|
1
|
Ryoo BY, Palmer DH, Park SR, Rimassa L, Daniele B, Steinberg J, López B, Lim HY. Efficacy and Safety Results from a Phase 2, Randomized, Double-Blind Study of Enzalutamide Versus Placebo in Advanced Hepatocellular Carcinoma. Clin Drug Investig 2021; 41:795-808. [PMID: 34351608 DOI: 10.1007/s40261-021-01063-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Despite recent advances, more effective therapeutic options for patients with advanced HCC are still required. The aim of this Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled study (NCT02528643) was to investigate the potential benefit of enzalutamide in the treatment of patients with advanced HCC. METHODS Patients aged ≥ 18 years diagnosed with advanced HCC (Barcelona Clinic Liver Cancer stage B or C and Child-Pugh class A at screening who had progressed on, or were intolerant to, sorafenib or other anti-vascular endothelial growth factor therapies) were randomized 2:1 to receive either enzalutamide 160 mg daily or placebo. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and safety. RESULTS In total, 165 patients were randomized to enzalutamide (n = 110) or placebo (n = 55). The hazard ratio (HR) (95% confidence interval [CI]) for OS was 1.15 (0.774-1.696) and median OS was 7.8 months and 7.7 months for enzalutamide and placebo, respectively. The HR (95% CI) for PFS was 1.04 (0.732-1.474) and median PFS was 2.2 months and 1.9 months for enzalutamide and placebo, respectively. The overall frequency of treatment-emergent adverse events (TEAEs) was broadly similar between the groups: 105 (98.1%) enzalutamide patients experienced ≥1 TEAEs compared with 49 (89.1%) placebo patients. CONCLUSIONS The results of this study indicate that enzalutamide does not provide a benefit in patients with advanced HCC. No unexpected safety findings were observed in the trial. CLINICALTRIALS. GOV IDENTIFIER NCT02528643.
Collapse
Affiliation(s)
- Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
| | - Daniel H Palmer
- Liverpool CR UK/NIHR Experimental Cancer Medicine Centre, and The Clatterbridge Cancer Centre, Liverpool, UK
| | - Sook Ryun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Bruno Daniele
- Department of Oncology, G. Rummo Hospital, Benevento, Italy
- Oncology Unit, Ospedale del Mare, Naples, Italy
| | | | - Beatriz López
- Data Science, Astellas Pharma Inc., Leiden, The Netherlands
- Quantitative Sciences, Janssen R&D, Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands
| | - Ho Yeong Lim
- Division of Hematology-OncologyDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| |
Collapse
|
|
2
|
Costa-Santos MP, Gonçalves A, Ferreira AO, Nunes J. Spontaneous regression of hepatocellular carcinoma: myth or reality? BMJ Case Rep 2020; 13:13/2/e233509. [PMID: 32047089 DOI: 10.1136/bcr-2019-233509] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We present a case of a 68-year-old man with chronic hepatitis C infection, with no evidence of chronic liver disease during the first years of follow-up, diagnosed with a hepatocellular carcinoma (HCC) with 40 mm (α-fetoprotein (AFP) 205 ng/mL). He underwent segmental liver resection and pathology analysis was consistent with HCC and cirrhosis in the adjacent liver. Four months after surgery, AFP raised up to 126 661 ng/mL and abdominal MRI revealed a multinodular HCC. Patient rejected treatment with sorafenib and started megestrol and an herbal medicine, soursop (Annona muricata). Six months later, AFP markedly decreased (28 ng/mL) and abdominal MRI showed decreasing size and number of lesions. At 5 years of follow-up, he has no evidence of HCC. Spontaneous regression of HCC is a rare condition and the underlying mechanism is unclear. In this case there is a temporal relation between the start of megestrol and Annona muricata and HCC regression.
Collapse
Affiliation(s)
| | | | | | - Joana Nunes
- Gastroenterology Department, Hospital Beatriz Ângelo, Loures, Portugal
| |
Collapse
|
|
3
|
Mardian Y, Yano Y, Ratnasari N, Choridah L, Wasityastuti W, Setyawan NH, Hayashi Y. "Sarcopenia and intramuscular fat deposition are associated with poor survival in Indonesian patients with hepatocellular carcinoma: a retrospective study". BMC Gastroenterol 2019; 19:229. [PMID: 31888500 PMCID: PMC6937974 DOI: 10.1186/s12876-019-1152-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/18/2019] [Indexed: 02/08/2023] Open
Abstract
Background A large-scale Japanese study showed that low skeletal muscle index (SMI) and intramuscular fat (IMF) deposition are associated with hepatocellular carcinoma (HCC) survival. Here, we evaluated the effects of SMI and IMF on the survival of Indonesian HCC patients, whose characteristics differ from those of Japanese patients. Methods SMI and mean muscle attenuation (MA) were evaluated using computed tomography images of the third lumbar vertebra (L3) in a prospective cohort of 100 Indonesian HCC patients. Clinical, laboratory and body composition data were analysed using the Kaplan–Meier method and Cox regression model to investigate which factors are associated with prognosis. Results Of 100 patients, 31 were diagnosed with sarcopenia (L3 SMI value ≤36.2 cm2/m2 for men and ≤ 29.6 cm2/m2 for women), and 65 had IMF deposition (MA value ≤44.4 HU for men and ≤ 39.3 HU for women). These groups had shorter median survival than the reference groups (both P < 0.0001). In multivariable analysis, sarcopenia (hazard ratio [HR], 1.921; P = 0.016), IMF deposition (HR, 3.580; P < 0.001), Barcelona Clinic Liver Cancer (BCLC) stages C and D (HR: 2.396, P < 0.01 and HR: 6.131, P < 0.01, respectively), Japan Integrated Staging (JIS) score 4 (HR: 2.067, P = 0.020), and male gender (HR: 3.211, P < 0.001) were independently associated with mortality. Conclusion Sarcopenia and IMF deposition showed superior value in combination with BCLC stage and JIS score for predicting the survival of Indonesian HCC patients. Increased awareness and strategies to prevent or reverse these factors might improve patient outcomes. (Electric word counts: 249).
