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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Efficacy of a Glass Membrane Emulsification Device to Form Mixture of Cisplatin Powder with Lipiodol on Transarterial Therapy for Hepatocellular Carcinoma. Cardiovasc Intervent Radiol 2021; 44:766-773. [PMID: 33415417 DOI: 10.1007/s00270-020-02757-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To examine physiochemical characteristics and drug release properties of cisplatin powder and lipiodol mixtures formed by a glass membrane emulsification device compared with a 3-way stopcock. MATERIALS AND METHODS Seven different types of mixtures were evaluated: cisplatin powder and lipiodol directly mixed (suspension), complete cisplatin solution and lipiodol mixed by a 3-way stopcock or the device (emulsion), incomplete cisplatin solution and lipiodol mixed by a 3-way stopcock or the device (solid-in-water emulsion), and contrast material and cisplatin suspension mixed by a 3-way stopcock or the device (solid-in-oil emulsion). RESULT The percentages of water-in-oil were 98.08 ± 0.27% in the emulsion formed by the device, while 70.3 ± 4.63% in the emulsion formed by a 3-way stopcock (P = 0.037). Solid-in-water and solid-in-oil emulsions formed by the device showed 98.09 ± 0.38% and 98.70 ± 0.40% of water-in-oil, respectively, whereas both solid-in-water and solid-in-oil emulsions formed by a 3-way stopcock showed 0.00%. Homogenous droplet sizes were shown by using the device. The half release times of cisplatin in the emulsions formed by the device were 197 ± 19, 244 ± 24 and 478 ± 52 min, respectively, which were significantly longer than the emulsion formed by a 3-way stopcock of 8 ± 8 min (P = 0.046-0.050). Suspension showed the longest release time; however, the viscosity was lowest. CONCLUSION The glass membrane emulsification device formed almost 100% water-in-oil, whereas 3-way stopcock produced 100% oil-in-water when incomplete solution or suspension was mixed. Slower cisplatin release was shown in the emulsions formed by the device.
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kim MS, Hong HP, Park K, Kang KA, Lee SR. In Vitro Bovine Liver Experiment of Cisplatin-Infused and Normal Saline-Infused Radiofrequency Ablation with an Internally Cooled Perfusion Electrode. Cardiovasc Intervent Radiol 2019; 42:886-892. [PMID: 30761412 DOI: 10.1007/s00270-019-02178-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 02/02/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE To evaluate the efficacy of cisplatin-infused and normal saline-infused radiofrequency ablation (RFA) with internally cooled perfusion (ICP) electrode. MATERIALS AND METHODS Using a 200 W generator, thirty ablation zones were created and divided into three groups of 10 each as follows: group A, RFA alone with 16 gauge monopolar internally cooled (IC) electrode; group B, cisplatin-infused RFA with 16 gauge ICP electrode; and group C, normal saline-infused RFA with 16 gauge ICP electrode. Radiofrequency was applied to the explanted bovine liver for 12 min. During RFA, cisplatin and normal saline were injected into tissue at a rate of 0.5 mL/min through the ICP electrode by injection pump. Dimensions of the ablation zone and technical parameters were compared between the three groups. RESULT In the cisplatin-infused RFA group, the ablation zone size was significantly larger than that of the RFA-alone group but significantly smaller than normal saline-infused RFA group. The width of longitudinal section and volume were 3.39 ± 0.22 cm2 and 26.55 ± 4.62 cm3 in RFA-alone group, 3.88 ± 0.32 cm2 and 36.45 ± 5.46 cm3 in cisplatin-infused RFA group, and 4.52 ± 0.50 cm2 and 49.44 ± 7.55 cm3 in normal saline-infused RFA group, respectively (p < 0.05 between any two groups). The mean impedance in group A, B, and C were 60.0 ± 7.2, 50.3 ± 2.5, and 40.3 ± 4.0 Ω, respectively (p < 0.05 between any two groups). CONCLUSION Cisplatin-infused RFA with ICP electrode created the larger size of ablation zone than that of monopolar RFA with an IC electrode, but created the smaller size of ablation zone than that of normal saline-infused RFA.
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Affiliation(s)
- Myung Sub Kim
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea
| | - Hyun Pyo Hong
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea.
| | - Kyungmin Park
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea
| | - Kyung A Kang
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Republic of Korea
| | - Sung Ryol Lee
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Thillai K, Srikandarajah K, Ross P. Regorafenib as treatment for patients with advanced hepatocellular cancer. Future Oncol 2017; 13:2223-2232. [PMID: 28766967 DOI: 10.2217/fon-2017-0204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma is one of the fastest growing causes of cancer-related mortality worldwide. Sorafenib was the first and only drug to improve survival for patients with advanced disease, and has been the cornerstone of treatment for nearly a decade. Regorafenib is a multikinase inhibitor that has recently been shown to significantly improve survival in patients who have progressed on first-line sorafenib. In this review, we discuss the pharmacokinetic and pharmacodynamics properties of regorafenib and its efficacy and tolerability in patients with advanced hepatocellular carcinoma.
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Affiliation(s)
- Kiruthikah Thillai
- Department of Medical Oncology, Guy's & St Thomas' NHS Trust, Great Maze Pond, London Bridge, London SE1 9RT, UK
| | - Krishnie Srikandarajah
- Department of Medical Oncology, Guy's & St Thomas' NHS Trust, Great Maze Pond, London Bridge, London SE1 9RT, UK
| | - Paul Ross
- Department of Medical Oncology, Guy's & St Thomas' NHS Trust, Great Maze Pond, London Bridge, London SE1 9RT, UK
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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: 51] [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] [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.
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Affiliation(s)
- Esther Una Cidon
- Esther Una Cidon, Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom
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de Rosamel L, Blanc JF. Emerging tyrosine kinase inhibitors for the treatment of hepatocellular carcinoma. Expert Opin Emerg Drugs 2017; 22:175-190. [PMID: 28604110 DOI: 10.1080/14728214.2017.1336538] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer in the world and the third leading cause of death. Unfortunately, when diagnosed two thirds of patients have an advanced disease for which only palliative treatment can be proposed and most likely systemic therapy. Areas covered: As of today only one systemic therapy is validated in the treatment of advanced HCC, a tyrosine kinase inhibitor (TKI): Sorafenib. Treatment options are therefore lacking. With the advent of Sorafenib other TKIs have been studied with some disappointing results. Many explanations can be found to the failure of these tested TKIs such as the underlying cirrhosis leading to rapidly serious adverse events, or trial design imperfections. Expert opinion: Taking into account these failures, new trials with more appropriate designs have led to recent success with multi-target TKIs (Regorafenib and Lenvatinib). This multi-target approach allows to overcome the molecular heterogeneity of advanced HCC which is associated with multiple simultaneously dysregulated signaling pathways. On the contrary, another lead is to study target a specific TKI such as c-MET inhibitors or TGFβR inhibitors in HCC sub-populations with promising results in early phase trials. These results will have to be validated in the ongoing phase III trials.
