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Raoof M, Fong Y. Importance of magnetic resonance imaging and positron emission tomography as preoperative staging tests prior to liver resection. Transl Gastroenterol Hepatol 2024; 9:58. [PMID: 39503031 PMCID: PMC11535783 DOI: 10.21037/tgh-24-42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/03/2024] [Indexed: 11/08/2024] Open
Affiliation(s)
- Mustafa Raoof
- Department of Surgery, City of Hope National Cancer Center, Duarte, CA, USA
| | - Yuman Fong
- Department of Surgery, City of Hope National Cancer Center, Duarte, CA, USA
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The past, present, and future of chemotherapy with a focus on individualization of drug dosing. J Control Release 2022; 352:840-860. [PMID: 36334860 DOI: 10.1016/j.jconrel.2022.10.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 10/14/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022]
Abstract
While there have been rapid advances in developing new and more targeted drugs to treat cancer, much less progress has been made in individualizing dosing. Even though the introduction of immunotherapies such as CAR T-cells and checkpoint inhibitors, as well as personalized therapies that target specific mutations, have transformed clinical treatment of cancers, chemotherapy remains a mainstay in oncology. Chemotherapies are typically dosed on either a body surface area (BSA) or weight basis, which fails to account for pharmacokinetic differences between patients. Drug absorption, distribution, metabolism, and excretion rates can vary between patients, resulting in considerable differences in exposure to the active drugs. These differences result in suboptimal dosing, which can reduce efficacy and increase side-effects. Therapeutic drug monitoring (TDM), genotype guided dosing, and chronomodulation have been developed to address this challenge; however, despite improving clinical outcomes, they are rarely implemented in clinical practice for chemotherapies. Thus, there is a need to develop interventions that allow for individualized drug dosing of chemotherapies, which can help maximize the number of patients that reach the most efficacious level of drug in the blood while mitigating the risks of underdosing or overdosing. In this review, we discuss the history of the development of chemotherapies, their mechanisms of action and how they are dosed. We discuss substantial intraindividual and interindividual variability in chemotherapy pharmacokinetics. We then propose potential engineering solutions that could enable individualized dosing of chemotherapies, such as closed-loop drug delivery systems and bioresponsive biomaterials.
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Monirujjaman M, Bathe OF, Mazurak VC. Dietary EPA+DHA Mitigate Hepatic Toxicity and Modify the Oxylipin Profile in an Animal Model of Colorectal Cancer Treated with Chemotherapy. Cancers (Basel) 2022; 14:cancers14225703. [PMID: 36428795 PMCID: PMC9688617 DOI: 10.3390/cancers14225703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are commonly used to treat metastatic colorectal cancer, but chemotherapy-associated steatosis/steatohepatitis (CASSH) frequently accompanies their use. The objective of this study was to determine effect of CPT-11+5-FU on liver toxicity, liver oxylipins, and cytokines, and to explore whether these alterations could be modified by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oil (EPA+DHA). Tumor-bearing animals were administered CPT-11+5-FU and maintained on a control diet or a diet containing EPA+DHA (2.3 g/100 g). Livers were collected one week after chemotherapy for the analysis of oxylipins, cytokines, and markers of liver pathology (oxidized glutathione, GSSH; 4-hydroxynonenal, 4-HNE, and type-I collagen fiber). Dietary EPA+DHA prevented the chemotherapy-induced increases in liver GSSH (p < 0.011) and 4-HNE (p < 0.006). Compared with the tumor-bearing animals, ten oxylipins were altered (three/ten n-6 oxylipins were elevated while seven/ten n-3 oxylipins were reduced) following chemotherapy. Reductions in the n-3 fatty-acid-derived oxylipins that were evident following chemotherapy were restored by dietary EPA+DHA. Liver TNF-α, IL-6 and IL-10 were elevated (p < 0.05) following chemotherapy; dietary EPA+DHA reduced IL-6 (p = 0.09) and eotaxin (p = 0.007) levels. Chemotherapy-induced liver injury results in distinct alterations in oxylipins and cytokines, and dietary EPA+DHA attenuates these pathophysiological effects.
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Affiliation(s)
- Md Monirujjaman
- Division of Human Nutrition, Department of Agricultural Food and Nutritional Science, Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Oliver F. Bathe
- Department of Surgery and Oncology, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Vera C. Mazurak
- Division of Human Nutrition, Department of Agricultural Food and Nutritional Science, Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB T6G 2P5, Canada
- Correspondence: ; Tel.: +1-780-492-8048
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Walia S, Kamal R, Kanwar SS, Dhawan DK. Hepato-protective role of chemo-preventive probiotics during DMH-induced CRC in rats. J Biochem Mol Toxicol 2021; 35:e22788. [PMID: 33866645 DOI: 10.1002/jbt.22788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/11/2021] [Accepted: 03/30/2021] [Indexed: 11/12/2022]
Abstract
The aim of the study was to assess the hepatotoxicity, and therefore pharmacological safety of probiotics Lactobacillus plantarum (AdF10) and Lactobacillus rhamnosus GG (LGG) for potential use in colorectal cancer (CRC) prevention. Thirty-six female Sprague Dawley (SD) rats were divided into six groups: normal control, AdF10-treated, LGG-treated, 1,2-Dimethyl hydrazine (DMH)-treated, AdF10 + DMH-treated, and LGG + DMH-treated groups. Antioxidant enzyme activity, lipid proxidation, and liver function were assessed. Administration of probiotics in both AdF10 + DMH-treated and LGG + DMH-treated groups downregulated DMH induced a rise in lipid peroxide (LPO), glutathione reductase (GR) activity, and increased the diminished glutathione reduced (GSH) content and catalase (CAT), glutathione-transferase (GST), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. DMH-treated rats receiving the probiotic treatment suffered less liver damage when compared with rats that did not receive probiotics. In conclusion, the study identifies the use of probiotics as an effective and nontoxic chemo-preventive interventional in CRC.
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Affiliation(s)
- Sohini Walia
- Department of Microbiology, CSK Himachal Pradesh Agricultural University, Palampur, Himachal Pradesh, India
| | - Rozy Kamal
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sarbjit S Kanwar
- Department of Microbiology, CSK Himachal Pradesh Agricultural University, Palampur, Himachal Pradesh, India
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Longbotham D, Young A, Nana G, Feltbower R, Hidalgo E, Toogood G, Lodge PA, Attia M, Rajendra Prasad K. The impact of age on post-operative liver function following right hepatectomy: a retrospective, single centre experience. HPB (Oxford) 2020; 22:151-160. [PMID: 31337601 DOI: 10.1016/j.hpb.2019.06.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/30/2019] [Accepted: 06/20/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND An increasing number of patients undergoing liver resection are of advancing age. The impact of ageing on liver regeneration and post-operative outcomes following a major resection are uncertain. We aimed to investigate risk factors for patients who developed Post Hepatectomy Liver Failure (PHLF) following right hepatectomy with age as the primary risk-factor. METHOD Patients undergoing right hepatectomy between July 2004-July 2018 were included. ROC analysis was performed to identify at which age PHLF development-risk increased. Secondary endpoints were length of stay (LOS), complications, and cost. RESULTS 332-patients were included. ROC demonstrated a cut-off age of 75-years in which PHLF risk increased. >75 there was an increased risk of PHLF (35% >75yrs vs. 7% <75yrs (p = <0.001), OR = 8.8 (95% CI = 3.6-21)) There was no difference between the age groups for any other PHLF risk factor. Patients >75yrs had longer LOS (11-days vs. 7-days (p = 0.04). Patients who developed PHLF had increased hospital costs: £10,987.50 (£6175-£46,050) vs. £2575 (£900-£46,050 p = 0.01). CONCLUSIONS Patients >75yrs have increased risk of developing PHLF after right hepatectomy, contributing to increased mortality and economic burden. Pre-operatively identifying patients at-risk of PHLF is important to consider liver volume optimization strategies and improve outcomes.