Collapse
Affiliation(s)
- Yan Mardian
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiko Yano
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, Kobe, Japan. .,Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Neneng Ratnasari
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia
| | - Lina Choridah
- Department of Radiology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia
| | - Widya Wasityastuti
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nurhuda Hendra Setyawan
- Department of Radiology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia
| | - Yoshitake Hayashi
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
4
|
Efficacy and safety of megestrol in the management of hepatocellular carcinoma: a systematic review of the literature. Contemp Oncol (Pozn) 2018; 22:209-214. [PMID: 30783383 PMCID: PMC6377423 DOI: 10.5114/wo.2018.82641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 09/24/2018] [Indexed: 01/06/2023] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. There is as yet no standard therapy for inoperable HCC. We aimed to systematically review all health-related evidence regarding the effectiveness and safety of megestrol in HCC patients. Material and methods We conducted a systematic computerised search in PubMed, Scopus, Web of Science, Embase, and Cochrane CENTRAL. All original human studies reporting the efficacy of megestrol in HCC patients were included in our review. Results Six studies including 357 patients were finally eligible. The overall mean survival time of 87 megestrol-treated patients, was 9.187 (95% CI 1.134–17.239) months. Eight patients had tumour size enlargement, and eight patients had tumour size reduction. From three studies including 76 patients, 42 patients reported having improvement of appetite and food intake after receiving megestrol. Diverse adverse events were noticed between studies; however, they were tolerable in most of the studies. Conclusions To summarise, no conclusive evidence should be declared regarding the effectiveness of megestrol in patients with inoperable HCC. However, previous studies have shown promising results at the level of prolonging the survival rate, tumour size reduction, and improving the quality of life. Therefore, we recommend that future research studies must examine the role of megestrol in large-population, randomised studies.
Collapse
|
|
5
|
Tsai HW, Ho CL, Cheng SW, Lin YJ, Chen CC, Cheng PN, Yen CJ, Chang TT, Chiang PM, Chan SH, Ho CH, Chen SH, Wang YW, Chow NH, Lin JC. Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma. World J Gastroenterol 2018; 24:1152-1166. [PMID: 29563759 PMCID: PMC5850134 DOI: 10.3748/wjg.v24.i10.1152] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/16/2018] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).
METHODS We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.
RESULTS We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P = 0.004), poorer tumor differentiation (P = 0.045) and liver capsule penetration (P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort (P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects.
CONCLUSION PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.
Collapse
Affiliation(s)
- Hung-Wen Tsai
- Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Shu-Wen Cheng
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Chou-Cheng Chen
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Ting-Tsung Chang
- Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Po-Min Chiang
- Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Shih-Huang Chan
- Department of Statistics, College of Management, National Cheng Kung University, Tainan 70403, Taiwan
| | - Cheng-Hsun Ho
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Shu-Hui Chen
- Department of Chemistry, College of Sciences, National Cheng Kung University, Tainan 70403, Taiwan
| | - Yi-Wen Wang
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Nan-Haw Chow
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Jou-Chun Lin
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| |
Collapse
|
|
6
|
Xia Y, Liu X, Liu B, Zhang X, Tian G. Enhanced antitumor activity of combined megestrol acetate and arsenic trioxide treatment in liver cancer cells. Exp Ther Med 2018; 15:4047-4055. [PMID: 29581752 DOI: 10.3892/etm.2018.5905] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/19/2018] [Indexed: 12/23/2022] Open
Abstract
Liver cancer is an aggressive malignancy with a very high fatality rate. Although megestrol acetate (MA) and arsenic trioxide (ATO) have shown an antitumor effect in liver cancer cells, the therapeutic benefits of MA or ATO alone in patients with liver cancer were limited. The aim of the present study was to elucidate whether the co-treatment of MA/ATO could enhance antitumor efficacy in liver cancer cell lines (Hep G2 and BEL 7402) and explore the underlying anti-cancer mechanisms. The cell viability, apoptotic response and expression levels of associated proteins were detected by Cell Counting Kit-8 assay, flow cytometry and western blotting, respectively. An xenograft model in nude mice bearing a Hep G2 tumor was used to estimate tumor growth in vivo. Co-treatment with MA/ATO markedly improved the inhibition of cell viability, enhanced apoptosis, and increased the phosphorylation of p38, c-Jun N-terminal kinase 1/2 and extracellular signal-regulated kinase 1/2 on liver cancer cell lines. Furthermore, the tumor growth in the murine Hep G2 cancer xenograft model was significantly inhibited by combined treatment with MA/ATO. The results indicated that MA/ATO combined treatment enhanced antitumor efficacy and possessed potential application for treating liver cancer.
Collapse
Affiliation(s)
- Yan Xia
- Department of Biotherapy Research Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| | - Xianhao Liu
- Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| | - Beibei Liu
- Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| | - Xiaoshi Zhang
- Department of Biotherapy Research Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Geng Tian
- Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Cidon EU. Systemic treatment of hepatocellular carcinoma: Past, present and future. World J Hepatol 2017; 9:797-807. [PMID: 28706578 PMCID: PMC5491402 DOI: 10.4254/wjh.v9.i18.797] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 05/07/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common neoplasia which represents the second leading cause of cancer related death. Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C. Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment. HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc. Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients. This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.