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Affiliation(s)
- Laure de Rosamel
- a Service d'Hépato-Gastroentérologie et d'Oncologie Digestive , Hôpital Haut-Lévêque, CHU , Pessac , France
| | - Jean-Frederic Blanc
- a Service d'Hépato-Gastroentérologie et d'Oncologie Digestive , Hôpital Haut-Lévêque, CHU , Pessac , France
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Thillai K, Ross P, Sarker D. Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis? World J Gastrointest Oncol 2016; 8:173-85. [PMID: 26909132 PMCID: PMC4753168 DOI: 10.4251/wjgo.v8.i2.173] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 11/16/2015] [Accepted: 12/09/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.
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Hagihara A, Ikeda M, Ueno H, Morizane C, Kondo S, Nakachi K, Mitsunaga S, Shimizu S, Kojima Y, Suzuki E, Katayama K, Imanaka K, Tamai C, Inaba Y, Sato Y, Kato M, Okusaka T. Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma. Cancer Sci 2014; 105:354-8. [PMID: 24438504 PMCID: PMC4317950 DOI: 10.1111/cas.12353] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/10/2013] [Accepted: 01/12/2014] [Indexed: 02/06/2023] Open
Abstract
The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m2/cycle; level 2, 50 mg/m2/cycle; and level 3, 65 mg/m2/cycle) from feeding arteries to the HCC. The treatment was repeated every 4–6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m2/cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.
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Affiliation(s)
- Atsushi Hagihara
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Hepatology, Osaka City University Hospital, Osaka, Japan
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Yang L, Xiao H, Yan L, Wang R, Huang Y, Xie Z, Jing X. Lactose targeting oxaliplatin prodrug loaded micelles for more effective chemotherapy of hepatocellular carcinoma. J Mater Chem B 2014; 2:2097-2106. [DOI: 10.1039/c3tb21709d] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Metronomic chemotherapy: possible clinical application in advanced hepatocellular carcinoma. Transl Oncol 2013; 6:511-9. [PMID: 24151531 DOI: 10.1593/tlo.13481] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 07/22/2013] [Accepted: 07/24/2013] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular highly angiogenic tumor usually associated with liver cirrhosis. Vascular endothelial growth factor plays a critical role in vascular development in HCC. In contrast to the treatment of early-stage HCC, the treatment options for advanced HCC are limited and prognosis is often poor, which contributes to this tumor type being the third leading cause of cancer-related deaths worldwide. Metronomic chemotherapy, which was originally designed to inhibit angiogenesis, involves low-dose chemotherapeutic agents administered in a frequent regular schedule with no prolonged breaks and minimizes severe toxicities. We reviewed the potential effects and impact of metronomic chemotherapy in preclinical studies with HCC models and in patients with advanced HCC, especially when combined with a molecular targeted agent. Metronomic chemotherapy involves multiple mechanisms that include antiangiogenesis and antivasculogenesis, immune stimulation by reducing regulatory T cells and inducing dendritic cell maturation, and possibly some direct tumor cell targeting effects, including the cancer stem cell subpopulation. The total number of preclinical studies with HCC models shows impressive results using metronomic chemotherapy-based protocols, especially in conjunction with molecular targeted agents. Four clinical trials and two case reports evaluating metronomic chemotherapy for HCC indicate it to be a safe and potentially useful treatment for HCC. Several preclinical and clinical HCC studies suggest that metronomic chemotherapy may become an alternative type of chemotherapy for advanced unresectable HCC and postsurgical adjuvant treatment of HCC.
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Chong DQ, Tan IB, Choo SP, Toh HC. The evolving landscape of therapeutic drug development for hepatocellular carcinoma. Contemp Clin Trials 2013; 36:605-15. [PMID: 23591326 DOI: 10.1016/j.cct.2013.03.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 03/12/2013] [Accepted: 03/15/2013] [Indexed: 12/16/2022]
Abstract
Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward.
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Affiliation(s)
- Dawn Qingqing Chong
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
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Golla K, Cherukuvada B, Ahmed F, Kondapi AK. Efficacy, safety and anticancer activity of protein nanoparticle-based delivery of doxorubicin through intravenous administration in rats. PLoS One 2012; 7:e51960. [PMID: 23284832 PMCID: PMC3528733 DOI: 10.1371/journal.pone.0051960] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 11/09/2012] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND AIMS Doxorubicin is a potent anticancer drug and a major limiting factor that hinders therapeutic use as its high levels of systemic circulation often associated with various off-target effects, particularly cardiotoxicity. The present study focuses on evaluation of the efficacy of doxorubicin when it is loaded into the protein nanoparticles and delivered intravenously in rats bearing Hepatocellular carcinoma (HCC). The proteins selected as carrier were Apotransferrin and Lactoferrin, since the receptors for these two proteins are known to be over expressed on cancer cells due to their iron transport capacity. METHODS Doxorubicin loaded apotransferrin (Apodoxonano) and lactoferrin nanoparticles (Lactodoxonano) were prepared by sol-oil chemistry. HCC in the rats was induced by 100 mg/l of diethylnitrosamine (DENA) in drinking water for 8 weeks. Rats received 5 doses of 2 mg/kg drug equivalent nanoparticles through intravenous administration. Pharmacokinetics and toxicity of nanoformulations was evaluated in healthy rats and anticancer activity was studied in DENA treated rats. The anticancer activity was evaluated through counting of the liver nodules, H & E analysis and by estimating the expression levels of angiogenic and antitumor markers. RESULTS In rats treated with nanoformulations, the numbers of liver nodules were found to be significantly reduced. They showed highest drug accumulation in liver (22.4 and 19.5 µg/g). Both nanoformulations showed higher localization compared to doxorubicin (Doxo) when delivered in the absence of a carrier. Higher amounts of Doxo (195 µg/g) were removed through kidney, while Apodoxonano and Lactodoxonano showed only a minimal amount of removal (<40 µg/g), suggesting the extended bioavailability of Doxo when delivered through nanoformulation. Safety analysis shows minimal cardiotoxicity due to lower drug accumulation in heart in the case of nanoformulation. CONCLUSION Drug delivery through nanoformulations not only minimizes the cardiotoxicity of doxorubicin but also enhances the efficacy and bioavailability of the drug in a target-specific manner.