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Affiliation(s)
- David Longbotham
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Alastair Young
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Gael Nana
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Richard Feltbower
- Division of Epidemiology and Biostatistics, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Ernest Hidalgo
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Giles Toogood
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Peter A Lodge
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
| | - Magdy Attia
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom.
| | - K Rajendra Prasad
- Division of Surgery, Department of Hepatobiliary and Transplantation Surgery St James's University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, United Kingdom
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Madkhali A, Alalem F, Aljuhani G, Alsharaabi A, Alsaif F, Hassanain M. Preoperative Selection and Optimization for Liver Resection in Colorectal Cancer Liver Metastases. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0405-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Hardesty JE, Al-Eryani L, Wahlang B, Falkner KC, Shi H, Jin J, Vivace BJ, Ceresa BP, Prough RA, Cave MC. Epidermal Growth Factor Receptor Signaling Disruption by Endocrine and Metabolic Disrupting Chemicals. Toxicol Sci 2018; 162:622-634. [PMID: 29329451 PMCID: PMC5888991 DOI: 10.1093/toxsci/kfy004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The purpose of this study is to identify an environmentally relevant shared receptor target for endocrine and metabolism disrupting chemical pollutants. A feature of the tested chemicals was that they induced Cyp2b10 in vivo implicating activation of the constitutive androstane receptor (CAR). Recent studies suggest that these compounds could be indirect CAR activators via epidermal growth factor receptor (EGFR) inhibition. Assays included a CAR activity reporter assay, EGF endocytosis assay, and EGFR phosphorylation assay. Docking simulations were used to identify putative binding sites for environmental chemicals on the EGFR. Whole-weight and lipid-adjusted serum mean pollutant exposures were determined using data from the National Health and Examination Survey (NHANES) and compared with the IC50 values determined in vitro. Chlordane, trans-nonachlor, PCB-126, PCB-153, and atrazine were the most potent EGFR inhibitors tested. PCB-126, PCB-153, and trans-nonachlor appeared to be competitive EGFR antagonists as they displaced bound EGF from EGFR. However, atrazine acted through a different mechanism and could be an EGFR tyrosine kinase inhibitor. EGFR inhibition relative effect potencies were determined for these compounds. In NHANES, serum concentrations of trans-nonachlor, PCB-126, and PCB-153 greatly exceeded their calculated IC50 values. A common mechanism of action through EGFR inhibition for three diverse classes of metabolic disrupting chemicals was characterized by measuring inhibition of EGFR phosphorylation and EGF-EGFR endocytosis. Based on NHANES data, EGFR inhibition may be an environmentally relevant mode of action for some PCBs, pesticides, and herbicides.
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Affiliation(s)
| | | | - Banrida Wahlang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202
| | - K Cameron Falkner
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202
| | | | - Jian Jin
- Department of Pharmacology and Toxicology
| | - Brad J Vivace
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202
| | | | | | - Matthew C Cave
- Department of Biochemistry and Molecular Genetics
- Department of Pharmacology and Toxicology
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202
- The Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky 40206
- The Jewish Hospital Liver Transplant Program, Louisville, Kentucky 40202
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Yang Q, Ji G, Pan R, Zhao Y, Yan P. Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. Mol Clin Oncol 2017; 7:891-896. [PMID: 29142752 PMCID: PMC5666661 DOI: 10.3892/mco.2017.1409] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/23/2017] [Indexed: 12/13/2022] Open
Abstract
The present study was conducted to investigate the protective effect of hydrogen-rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy. A controlled, randomized, single-blind clinical trial was designed. A total of 152 patients with CRC were recruited by the Department of Oncology of Taishan Hospital (Taian, China) between June 2010 and February 2016, among whom 146 met the inclusion criteria. Subsequently, 144 patients were randomized into the treatment (n=80) and placebo (n=64) groups. At the end of the study, 76 patients in the hydrogen treatment group and 60 patients in the placebo group were included in the final analysis. The changes in liver function after the chemotherapy, such as altered levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, indirect bilirubin (IBIL) and direct bilirubin, were observed. The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels. The hydrogen-rich water group exhibited no significant differences in liver function before and after treatment, whereas the placebo group exhibited significantly elevated levels of ALT, AST and IBIL. Thus, hydrogen-rich water appeared to alleviate the mFOLFOX6-related liver injury.
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Affiliation(s)
- Qingxi Yang
- Department of Oncology, Shandong Provincial Taishan Hospital, Taian, Shandong 271000, P.R. China
| | - Guangdong Ji
- Department of Oncology, Shandong Provincial Taishan Hospital, Taian, Shandong 271000, P.R. China
| | - Rongtao Pan
- Department of Oncology, Shandong Provincial Taishan Hospital, Taian, Shandong 271000, P.R. China
| | - Yinghui Zhao
- Department of Pathology, Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Peng Yan
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
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Alessandrino F, Tirumani SH, Krajewski KM, Shinagare AB, Jagannathan JP, Ramaiya NH, Di Salvo DN. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol 2017; 72:521-533. [PMID: 28476244 DOI: 10.1016/j.crad.2017.04.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/28/2017] [Accepted: 04/03/2017] [Indexed: 12/13/2022]
Abstract
The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. The recent arrival of immune checkpoint inhibitors in oncology has introduced a new range of immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. High-dose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome. Management of hepatic toxicity depends on the clinical scenario, the drug in use, and the severity of the findings. In this article, we will (1) present the most common types of oncological drugs associated with hepatic toxicity and associated liver injuries; (2) illustrate imaging findings of hepatic toxicities and the possible differential diagnosis; and (3) provide a guide for management of these conditions.