Collapse
Affiliation(s)
- Esther Una Cidon
- Esther Una Cidon, Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom
| |
Collapse
|
|
9
|
Li Y, Li H, Spitsbergen JM, Gong Z. Males develop faster and more severe hepatocellular carcinoma than females in kras V12 transgenic zebrafish. Sci Rep 2017; 7:41280. [PMID: 28117409 PMCID: PMC5259773 DOI: 10.1038/srep41280] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 12/19/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is more prevalent in men than women, but the reason for this gender disparity is not well understood. To investigate whether zebrafish could be used to study the gender disparity of HCC, we compared the difference of liver tumorigenesis between female and male fish during early tumorigenesis and long-term tumor progression in our previously established inducible and reversible HCC model - the krasV12 transgenic zebrafish. We found that male fish developed HCC faster than females. The male tumors were more severe from the initiation stage, characteristic of higher proliferation, activation of WNT/β-catenin pathway and loss of cell adhesion. During long-term tumor progression, the male tumors developed into more advanced multi-nodular tumors, whereas the female tumors remain uniform and homogenous. Moreover, regression of male tumors required longer time. We further investigated the role of sex hormones in krasV12 transgenic fish. Estrogen treatment showed tumor suppressing effect during early tumorigenesis through inhibiting cell proliferation, whereas androgen accelerated tumor growth by promoting cell proliferation. Overall, our study presented the zebrafish as a useful animal model for study of gender disparity of HCC.
Collapse
Affiliation(s)
- Yan Li
- Department of Biological Sciences, National University of Singapore, 117543, Singapore
| | - Hankun Li
- Department of Biological Sciences, National University of Singapore, 117543, Singapore
| | - Jan M. Spitsbergen
- Department of Microbiology, Oregon State University, Corvallis, Oregon, 97331, USA
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, 117543, Singapore
| |
Collapse
|
|
10
|
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.
Collapse
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.
| |
Collapse
|
|
11
|
Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, Umemoto K, Okusaka T. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future. Diseases 2015; 3:360-381. [PMID: 28943630 PMCID: PMC5548259 DOI: 10.3390/diseases3040360] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 12/18/2022] Open
Abstract
Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected.
Collapse
Affiliation(s)
- Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Shuichi Mitsunaga
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Izumi Ohno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Yusuke Hashimoto
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Hideaki Takahashi
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Kazuo Watanabe
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Kumiko Umemoto
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
| |
Collapse
|
|
12
|
Chen KW, Ou TM, Hsu CW, Horng CT, Lee CC, Tsai YY, Tsai CC, Liou YS, Yang CC, Hsueh CW, Kuo WH. Current systemic treatment of hepatocellular carcinoma: A review of the literature. World J Hepatol 2015; 7:1412-20. [PMID: 26052386 PMCID: PMC4450204 DOI: 10.4254/wjh.v7.i10.1412] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/29/2014] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient's performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.
Collapse
Affiliation(s)
- Kai-Wen Chen
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Tzu-Ming Ou
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chin-Wen Hsu
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chi-Ting Horng
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Ching-Chang Lee
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Yuh-Yuan Tsai
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chi-Chang Tsai
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Yi-Sheng Liou
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chen-Chieh Yang
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Chao-Wen Hsueh
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| | - Wu-Hsien Kuo
- Kai-Wen Chen, Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan
| |
Collapse
|
|
13
|
Progesterone increases apoptosis and inversely decreases autophagy in human hepatoma HA22T/VGH cells treated with epirubicin. ScientificWorldJournal 2014; 2014:567148. [PMID: 24971383 PMCID: PMC4055367 DOI: 10.1155/2014/567148] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/01/2014] [Indexed: 01/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. Epirubicin can induce intracellular reactive oxygen species and is widely used to treat unresectable HCC. Progesterone has been found to inhibit the proliferation of hepatoma cells. This study was designed to test the combined effects of epirubicin and progesterone on human hepatoma cell line, HA22T/VGH. These cells were treated with different concentrations of epirubicin with or without the coaddition of 30 μM progesterone and then analyzed for apoptosis, autophagy, and expressions of apoptotic-related proteins and multidrug-resistant gene. Epirubicin treatment dose-dependently inhibited the growth of HA22T/VGH cells. Addition of 30 μM progesterone, which was inactive alone, augmented the effect of epirubicin on the inhibition of growth of HA22T/VGH cells. Cotreatment with progesterone enhanced epirubicin-induced apoptosis, as evidenced by greater increase in caspase-3 activity and in the ratio of the apoptosis-regulating protein, Bax/Bcl-XL. The combination also caused a decrease in autophagy and in the expression of multidrug resistance-related protein 1 mRNA compared to epirubicin alone. This study shows the epirubicin/progesterone combination was more effective in increasing apoptosis and inversely decreasing autophagy on HA22T/VGH cells treated with epirubicin alone, suggesting that this combination can potentially be used to treat HCC.
Collapse
|
|
14
|
Progesterone augments epirubicin-induced apoptosis in HA22T/VGH cells by increasing oxidative stress and upregulating Fas/FasL. J Surg Res 2014; 188:432-41. [DOI: 10.1016/j.jss.2014.01.063] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/05/2014] [Accepted: 01/31/2014] [Indexed: 12/15/2022]
|
|
15
|
Shi L, Feng Y, Lin H, Ma R, Cai X. Role of estrogen in hepatocellular carcinoma: is inflammation the key? J Transl Med 2014; 12:93. [PMID: 24708807 PMCID: PMC3992128 DOI: 10.1186/1479-5876-12-93] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 03/28/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease.