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Affiliation(s)
- Kishore Golla
- Department of Biochemistry, University of Hyderabad, Hyderabad, India
- Centre for Nanotechnology, University of Hyderabad, Hyderabad, India
| | | | - Farhan Ahmed
- Department of Biotechnology, University of Hyderabad, Hyderabad, India
| | - Anand K. Kondapi
- Department of Biotechnology, University of Hyderabad, Hyderabad, India
- Department of Biochemistry, University of Hyderabad, Hyderabad, India
- Centre for Nanotechnology, University of Hyderabad, Hyderabad, India
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Kawano Y, Nagata M, Kohno T, Ichimiya A, Iwakiri T, Okumura M, Arimori K. Caffeine increases the antitumor effect of Cisplatin in human hepatocellular carcinoma cells. Biol Pharm Bull 2012; 35:400-7. [PMID: 22382328 DOI: 10.1248/bpb.35.400] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Caffeine is thought to increase the antitumor effect of cisplatin or DNA-damaging agents because it is known that caffeine inhibits DNA repair. Caffeine-assisted chemotherapy has been used in the treatment of osteosarcomas. In addition, there are several reports about combination chemotherapy with caffeine for certain malignancies other than osteosarcomas. However, there are no reports that show the utility of combination chemotherapy with caffeine for hepatocellular carcinoma (HCC). We examined the combined effects of caffeine and cisplatin in human HCC cell lines, and screened for a more effective administration method of caffeine in vitro. Human HCC cell lines (HepG2, HLF, HuH-7, and Li-7) were exposed to caffeine (0-0.5 mM) and cisplatin (0-1.2 μg/mL) for 72 h, either alone or in combination. Cell numbers were measured by WST-8 assay, and cell apoptosis was determined by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) binding assay. As a result, caffeine increased the antitumor effect of cisplatin on cell proliferation and cell apoptosis in the HCC cell lines. Moreover, this effect was dependent on the amount of exposure to caffeine. These results suggest that caffeine-assisted chemotherapy is useful for HCC treatment.
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Affiliation(s)
- Yohei Kawano
- Department of Pharmacy, University of Miyazaki Hospital, Kiyotake-cho, Miyazaki, Japan
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Mine T, Murata S, Ueda T, Onozawa S, Onda M, Naito Z, Kumita S. Comparative study of cisplatin-iodized oil suspension and emulsion for transcatheter arterial chemoembolization of rabbit VX2 liver tumors. Hepatol Res 2012; 42:473-81. [PMID: 22176437 DOI: 10.1111/j.1872-034x.2011.00942.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To evaluate the antitumor effects and hepatotoxicity of transcatheter arterial chemoembolization (TACE) with cisplatin-iodized oil suspension and emulsion in a rabbit tumor model. METHODS Transcatheter arterial chemoembolization was performed on 12 rabbits with hepatic VX2 tumors using a cisplatin suspension (1 mg/kg cisplatin and 0.1 mL/kg iodized oil, n = 6) or emulsion (1 mg/kg cisplatin, 0.1 mL/kg of iodized oil, and 0.1 mL/kg saline solution, n = 6). Time series changes in plasma platinum concentration were compared over 24 h. All rabbits were killed at 7 days after TACE, and the growth ratio and residual viable proportion of tumors were calculated on the basis of ultrasonographic and histopathological findings. Hepatotoxicity was also evaluated. Differences between the two groups were statistically assessed with the Mann-Whitney U-test. The animal care committee of our institute approved this study. RESULTS Plasma platinum concentrations were significantly higher in the suspension group than in the emulsion group at 0.5-24 h after TACE (P < 0.05). Growth ratios (-24.6 ± 9.98% vs. 21.4 ± 8.87%, respectively; P = 0.004) and residual viable proportions of tumors (25.8 ± 5.02% vs. 51.1 ± 11.4%, respectively; P = 0.009) were significantly lower in the suspension group than in the emulsion group. Hepatotoxicity was transient in all rabbits. CONCLUSION Cisplatin-iodized oil suspensions facilitated the slow release of cisplatin at the tumor border. A suspension is preferable to an emulsion for drug delivery and the antitumor effect during the treatment of VX2 liver tumors with TACE.
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Affiliation(s)
- Takahiko Mine
- Departments of Radiology Integrative Pathology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
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Effect of paeonol on antioxidant and immune regulatory activity in hepatocellular carcinoma rats. Molecules 2012; 17:4672-83. [PMID: 22522397 PMCID: PMC6268820 DOI: 10.3390/molecules17044672] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 03/27/2012] [Accepted: 04/05/2012] [Indexed: 12/26/2022] Open
Abstract
The study investigated the immunity and antioxidant potential of paeonol by employing a hepatocellular carcinoma (HCC) rat model. Three doses of paeonol (20, 40, 60 mg/kg b.w. orally) were administrated to diethylnitrosamine (DEN)-induced HCC rats. Results showed that paeonol significantly reduced the serum AST, ALT, ALP, GGT, AFU and liver MDA levels, increased serum WBC, TP, ALB, A/G, TNF-α and IFN-γ and liver antioxidant enzymes activities (SOD, CAT, GSH-Px, GR) in HCC rats. Altogether, these results suggest that the paeonol could effectively decrease oxidative injury and improve immunity function in HCC rats.
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Chua CWL, Choo SP. Targeted therapy in hepatocellular carcinoma. Int J Hepatol 2011; 2011:348297. [PMID: 21994852 PMCID: PMC3170762 DOI: 10.4061/2011/348297] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 03/01/2011] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, as well as a common cause of cancer-related death. HCC frequently occurs in the setting of a diseased cirrhotic liver and many patients present at an advanced stage of disease. Together with a poor functional status, this often precludes the use of systemic therapy, especially conventional cytotoxic drugs. Moreover, HCC is known to be a relatively chemo-refractory tumor. There have been many targeted drugs that have shown potential in the treatment of HCC. Many clinical trials have been carried out with many more in progress. They include trials evaluating a single targeted therapy alone, two or more targeted therapy in tandem or a combination of targeted therapy and conventional chemotherapy. In this article, we seek to review some of the more important trials examining the use of targeted therapy in HCC and to look into what the future holds in terms of targeted treatment of HCC.