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Affiliation(s)
- F Alessandrino
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
| | - S H Tirumani
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - K M Krajewski
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - A B Shinagare
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - J P Jagannathan
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - N H Ramaiya
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - D N Di Salvo
- Department of Imaging, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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Fukuoka K, Nara S, Honma Y, Kishi Y, Esaki M, Shimada K. Hepatectomy for Colorectal Cancer Liver Metastases in the Era of Modern Preoperative Chemotherapy: Evaluation of Postoperative Complications. World J Surg 2017; 41:1073-1081. [PMID: 27679508 DOI: 10.1007/s00268-016-3724-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Recently, an increasing number of patients with liver metastases from colorectal cancer have received chemotherapy before hepatectomy. However, the effect of chemotherapy on postoperative short-term outcome is not well defined. METHODS We retrospectively investigated the postoperative complications of 439 patients who underwent hepatectomy for colorectal liver metastases in our division from 2005 to 2014. Patients were classified into two groups according to the presence (Cx; 84 patients) or absence (NCx; 355 patients) of preoperative chemotherapy. Univariate and multivariate analyses were conducted to determine the predictive factors for postoperative complications. RESULTS There was neither mortality nor liver failure after surgery. There was no significant difference in the frequency of postoperative complications between Groups Cx and NCx [29 vs 26 % for all complications; both 6 % for bile leakage that required therapeutic intervention; and 2 vs 3 % for Clavien-Dindo (CD) Grade ≥ IIIa, respectively]. In Group Cx, morbidity rates were similar among patients with different chemotherapy regimens. Chemotherapy-related factors (administration of bevacizumab, oxaliplatin or irinotecan, duration of chemotherapy >150 days, and timing of hepatectomy) were not significantly associated with clinically relevant bile leakage and CD ≥ IIIa in multivariate analysis. CONCLUSION Even after combination chemotherapy including targeted therapy, hepatectomy for colorectal liver metastases can be performed safely without increasing morbidity or mortality, if the patients fulfill the conventional criteria for surgery.
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Affiliation(s)
- Kengo Fukuoka
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Yoshitaka Honma
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoji Kishi
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Minoru Esaki
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kazuaki Shimada
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
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Abstract
INTRODUCTION Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH). Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH. Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organotypic tissue models, coupled with translational functional biomarkers and next-generational pan-omic measurements, may offer the best shot at gathering mechanistic knowledge and potential of a drug causing steatohepatitis. Ultimately this information could also help predict, detect or guide the development of specific treatments for DISH, which is an unmet need as of today.
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Affiliation(s)
- Ajit Dash
- a HemoShear Therapeutics LLC , Charlottesville , VA , USA
| | | | - Arun J Sanyal
- b Department of Internal Medicine, School of Medicine , Virginia Commonwealth University , Richmond , VA , USA
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Peres LAB, Bredt LC, Cipriani RFF. Acute renal injury after partial hepatectomy. World J Hepatol 2016; 8:891-901. [PMID: 27478539 PMCID: PMC4958699 DOI: 10.4254/wjh.v8.i21.891] [Citation(s) in RCA: 18] [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: 02/25/2016] [Revised: 06/02/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023] Open
Abstract
Currently, partial hepatectomy is the treatment of choice for a wide variety of liver and biliary conditions. Among the possible complications of partial hepatectomy, acute kidney injury (AKI) should be considered as an important cause of increased morbidity and postoperative mortality. Difficulties in the data analysis related to postoperative AKI after liver resections are mainly due to the multiplicity of factors to be considered in the surgical patients, moreover, there is no consensus of the exact definition of AKI after liver resection in the literature, which hampers comparison and analysis of the scarce data published on the subject. Despite this multiplicity of risk factors for postoperative AKI after partial hepatectomy, there are main factors that clearly contribute to its occurrence. First factor relates to large blood losses with renal hypoperfusion during the operation, second factor relates to the occurrence of post-hepatectomy liver failure with consequent distributive circulatory changes and hepatorenal syndrome. Eventually, patients can have more than one factor contributing to post-operative AKI, and frequently these combinations of acute insults can be aggravated by sepsis or exposure to nephrotoxic drugs.
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Affiliation(s)
- Luis Alberto Batista Peres
- Luis Alberto Batista Peres, Department of Nephrology, University Hospital of Western Paraná, State University of Western Paraná, Cascavel, Paraná 85819-110, Brazil
| | - Luis Cesar Bredt
- Luis Alberto Batista Peres, Department of Nephrology, University Hospital of Western Paraná, State University of Western Paraná, Cascavel, Paraná 85819-110, Brazil
| | - Raphael Flavio Fachini Cipriani
- Luis Alberto Batista Peres, Department of Nephrology, University Hospital of Western Paraná, State University of Western Paraná, Cascavel, Paraná 85819-110, Brazil
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Russolillo N, Langella S, Perotti S, Lo Tesoriere R, Forchino F, Ferrero A. Preoperative assessment of chemotherapeutic associated liver injury based on indocyanine green retention test. Int J Surg 2016; 31:80-5. [DOI: 10.1016/j.ijsu.2016.05.065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/27/2016] [Accepted: 05/28/2016] [Indexed: 01/22/2023]
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15
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Qadan M, Garden OJ, Corvera CU, Visser BC. Management of Postoperative Hepatic Failure. J Am Coll Surg 2015; 222:195-208. [PMID: 26705902 DOI: 10.1016/j.jamcollsurg.2015.11.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 11/02/2015] [Accepted: 11/02/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Motaz Qadan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - O James Garden
- Department of Surgery, University of Edinburgh, Royal Infirmary, Edinburgh, Scotland
| | - Carlos U Corvera
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Brendan C Visser
- Department of Surgery, Stanford University Medical Center, Stanford, CA.
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Green CJ, Pramfalk C, Morten KJ, Hodson L. From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations. Am J Physiol Endocrinol Metab 2015; 308:E1-20. [PMID: 25352434 PMCID: PMC4281685 DOI: 10.1152/ajpendo.00192.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD.
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Affiliation(s)
- Charlotte J Green
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford United Kingdom; and
| | - Camilla Pramfalk
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford United Kingdom; and
| | - Karl J Morten
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford United Kingdom; and
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17
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Kauffmann R, Fong Y. Post-hepatectomy liver failure. Hepatobiliary Surg Nutr 2014; 3:238-46. [PMID: 25392835 DOI: 10.3978/j.issn.2304-3881.2014.09.01] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/21/2014] [Indexed: 12/11/2022]
Abstract
Hepatectomies are among some of the most complex operative interventions performed. Mortality rates after major hepatectomy are as high as 30%, with post-hepatic liver failure (PHLF) representing the major source of morbidity and mortality. We present a review of PHLF, including the current definition, predictive factors, pre-operative risk assessment, techniques to prevent PHLF, identification and management. Despite great improvements in morbidity and mortality, liver surgery continues to demand excellent clinical judgement in selecting patients for surgery. Appropriate choice of pre-operative techniques to improve the functional liver remnant (FLR), fastidious surgical technique, and excellent post-operative management are essential to optimize patient outcomes.
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Affiliation(s)
- Rondi Kauffmann
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
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18
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Orci LA, Lacotte S, Oldani G, Morel P, Mentha G, Toso C. The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence. Dig Dis Sci 2014; 59:2058-68. [PMID: 24795038 DOI: 10.1007/s10620-014-3182-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 04/20/2014] [Indexed: 12/29/2022]
Abstract
Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence.