Collapse
Affiliation(s)
| | | | | | | | - Xiujun Cai
- Chawnshang Chang Live Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
| |
Collapse
|
|
16
|
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; 9:845-54. [PMID: 23718305 DOI: 10.2217/fon.13.33] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [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.
Collapse
Affiliation(s)
- Marcello Maida
- Section of Gastroenterology, DIBIMIS, University of Palermo, Piazza delle Cliniche 2, Palermo, Italy
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Progesterone and related compounds in hepatocellular carcinoma: basic and clinical aspects. BIOMED RESEARCH INTERNATIONAL 2013; 2013:290575. [PMID: 23484104 PMCID: PMC3581253 DOI: 10.1155/2013/290575] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 12/20/2012] [Accepted: 12/26/2012] [Indexed: 12/28/2022]
Abstract
Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers. Major risk factors for HCC include infection with HBV or HCV, alcoholic liver disease, and most probably nonalcoholic fatty liver disease. In general, men are two to four times more often associated with HCC than women. It can be suggested that sex hormones including progesterone may play some roles in HCC. Rather, very limited information discusses its potential involvement in HCC. This paper thus collects some recent studies of the potential involvement of progesterone and related compounds in HCC from basic and clinical aspects. In addition, two synthetic progestins, megestrol acetate (MA) and medroxyprogesterone acetate (MPA), will be discussed thoroughly. It is noted that progesterone can also serve as the precursor for androgens and estrogens produced by the gonadal and adrenal cortical tissues, while men have a higher incidence of HCC than women might be due to the stimulatory effects of androgen and the protective effects of estrogen. Eventually, this paper suggests a new insight on the associations of progesterone and related compounds with HCC development and treatment.
Collapse
|
|
18
|
Shindoh J, Kaseb A, Vauthey JN. Surgical strategy for liver cancers in the era of effective chemotherapy. Liver Cancer 2013; 2:47-54. [PMID: 24159596 PMCID: PMC3747536 DOI: 10.1159/000346222] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Systemic chemotherapy is the only option for advanced and/or disseminated disease in patients with hepatocellular carcinoma (HCC). For decades, various systemic therapies have been explored for the treatment of advanced HCC. Nevertheless, no satisfactory results have been obtained in cytotoxic chemotherapy so far. However, with the recent introduction of effective chemotherapy agents including sorafenib, the role of systemic therapy for the treatment of HCC is changing. The goals of systemic therapy include prolongation of survival with stabilization of disease progression and, in selected patients, downsizing of primarily unresectable tumors. In the era of effective chemotherapy, patients with advanced HCC should be managed with individualized approaches to optimize outcome.
Collapse
Affiliation(s)
- Junichi Shindoh
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA,*Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, Unit 1484, Houston, TX 77030 (USA), E-Mail
| |
Collapse
|
|
19
|
Chow PKH, Machin D, Chen Y, Zhang X, Win KM, Hoang HH, Nguyen BD, Jin MY, Lobo R, Findlay M, Lim CH, Tan SB, Gandhi M, Soo KC. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer 2011; 105:945-52. [PMID: 21863030 PMCID: PMC3185948 DOI: 10.1038/bjc.2011.333] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. We tested megestrol acetate (MA) against placebo in the treatment of advanced HCC. Methods: From 2002 through 2007, this randomised double-blind trial enrolled 204 patients with treatment-naive advanced HCC (Eastern Cooperative Oncology Group (ECOG) performance rating of 0-3) from specialist care centres in six Asia-Pacific nations. Patients received placebo or MA (320 mg day−1). End points were overall survival (OS) and quality of life. Results: An adverse but not statistically significant difference in OS was found for MA vs placebo: median values 1.88 and 2.14 months, respectively (hazard ratio (HR)=1.25, 95% CI=0.92–1.71, P=0.16). However, OS was similar among patients of good functional status (Child-Pugh A and ECOG 0, 1 or 2) (44.3%) in both treatment groups, with the adverse effect of MA confined to those of poor status. Megestrol acetate patients had a worse global health status (not statistically significant) but reduced levels of appetite loss and nausea/vomiting. Conclusion: Megestrol acetate has no role in prolonging OS in advanced treatment-naive HCC. Overall survival with placebo differed markedly from that in similar trials conducted elsewhere, suggesting therapeutic outcomes may be strongly dependent on ECOG status and Child-Pugh score.
Collapse
Affiliation(s)
- P K H Chow
- Department of General Surgery, Singapore General Hospital, Outram Road, 169608 Singapore.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011; 11:20. [PMID: 21241523 PMCID: PMC3031263 DOI: 10.1186/1471-2407-11-20] [Citation(s) in RCA: 357] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 01/18/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Metformin protection against cancer risk in Orientals is uncertain. We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort. METHODS A representative sample of 800,000 was drawn from the Taiwanese National Health Insurance data of 2000. A cohort of 480,984 participants 20 years or older, diabetes-cancer-free on 1st January 2000 was formed and categorized as four groups by DM and metformin usage status. Eligible incident cancer events had to occur one year after the index date until the end of 2007. The Cox proportional-hazards model evaluated relative risk of cancer for treated DM patients with or without metformin. The covariates included age, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index (CCI) score and metformin exposure dosage and duration. RESULTS With diabetes but no anti-hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men). Adjustment for other oral anti-hyperglycemic agents usage and CCI made the benefit of metformin more evident [hazard ratios (95% confidence intervals): total 0.12 (0.08-0.19), CRC 0.36 (0.13-0.98), liver 0.06 (0.02-0.16), pancreas 0.15 (0.03-0.79)]. There was a significant gender interaction with metformin in CRC which favored women. Metformin dosage for a significant decrease in cancer incidence was ≤ 500 mg/day. CONCLUSIONS Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes.
