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      Impact of pre-sarcopenia in sorafenib treatment for advanced hepatocellular carcinoma

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          Abstract

          Background

          The present study aimed to investigate the impact of pre-sarcopenia on the prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.

          Methods

          We enrolled 214 patients (71 ± 10 years old; 166 men and 48 women; 90% Child–Pugh grade A and 10% Child–Pugh grade B) treated with sorafenib in our hospital from July 2009 to August 2016. The muscle volume was measured from CT images just before sorafenib administration using software (SliceOmatic). Skeletal muscle mass index was calculated, and the presence of pre-sarcopenia was judged according to the standard (42 cm 2/m 2 for men and 38 cm 2/m 2 for women) proposed by the Japan Society of Hepatology.

          Results

          Pre-sarcopenia was found in 123 patients (57%). The overall survival (OS) in patients with pre-sarcopenia tended to be worse than in patients without pre-sarcopenia (median 252 vs. 284 days, respectively; p = 0.16). Multivariate Cox hazard analysis revealed a baseline serum albumin level of ≤3.5 g/dl [hazard ratio (HR) 1.9; p = 0.0006], a baseline alpha-fetoprotein(AFP) level of ≥100 ng/ml (HR 2.1; p = 0.002), presence of lesions in bilateral hepatic lobes (HR 1.7; p = 0.03), and presence of major portal vein invasion (HR 1.8; p = 0.01) to be independent prognostic factors. In the 68 patients who had three or more negative prognostic factors, the presence of pre-sarcopenia did not correlate with prognosis. Of the 146 patients who had two or less prognostic factors, OS was significantly worse in 84 patients (58%) with pre-sarcopenia than in 62 patients without pre-sarcopenia (median 417 vs. 562 days, respectively; p = 0.047), and Cox hazard analysis revealed pre-sarcopenia to be an important prognostic factor (HR 1.6; p = 0.047).

          Conclusion

          In sorafenib treatment for advanced HCC, pre-sarcopenia is a significant prognostic factor in patients with two or less negative prognostic factors, and could be the target of intervention to improve prognosis.

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          Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis

          Aldo Montano-Loza, Paul Angulo, Judith Meza-Junco … (2015)
          Abstract Background and aims Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients. Methods We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using previously validated gender‐and body mass index‐specific cutoffs. Results Patients were predominately men (n = 457, 67%), and cirrhosis aetiology was hepatitis C virus in 269 patients (40%), alcohol in 153 (23%), non‐alcoholic steatohepatitis/cryptogenic in 96 (14%), autoimmune liver disease in 55 (8%), hepatitis B virus in 43 (6%), and others in 5 patients (1%). Sarcopenia was present in 292 (43%), 135 had sarcopenic obesity (20%) and 353 had myosteatosis (52%). Patients with sarcopenia (22 ± 3 vs. 95 ± 22 months, P < 0.001), sarcopenic obesity (22 ± 3 vs. 95 ± 22 months, P < 0.001), and myosteatosis (28 ± 5 vs. 95 ± 22 months, P < 0.001) had worse median survival than patients without muscular abnormalities. By multivariate Cox regression analysis, both sarcopenia [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.44–2.77, P < 0.001], and myosteatosis (HR 1.42, 95% CI 1.02–1.07, P = 0.04) were associated with mortality. Conclusions Sarcopenia, sarcopenic obesity and myosteatosis are often present in patients with cirrhosis, and sarcopenia and myosteatosis are independently associated with a higher long‐term mortality in cirrhosis.
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            Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

            Olivier Mir, Romain Coriat, Benoit Blanchet … (2012)
            Background Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. Patients and Methods The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Results Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Conclusions Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.
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              Clinical relevance of sarcopenia in patients with cirrhosis.

              Aldo Montano-Loza (2014)
              The most commonly recognized complications in cirrhotic patients include ascites, hepatic encephalopathy, variceal bleeding, susceptibility for infections, kidney dysfunction, and hepatocellular carcinoma; however, severe muscle wasting or sarcopenia are the most common and frequently unseen complications which negatively impact survival, quality of life, and response to stressor, such as infections and surgeries. At present, D'Amico stage classification, Child-Pugh, and MELD scores constitute the best tools to predict mortality in patients with cirrhosis; however, one of their main limitations is the lack of assessing the nutritional and functional status. Currently, numerous methods are available to evaluate the nutrition status of the cirrhotic patient; nevertheless, most of these techniques have limitations primarily because lack of objectivity, reproducibility, and prognosis discrimination. In this regard, an objective and reproducible technique, such as muscle mass quantification with cross-sectional imaging studies (computed tomography scan or magnetic resonance imaging) constitute an attractive index of nutritional status in cirrhosis. Sarcopenia is part of the frailty complex present in cirrhotic patients, resulting from cumulative declines across multiple physiologic systems and characterized by impaired functional capacity, decreased reserve, resistance to stressors, and predisposition to poor outcomes. In this review, we discuss the current accepted and new methods to evaluate prognosis in cirrhosis. Also, we analyze the current knowledge regarding incidence and clinical impact of malnutrition and sarcopenia in patients with cirrhosis and their impact after liver transplantation. Finally, we discuss existing and potential novel therapeutic approaches for malnutrition in cirrhosis, emphasizing the recognition of sarcopenia in an effort to reduced morbidity related and improved survival in cirrhosis.
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                Author and article information

                Contributors
                Hitomi Takada: Role: Conceptualization
                Masayuki Kurosaki: Role: Conceptualization
                Hiroyuki Nakanishi: Role: Conceptualization
                Yuka Takahashi: Role: Conceptualization
                Jun Itakura: Role: Conceptualization
                Kaoru Tsuchiya: Role: Conceptualization
                Yutaka Yasui: Role: Conceptualization
                Nobuharu Tamaki: Role: Conceptualization
                Kenta Takaura: Role: Conceptualization
                Yasuyuki Komiyama: Role: Conceptualization
                Mayu Higuchi: Role: Conceptualization
                Youhei Kubota: Role: Conceptualization
                Wann Wang: Role: Conceptualization
                Mao Okada: Role: Conceptualization
                Nobuyuki Enomoto: Role: Conceptualization
                Namiki Izumi: Role: Conceptualization
                Han-Chieh Lin: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 18 June 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 6
                Electronic Location Identifier: e0198812
                Affiliations
                [1 ] Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
                [2 ] First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
                Taipei Veterans General Hospital, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                Publisher ID: PONE-D-17-41079
                DOI: 10.1371/journal.pone.0198812
                PMC ID: 6005492
                PubMed ID: 29912922
                SO-VID: bda447ec-3c51-498d-82d7-540322db42b1
                Copyright © © 2018 Takada et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 21 November 2017
                Date accepted : 27 May 2018
                Page count
                Figures: 4, Tables: 3, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Prognosis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Carcinomas
                Subject: Hepatocellular Carcinoma
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Hepatocellular Carcinoma
                Subject: Medicine and Health Sciences
                Subject: Gastroenterology and Hepatology
                Subject: Liver Diseases
                Subject: Hepatocellular Carcinoma
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Signs and Symptoms
                Subject: Sarcopenia
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Signs and Symptoms
                Subject: Sarcopenia
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Blood Vessels
                Subject: Veins
                Subject: Portal Veins
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Cardiovascular Anatomy
                Subject: Blood Vessels
                Subject: Veins
                Subject: Portal Veins
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Signs and Symptoms
                Subject: Lesions
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Signs and Symptoms
                Subject: Lesions
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Skeletal Muscles
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Skeletal Muscles
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Metastasis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Metastasis
                Custom metadata
                Data Availability All relevant data are within the paper.

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