomized trial in the pre-sorafenib era. Hepatol Res 2010; 40:153-60. [PMID: 20070403 DOI: 10.1111/j.1872-034x.2009.00588.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma (HCC) achieved significant results by the new treatment with sorafenib (a multi-tyrosine kinase inhibitor), but, because it has been tested mainly in Child A cirrhosis, patients with impaired liver function are not eligible for the treatment. METHODS This study was an open label phase III randomized trial comparing Synchro-Levels (Alphrema, Varese, Italy) and megestrol, with a 2:1 design, in patients with advanced HCC, planned before the sorafenib registration. End-points were objective response and impact on performance status (primary) and biochemical response (secondary). RESULTS The patients enrolled were 61 (43 men, 18 women; Child A in 28 [48%] and B in 33 [52%]). Forty-three were assigned to Synchro-Levels, 18 to megestrol. Most patients had multifocal disease (75% in megestrol and 59% in Synchro-Levels) and there was a significant difference in tumor burden, with more advanced disease in the megestrol arm (P = 0.0002). At 3 months, tumor burden was more frequently stable with megestrol, while performance status was significantly better in patients treated with Synchro-Levels. At 6 months, alpha-fetoprotein was more frequently stable or reduced with megestrol. An objective response was observed in a megestrol-treated patient. Mortality was significantly lower and long-term survival significantly more frequent with megestrol. CONCLUSION Megestrol treatment shows good results in advanced HCC and could become part of best supportive care in patients not suitable for other treatments, that, despite sorafenib, remain an important share.
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Affiliation(s)
- Anna Giacomin
- Department of Surgical and Gastroenterological Sciences, Padua University, Via Giustiniani,Padua, Italy
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[Practice guidelines for management of hepatocellular carcinoma 2009]. THE KOREAN JOURNAL OF HEPATOLOGY 2010; 15:391-423. [PMID: 19783891 DOI: 10.3350/kjhep.2009.15.3.391] [Citation(s) in RCA: 221] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major cancer in Korea, typically has a poor prognosis, and constitutes the majority of primary hepatic malignancies. It is the number one cause of death among people in their 50s in Korea. The five-year survival rate of liver cancer is poor; at 18.9%. Efforts to increase the survival rate through early diagnosis of HCC and optimal treatments are keenly needed. Western guideline for the management of HCC were developed, but these guidelines are somewhat unsuitable for Korean patients. Thus, the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC), Korea jointly produced the Clinical Practice Guidelines for HCC for the first time in Korea in 2003. Owing to medical advances over the following six years, diagnosis and treatment of HCC has changed considerably. As more national and foreign data are accumulated, KLCSG and NCC, Korea recently revised the Clinical Practice Guidelines for HCC. Forty or more specialists in the field of hepatology, general surgery, radiology and radiation oncology participated, and meticulously reviewed national and foreign papers, and collected opinions through advisory committee conferences. These multidisciplinary, evidence-based guidelines summarized diagnosis, surgical resection, liver transplantation, local treatments, transarterial chemoembolization, radiation therapy, chemotherapy, preemptive antiviral treatments, and response evaluation of HCC. These Korean guidelines are expected to be useful for clinical management of and research on HCC.
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Affiliation(s)
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- Korean Liver Cancer Study Group and National Cancer Center, Korea.
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Geographic difference in survival outcome for advanced hepatocellular carcinoma: Implications on future clinical trial design. Contemp Clin Trials 2010; 31:55-61. [PMID: 19737631 DOI: 10.1016/j.cct.2009.08.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2009] [Revised: 08/19/2009] [Accepted: 08/31/2009] [Indexed: 01/15/2023]
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Guo TK, Hao XY, Ma B, Yang KH, Li YP, Li HL, Gu YH, Cai H, Liu YL, Li Y, Zhan WP. Octreotide for advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials. J Cancer Res Clin Oncol 2009; 135:1685-92. [PMID: 19536563 DOI: 10.1007/s00432-009-0615-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2008] [Accepted: 05/27/2009] [Indexed: 12/20/2022]
Abstract
PURPOSE To evaluate the effectiveness of octreotide in advanced hepatocellular carcinoma participants on the basis of randomized controlled trials. METHODS We searched the Cochrane Center Register of Controlled Trials in The Cochrane Library, PubMed, EMBASE, Chinese Biomedical Literature Database, China Journal Full-text Database, Chinese Scientific Journals Database up to June 2008 in any language. Randomized controlled trials of octreotide for advanced hepatocellular carcinoma were selected and evaluated by two investigators. Any disagreement was solved by discussion. Analyses were performed using Review Manager 4.2. RESULTS Six randomized controlled trials totaling 352 participants were included. The median survival time was reported in four randomized controlled trials. The results between the octreotide group and the control group (the placebo or best supportive care group) were as follows: 13.0 versus 4.0 months, 1.93 versus 1.97 months, 4.7 versus 5.3 months, and 7.0 versus 2.5 months. Three randomized controlled trials reported 6-month survival rates and 12-month survival rates and meta-analysis results in these two outcomes [(RR 1.35, 95% CI 0.92-1.97); (RR 1.35, 95% CI 0.66-11.16) respectively] were not found to be statistically significant by random-effects model. When we analyzed 6-month survival rates by fixed-effect model (RR 1.30, 95% CI 1.02-1.66), meta-analysis result reached statistical significance. CONCLUSIONS As for the limitations of the included trials, the result may not demonstrate a significant superiority of octreotide administration in participants with advanced hepatocellular carcinoma from the available evidence.