Collapse
Affiliation(s)
- Meei-Shyuan Lee
- School of Public Health, National Defense Medical Center, Taipei, ROC.
| | | | | | | | | | | |
Collapse
|
|
21
|
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]
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
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.
Collapse
Affiliation(s)
- Giuseppe Cabibbo
- Cattedra di Gastroenterologia, DIBIMIS, University of Palermo, Italy
| | | | | | | | | | | |
Collapse
|
|
24
|
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.
Collapse
Affiliation(s)
- Alejandro Forner
- Unidad de Oncología Hepática (BCLC), Servicio de Hepatología, ICMDM, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España.
| | | | | | | |
Collapse
|
|
25
|
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.
Collapse
Affiliation(s)
- Anna Giacomin
- Department of Surgical and Gastroenterological Sciences, Padua University, Via Giustiniani,Padua, Italy
| | | | | | | | | | | | | |
Collapse
|
|
26
|
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]
|
|
27
|
Abstract
OBJECTIVE As sex favorably modulates the natural history of chronic liver diseases and the risk for neoplastic evolution, our study aimed to ascertain whether female hepatocellular carcinoma (HCC) patients are also characterized by better prognosis. METHODS The ITA.LI.CA (Italian Liver Cancer) database was used, including 1834 HCC patients (482 females, 1352 males) that were consecutively diagnosed. The following variables were considered: age, etiology, modality of diagnosis, earlier interferon treatment, bilirubin, alpha-fetoprotein levels, constitutional syndrome, portal thrombosis, metastasis, number and size of nodules, grading, Child-Pugh class, tumor-nodes-metastases and Cancer of the Liver Italian Program staging, and treatment. RESULTS Female HCC patients were characterized by older age (P=0.0001), higher prevalence of HCV infection (P=0.0001), diagnosis more frequently by surveillance (P=0.003), higher alpha-fetoprotein levels (P=0.0055), lower prevalence of constitutional syndrome (P=0.03), portal thrombosis (P=0.04), and metastasis (P=0.0001). HCC in females was more frequently unifocal (P=0.0001), smaller (P=0.001), well differentiated (P=0.001), and of lower Cancer of the Liver Italian Program and tumor-nodes-metastases stage (P=0.0001 and 0.0001). However, females underwent curative treatments (transplantation, resection, percutaneous ablation) in the same percentage of cases as males. Finally, females had a significantly longer survival (median 29 [95% confidence interval (CI): 24-33] vs. 24 (22-25) months, P=0.0001). The difference was sharper [median 36 (CI: 31-41] vs. 17 (CI: 15-19)] when females undergoing surveillance were compared with males diagnosed incidentally or for symptoms. The Cox model also identified sex as an independent predictor of survival. When only patients undergoing surveillance were considered, no significant difference was observed. CONCLUSION HCC in females has better prognosis, but this is possibly more because of higher compliance with surveillance than to real biological differences.
Collapse
|
|
28
|
Quek R, Lim ST, Ong S. Hepatocellular carcinoma--Pathological complete response to oral capecitabine, megestrol and thalidomide. Acta Oncol 2009; 45:95-7. [PMID: 16464803 DOI: 10.1080/02841860500341140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
|
|
29
|
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.
Collapse
|
|
30
|
Abstract
Liver cancer is the fifth most common cancer worldwide and despite increasing implementation of ultrasonographic surveillance strategies, its incidence is rising, especially in western countries. A universal characteristic of hepatocellular carcinoma is the striking male prevalence that is found, with few exceptions, both in animals and in humans. Many different hypotheses have been put forward in an attempt to explain this finding, which is not a simple epidemiological oddity but could also have pathogenetic implications. An obvious trail to follow, as gender susceptibility is implicated, is the role played by sex hormones, namely estrogens. Estrogens are not simply involved in reproductive mechanisms; instead, it is increasingly evident that they have a role in such an enormous variety of cellular processes that their implication in liver carcinogenesis may be manifold. The purpose of this review is to provide an overview of the available data, with a special focus on the hormonal mechanisms potentially implicated in the development of liver cancer.
Collapse
Affiliation(s)
- Erica Villa
- University of Modena and Reggio Emilia, Gastroenterology Unit, Via del Pozzo 71, 41100 Modena, Italy.
| |
Collapse
|
|
31
|
[Diagnosis and treatment of hepatocellular carcinoma]. Med Clin (Barc) 2009; 132:272-87. [PMID: 19248879 DOI: 10.1016/j.medcli.2008.11.024] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2008] [Accepted: 12/11/2008] [Indexed: 12/25/2022]
|
|
32
|
Granata OM, Cocciadifero L, Campisi I, Miceli V, Montalto G, Polito LM, Agostara B, Carruba G. Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells. J Steroid Biochem Mol Biol 2009; 113:290-5. [PMID: 19429435 DOI: 10.1016/j.jsbmb.2009.01.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2008] [Revised: 01/16/2009] [Accepted: 01/19/2009] [Indexed: 02/07/2023]
Abstract
There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17betaoxidation of T to Ad (cells: 28-77%; tissues: 35-50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5alpha-reductase enzyme products (18% and 15%, respectively), while 5beta-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4-11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50-55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17betaoxidation of T to Ad (35-50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5beta-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients.
Collapse
Affiliation(s)
- Orazia M Granata
- Experimental Oncology, Department of Oncology, M. Ascoli Cancer Hospital Center, ARNAS-Civico, Piazzale N. Leotta 2, Palermo, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%-50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed.Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery.
