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Oura K, Morishita A, Takuma K, Nakahara M, Tadokoro T, Fujita K, Mimura S, Tani J, Ono M, Himoto T, Masaki T. Efficacy and outcome of molecular targeted therapies in elderly patients with hepatocellular carcinoma: Relative dose intensity associated with overall survival. Cancer Med 2023; 12:22023-22037. [PMID: 38062925 PMCID: PMC10757153 DOI: 10.1002/cam4.6783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/31/2023] Open
Abstract
AIM Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting. METHODS In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old). RESULTS Overall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI. CONCLUSIONS MTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
| | - Takashi Himoto
- Department of Medical TechnologyKagawa Prefectural University of Health SciencesKagawaJapan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of MedicineKagawa UniversityKagawaJapan
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Li D, Gruber SB, Iyer S, Gupta S, Tejani M. Real-world clinical effectiveness of sorafenib among patients with unresectable hepatocellular carcinoma at two centers in the United States. World J Gastrointest Oncol 2023; 15:1796-1806. [PMID: 37969411 PMCID: PMC10631438 DOI: 10.4251/wjgo.v15.i10.1796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/07/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND In the United States, sorafenib monotherapy was approved in 2007 for first-line (1L) treatment of patients with unresectable hepatocellular carcinoma (uHCC). As other therapies have been approved in recent years for hepatocellular carcinoma treatment in later lines, it is essential to assess clinical effectiveness of older therapies in actual clinical practice to inform healthcare practitioners' decisions for better patient care. AIM To assess patient characteristics/clinical effectiveness of 1L sorafenib in uHCC patients treated in United States academic and community practice settings. METHODS A retrospective observational study was conducted among adult patients (≥ 18 years) in the United States initiating sorafenib monotherapy as 1L systemic therapy for uHCC with Eastern Cooperative Oncology Group status of 0 or 1 between January 2016 and December 2019 at City of Hope and Advent Health. Data were extracted by trained abstractionists from individual patients' electronic health records and captured in electronic case report forms. Institutional Review Board approvals were obtained prior to study initiation. Data were captured from the time of sorafenib initiation until death or the end of follow-up. All data were de-identified prior to analyses. Clinical outcomes assessed included provider-reported best response, progression-free survival (PFS), and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. RESULTS Among 134 uHCC patients treated with 1L sorafenib, majority were male (75%), and most were Caucasian (62%) or Asian (19%). Median patient age was 64 years. The most common etiologies of liver disease were hepatitis C (54%), alcohol-related liver disease (16%), and hepatitis B (11%). Most patients were reported to have Barcelona Clinic Liver Cancer stage B (19%) or stage C (70%) disease. Of 134 patients, 110 (82%) were reported to have discontinued treatment or died during follow-up. Primary reasons for sorafenib discontinuation were reported as progression (35%) and toxicity (30%). Best overall response was reported for 124 patients, of which 7.3% reported complete or partial response. Median time to treatment discontinuation was 2.3 mo. Overall, 103 patients (77%) had disease progression or died during sorafenib therapy. Median PFS was estimated to be 2.9 mo. At the end of follow-up, 82 patients (61%) were deceased. Median OS was 8.5 mo. CONCLUSION Newer therapeutic options that have reported higher PFS and OS in real-world clinical practice should be considered to enhance patient outcomes.