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Affiliation(s)
- Lorenzo A Orci
- Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, 4 rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland,
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19
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Akgül &O, Çetinkaya E, Ersöz Ş, Tez M. Role of surgery in colorectal cancer liver metastases. World J Gastroenterol 2014; 20:6113-6122. [PMID: 24876733 PMCID: PMC4033450 DOI: 10.3748/wjg.v20.i20.6113] [Citation(s) in RCA: 184] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/26/2013] [Accepted: 02/16/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal carcinoma (CRC) is the third most common cancer, and approximately 35%-55% of patients with CRC will develop hepatic metastases during the course of their disease. Surgical resection represents the only chance of long-term survival. The goal of surgery should be to resect all metastases with negative histological margins while preserving sufficient functional hepatic parenchyma. Although resection remains the only chance of long-term survival, management strategies should be tailored for each case. For patients with extensive metastatic disease who would otherwise be unresectable, the combination of advances in medical therapy, such as systemic chemotherapy (CTX), and the improvement in surgical techniques for metastatic disease, have enhanced prognosis with prolongation of the median survival rate and cure. The use of portal vein embolization and preoperative CTX may also increase the number of patients suitable for surgical treatment. Despite current treatment options, many patients still experience a recurrence after hepatic resection. More active systemic CTX agents are being used increasingly as adjuvant therapy either before or after surgery. Local tumor ablative therapies, such as microwave coagulation therapy and radiofrequency ablation therapy, should be considered as an adjunct to hepatic resection, in which resection cannot deal with all of the tumor lesions. Formulation of an individualized plan, which combines surgery with systemic CTX, is a necessary task of the multidisciplinary team. The aim of this paper is to discuss different approaches for patients that are treated due to CRC liver metastasis.
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20
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Unresectable colorectal liver metastases: the safety and efficacy of conversion therapy using hepatic arterial infusion immunochemotherapy with 5-fluorouracil and polyethylene glycol-interferon α-2a. World J Surg 2014; 37:1919-26. [PMID: 23564218 DOI: 10.1007/s00268-013-2043-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy. METHODS Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors. RESULTS With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09). CONCLUSIONS Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.
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21
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Blockade of the renin-angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver. Clin Exp Metastasis 2014; 31:395-405. [PMID: 24442969 DOI: 10.1007/s10585-014-9635-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 01/02/2014] [Indexed: 01/19/2023]
Abstract
Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40-80% tumor recurrence rates. Renin-angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70% PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T test or Mann-Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7% control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm(3), 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm(2), 43.1 ± 7.6; p = 0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2%, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.
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22
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Importance of Response to Neoadjuvant Therapy in Patients With Liver-Limited mCRC When the Intent Is Resection and/or Ablation. Clin Colorectal Cancer 2013; 12:223-32. [DOI: 10.1016/j.clcc.2013.06.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 05/30/2013] [Accepted: 06/17/2013] [Indexed: 01/04/2023]
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23
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Maor Y, Malnick S. Liver injury induced by anticancer chemotherapy and radiation therapy. Int J Hepatol 2013; 2013:815105. [PMID: 23970972 PMCID: PMC3732607 DOI: 10.1155/2013/815105] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 05/03/2013] [Indexed: 12/12/2022] Open
Abstract
Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies.
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Affiliation(s)
- Y. Maor
- Department of Gastroenterology and Hepatology, Sheba Medical Center, 52621 Tel-Hashomer, Israel
| | - S. Malnick
- Department of Internal Medicine C, Kaplan Medical Center, The Hebrew University of Jerusalem, 76100 Rehovot, Israel
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24
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Golse N, Bucur PO, Adam R, Castaing D, Sa Cunha A, Vibert E. New paradigms in post-hepatectomy liver failure. J Gastrointest Surg 2013; 17:593-605. [PMID: 23161285 DOI: 10.1007/s11605-012-2048-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver failure after hepatectomy remains the most feared postoperative complication. Many risk factors are already known, related to patient's comorbidities, underlying liver disease, received treatments and type of resection. Preoperative assessment of functional liver reserve must be a priority for the surgeon. METHODS Physiopathology of post-hepatectomy liver failure is not comparable to fulminant liver failure. Liver regeneration is an early phenomenon whose cellular mechanisms are beginning to be elucidated and allowing most of the time to quickly recover a functional organ. In some cases, microscopic and macroscopic disorganization appears. The hepatocyte hyperproliferation and the asynchronism between hepatocytes and non-hepatocyte cells mitosis probably play a major role in this pathogenesis. RESULTS Many peri- or intra-operative techniques try to prevent the occurrence of this potentially lethal complication, but a better understanding of involved mechanisms might help to completely avoid it, or even to extend the possibilities of resection. CONCLUSION Future prevention and management may include pharmacological slowing of proliferation, drug or physical modulation of portal flow to reduce shear-stress, stem cells or immortalized hepatocytes injection, and liver bioreactors. Everything must be done to avoid the need for transplantation, which remains today the most efficient treatment of liver failure.
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Affiliation(s)
- Nicolas Golse
- Centre Hépatobiliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris XI, Paris, France.
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25
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Qi J, Fong Y, Saltz L, D'Angelica MI, Kemeny NE, Gonen M, Shia J, Shukla-Dave A, Jarnagin WM, Do RKG, Schwartz LH, Koutcher JA, Zakian KL. Serial measurement of hepatic lipids during chemotherapy in patients with colorectal cancer: a 1 H MRS study. NMR IN BIOMEDICINE 2013; 26:204-12. [PMID: 22961714 PMCID: PMC3519948 DOI: 10.1002/nbm.2837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 06/20/2012] [Accepted: 06/21/2012] [Indexed: 05/12/2023]
Abstract
Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n=21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.
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Affiliation(s)
- Jing Qi
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Yuman Fong
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Leonard Saltz
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | | | - Nancy E. Kemeny
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Mithat Gonen
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Jinru Shia
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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Kataoka K, Kanazawa A, Nakajima A, Yamaguchi A, Arimoto A, Kohno Y. Feasibility and potential benefit of preoperative chemotherapy for colorectal liver metastasis (CLM): a single-centered retrospective study. Surg Today 2012; 43:1154-61. [PMID: 23139049 DOI: 10.1007/s00595-012-0410-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 07/30/2012] [Indexed: 12/11/2022]
Abstract
PURPOSES The benefit of neo-adjuvant chemotherapy for liver-limited metastatic colorectal cancer is still controversial. This study defined the resectability regardless of the size and number of liver metastases, and attempted curative hepatic resection in all cases. METHODS Sixty-four patients that tolerated chemotherapy were diagnosed with CLM (colorectal liver metastases) without extrahepatic metastase from January 2007 to November 2010, and received an oxaliplatin-based regimen. This study assessed the resectability after chemotherapy, and the patients were divided in two groups; the resected and unresected group. Sixteen patients underwent hepatic resection without chemotherapy. RESULTS Thirty-five patients underwent surgical resection (resected group) and twenty-nine patients were considered unresectable (unresected group). All 35 patients in the resected group safely received oxaliplatin-based chemotherapy safely without serious adverse effects. No serious postoperative complications were observed. The median overall survival (MST) was significantly higher in the resected than in the unresected group (56.93 [95% CI 38.13-75.73] and 25.07 months [95% CI 17.87-32.26], respectively; P < 0.001). The median disease-free survival was 20.2 [95% CI 8.82-31.65] months in the resected group. CONCLUSION Preoperative chemotherapy for CLM is well tolerated and does not increase postoperative complications. Curative surgery with preoperative chemotherapy has the potential to improve the overall survival in patients with CLM.