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Affiliation(s)
- Clarinda W. L. Chua
- Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore
| | - Su Pin Choo
- Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore
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Ishikawa T, Higuchi K, Kubota T, Seki K, Honma T, Yoshida T, Kamimura T. Prevention of intrahepatic distant recurrence by transcatheter arterial infusion chemotherapy with platinum agents for stage I/II hepatocellular carcinoma. Cancer 2011; 117:4018-25. [PMID: 21365625 DOI: 10.1002/cncr.25989] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2010] [Revised: 12/27/2010] [Accepted: 12/28/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND The effectiveness of additional chemotherapy in preventing intrahepatic distant tumor recurrence of hepatocellular carcinoma (HCC) has not been fully established. The authors compared the efficacy of 2 platinum-based chemotherapeutic agents in combination with radical local treatment for preventing intrahepatic distant recurrence (IDR). METHODS Seventy-eight patients with stage I/II HCC aged 45 to 85 years underwent transcatheter arterial chemoembolization and/or radiofrequency ablation after they received hepatic arterial infusion (HAI) of platinum compounds. The HAI consisted of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin) in 25 patients and cis-diamminedichloroplatinum (II) (cisplatin) in 53 patients. Multivariate analysis was used to identify independent factors that were associated with IDR. RESULTS Cumulative IDR rates at 1 year, 2 years, and 3 years were 21.7%, 52.2% and 75.7%, respectively, in the carboplatin group and 8.1%, 22.7%, and 36.9%, respectively, in the cisplatin group. The cisplatin group had a significantly lower IDR rate compared with the carboplatin group. The selection of a platinum agent was 1 of the independent factors for IDR in a multivariate Cox proportional hazards model. CONCLUSIONS HAI chemotherapy with cisplatin before radical local treatment was effective in patients with HCC. The authors concluded that radical local treatment with concurrent HAI using cisplatin may contribute to a longer progression-free period, which could be predicted with intrahepatic imaging in patients with stage I/II HCC.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata, Japan.
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Kim NY, Sun JM, Kim YJ, Lee KW, Kim JH, Bang SM, Kim JW, Jeong SH, Lee JS. Cisplatin-Based Combination Chemotherapy for Advanced Hepatocellular Carcinoma: A Single Center Experience before the Sorafenib Era. Cancer Res Treat 2010; 42:203-9. [PMID: 21253322 PMCID: PMC3021739 DOI: 10.4143/crt.2010.42.4.203] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Accepted: 06/17/2010] [Indexed: 01/14/2023] Open
Abstract
PURPOSE Systemic chemotherapy is the only option for patients with unresectable/metastatic hepatocellular carcinoma (HCC) who are not candidates for local/regional treatment. However, the response to such treatment and survival are poor, especially in hepatitis B virus (HBV) endemic areas. The aim of this study was to determine the efficacy of cisplatin-based combination chemotherapy and identify a subgroup of advanced HCC patients with favorable responses. MATERIALS AND METHODS The medical records of all consecutive patients with unresectable/metastatic HCC who received cisplatin-based combination chemotherapy between January 2003 and October 2009 were reviewed. Time to progression (TTP) and overall survival (OS) were determined using Kaplan-Meier analysis. Univariate and multivariate analyses were performed to identify prognostic factors for TTP and OS. RESULTS Data for 46 patients were analyzed. First-line chemotherapies consisted of cisplatin-based combination treatment with doxorubicin, fluoropyrimidines and gemcitabine. The response rate for all patients was 4.3%. The median TTP and OS were 1.8 (95%confidence interval [CI], 1.1 to 2.5) and 7.2 (95% CI, 3.0 to 11.5) months, respectively. Eastern Cooperative Oncology Group (ECOG) performance status (PS), Child classification, Cancer of the Liver Italian Program (CLIP) score and portal vein thrombosis (PVT) were identified by univariate analyses as prognostic factors for TTP and OS. ECOG PS (hazard ratio [HR], 4.51; 95% CI, 1.61 to 12.6; p=0.004) and PVT (HR, 2.12; 95% CI, 1.10 to 4.11; p=0.026) were independent prognostic factors for TTP. CONCLUSION Cisplatin-based combination chemotherapy in patients with advanced HCC has a low response rate and short TTP regardless of the chemotherapy regimen used. Patients with a good ECOG PS and without PVT can be considered candidates for cisplatin-based combination chemotherapy.
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Affiliation(s)
- Nae Yu Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Affiliation(s)
- Charles H Cha
- Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
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Ishikawa T. Future perspectives on the treatment of hepatocellular carcinoma with cisplatin. World J Hepatol 2009; 1:8-16. [PMID: 21160960 PMCID: PMC2998955 DOI: 10.4254/wjh.v1.i1.8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Revised: 09/09/2009] [Accepted: 09/16/2009] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the commonest primary liver malignancy. Its incidence is increasing worldwide. Surgery, including transplantation resection, is currently the most effective treatment for HCC. However, recurrence rates are high and long-term survival is poor. Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. Cisplatin (CDDP) is a key drug for the standard regimens of various cancers in the respiratory, digestive and genitourinary organs. Recently, several encouraging results have been shown in using CDDP in the treatment of advanced HCC patients. This review examines current knowledge regarding the chemotherapeutic potential of CDDP.
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Affiliation(s)
- Toru Ishikawa
- Toru Ishikawa, Department of Gastroenterology and Hepatology, Saiseikai Niigata Second Hospital, Niigata 950-1104, Japan
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Lee JO, Lee KW, Oh DY, Kim JH, Im SA, Kim TY, Bang YJ. Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol 2009; 20:1402-7. [PMID: 19502532 DOI: 10.1093/annonc/mdp010] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS From September 2003 to July 2007, we enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2000 mg/m(2)/day) with a schedule of 2 weeks on and 1 week off and cisplatin (60 mg/m(2)) on the first day of the 3-week cycle. RESULTS The study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was 2.0 months [95% confidence interval (CI) 1.5-2.4] and the median overall survival (OS) time was 12.2 months (95% CI 6.5-17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%) and anemia (2.1%). The grade 3/4 non-hematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%) and nausea (3.2%). There was no treatment-related mortality. CONCLUSIONS Based on the observed response rate and TTP, XP combination chemotherapy showed modest antitumor efficacy in patients with metastatic HCC as systemic first-line treatment. However, XP combination chemotherapy showed tolerable toxicity and demonstrated favorable OS time.
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Affiliation(s)
- J O Lee
- Department of Internal Medicine, Seoul National University Hospital, Chongno-gu, Seoul, Korea
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Chaparro M, González Moreno L, Trapero-Marugán M, Medina J, Moreno-Otero R. Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents. Aliment Pharmacol Ther 2008; 28:1269-77. [PMID: 18808443 DOI: 10.1111/j.1365-2036.2008.03857.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. AIM To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. METHODS A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. RESULTS Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor beta tyrosine kinases. CONCLUSIONS Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients.