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Affiliation(s)
- Daneng Li
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States
| | - Stephen B Gruber
- Center for Precision Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States
| | - Shrividya Iyer
- Department of Oncology, Worldwide Real-World Evidence, Eisai Inc., Nutley, NJ 07110, United States
| | - Sanjay Gupta
- Department of Oncology, Worldwide Real-World Evidence, Eisai Inc., Nutley, NJ 07110, United States
| | - Mohamedtaki Tejani
- Department of Oncology and Hematology, Advent Health Cancer Institute, Orlando, FL 32804, United States
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van Holstein Y, van den Berkmortel PJE, Trompet S, van Heemst D, van den Bos F, Roemeling-van Rhijn M, de Glas NA, Beekman M, Slagboom PE, Portielje JEA, Mooijaart SP, van Munster BC. The association of blood biomarkers with treatment response and adverse health outcomes in older patients with solid tumors: A systematic review. J Geriatr Oncol 2023; 14:101567. [PMID: 37453811 DOI: 10.1016/j.jgo.2023.101567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 06/01/2023] [Accepted: 06/22/2023] [Indexed: 07/18/2023]
Abstract
INTRODUCTION Blood biomarkers are potentially useful prognostic markers and may support treatment decisions, but it is unknown if and which biomarkers are most useful in older patients with solid tumors. The aim of this systematic review was to evaluate the evidence on the association of blood biomarkers with treatment response and adverse health outcomes in older patients with solid tumors. MATERIALS AND METHODS A literature search was conducted in five databases in December 2022 to identify studies on blood biomarkers measured before treatment initiation, not tumor specific, and outcomes in patients with solid tumors aged ≥60 years. Studies on any type or line of oncologic treatment could be included. Titles and abstracts were screened by three authors. Data extraction and quality assessment, using the Quality in Prognosis Studies (QUIPS) checklist, were performed by two authors. RESULTS Sixty-three studies were included, with a median sample size of 138 patients (Interquartile range [IQR] 99-244) aged 76 years (IQR 72-78). Most studies were retrospective cohort studies (63%). The risk of bias was moderate in 52% and high in 43%. Less than one-third reported geriatric parameters. Eighty-six percent examined mortality outcomes, 37% therapeutic response, and 37% adverse events. In total, 77 unique markers were studied in patients with a large variety of tumor types and treatment modalities. Neutrophil-to-lymphocyte ratio (20 studies), albumin (19), C-reactive protein (16), hemoglobin (14) and (modified) Glasgow Prognostic Score ((m)GPS) (12) were studied most often. The vast majority showed no significant association of these biomarkers with outcomes, except for associations between low albumin and adverse events and high (m)GPS with mortality. DISCUSSION Most studies did not find a significant association between blood biomarkers and clinical outcomes. The interpretation of current evidence on prognostic blood biomarkers is hampered by small sample sizes and inconsistent results across heterogeneous studies. The choice for blood biomarkers in the majority of included studies seemed driven by availability in clinical practice in retrospective cohort studies. Ageing biomarkers are rarely studied in older patients with solid tumors. Further research is needed in larger and more homogenous cohorts that combine clinical parameters and biomarkers before these can be used in clinical practice.
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Affiliation(s)
- Yara van Holstein
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands.
| | - P Janne E van den Berkmortel
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
| | - Stella Trompet
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
| | - Diana van Heemst
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
| | - Frederiek van den Bos
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
| | | | - Nienke A de Glas
- Department of Medical Oncology, Leiden University Medical Center, the Netherlands
| | - Marian Beekman
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, the Netherlands
| | - P Eline Slagboom
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, the Netherlands
| | | | - Simon P Mooijaart
- Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
| | - Barbara C van Munster
- Department of Internal Medicine, University Medical Center Groningen, the Netherlands
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Ohama H, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Naganuma A, Kosaka H, Matono T, Shibata H, Aoki T, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Koizumi Y, Nakamura S, Iijima H, Kaibori M, Hiasa Y, Kudo M, Kumada T. Comparison between Atezolizumab Plus Bevacizumab and Lenvatinib for Hepatocellular Carcinoma in Patients with Child-Pugh Class B in Real-World Clinical Settings. Oncology 2023; 101:542-552. [PMID: 37552968 DOI: 10.1159/000530028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/24/2023] [Indexed: 08/10/2023]
Abstract
INTRODUCTION Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. METHODS From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score -1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. RESULTS There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4-7] vs. 5.5 [95% CI: 3.4-7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3-11] vs. 8.8 [95% CI: 6.1-12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). DISCUSSION This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC.