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Affiliation(s)
- Tian-Kang Guo
- The People's Hospital of Gansu Province, Dong Gang West Road No. 160, Lanzhou City, Gansu Province, People's Republic of China
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Schöniger-Hekele M, Kettenbach J, Peck-Radosavljevic M, Müller C. Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2009; 28:142. [PMID: 19887008 PMCID: PMC2779805 DOI: 10.1186/1756-9966-28-142] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Accepted: 11/03/2009] [Indexed: 12/12/2022]
Abstract
Background Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care. Methods 95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study. Results Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy. Conclusion Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.
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Affiliation(s)
- Maximilian Schöniger-Hekele
- Universitätsklinik für Innere Medizin III, Klinische Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria.
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Fenoglio L, Castagna E, Serraino C, Cardellicchio A, Pomero F, Bracco C, Grosso M. Gestione del carcinoma epatocellulare: le linee guida internazionali. ITALIAN JOURNAL OF MEDICINE 2009. [DOI: 10.1016/j.itjm.2008.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Rampone B, Schiavone B, Martino A, Viviano C, Confuorto G. Current management strategy of hepatocellular carcinoma. World J Gastroenterol 2009; 15:3210-6. [PMID: 19598295 PMCID: PMC2710775 DOI: 10.3748/wjg.15.3210] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) still remains a considerable challenge for surgeons. Surgery, including liver transplantation, is the most important therapeutic approach for patients with this disease. HCC is frequently diagnosed at advanced stages and has a poor prognosis with a high mortality rate even when surgical resection has been considered potentially curative. This brief report summarizes the current status of the management of this malignancy and includes a short description of new pharmacological approaches in HCC treatment.
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for development of HCC are well defined and some steps of hepatocellular carcinogenesis have been elucidated. Despite these scientific advances and the implementation of measures for early detection of HCC in patients who are at risk of this disease, survival of patients has not improved greatly over the past three decades. This situation is partly due to the limited therapeutic options available. While surgery and percutaneous or transarterial interventions are effective for patients with limited or compensated underlying liver disease, more than 80% of patients present with multifocal HCC and/or advanced liver disease, or have comorbidities at the time of diagnosis. Treatment options for these patients have previously been limited to best supportive care. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In 2007, the multitargeted kinase inhibitor, sorafenib, was found to prolong survival significantly for patients with advanced HCC. This Review discusses the mechanisms of targeted therapies and clinical studies that have investigated these therapies in patients with HCC. Perspectives for future developments are also provided.
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AZAD A, CHIONH F, CEBON J. Targeted agents for the systemic treatment of advanced hepatocellular carcinoma. Asia Pac J Clin Oncol 2009. [DOI: 10.1111/j.1743-7563.2009.01202.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Barbare JC, Bouché O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, Raoul JL, Cattan S, Lemoine A, Blanc JF, Bronowicki JP, Zarski JP, Cazorla S, Gargot D, Thevenot T, Diaz E, Bastie A, Aparicio T, Bedenne L. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer 2009; 45:1788-97. [PMID: 19303768 DOI: 10.1016/j.ejca.2009.02.018] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 02/10/2009] [Accepted: 02/13/2009] [Indexed: 12/27/2022]
Abstract
BACKGROUND A previous study reported a significant survival benefit for octreotide compared with no treatment in patients with advanced hepatocellular carcinoma (HCC). This was investigated further in this multicentre study. PATIENTS AND METHODS Two hundred and seventy two patients with HCC who were ineligible for curative treatments or had relapsed following potentially curative therapies were randomised to receive long-acting octreotide, 30 mg as an intramuscular injection once every 4 weeks for up to 2 years, or placebo. RESULTS At the time of the final analysis, median overall survival (OS) was 6.53 months (95% confidence interval [CI], 4.8-8.3) for octreotide versus 7.03 months (95% CI, 5.43-8.53) for placebo (p=0.34). Progression-free survival (p=0.26) also did not differ significantly between the two treatment groups. No objective responses were achieved in the octreotide group but 33% of patients achieved disease stabilisation for a mean time of 5.5 months (95% CI, 1.1-9.9). The median time until definitive global health score deterioration (according to QLQ-C30) was 2.3 months (95% CI, 1.4-3.7) in the octreotide and 4 months (95% CI, 2.2-5.7) in the placebo group (p=0.09). There were four objective responses in the placebo group. Octreotide was well tolerated; seven patients reported severe adverse events possibly related to octreotide and there were no cases of haematoma or cholecystitis. CONCLUSIONS In patients with advanced HCC, octreotide has a favourable safety profile but does not improve OS and could have a negative impact on quality of life.
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Affiliation(s)
- Jean-Claude Barbare
- Fédération Francophone de Cancérologie Digestive, Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux, France.
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Abstract
OBJECTIVE To estimate the actual frequency of spontaneous regression of hepatocellular carcinoma. METHODS A systematic review of the literature published during 1978-2007 has been carried out to identify randomized clinical trials of hepatocellular carcinoma that included a control arm receiving either placebo or best supportive care, and in which patients were followed prospectively for tumor response using predefined criteria. Data extraction was conducted independently by two investigators. A meta-analysis to provide a global estimation of regressions in the control arms was performed using an empiric Bayesian random-effects model. RESULTS We identified 16 cases of regression (including minor and partial responses) in 10 phase III clinical trials. The rate of spontaneous objective partial regression among patients with hepatocellular carcinoma was 0.406% [95% confidence interval: 0.067-1.043%]. CONCLUSION Although very infrequent, spontaneous regression is not an extraordinary event among patients with hepatocellular carcinoma. Therefore, individual responses to any given therapy should be assessed with caution and this fact may be considered at the time of calculating sample size of pilot clinical trials of new agents.
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