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Affiliation(s)
- M Chaparro
- Department of Hepatology and Ciberehd, University Hospital La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
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Phase II study of oxaliplatin in patients with unresectable, metastatic, or recurrent hepatocellular cancer: a California Cancer Consortium Trial. Am J Clin Oncol 2008; 31:317-22. [PMID: 18845988 DOI: 10.1097/coc.0b013e318162f57d] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Prolonged survival for patients with unresectable hepatocellular carcinoma (HCC) is consistently reported at lower than 6 months. Oxaliplatin has recently demonstrated activity in HCC. The objective of this study was to determine the response rate, survival, time to progression, and toxicity in patients with poor prognosis HCC when treated with oxaliplatin. EXPERIMENTAL DESIGN Patients were required to have measurable recurrent, metastatic or unresectable HCC, and to have previously been exposed to no more than 2 prior chemotherapy regimens. Karnofsky performance of 70% or above and adequate organ and hematologic function were required. All patients received treatment with oxaliplatin 100 mg/m on day 1 and 15 as a 2-hour intravenous infusion and were pretreated with antiemetics. Treatment was repeated every 28 days. RESULTS Thirty-six patients were enrolled and evaluated, although 6 expired before the first planned evaluation. Karnofsky performance status was 70/80/90/100% in 5/9/9/13 patients, respectively. The median time to progression was 2 months; median survival was 6 months. The 6-month overall survival was 55% (95% confidence interval 41%-74%), and the 6 month event-free survival was 11% (95% confidence interval 4%-28%). CONCLUSION Single agent, oxaliplatin, has produced one partial response of good duration in 36 patients, but failed to meet the a priori criterion for promise in this trial. Sixteen patients were observed to have stable disease with a well tolerated toxicity profile. The combination of oxaliplatin and other agents should be considered to treat HCC in those patients with good functional status.
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Transarterial chemoembolization using cisplatin powder in a rabbit model of liver cancer. Cardiovasc Intervent Radiol 2008; 31:981-5. [PMID: 18535857 DOI: 10.1007/s00270-008-9367-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2007] [Revised: 04/22/2008] [Accepted: 05/13/2008] [Indexed: 10/22/2022]
Abstract
The purpose of this study was to investigate the pharmacological advantages of transarterial chemoembolization (TACE) with cisplatin powder for hypervascular hepatic tumors in animal experiments. VX2 tumors were transplanted to the livers of nine rabbits. Cisplatin (1 mg/kg) was infused into the proper hepatic artery. In the cisplatin-HAI group, cisplatin solution was infused. In the cisplatin-GS-TACE group, after infusion of cisplatin solution, gelatin sponge particles were used for embolization. In the cisplatin-Lp-TACE group, after infusion of a cisplatin powder and lipiodol (10 mg/ml) suspension, gelatin sponge particles were used for embolization. Before and after administration, platinum concentrations in plasma were measured. Using liver specimens that were excised 60 min after infusion, platinum concentrations in tumorous and nontumorous liver tissues were measured. The mean platinum concentration in tumorous tissue was 0.88 microg/ml for the cisplatin-HAI group, 1.23 microg/ml for the cisplatin-GS-TACE group, and 12.65 microg/ml for the cisplatin-Lp-TACE group. The platinum concentration for the cisplatin-Lp-TACE group was significantly higher than that for the cisplatin-HAI group (p = 0.004) and the cisplatin-GS-TAE group (p = 0.004). The mean platinum concentration in nontumorous liver tissue was 0.98 microg/ml for the cisplatin-HAI group, 1.13 microg/ml for the cisplatin-GS-TACE group, and 1.09 microg/ml for the cisplatin-Lp-TACE group; no significant differences were seen. At both 5 and 10 min after infusion, the platinum concentrations for the cisplatin-Lp-TACE group were lower than those for the other two groups. The present results suggest that TACE using cisplatin powder/lipiodol suspension and gelatin sponge for hypervascular hepatic tumors has a number of pharmacological advantages.
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Yoshikawa M, Ono N, Yodono H, Ichida T, Nakamura H. Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 2008; 38:474-83. [PMID: 18430093 DOI: 10.1111/j.1872-034x.2008.00338.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Intra-arterial cisplatin appears to have high therapeutic efficacy, but this has not been studied in detail. Accordingly, we developed a fine-powder cisplatin formulation and tested it in advanced hepatocellular carcinoma (HCC) patients in an open-label, uncontrolled study in which 27 institutions participated. METHODS The patients in this study had inoperable advanced HCC without extrahepatic metastases. All received two infusions of high-concentration cisplatin (1.43 mg/mL) via the hepatic artery at a dose of 65 mg/m(2), with an intervening 4-6 week interval. RESULTS Cisplatin efficacy and safety were assessed in 80 patients. We found partial responses in 27 cases, no change in 37, and progressive disease in 11 (five were not evaluated). The overall response rate was 33.8%. The 1-year survival rate was 67.5% and the 2-year survival rate was 50.8%. Severe adverse effects (>/=grade 3) included anorexia in 22.5%, vomiting in 6.3%, abdominal pain in 1.3%, thrombocytopenia in 25%, neutropenia in 13%, leukopenia in 1.3%, hypochromia in 1.3%, elevated serum aspartate aminotransferase in 32.5%, elevated serum alanine aminotransferase in 11.3%, elevated serum bilirubin in 3.8%, decreased serum albumin in 1.3%, elevated serum alkaline phosphatase in 1.3%, elevated gamma-glutamyltranspeptidase in 3.8%, and elevated serum creatinine in 2.5%. Death from myocardial infarction occurred as an incidental event in one case, and no other life-threatening, adverse events were observed. CONCLUSION Although intra-arterial cisplatin has substantial local and systemic toxicity, high therapeutic efficacy suggests the potential usefulness of this agent in the treatment of advanced HCC.