Collapse
|
|
34
|
Kalra M, Mayes J, Assefa S, Kaul AK, Kaul R. Role of sex steroid receptors in pathobiology of hepatocellular carcinoma. World J Gastroenterol 2008; 14:5945-61. [PMID: 18932272 PMCID: PMC2760195 DOI: 10.3748/wjg.14.5945] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.4] [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
The striking gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor (ER) and androgen receptor (AR) in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.
Collapse
|
|
35
|
Maio MD, Daniele B, Pignata S, Gallo C, Maio ED, Morabito A, Piccirillo MC, Perrone F. Is human hepatocellular carcinoma a hormone-responsive tumor? World J Gastroenterol 2008; 14:1682-9. [PMID: 18350599 PMCID: PMC2695908 DOI: 10.3748/wjg.14.1682] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [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
Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib, there was no standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Sex hormones receptors are expressed in a significant proportion of HCC samples. Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis, several randomized controlled trials (RCTs) tested the efficacy of the anti-estrogen tamoxifen as systemic treatment. Largest among these trials showed no survival advantage from the administration of tamoxifen, and the recent Cochrane systematic review produced a completely negative result. This questions the relevance of estrogen receptor-mediated pathways in HCC. However, a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression, but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately. It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway, that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative. Interesting, preliminary results have been obtained when hormonal treatment (tamoxifen or megestrol) has been selected according to the presence of wild-type or variant estrogen receptors respectively, but no large RCTs are available to support this strategy. Negative results have been obtained also with anti-androgen therapy. In conclusion, there is no robust evidence to consider HCC a hormone-responsive tumor. Hormonal treatments should not be part of the current management of HCC.
Collapse
|
|
36
|
Han CJ. Recent developments in systemic chemotherapy for hepatocellular carcinoma. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:4-11. [DOI: 10.3350/kjhep.2008.14.1.4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Chul Ju Han
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul, Korea
| |
Collapse
|
|
37
|
Abstract
This article reviews the current developments and significant trends in the treatment of hepatocarcinoma (HCC). Prevention programs should be based on large vaccination campaigns and the use of immunologic or biologic molecules to delay the onset of HCC in already cirrhotic patients. Surgery remains the therapy of choice in patients with a small and limited number of tumor nodules. To date, no preoperative treatment has been proven useful. Adjuvant treatments involving systemic chemotherapy, intra-arterial infusion, or chemoembolization failed to improve survival, whereas immune therapy, retinoids, radiolabeled isotopes, and antiangiogenic agents seem promising. Such local treatments as percutaneous ethanol injection, cryotherapy, and radiofrequency are proposed for patients with limited hepatic function and should be combined with other treatment modalities to optimize their efficacy and limit their toxicity. Regional therapy should take a selective, subsegmental approach at intervals depending on tumor response and possibly combined with other treatment modalities. Systemic therapy with cytotoxic agents remains disappointing. Hormonal therapy with tamoxifen or antiandrogens has shown no efficacy and might even be detrimental. Further progress may be expected from targeted therapy.
Collapse
Affiliation(s)
- Beatrice Gerard
- Institut Jules Bordet, 1 Rue Heger-Bordet, Brussels, 1000, Belgium
| | | |
Collapse
|
|
38
|
Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol 2007. [PMID: 17589893 DOI: 10.3748/wjg.v13.i13.3164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). METHODS A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5 mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30 mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. RESULTS Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49+/-6 wk) as compared to the control group (28+/-1 wk) and to the SSTR negative group (28+/-2 wk), LR=20.39, df=2, P<0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group, respectively. CONCLUSION The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.
Collapse
Affiliation(s)
- D Dimitroulopoulos
- Liver Cancer Unit, Agios Savvas Cancer Hospital, 35 Parnassou str., GR-152 34 Halandri-Athens, and Laboratory of Biostatistics, Department of Nursing, University of Athens, Greece.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial. World J Gastroenterol 2007; 13:3164-70. [PMID: 17589893 PMCID: PMC4436600 DOI: 10.3748/wjg.v13.i23.3164] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC).
METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner.
RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49 ± 6 wk) as compared to the control group (28 ± 1 wk) and to the SSTR negative group (28 ± 2 wk), LR = 20.39, df = 2, P < 0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group respectively.
CONCLUSION: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.
Collapse
Affiliation(s)
- D Dimitroulopoulos
- Liver Cancer Unit, Agios Savvas Cancer Hospital, 35 Parnassou str., GR-152 34 Halandri-Athens, and Laboratory of Biostatistics, Department of Nursing, University of Athens, Greece.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Trevisani F, Magini G, Santi V, Morselli-Labate AM, Cantarini MC, Di Nolfo MA, Del Poggio P, Benvegnù L, Rapaccini G, Farinati F, Zoli M, Borzio F, Giannini EG, Caturelli E, Bernardi M. Impact of etiology of cirrhosis on the survival of patients diagnosed with hepatocellular carcinoma during surveillance. Am J Gastroenterol 2007; 102:1022-31. [PMID: 17313497 DOI: 10.1111/j.1572-0241.2007.01100.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Although the etiology of liver disease affects the features of hepatocellular carcinoma (HCC) diagnosed during surveillance, it is not known whether it influences patients' survival. We analyzed the impact of etiology on the characteristics and outcome of HCC detected during surveillance. METHODS In this cohort study, 742 patients with HCC detected during semiannual or annual surveillance were selected from the ITA.LI.CA database, including 1,834 consecutive patients observed in three primary and seven tertiary care settings for HCC. Patients were grouped according to etiology: hepatitis B virus (HBV, 87), hepatitis C virus (HCV, 461), alcohol (59), and multietiology (135). RESULTS In all etiologic groups, most HCCs were unifocal (51-68%) and most of them were <or=3 cm (60-69%). Unifocal HCCs were less common in the multietiology group (P=0.050) and slightly more frequent in the HCV group (P=0.087). Besides etiology, only age was associated with gross pathology (P=0.023). About two-thirds of HCCs in all groups were discovered at Cancer of the Liver Italyn Program (CLIP) stage 0 or 1. The 1-, 3-, and 5-yr survival rates were comparable among groups (HBV 81%, 47%, and 22%; HCV 86%, 49%, and 24%; alcohol 76%, 41%, and 25%; multietiology 75%, 37%, and 24%; P=0.446). The surveillance interval did not influence survival, which was independently predicted by serum alpha-fetoprotein, Child-Pugh class, gross pathology, cancer size, vascular invasion, and treatment. CONCLUSION In patients with HCC diagnosed during surveillance: (a) single nodules are less common in multietiology cases and (b) prognosis is independent of etiology, being dictated by liver function, oncologic features, and treatment.