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Affiliation(s)
- Kozo Kataoka
- Department of Surgery, Osaka Red-Cross Hospital, 5-30, Fudegasaki, Tennnoji, Osaka, 543-8555, Japan,
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27
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Weiss MJ, D'Angelica MI. Patient selection for hepatic resection for metastatic colorectal cancer. J Gastrointest Oncol 2012; 3:3-10. [PMID: 22811864 DOI: 10.3978/j.issn.2078-6891.2012.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 01/12/2012] [Indexed: 12/12/2022] Open
Affiliation(s)
- Matthew J Weiss
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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28
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Neeff HP, Drognitz O, Klock A, Illerhaus G, Opitz OG, Hopt UT, Makowiec F. Impact of preoperative targeted therapy on postoperative complications after resection of colorectal liver metastases. Int J Colorectal Dis 2012; 27:635-45. [PMID: 22139030 DOI: 10.1007/s00384-011-1360-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2011] [Indexed: 02/06/2023]
Abstract
PURPOSE The impact of chemotherapy (CTx) on morbidity after liver resection for colorectal metastases (CRC-LM) has been increasingly investigated during recent years. Biologic agents like bevacizumab (BEV) or cetuximab (CET) are now added as "targeted therapy" (TT), also in neoadjuvant settings. Initial series could demonstrate the safety of those regimens in liver resection but data are still scarce. We evaluated the impact of CTx with BEV or CET (CTx + TT) on perioperative morbidity and mortality. METHODS Two hundred thirty-seven patients who underwent liver resections for CRC-LM after chemotherapy before surgery since 1999 were included. One hundred eighty-five patients (78%) had preoperative CTx regimen without biologic agents (fluoropyrimidine-, oxaliplatin-, or irinotecan-based) and 52 (22%) had CTx + TT (39 BEV, 11 CET, 2 CET/BEV). After preoperative CTx + TT, a time interval of at least 4-6 weeks and a residual liver volume of >35% before surgery were required. RESULTS Hemihepatectomy or more was performed in about half of the patients. The median amount of intraoperatively transfused blood was 0 ml in both groups (p = 0.34). Overall mortality was 1.7% and slightly elevated in patients with CTx + TT (3.8% vs. 1.1%, p = 0.17). Any complication occurred in (CTx + TT vs. CTx) 52% and 46%, respectively (p = 0.47). The rates of liver failure (9.6% vs. 9.7%, p = 0.98), infectious complications such as wound infection (19% vs. 16%, p = 0.62) and abdominal abscess (8% vs. 6.5%, p = 0.71), as well as the rate of relaparotomies (11.5% vs. 7.0%, p = 0.29) showed no significant differences between the groups with TT or without. In multivariate analyses, neither type nor duration of CTx nor the time interval between CTx and surgery showed any influence on complication rates. CONCLUSIONS Our data confirm the safety of targeted therapy before liver resection for CRC-LM. This effect may in part be due to our treatment policy (time interval to resection and residual liver volume) after intensive preoperative CTx.
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Affiliation(s)
- Hannes P Neeff
- Department of Surgery, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
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29
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Young AL, Wilson D, Ward J, Biglands J, Guthrie JA, Prasad KR, Toogood GJ, Robinson PJ, Lodge JPA. Role of quantification of hepatic steatosis and future remnant volume in predicting hepatic dysfunction and complications after liver resection for colorectal metastases: a pilot study. HPB (Oxford) 2012; 14:194-200. [PMID: 22321038 PMCID: PMC3371202 DOI: 10.1111/j.1477-2574.2011.00426.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Accurate prediction of safe remnant liver volume to minimize complications following liver resection remains challenging. The aim of this study was to assess whether quantification of steatosis improved the predictive value of preoperative volumetric analysis. METHODS Thirty patients undergoing planned right or extended right hemi-hepatectomy for colorectal metastases were recruited prospectively. Magnetic resonance imaging was used to assess the level of hepatic steatosis and future remnant liver volume. These data were correlated with data on postoperative hepatic insufficiency, complications and hospital stay. Correlations of remnant percentage, remnant mass to patient mass and remnant mass to body surface area with and without steatosis measurements were assessed. RESULTS In 10 of the 30 patients the planned liver resection was altered. Moderate-severe postoperative hepatic dysfunction was seen in 17 patients. Complications arose in 14 patients. The median level of steatosis was 3.8% (range: 1.2-17.6%), but was higher in patients (n= 10) who received preoperative chemotherapy (P= 0.124), in whom the median level was 4.8% (range: 1.5-17.6%). The strongest correlation was that of remnant liver mass to patient mass (r= 0.77, P < 0.001). However, the addition of steatosis quantification did not improve this correlation (r= 0.76, P < 0.001). CONCLUSIONS This is the first study to combine volumetric with steatosis quantifications. No significant benefit was seen in this small pilot. However, these techniques may be useful in operative planning, particularly in patients receiving preoperative chemotherapy.
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Affiliation(s)
- Alastair L Young
- Department of Hepatobiliary Surgery, St James's University HospitalLeeds, UK
| | - Dan Wilson
- Department of Medical Physics, St James's University HospitalLeeds, UK
| | - Janice Ward
- Department of Radiology, St James's University HospitalLeeds, UK
| | - John Biglands
- Department of Medical Physics, St James's University HospitalLeeds, UK
| | - J Ashley Guthrie
- Department of Radiology, St James's University HospitalLeeds, UK
| | - K Rajendra Prasad
- Department of Hepatobiliary Surgery, St James's University HospitalLeeds, UK
| | - Giles J Toogood
- Department of Hepatobiliary Surgery, St James's University HospitalLeeds, UK
| | | | - J Peter A Lodge
- Department of Hepatobiliary Surgery, St James's University HospitalLeeds, UK
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Page AJ, Kooby DA. Perioperative management of hepatic resection. J Gastrointest Oncol 2012; 3:19-27. [PMID: 22811866 PMCID: PMC3397643 DOI: 10.3978/j.issn.2078-6891.2012.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 01/12/2012] [Indexed: 12/19/2022] Open
Affiliation(s)
- Andrew J Page
- Department of Surgery, Emory University, Atlanta, Georgia, USA
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Abstract
Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended.
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Affiliation(s)
- Bengt Gustavsson
- Department of Surgery, University of Gothenburg, Sahlgrenska University Hospital/Östra Institute of Clinical Sciences, Göteborg, Sweden.
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Qi J, Shukla-Dave A, Fong Y, Gönen M, Schwartz LH, Jarnagin WM, Koutcher JA, Zakian KL. 31P MR spectroscopic imaging detects regenerative changes in human liver stimulated by portal vein embolization. J Magn Reson Imaging 2012; 34:336-44. [PMID: 21780228 DOI: 10.1002/jmri.22616] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
PURPOSE First, to evaluate hepatocyte phospholipid metabolism and energetics during liver regeneration stimulated by portal vein embolization (PVE) using proton-decoupled (31)P MR spectroscopic imaging ((31)P-MRSI). Second, to compare the biophysiologic differences between hepatic regeneration stimulated by PVE and by partial hepatectomy (PH). MATERIALS AND METHODS Subjects included six patients with hepatic metastases from colorectal cancer who were scheduled to undergo right PVE before definitive resection of right-sided tumor. (31)P-MRSI was performed on the left liver lobe before PVE and 48 h following PVE. Normalized quantities of phosphorus-containing hepatic metabolites were analyzed from both visits. In addition, MRSI data at 48 h following partial hepatectomy were compared with the data from the PVE patients. RESULTS At 48 h after PVE, the ratio of phosphomonoesters to phosphodiesters in the nonembolized lobe was significantly elevated. No significant changes were found in nucleoside triphosphates (NTP) and Pi values. The phosphomonoester (PME) to phosphodiester (PDE) ratio in regenerating liver 48 h after partial hepatectomy was significantly greater than PME/PDE 48 h after PVE. CONCLUSION (31)P-MRSI is a valid technique to noninvasively evaluate cell membrane metabolism following PVE. The different degree of biochemical change between partial hepatectomy and PVE indicates that hepatic growth following these two procedures does not follow the same course.