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Affiliation(s)
- Masaharu Yoshikawa
- Department of Medicine and Clinical Oncology, Chiba University, Chiba, Japan
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Yoon KT, Choi JW, Park JY, Ahn SH, Paik YH, Lee KS, Han KH, Chon CY, Kim DY. Clinical outcomes of systemic chemotherapy in hepatocellular carcinoma patients with multiple lung metastases. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:360-70. [DOI: 10.3350/kjhep.2008.14.3.360] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Ki Tae Yoon
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Jong Won Choi
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Yong Han Paik
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Kwang Hyub Han
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Chae Yoon Chon
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Liver Cirrhosis Clinical Research Center, Seoul, Korea
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Cancer of the Liver and Bile Ducts. Oncology 2007. [DOI: 10.1007/0-387-31056-8_44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Xu SP, Sun GP, Shen YX, Wei W, Peng WR, Wang H. Antiproliferation and apoptosis induction of paeonol in HepG 2 cells. World J Gastroenterol 2007; 13:250-6. [PMID: 17226904 PMCID: PMC4065953 DOI: 10.3748/wjg.v13.i2.250] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [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 investigate the antiproliferative effect of paeonol (Pae) used alone or in combination with chemotherapeutic agents [cisplatin (CDDP), doxorubicin (DOX) and 5-fluorouracil (5-FU)] on human hepatoma cell line HepG2 and the possible mechanisms.
METHODS: The cytotoxic effect of drugs on HepG2 cells was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetra-zolium bromide (MTT) assay. Morphologic changes were observed by acridine orange (AO) fluorescence staining. Cell cycle and apoptosis rate were detected by flow cytometry (FCM). Drug-drug interactions were analyzed by the coefficient of drug interaction (CDI).
RESULTS: Pae (7.81-250 mg/L) had an inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner, with the IC50 value of (104.77 ± 7.28) mg/L. AO fluorescence staining and FCM assays showed that Pae induced apoptosis and arrested cell cycle at S phase in HepG2 cells. Further, different extent synergisms were observed when Pae (15.63, 31.25, 62.5 mg/L) was combined with CDDP (0.31-2.5 mg/L), DOX (0.16-1.25 mg/L), or 5-FU (12.5-100 mg/L) at appropriate concentrations. The IC50 value of the three drugs decreased dramatically when combined with Pae (p < 0.01). Of the three different combinations, the sensitivity of cells to drugs was considerably different.
CONCLUSION: Pae had a significant growth-inhibitory effect on the human hepatoma cell line HepG2, which may be related to apoptosis induction and cell cycle arrest. It also can enhance the cytotoxicity of chemotherapeutic agents on HepG2 cells, and the S phase arrest induced by Pae may be one of the mechanisms of these interactions.
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Affiliation(s)
- Shu-Ping Xu
- Institute of Clinical Pharmacology of Anhui Medical University, Key Laboratory of Antiinflammatory and Immunological Pharmacology in Anhui Province, Hefei 230032, Anhui Province, China
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Ishikawa T, Kamimura H, Tsuchiya A, Watanabe K, Seki K, Ohta H, Yoshida T, Tsubono T, Takeda K, Ishihara N, Kamimura T. A case of advanced hepatocellular carcinoma showing marked tumor necrosis after administration of CDDP powder for intraarterial use. KANZO 2007; 48:27-32. [DOI: 10.2957/kanzo.48.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
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Abstract
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
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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.
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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
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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.
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Affiliation(s)
- Daniel H Palmer
- Cancer Research UK Institute for Cancer Studies, Clinical Research Block, University of Birmingham, Birmingham B15 2TA, UK.
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Raoul JL, Boucher E, Olivie D, Guillygomarc'h A, Boudjema K, Garin E. Association of cisplatin and intra-arterial injection of 131I-lipiodol in treatment of hepatocellular carcinoma: results of phase II trial. Int J Radiat Oncol Biol Phys 2005; 64:745-50. [PMID: 16289908 DOI: 10.1016/j.ijrobp.2005.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Revised: 09/02/2005] [Accepted: 09/04/2005] [Indexed: 01/03/2023]
Abstract
PURPOSE Intra-arterial injections of 131I-lipiodol (131I-Lip) provide an effective treatment for hepatocellular carcinoma. In hepatocellular carcinoma cell cultures, concurrent administration of cisplatin increases the cytotoxicity of 131I. The efficacy and tolerance of intra-arterial injections of 131I-Lip combined with systemic cisplatin was tested in a phase II trial. METHODS AND MATERIALS The inclusion criteria were proven unresectable nonmetastatic hepatocellular carcinoma, compensated liver disease, and adequate laboratory test findings. Treatment comprised the combination of intra-arterial injection of 131I-Lip (2.2 GBq) with intravenous infusion of low-dose cisplatin. The combined treatment could be repeated. RESULTS A total of 41 patients were included; 37 had cirrhosis and 38 had measurable tumors. One to four treatments (median, two) were given. The cisplatin dose was 75 mg for the first course and 72 mg for the second. Grade 3-4 (n/n) adverse effects were observed in 14 patients, polymorphonuclear leukocytes (3/0), platelets (5/1), asthenia (1/0), pain (1/0), and vomiting (1/0). Four patients developed pulmonary toxicity; 2 cases were likely related to 131I-Lip administration and 1 was fatal. The response rate was 47% (18 of 38), and the 1- and 2-year survival rate was 73% +/- 7% and 48% +/- 9%, respectively. CONCLUSION This combination had a tolerable toxicity profile and provided an objective response rate, warranting a phase III trial.
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Affiliation(s)
- Jean-Luc Raoul
- Department of Medical Oncology, Centre E Marquis, Rennes, France.
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35
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Kim SJ, Seo HY, Choi JG, Sul HR, Sung HJ, Park KH, Choi IK, Oh SC, Yoon SY, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS. Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2005; 57:436-42. [PMID: 16049620 DOI: 10.1007/s00280-005-0067-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2005] [Accepted: 06/14/2005] [Indexed: 01/25/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC. PATIENTS AND METHODS All 53 patients received epirubicin (50 mg/m2 i.v.) on day 1 and cisplatin (60 mg/m2 i.v.) after epirubicin administration. Oral UFT 400-600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval. RESULTS Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0-26.8%) with median response duration of 17.1 weeks (95% CI; 5.0-29.3 weeks, range; 7.1-51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3-31.9 weeks, range; 3.0-131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%). CONCLUSION The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.