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Affiliation(s)
- Hideko Ohama
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kazuya Kariyama
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Joji Tani
- Department of Gastroenterology and Hepatology, Kagawa University, Takamatsu, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Shinya Fukunishi
- Department of Gastroenterology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Hironori Ochi
- Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Chikara Ogawa
- Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan
| | - Takashi Nishimura
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Hisashi Kosaka
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | | | - Hiroshi Shibata
- Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan
| | - Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Fujimasa Tada
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Kazuhiro Nouso
- Department of Gastroenterology, Okayama City Hospital, Okayama, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Hepatology, Kagawa University, Takamatsu, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Michitaka Imai
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Hiroko Iijima
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masaki Kaibori
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
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Shimose S, Hiraoka A, Tanaka M, Iwamoto H, Tanaka T, Noguchi K, Aino H, Yamaguchi T, Itano S, Suga H, Niizeki T, Moriyama E, Shirono T, Noda Y, Kamachi N, Okamura S, Nakano M, Kawaguchi T, Kuromatsu R, Koga H, Torimura T. Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma. Sci Rep 2022; 12:17018. [PMID: 36220865 PMCID: PMC9554046 DOI: 10.1038/s41598-022-21528-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/28/2022] [Indexed: 12/29/2022] Open
Abstract
This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.
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Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, 790-0024, Japan
| | - Masatoshi Tanaka
- Clinical Research Center, Yokokura Hospital, Miyama, Fukuoka, 839-0295, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
- Iwamoto Internal Medical Clinic, Kitakyusyu, 802-0832, Japan
| | - Takaaki Tanaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, 790-0024, Japan
| | - Kazunori Noguchi
- Department of Gastroenterology, Omuta City Hospital, Omuta, 836-0861, Japan
| | - Hajime Aino
- Division of Gastroenterology, Department of Medicine, Social Insurance Tagawa Hospital, Tagawa, 826-0023, Japan
| | - Taizo Yamaguchi
- Iwamoto Internal Medical Clinic, Kitakyusyu, 802-0832, Japan
| | - Satoshi Itano
- Department of Gastroenterology, Kurume Central Hospital, Kurume, 830-0001, Japan
| | - Hideya Suga
- Department of Gastroenterology and Hepatology, Yanagawa Hospital, Yanagawa, 832-0077, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Etsuko Moriyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
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Association between Adverse Events and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab: A Multicenter Retrospective Study. Cancers (Basel) 2022; 14:cancers14174284. [PMID: 36077816 PMCID: PMC9454839 DOI: 10.3390/cancers14174284] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin–bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.
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Soria A, Calvo M, Casas M, Vidales Z, Muñoz-Martínez S, Sapena V, Puigvehi M, Canillas L, Guardeño R, Gallego A, Mínguez B, Horta D, Clos A, Montoliu S, Roget M, Reig M, Vergara M. Survival and adverse events of elderly patients treated with sorafenib for hepatocellular carcinoma. Front Oncol 2022; 12:829483. [PMID: 35982971 PMCID: PMC9380437 DOI: 10.3389/fonc.2022.829483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The first-line treatment for advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab, but its availability is not universal and elderly patients are underrepresented in clinical trials. There is little evidence of efficacy and tolerability in elderly patients under systemic treatment. The aims of this study were to characterize the profile of elderly patients treated with sorafenib, assess their survival and safety profile in order to extrapolate their eligibility for systemic treatment. Methods Retrospective multicentre study of HCC patients aged ≥75 years old treated with sorafenib from January 2008 to December 2019. Demographic data, baseline characteristics, and variables related to HCC and sorafenib were recorded. Overall survival (OS) and safety were analyzed. Results The study included 206 patients from 11 hospitals, median age 77.9 years; 71.4% men and 62.6% stage Barcelona Clinic Liver Cancer- C (BCLC-C). The main causes of cirrhosis were hepatitis C (60.7%) and alcohol (14.7%). Most patients (84.5%) started with sorafenib 800mg and 15.5% at lower dosage. Arterial hypertension (AHT) (74.2 vs 62.2%; standardized mean differences (STD): 26) and baseline ECOG-PS>0 (45.3 vs 34.7%; STD: 38.2) differed significantly between patients receiving low and full doses. Median OS was 15.4 months (18.2 in BCLC-B vs 13.6 in BCLC-C). OS was not modified by comorbidities, age or period with more expertise. Conclusions Sorafenib appears to be safe in elderly patients with HCC. This is the first study to characterize the profile of elderly patients to be considered for systemic treatment. These findings could be used as the reference profile for elderly candidates for atezolizumab-bevacizumab.