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Affiliation(s)
- Jing Qi
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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Cucchetti A, Ercolani G, Cescon M, Di Gioia P, Peri E, Brandi G, Pellegrini S, Pinna AD. Safety of hepatic resection for colorectal metastases in the era of neo-adjuvant chemotherapy. Langenbecks Arch Surg 2011; 397:397-405. [PMID: 22198370 DOI: 10.1007/s00423-011-0894-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 12/08/2011] [Indexed: 12/16/2022]
Abstract
PURPOSE The relationship between neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases and post-operative morbidity still has to be clarified. METHODS Data from 242 patients undergoing hepatectomy for colorectal liver metastases, judged resectable at first observation, were reviewed and their clinical outcome was related to neo-adjuvant chemotherapy (125 patients). Selection biases were outlined and properly handled by means of propensity score analysis. RESULTS Post-operative death was 1.2% and morbidity 40.9%. Pre-operative chemotherapy was only apparently related to higher morbidity (P = 0.021): multivariate analysis identified extension of hepatectomy and intra-operative blood loss as independent prognostic variables (P < 0.05). Patients receiving and not receiving neo-adjuvant chemotherapy were significantly different for several covariates, including extension of hepatectomy (P = 0.049). After propensity score adjustment, 94 patients were identified as having similar covariate distribution (standardized differences <|0.1|) except for neo-adjuvant treatment (47 patients for each group). In this matched sample, mortality was similar and post-operative complications were only slightly higher (hazard ratio = 1.38) in treated patients. A significantly higher need for fluid replacement was only observed in patients receiving neo-adjuvant chemotherapy (P = 0.038). CONCLUSIONS Neo-adjuvant chemotherapy showed a limited role in determining post-operative morbidity after hepatic resection and did not modify mortality.
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Affiliation(s)
- Alessandro Cucchetti
- Liver and Multiorgan Transplant Unit, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
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Tanaka K, Ichikawa Y, Endo I. Liver resection for advanced or aggressive colorectal cancer metastases in the era of effective chemotherapy: a review. Int J Clin Oncol 2011; 16:452-63. [PMID: 21786210 DOI: 10.1007/s10147-011-0291-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Indexed: 02/06/2023]
Abstract
Liver surgery has been known to cure metastatic colorectal cancer in a small proportion of patients. However, advances in procedural technique and chemotherapy now allow more patients to have safe, potentially curative surgery. Here we review surgery for unresectable colorectal liver metastases using an expert multidisciplinary approach. With multidisciplinary management of patients with effective chemotherapy that can downstage metastases, more patients with previously inoperable disease can benefit from surgery. Portal vein embolization results in hypertrophy of the future liver remnant; on occasions, combining embolization with staged liver resection permits potentially curative surgery for patients previously unable to survive resection. However, increasing use of chemotherapy has raised awareness of potential hepatotoxicity and other deleterious effects of cytotoxic agents. Prolonged prehepatectomy chemotherapy therefore can reduce resectability even using a 2-stage procedure. Suitable timing of surgery for unresectable liver metastases during chemotherapy is critical. Because of advances in chemotherapy, colorectal cancer, like ovarian cancer, can now show survival benefit from maximum surgical debulking. Benefit from such maximum hepatic debulking surgery for metastatic colorectal disease is uncertain, but likely. Surgery in isolation may be approaching technical limits, but is now likely to help more patients because of the success of complementary strategies, particularly newer chemotherapy and targeted therapy. Expert individualized multidisciplinary treatment planning and problem-solving is essential.
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Affiliation(s)
- Kuniya Tanaka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
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Rickenbacher A, DeOliveira ML, Tian Y, Jang JH, Riener MO, Graf R, Moritz W, Clavien PA. Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy. Liver Int 2011; 31:313-21. [PMID: 21281431 DOI: 10.1111/j.1478-3231.2010.02446.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND New chemotherapy regimens are increasingly used in metastatic colorectal cancer to the liver before surgery. Some clinical observations have suggested that chemotherapy may affect liver regeneration. AIMS The aim of this study was to evaluate liver damage and liver regeneration after chemotherapy treatment in a model of partial hepatectomy. METHODS C57BL/6 mice were repeatedly treated with intraperitoneal injections of either saline or different chemotherapy regimens including the drugs 5-fluorouracyl (5-FU), irinotecan, oxaliplatin, gemcitabine and combined treatments with 5-FU/irinotecan, 5-FU/oxaliplatin. A 70% partial hepatectomy was performed 1 week after the last injection. Ki-67 and PCNA immunohistochemistry were performed to assess liver regeneration, serum liver enzymes and histology analysis to evaluate injury. RESULTS A variety of chemotherapeutic agents used at maximum tolerated doses compatible with survival affected body weight and blood cell levels. However, these regimens did not affect liver injury before and after hepatectomy nor did they impair liver regeneration. Liver histology showed no steatosis, fibrosis or inflammation before hepatectomy. We therefore tested whether chemotherapy in presence of diet-induced steatosis may trigger injury. Even under these conditions, we did not observe histological signs of inflammation or sinusoidal injury. CONCLUSIONS Liver injury and liver regeneration are not impaired after neoadjuvant chemotherapy with 5-FU, irinotecan, oxaliplatin and gemcitabine in non-tumoural liver parenchyma. In addition, combined treatments disclose no adverse effects on liver regeneration. Chemotherapy alone induces no histological alterations even in the presence of steatosis.
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Affiliation(s)
- Andreas Rickenbacher
- Department of Surgery, Swiss Hepato-Pancreatico-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
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Abstract
BACKGROUND Chemotherapy is increasingly used in colorectal liver metastases (CRLMs) even when they are initially resectable. The aim of our study was to address the still pending question of whether perioperative chemotherapy is really beneficial in patients developing solitary metastases at a distance from surgery of the primary. METHODS We analyzed a multicentric cohort of 1471 patients resected for solitary, metachronous, primarily resectable CRLMs without extrahepatic disease in the LiverMetSurvey International Registry over a 15-year period. Patients who received at least 3 cycles of oxaliplatin- or irinotecan-based chemotherapy before liver surgery (group CS, n = 169) were compared with those who were resected upfront (group S, n = 1302). RESULTS Patients of group CS were more frequently females (49% vs 36%, P = 0.001) and had larger metastases (≥5 cm, 33% vs 23%, P = 0.007); no difference was observed with regard to age, site of the primary tumour, time delay to occurrence of metastases, and carcinoembryonic antigen (CEA) levels at the time of diagnosis in the 2 groups. The rate of postoperative complications was significantly higher in group CS (37.2% vs 24% in group S, P = 0.006). At univariate analysis, preoperative chemotherapy did not impact the overall survival (OS) (60% at 5 years in both groups); however, postoperative chemotherapy was associated with better OS (65% vs 55% at 5 years, P < 0.01). At multivariate analysis, age 70 years or older (P = 0.05), lymph node positivity in the primary tumor (P = 0.02), a primary-to-metastases time delay of less than 12 months (P = 0.04), raised CEA levels of more than 5 ng/mL at diagnosis (P < 0.01), a tumor diameter of 5 cm or more (P < 0.01), noncurative liver resection (P < 0.01), and the absence of postoperative chemotherapy (P < 0.01) were independent prognostic factors of survival. The disease-free survival (DFS) was negatively influenced by CEA level of more than 5 ng/mL (P < 0.01), size of the metastases 5 cm or more (P = 0.05), and the absence of postoperative chemotherapy (P < 0.01). When patients with metastases of less than 5 cm in size were compared to those with metastases of size 5 cm or more, preoperative chemotherapy did not influence the OS or DFS in either group. Postoperative chemotherapy, on the other hand, improved OS and DFS in patients with metastases of size 5 cm or more but not in patients with metastases of less than 5 cm in size. CONCLUSIONS Although preoperative chemotherapy does not seem to benefit the outcome of patients with solitary, metachronous CRLM, postoperative chemotherapy is associated with better OS and DFS, mainly when the tumor diameter exceeds 5 cm.