Collapse
Affiliation(s)
- Franco Trevisani
- Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Di Maio M, De Maio E, Morabito A, D'Aniello R, De Feo G, Gallo C, Perrone F. Hormonal treatment of human hepatocellular carcinoma. Ann N Y Acad Sci 2007; 1089:252-61. [PMID: 17261772 DOI: 10.1196/annals.1386.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Animal models of experimental liver carcinogenesis and epidemiological studies in humans suggest a relationship between sex hormones and hepatocellular carcinoma (HCC). In 1997, a systematic review of the existing, small randomized trials evaluating the antiestrogen tamoxifen yielded a positive result, but the large randomized CLIP-1 trial showed no survival advantage from the addition of tamoxifen to best supportive care. A possible explanation for the negative results is the lack of patient selection, but the expression of estrogen (ER) and progesterone (PgR) receptors in HCC does not clearly affect the survival outcome of the patients treated with tamoxifen. In the last years, it has been proposed that negative results might be due to the fact that tamoxifen in HCC could act via an ER-independent pathway, which requires much higher doses than those usually administered, but a double-blind Asian randomized trial conducted to assess possible dose-response effect showed no efficacy for tamoxifen, with an inversely negative impact with increasing dose. According to the results of large trials and of the Cochrane systematic review, neither further trials are warranted with tamoxifen in HCC, nor should any use in clinical practice be considered. Interesting results have been obtained when the type of hormonal treatment (tamoxifen or megestrol) has been chosen according to the presence of wild-type or variant ER, but these results should be confirmed in large randomized trials. Negative results have been obtained with antiandrogen therapy. In conclusion, hormonal treatment should not be a part of the current management of HCC patients.
Collapse
Affiliation(s)
- Massimo Di Maio
- Clinical Trials Unit, National Cancer Institute, via Mariano Semmola, 80131 Napoli, Italy
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Almhanna K, Kim R, Kalmadi S. Treatment Approaches for Hepatocellular Carcinoma. Clin Med Oncol 2007. [DOI: 10.1177/117955490700100002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and it is responsible for up to one million deaths annually. Although multiple risk factors for HCC have been identified, and despite preventive measures, the incidence of HCC continues to rise to epidemiologic proportions in the United States. In general, tumor resection and orthotopic liver transplantation are the treatment with the best outcome; however, HCC is generally diagnosed late in its course when patients are not eligible for curative treatment options. HCC is a relatively Chemo-refractory tumor secondary to heterogeneity of the tumor and the high rate of multidrug resistant gene expression. There are no standard treatments for HCC, multiple palliative treatment modalities have been used for patients with unresectable disease. None of these modalities have shown any superiority; and the retrospective nature of these available data has confounded any reasonable conclusions. Different institutions use different treatment schema dependent on the center expertise. Sorafenib, a tyrosine kinase inhibitor, has recently demonstrated a survival advantage in metastatic HCC, and if approved by the FDA, might become the standard of care. In this article we will review the rationale behind the currently available treatment options for HCC.
Collapse
Affiliation(s)
- Khaldoun Almhanna
- Gastrointestinal Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Richard Kim
- Gastrointestinal Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Sujith Kalmadi
- Gastrointestinal Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| |
Collapse
|
|
43
|
Abstract
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC.
Collapse
Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
| |
Collapse
|
|
44
|
Müller C. Hepatocellular carcinoma – Rising incidence, changing therapeutic strategies. Wien Med Wochenschr 2006; 156:404-9. [PMID: 16937043 DOI: 10.1007/s10354-006-0316-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2005] [Accepted: 04/05/2006] [Indexed: 12/13/2022]
Abstract
Despite considerable efforts no ideal treatment exists for HCC. The disease is usually detected late and few patients are candidates for potentially curative treatment options such as surgical resection or liver transplantation. Surgical resection is limited mostly by the impaired liver function in cirrhotic livers, whereas liver transplantation is limited by tumor size, multi-localized disease and, most important, by shortage of donor organs. TACE as a local ablative treatment is able to induce local disease control and to prolong survival and might even achieve survival similar to surgical resection. The high rates of recurrence of HCC after successful control of local tumor spread is the reason to consider that procedure as a non-curative treatment option. PEI and RFA are able to control local tumor growth, but cannot influence tumor recurrence or de novo tumor growth. Systemic therapies need to be investigated in large randomized trials, especially to evaluate the use of somatostain analogues, HMGCoA reductase inhibitors, or other drugs such as rapamycin or inhibitors of vascular endothelial growth factor (VEGF).