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Affiliation(s)
- Seok Jin Kim
- Division of Hematology/Oncology Department of Internal Medicine, Korea University Medical Center, 126-1, Anam-dong 5-ga, Sungbuk-ku, Seoul, 136-705, Korea
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Ikeda M, Okusaka T, Ueno H, Takezako Y, Morizane C. A phase II trial of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma. Cancer 2005; 103:756-62. [PMID: 15637692 DOI: 10.1002/cncr.20841] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND The aim of the current study was to evaluate the antitumor activity and toxicity of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin (FMP therapy) in chemotherapy-naive patients with metastatic hepatocellular carcinoma (HCC). METHODS Fifty-one patients with metastatic HCC who had not undergone previous systemic chemotherapy were enrolled. The therapy consisted of intravenous administration of 80 mg/m2 cisplatin and 6 mg/m2 mitoxantrone on Day 1 and continuous intravenous infusion of 450 mg/m2 5-fluorouracil per day on Days 1-5. The treatment was repeated every 4 weeks for a maximum of 6 courses with dose adjustments based on the observed toxic effects if there was no evidence of tumor progression or unacceptable toxicity. RESULTS Of the 51 enrolled patients, 14 (27%) achieved a partial response (95% confidence interval, 16-42%) with a median duration of 7.6 months (range, 2.3-18.4 months). Twenty-seven patients (53%) showed no change and 9 (18%) had progressive disease. The median survival time, 1-year survival rate, and median progression-free survival time for all patients were 11.6 months, 44.3%, and 4.0 months, respectively. The main Grade 3 and 4 toxicities were leukocytopenia (67%), neutropenia (71%), thrombocytopenia (27%), and elevated levels of aspartate aminotransferase (37%) and alanine aminotransferase (41%). These symptoms were generally brief and reversible, with the exception of one treatment-related death due to acute hepatic failure. CONCLUSIONS FMP therapy had significant antitumor activity with acceptable toxicity in patients with metastatic HCC.
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Affiliation(s)
- Masafumi Ikeda
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
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Nowak AK, Chow PKH, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review. Eur J Cancer 2004; 40:1474-84. [PMID: 15196530 DOI: 10.1016/j.ejca.2004.02.027] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2004] [Accepted: 02/13/2004] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.
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Affiliation(s)
- Anna K Nowak
- NHMRC Clinical Trials Centre, University of Sydney, Locked Bag 77 Camperdown, NSW 1450, Australia.
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Mabed M, El-Helw L, Shamaa S. Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer 2004; 90:65-9. [PMID: 14710208 PMCID: PMC2395314 DOI: 10.1038/sj.bjc.6601463] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2003] [Revised: 10/02/2003] [Accepted: 10/06/2003] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of patients with HCC remain very poor. This study was conducted to evaluate the efficacy and safety of viscum fraxini-2 in patients with chemotherapy-naïve, advanced hepatocellular carcinoma. 23 patients with unrespectable HCC who had received no prior systemic chemotherapy with objectively measurable tumors were enrolled on this study. The mistletoe preparation for the study is an aqueous injectable solution. It contains one milliliter of viscum fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe herb from ash tree, diluted in di-natrium-mono-hydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/ml injection ampoules. 2 ampoules of viscum fraxini-2 were administered subcutaneously once weekly. As assessed by conventional imaging criteria, 3 (13.1%) patients have achieved complete response, 2 (8.1%) patients have achieved a partial response. 9 (39.1%) had progressive disease while 9 (39.1%) patients didn't have evaluation of response due to early death. The median overall survival time for all patients was 5 months (range 2-38 months), for those who achieved a CR was 29 months (range 12-38 months) and, for those who achieved a PR was 6.5 months (range 6-7 months). The median progression free survival for all patients was 2 months (range 1-38 months), for those who achieved a CR, it was 29 months (range 8-38 months) and for those who achieved a partial response, it was 5 months (range 4-6 months). No hematologic toxicity has been encountered. The spectrum of non-hematologic toxicity was mild. The WHO toxicity criteria grade 3-4 were 34.8% drug related fever, 13.1% erthyma at injection site and 17.4% pain at the site of injection. No drug related discontinuation or toxic deaths have occurred. Viscum fraxini-2 seems to be particularly promising in patients with advanced HCC, it shows antitumor activity and low toxicity profile. Further studies in combination with other active agents are clearly warranted.
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Affiliation(s)
- M Mabed
- Hematology and Medical Oncology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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Abstract
Hepatocellular carcinoma is a very prevalent malignancy worldwide, with increasing incidence in the United States. Despite many available treatment options, the prognosis remains poor. Surgical resection or liver transplantation still represents the only potentially curative treatments for HCC. Until more effective systemic therapies are available, different localized treatment approaches will continue to be applied in the management of this disease. Although systemic chemotherapy has been disappointing, increased understanding of the tumor biology in HCC coupled with new drug development may lead to newer agents with novel mechanisms of action that are more efficacious. The poor treatment outcome and dismal prognosis make prevention of HCC an important strategy in controlling this aggressive type of malignancy. Vaccine programs for HBV are ongoing. Efforts are underway to develop a vaccine for HCV. Interferon therapy appears to decrease the risk of developing HCC in patients with hepatitis, especially those with HCV. A number of other approaches for decreasing risk in these patients as well as in those with alcoholic-related cirrhosis are currently being evaluated.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital, Dana-Farber/Partners Cancer Care, Harvard Medical School, Boston, Massachusetts, USA.
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Court WS, Order SE, Siegel JA, Johnson E, DeNittis AS, Principato R, Martz K, Zeiger LS. Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma. Cancer Invest 2002; 20:613-25. [PMID: 12197216 DOI: 10.1081/cnv-120002486] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PRECIS Intraarterial delivery of 50 mg/m2 cisplatinum on a monthly basis is a well-tolerated regimen for patients with nonresectable hepatoma. The selective uptake of cisplatinum delivered intraarterially suggests other selective intraarterial protocols would be of use in regional cancers treated with cisplatinum. BACKGROUND Sixty-seven patients with nonresectable hepatoma were treated with hepatic artery infusions (HAI) of 50 mg/m2 cisplatinum on a monthly basis. METHODS Forty-eight patients received an initial course of whole liver external radiation with intravenous (i.v.) cisplatinum 50 mg/m2. Nineteen patients did not receive radiation and received HAI cisplatinum only. All patients then received HAI cisplatinum at 50 mg/m2 on a monthly basis. Six patients were given a tracer dose of radioactive 195m cisplatinum for quantitation by the HAI and i.v. routes. RESULTS Monthly HAI cisplatinum was well tolerated and could be repeated indefinitely. Median survival for primarily treated nonresectable hepatomas was 12 months [alpha fetoprotein (AFP) elevated] and 17.5 months (AFP negative). Radioactive cisplatinum given by HAI yielded 34-55% tumor uptake of cisplatinum vs. < 5% by i.v. delivery. CONCLUSIONS Hepatic intraarterial cisplatinum at 50 mg/m2 is a well-tolerated monthly regimen for patients with nonresectable hepatoma.
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Affiliation(s)
- Wayne S Court
- Center for Molecular Medicine, 700 Stewart Avenue, Garden City, NY 11530, USA.