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Surgical treatment of hepatic colorectal metastasis: evolving role in the setting of improving systemic therapies and ablative treatments in the 21st century. Cancer J 2010; 16:103-10. [PMID: 20404606 DOI: 10.1097/ppo.0b013e3181d7e8e5] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Liver resection has clearly been established as the standard treatment for resectable colorectal liver metastases. This article will review the expanding role for hepatectomy in this disease. Faster and safer hepatectomies are allowing combined resections of the primary cancer and synchronous hepatic metastases. Effective neoadjuvant chemotherapy, as well as increasing data demonstrating effectiveness and safety of combined hepatectomy and ablative therapies, have further expanded the pool of patients now selected for resection. The end result is that increasing numbers of patients are undergoing acceptably aggressive surgical therapies with extension of life and possible cure. Successful multimodality therapies are also now allowing for long-term survival even in patients not cured of cancer. The prolonged survival of most patients treated by hepatectomy has allowed a long-term analysis of the patterns of recurrence, which emphasize the importance of controlling liver disease for prolongation of life. These improvements in treatments for hepatic metastases have come with a precipitous escalation of the costs of care. This will likely require that future clinical trials and algorithms of care not only be based on cancer outcome data but also on value analysis of treatment and follow-up regimens.
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Abstract
The response rate of colorectal metastases to chemotherapy, ranging from 50 to 60%, has been shown to be a prognostic factor. Complete pathologic and radiological response rates are approximately 4 and 7%, respectively. Hepatotoxic effects of oxaliplatin and irinotecan on the non-tumoral liver parenchyma have been reported and are incriminated in vascular changes (sinusoidal obstruction syndrome [SOS]) and chemotherapy-associated steatohepatitis (CASH). Oxaliplatin-based regimens are associated with an increased risk of vascular lesions and irinotecan-based regimens are associated with increased risks of steatosis and steatohepatitis. SOS increases morbidity after major liver resection, mostly after administration of more than six cycles of neoadjuvant systemic chemotherapy. CASH increases morbidity and mortality rates after hepatectomy. Preliminary results have shown that the addition of targeted molecular therapy (bevacizumab or cetuximab) to conventional chemotherapy does not increase the postoperative morbidity or mortality rates after hepatectomy and does not create additional injury to the non-tumoral liver parenchyma. However, bevacizumab may impair regeneration of the future remnant. Chemotherapy may reduce the sensitivity of CT scan and PET scan in the detection of metastases.
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Kneuertz PJ, Maithel SK, Staley CA, Kooby DA. Chemotherapy-associated liver injury: impact on surgical management of colorectal cancer liver metastases. Ann Surg Oncol 2010; 18:181-90. [PMID: 20645011 DOI: 10.1245/s10434-010-1201-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Indexed: 12/14/2022]
Abstract
Chemotherapy is integral to the management of patients with advanced colorectal cancer liver metastases. Due to their improved efficacy, modern regimens can sometimes convert unresectable disease to a resectable state. As chemotherapy is often administered prior to hepatic resection, adverse effects on the liver are increasingly being recognized. Investigators have identified a wide spectrum of effects on the underlying liver parenchyma, ranging from mild forms of steatosis to severe steatohepatitis and sinusoidal obstruction syndrome. As the histopathologic definitions of these changes evolve, studies have identified specific patterns of hepatic injury related to the various chemotherapeutic agents. The impact of these changes on perioperative outcome after partial hepatectomy remains controversial. Timing and duration of chemotherapy may play a key role and account for discrepancies in outcomes seen among studies. In this review, we provide an overview of the spectrum of chemotherapy-associated liver injury and discuss its relevance to perioperative management of patients undergoing hepatic resection of colorectal cancer liver metastases.
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Affiliation(s)
- Peter J Kneuertz
- Department of Surgery, Division of Surgical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
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Aloia TA, Fahy BN. Chemotherapy-associated hepatotoxicity: how concerned should we be? Expert Rev Anticancer Ther 2010; 10:521-7. [PMID: 20397917 DOI: 10.1586/era.09.185] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Modern oncosurgical strategies are producing dramatic response rates and remarkable long-term survival rates for patients with hepatic colorectal cancer metastases. However, the increasing delivery of preoperative systemic chemotherapy to patients has coincided with recognition of possible chemotherapy-associated injury to the nontumoral liver. Although multiple groups have described gross changes in the appearance of the liver following systemic chemotherapy, the exact histopathologic lesions have not been clearly defined. A review of the literature on the topic indicates that host factors (e.g., diabetes mellitus and obesity) may be responsible for the development of liver injury as much as the drugs being delivered. With a lack of published evidence indicating that chemotherapy-associated liver injury results in adverse outcomes, several groups have recently questioned the clinical significance of this entity. This review describes the current understanding of this topic and seeks to answer the question of whether chemotherapy-associated liver injury actually impacts outcomes.
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Affiliation(s)
- Thomas A Aloia
- Department of Surgery, The Methodist Hospital Research Institute, 6550 Fannin Street, SM1661, Houston, TX 77030, USA.
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Chemotherapy-induced Liver Injury in Metastatic Colorectal Cancer: Semiquantitative Histologic Analysis of 334 Resected Liver Specimens Shows That Vascular Injury but not Steatohepatitis Is Associated With Preoperative Chemotherapy. Am J Surg Pathol 2010; 34:784-91. [DOI: 10.1097/pas.0b013e3181dc242c] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
In this review the surgery of colorectal liver metastases is discussed. It has long been known that liver surgery can cure metastatic colorectal cancer although in only a small proportion of the population with the disease. However with better understanding of the natural history of the condition and advances in technique more patients can have safe, potentially curative surgery. The multidiscipline management of patients with effective chemotherapy has led to more patients benefiting from surgery after reducing the size of the metastases and allowing operation on patients who were previously inoperable. Chemotherapy also improves at least the medium-term outcome in those who are operable at the outset. Minimally invasive techniques have been developed so that major hepatectomy may be accomplished in up to half of such cases with a very short hospital stay and limited interference with quality of life. Lastly, using portal vein embolisation to cause hypertrophy of the future liver remnant and on occasions combining it with staged liver resection allows potentially curative surgery on patients who previously could not have survived resection. These developments have led to more patients being cured of advanced colorectal cancer.