Collapse
Affiliation(s)
- Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine IV, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
45
|
Karp SJ, Ku Y, Johnson S, Khwaja K, Curry M, Hanto D. Surgical and non-surgical approaches to hepatocellular cancer. Curr Opin Organ Transplant 2006. [DOI: 10.1097/01.mot.0000227837.06582.94] [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]
|
|
46
|
Wang SN, Yeh YT, Yang SF, Chai CY, Lee KT. Potential role of leptin expression in hepatocellular carcinoma. J Clin Pathol 2006; 59:930-4. [PMID: 16565221 PMCID: PMC1860468 DOI: 10.1136/jcp.2005.035477] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Obesity is associated with hepatocellular carcinoma (HCC). The association may result from the aberrant expression of adipokines. AIM To explore the potential biological effect and prognostic value of leptin, one of the adipokines, in HCC. METHODS Immunohistochemistry was used to evaluate the expression of leptin in 68 patients with HCC. The expression of Ki-67 and microvessel density (MVD) of tumorous lesions in HCC were also analysed. The result of leptin expression was further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics, overall survival and the postoperative use of medroxyprogesterone acetate (MPA). RESULTS High leptin expression was seen in 60.3% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.2 (standard deviation 3.2) v 44.2 (19.5), p = 0.004), but not with Ki-67 expression. No marked correlation was seen between leptin expression and clinicopathological characteristics. However, using a multivariate Cox's proportional hazards model, leptin expression was a predictor for improved overall survival of patients with HCC (odds ratio 0.16; 95% confidence interval 0.03 to 0.87; p = 0.033). In addition, the Kaplan-Meier survival curve showed that high leptin expression was associated with a better survival in patients with HCC, treated postoperatively with MPA (p = 0.008, log rank test). CONCLUSION High leptin expression was associated with an increased intratumour MVD and thus may be associated with HCC development. In addition, high leptin expression was a predictor for improved survival of patients with HCC, treated postoperatively with MPA.
Collapse
Affiliation(s)
- S-N Wang
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | | | | | | | | |
Collapse
|
|
47
|
Brown KS. Chemotherapy and other systemic therapies for hepatocellular carcinoma and liver metastases. Semin Intervent Radiol 2006; 23:99-108. [PMID: 21326724 PMCID: PMC3036302 DOI: 10.1055/s-2006-939845] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
For hepatocellular carcinoma (HCC) that has advanced to the point that it is no longer amenable to local therapies, systemic therapy can be considered in select patients who have a good performance status. No systemic therapy has been clearly shown to improve overall survival compared with supportive care alone, although cancer-related symptoms can sometimes be palliated with therapy and some objective responses are seen. Systemic therapies for HCC include chemotherapy, both intravenous and infused via the hepatic artery, as well as hormonal therapy, immunotherapy, and targeted biologic agents. Colorectal, pancreatic, breast, and lung cancer are some of the most common tumors that metastasize to the liver. Response rates and effect on overall survival as a result of systemic therapy for liver metastases vary widely depending on primary tumor site. Targeted biologic agents are being integrated into standard treatment regimens for all of these cancer types, with variable effects on survival and other outcomes for all affected patients including those with liver metastases.
Collapse
Affiliation(s)
- Kevin S Brown
- Assistant Professor of Medicine, Denver Health Medical Center, University of Colorado Health Sciences Center, Department of Medicine, Division of Medical Oncology, Denver, Colorado
| |
Collapse
|
|
48
|
Abstract
For the minority of patients with hepatocellular carcinoma (HCC), surgical or locally ablative therapies may offer the prospect of cure. However, the majority of patients present with advanced disease such that treatment with curative intent is no longer possible. For some of these patients, with good hepatic reserve and a patent portal venous system, chemoembolisation may afford a modest survival benefit. The remainder of patients are frequently treated with systemic therapies with palliative intent. This review aims to summarise the current systemic treatment approaches for HCC in the adjuvant and palliative setting before reviewing the evidence for novel therapies emerging in this field. At present there are a number of interesting therapeutic agents with potential activity in HCC. The challenge now is the design of clinical trials to optimally evaluate these agents.
Collapse
Affiliation(s)
- Daniel H Palmer
- Cancer Research UK Institute for Cancer Studies, Clinical Research Block, University of Birmingham, Birmingham B15 2TA, UK.
| | | | | |
Collapse
|
|
49
|
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further elucidate the molecular events underlying HCC development and to identify novel diagnostic markers as well as therapeutic and preventive targets.
Collapse
Affiliation(s)
- Hubert E Blum
- Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
| |
Collapse
|
|
50
|
Abstract
Surgery is often not a treatment option in patients with hepatocellular carcinoma with the numerous limitations of liver transplantation or surgical resection due to coexisting cirrhosis in the later case. Non-surgical treatments deal with 3 types of methods: local ablation with curative purpose, transarterial treatments with many technical variants and systemic treatment. Local treatments rely on chemical or thermic agents to achieve ablation of liver lesions, which not exceed initially 3 cm in diameter. The use of radiofrequency ablation allows now larger limits. Intra-arterial treatment usually combines intra-arterial chemotherapy with embolisation of hepatic artery in a procedure called chemoembolisation. Its antitumoral effect mainly due to ischemia is well documented but the influence on survival remains controversial. Finally systemic treatments have yet to be demonstrated useful: new agents and new randomised trials are still needed.
Collapse
Affiliation(s)
- Michel Beaugrand
- Service d'hépatogastroentérologie, hôpital Jean-Verdier, Assistance-publique-hôpitaux-de-Paris et UFR SMBH-université Paris-XIII, 93143 Bondy cedex, France.
| | | |
Collapse
|