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Abstract
Primary hepatocellular cancer is a disease with a poor prognosis for which there is little consensus on treatment and a paucity of comparative trials. The coexistence of cancer with cirrhosis complicates treatment, and also confers a high risk for the development of further tumours. Surgery, either by hepatic resection or orthotopic liver transplantation, is only a feasible option in a minority of patients. This article surveys the non-surgical approaches to the treatment of hepatocellular cancers-local ablation techniques, arterial embolization with and without chemotherapy, conventional chemotherapy and hormonal modulation, and targeted and external irradiation.
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Affiliation(s)
- A M Alsowmely
- Centre for Hepatology, Royal Free and University College Medical School, London, UK
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Patt YZ, Hoque A, Roh M, Ellis L, Lozano R, Carrasco CH, Charnsangavej C, Cleary K. Durable clinical and pathologic response of hepatocellular carcinoma to systemic and hepatic arterial administration of platinol, recombinant interferon alpha 2B, doxorubicin, and 5-fluorouracil: a communication. Am J Clin Oncol 1999; 22:209-13. [PMID: 10199464 DOI: 10.1097/00000421-199904000-00024] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The case described here illustrates the antitumor activity of a four-drug systemic combination chemobiotherapy with platinol, recombinant interferon alpha 2b, doxorubicin (Adriamycin), and 5-fluorouracil (5-FU) (PIAF) in a patient with diffuse hepatocellular carcinoma involving the liver and lungs.
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Affiliation(s)
- Y Z Patt
- Department of Gastrointestinal Medical Oncology and Digestive Diseases, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
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Varkey M, Devi RS, Rao SB. Glycoprotein components in the serum of patients with cancer breast. Indian J Clin Biochem 1997; 12:63-6. [PMID: 23100866 PMCID: PMC3454043 DOI: 10.1007/bf02867958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The levels of total sialic acid, lipid bound sialic acid and fucose were estimated in the sera of patients with benign and malignant tumours of breast. An increase was noted in all the three parameters, with a more marked increase in malignancy, when compared with benign and controls. Consequent to surgery, there was an elevation in the serum levels of the above parameters than the values prior to surgery and a decline was noted two months after surgery although none of the values reached the normal range. These results suggest a close association of the glycoproteins with the tumour burden and further signify their role in early detection and staging of cancer breast.
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Affiliation(s)
- M Varkey
- Departments of Biochemistry, Medical College, 695 011 Thiruvananthapuram
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Ji SK, Park NH, Choi HM, Kim YW, Lee SH, Lee KH, Ahn SY, Lee SU, Han BH, Park BC. Combined cis-platinum and alpha interferon therapy of advanced hepatocellular carcinoma. Korean J Intern Med 1996; 11:58-68. [PMID: 8882477 PMCID: PMC4532007 DOI: 10.3904/kjim.1996.11.1.58] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
To evaluate the clinical efficacy of alpha-interferon(IFN-alpha) plus cis-platinum in hepatocellular carcinoma(HCC). 56 inoperable patients with HCC were divided into IFN-alpha plus cis-platinum treated group (n = 30) and no antitumor therapy group (n = 26). The survival of IFN-alpha plus cis-platinum treated patients was significantly better than that of patients who received no antitumor therapy (p = 0.001). Median survival time was 33 weeks and 14.0 weeks, respectively. The cumulative estimated survival rates of our IFN-alpha plus cis-platinum treated group (93.5% at 3mo, 75.0% at 6mo) were for longer than that of the no antitumor therapy group (84.6% at 3mo, 57.7% at 6mo). Objective tumor regression, greater than 50% was observed in 13.3% (4 of 30) of patients receiving IFN-alpha plus cis-platinum. By the univariate analysis, the absence of portal vein thrombus (p < 0.05), alkaline phosphatase lesser than 280 U/L (p = 0.001), total bilirubin less than 2.0 mg% (p < 0.05), serum triglyceride less than 155 mg/dl (p < 0.05) were shown to be the factors most significantly favoring a better survival. By the multivariate analysis, using Cox proportional hazards model, IFN-alpha plus cis-platinum treated group (p = 0.0001), alkaline phosphatase less than 280 mg/dl (p = 0.005), the absence of portal vein thrombus (p = 0.020) were independent favorable prognostic factors. We conclude that IFN-alpha plus cis-platinum is useful in patients with inoperable HCC and the above favorable prognostic factors may also be useful in the design and analysis of future clinical trials of systemic chemotherapy for HCC.
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Affiliation(s)
- S K Ji
- Department of Internal Medicine, Kosin Medical College, Pusan, Korea
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Denda T, Saisho H, Yoshikawa M, Ebara M, Ohto M, Fujimoto S, Tokita H. Chemosensitivity test for repeated arterial infusion chemotherapy by reservoir for unresectable hepatocellular carcinoma. J Gastroenterol Hepatol 1995; 10:446-53. [PMID: 8527712 DOI: 10.1111/j.1440-1746.1995.tb01598.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The experimental and clinical usefulness of a chemosensitivity test (Nuclear Damage Assay) was studied. Karyologic degenerative changes were observed as an indicator of drug sensitivity, in repeated arterial infusion chemotherapy (RAIC) using a reservoir for advanced hepatocellular carcinoma (HCC). In the experimental study, this sensitivity test was performed using five liver cell lines against 15 drugs. At the same time, the succinate dehydrogenase inhibition (SDI) test was also performed. Comparison of the results between these two tests gave a high consistency rate of 81%. Clinically, the karyologic sensitivity test was carried out in 135 patients with unresectable HCC. Drug sensitivity could be evaluated in as many as 89% of the total 135 patients. Of the patients, 43 received RAIC on an outpatient basis via a subcutaneously implanted reservoir. The objective response of RAIC on tumours of the 43 patients was evaluated as complete response, partial response, in 3 (9%) and 8 (23%) in 35 patients treated with positive drugs (positive group), and as 0 (0%) and 0 (0%) of 8 patients treated with negative drugs (negative group), respectively. As regards the prognosis, 1 year and 1.5 year survival rates were 70 and 45% in the positive group, and 42 and 0% in the negative group, respectively. As objective response in the positive group tended to be better than that in the negative group, and prognosis in the positive group was significantly better than that in the negative group, this sensitivity test appears to contribute to the improvement of therapeutic results if used to select drugs suitable for RAIC for advanced HCC.
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Affiliation(s)
- T Denda
- Division of Clinical Laboratory, Chiba Cancer Center Hospital, Japan
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