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Affiliation(s)
- J N Primrose
- University Surgical Unit, University of Southampton, Southampton General Hospital, Mailpoint 816, Tremona Road, Southampton SO16 6YD, UK.
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Abstract
Hepatotoxic effect of oxaliplatin and irinotecan on the non-tumourous liver parenchyma has been reported. These two main drugs have been linked to injuries such as vascular changes (sinusoidal obstruction syndrome (SOS) and chemotherapy-associated steatohepatitis (CASH)). Oxaliplatin-based regimens have been associated with an increased risk of vascular lesions and irinotecan-containing regimens have been also associated with increased risks of steatosis and steatohepatitis. SOS increased morbidity after major liver resection, mostly after administration of more than six cycles of neoadjuvant systemic chemotherapy. CASH increased morbidity and mortality rates after hepatectomy. Preliminary results demonstrated that the addition of targeted molecular therapy (bevacizumab or cetuximab) to conventional chemotherapy does not increase the postoperative morbidity and mortality rates after hepatectomy. Furthermore, there was no additional injury to the non-tumorous liver parenchyma.
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Mahfud M, Breitenstein S, El-Badry AM, Puhan M, Rickenbacher A, Samaras P, Pessaux P, Lopez-Ben S, Jaeck D, Figueras J, Alain-Clavien P. Impact of preoperative bevacizumab on complications after resection of colorectal liver metastases: case-matched control study. World J Surg 2010; 34:92-100. [PMID: 19838754 DOI: 10.1007/s00268-009-0251-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Chemotherapy may increase postoperative morbidity and mortality after liver surgery. Especially bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), could have a detrimental effect. To assess the impact of neoadjuvant bevacizumab on clinical outcome after hepatectomy for colorectal liver metastases (CRLMs) this case-matched control study was initiated. METHODS The multicentric data collection was performed in the Swiss HPB Center of the University Hospital Zurich (CH), the Department of Digestive Surgery and Transplantation Strasbourg (F), and the Division of Hepato-biliary-pancreatic surgery of "Josep Tureta" Hospital Girona (E). Consecutive patients operated onbetween July 2005 and December 2007 due to CRLMs who received neoadjuvant chemotherapy were assessed. Patients were divided in two groups: group A had neoadjuvant chemotherapy with bevacicumab, and group B had it without bevacizumab. RESULTS No differences in overall morbidity (56 vs. 40% in the bevacizumab and control groups, respectively, p = 0.23) or mortality could be documented. Similarly, the incidence of severe postoperative complications was not statistically different between the bevacizumab and control groups (31 and 18%, respectively, p = 0.31). Wound complications were comparable (11% in the bevacizumab group compared and 9% in the control group, p = 1.00). However, bevacizumab was associated with a significantly decreased incidence of postoperative hepatic insufficiency (7 vs. 20%, p = 0.03). CONCLUSIONS No impact on the incidence or severity of complications by bevacizumab could be shown. Bevacizumab may even reduce the incidence of liver failure after liver surgery.
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Affiliation(s)
- Mahfud Mahfud
- Department of Surgery, Swiss HPB (Hepato-Pancreatico-Biliary) Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland
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Hebbar M, Pruvot FR, Romano O, Triboulet JP, de Gramont A. Integration of neoadjuvant and adjuvant chemotherapy in patients with resectable liver metastases from colorectal cancer. Cancer Treat Rev 2009; 35:668-75. [DOI: 10.1016/j.ctrv.2009.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 08/07/2009] [Accepted: 08/11/2009] [Indexed: 01/14/2023]
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Nodular regenerative hyperplasia secondary to neoadjuvant chemotherapy for colorectal liver metastases. Case Rep Med 2009; 2009:457975. [PMID: 19997518 PMCID: PMC2787019 DOI: 10.1155/2009/457975] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 10/06/2009] [Indexed: 12/17/2022] Open
Abstract
Liver resection is the only curative treatment for patients with colorectal liver metastases (CLMs). Neoadjuvant chemotherapy can improve resectability but has a potential harmful effect on the nontumorous liver. Patients with chemotherapy-induced hepatic injury undergoing liver surgery have higher risks of post-resectional morbidity. We present two cases of patients without pre-existent liver disease treated with oxaliplatin-based chemotherapy followed by surgical resection of their CLMs. Their intra-operative liver specimen showed morphologic abnormalities characteristic of nodular regenerative hyperplasia (NRH). NRH led to portal hypertension in both patients that resulted in deleterious post-resectional complications and death of one patient. Interestingly, the other patient underwent two repeat nonanatomic liver resections because of recurrent CLMs. The intra-operative liver specimen still showed signs of NRH and sinusoidal congestion, but the post-resectional courses were uneventful. Nevertheless, caution is recommended in patients with suspected NRH. Careful volumetric analysis should guide the operative strategy. When future remnant liver volume is regarded insufficient, portal vein embolization or restrictive surgery should be considered.
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Is there a survival benefit to neoadjuvant versus adjuvant chemotherapy, combined with surgery for resectable colorectal liver metastases? World J Surg 2009; 33:1028-34. [PMID: 19234865 DOI: 10.1007/s00268-009-9945-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The benefits of adding chemotherapy to surgery in patients with hepatic colorectal metastases at moderate and high risk for recurrence and the optimal sequence of administration are undetermined. METHODS We followed the overall-survival and event-free survival rates after operation in patients with resectable colorectal metastases confined to the liver. The adjuvant patients first underwent surgery and then treatment, whereas the neoadjuvant patients underwent treatment, surgery, and re-treatment. Assignment was by oncologist and patient preferences. Chemotherapy was oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) based. RESULTS Fifty-six of 105 patients who underwent liver resections for colorectal metastases (2002-2005) are included. The two groups were comparable for demographics, characteristics of disease (including recurrence risk), treatment protocols, and follow-up. The respective 1-, 2-, and 3-year overall survival rates were 91%, 91%, and 84%, and the event-free survival rates were 63%, 49%, and 49% for the 19 adjuvant patients, and 95%, 91%, and 70%, and 94%, 50%, and 50% for the 37 neoadjuvant patients. CONCLUSIONS The midterm overall survival and disease-free survival rates in this group of patients with resectable colorectal metastases to the liver, who were treated with combination of resection and chemotherapy, were similar, regardless of the sequence of treatment.
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Karakousis G, Fong Y. The case for selective use of pre-operative chemotherapy for hepatic colorectal metastases: more is not always better. Ann Surg Oncol 2009; 16:2086-8. [PMID: 19513600 PMCID: PMC2711915 DOI: 10.1245/s10434-009-0539-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2009] [Accepted: 02/04/2009] [Indexed: 12/24/2022]
Affiliation(s)
| | - Yuman Fong
- Memorial Sloan-Kettering Cancer Center, New York, NY USA
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Chemotherapy-associated liver injury: Does it really matter? CURRENT COLORECTAL CANCER REPORTS 2009. [DOI: 10.1007/s11888-009-0016-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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