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Affiliation(s)
- Anna Soria
- Department of Digestive Diseases, Liver Unit, Parc Taulí University Hospital, Investigation and Innovation Institute Parc Taulí I3PT, Universitat Autònoma of Barcelona, Sabadell, Spain
| | - Mariona Calvo
- Medical Oncology Department, Catalan Institute of Oncology, Hospitalet, Barcelona, Spain
| | - Meritxell Casas
- Department of Digestive Diseases, Liver Unit, Parc Taulí University Hospital, Investigation and Innovation Institute Parc Taulí I3PT, Universitat Autònoma of Barcelona, Sabadell, Spain
| | - Zara Vidales
- Medical Oncology Department, Catalan Institute of Oncology, Hospitalet, Barcelona, Spain
| | - Sergio Muñoz-Martínez
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Clinical Insitute of Digestive and Metabolic Diseases (ICMDiM), Clinic Hospital, Barcelona University, Barcelona, Spain
- Biomedical Research Center in Digestive and Liver Diseases Network (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Victor Sapena
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Clinical Insitute of Digestive and Metabolic Diseases (ICMDiM), Clinic Hospital, Barcelona University, Barcelona, Spain
- Medical Statistics Core Facility, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona, Spain
- Liver Unit, University Hospital Vall d’Hebron, Liver Diseases Research Group, Vall d’Hebron Institut of Research (VHIR), Universitat Autònoma of Barcelona, Barcelona, Spain
| | - Marc Puigvehi
- Department of Digestive Diseases, Liver Unit, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Lidia Canillas
- Department of Digestive Diseases, Liver Unit, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Raquel Guardeño
- Medical Oncology Department, Josep Trueta University Hospital, Catalan Institute of Oncology, Girona, Spain
| | - Adolfo Gallego
- Department of Digestive Diseases, Sant Pau i Santa Creu University Hospital, Barcelona, Spain
| | - Beatriz Mínguez
- Biomedical Research Center in Digestive and Liver Diseases Network (CIBERehd), Instituto Carlos III, Madrid, Spain
- Liver Unit, University Hospital Vall d’Hebron, Liver Diseases Research Group, Vall d’Hebron Institut of Research (VHIR), Universitat Autònoma of Barcelona, Barcelona, Spain
| | - Diana Horta
- Biomedical Research Center in Digestive and Liver Diseases Network (CIBERehd), Instituto Carlos III, Madrid, Spain
- Department of Gastroenterology, University Hospital Mútua Terrassa, Barcelona University, Terrassa, Spain
| | - Ariadna Clos
- Department of Digestive Diseases, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Silvia Montoliu
- Department of Digestive Diseases, Joan XXIII University Hospital, Tarragona, Spain
| | - Mercè Roget
- Department of Digestive Diseases, Liver Unit, Consorci Sanitari de Terrassa, Terrassa, Spain
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Clinical Insitute of Digestive and Metabolic Diseases (ICMDiM), Clinic Hospital, Barcelona University, Barcelona, Spain
- Biomedical Research Center in Digestive and Liver Diseases Network (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Mercedes Vergara
- Department of Digestive Diseases, Liver Unit, Parc Taulí University Hospital, Investigation and Innovation Institute Parc Taulí I3PT, Universitat Autònoma of Barcelona, Sabadell, Spain
- Biomedical Research Center in Digestive and Liver Diseases Network (CIBERehd), Instituto Carlos III, Madrid, Spain
- *Correspondence: Mercedes Vergara,
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8
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Ogushi K, Chuma M, Numata K, Nozaki A, Moriya S, Uojima H, Kondo M, Morimoto M, Maeda S. Impact of psoas muscle index assessed by a simple measurement method on tolerability and duration of continued treatment with sorafenib in hepatocellular carcinoma patients. Eur J Gastroenterol Hepatol 2022; 34:774-781. [PMID: 35102114 DOI: 10.1097/meg.0000000000002346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib. METHOD This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI. RESULT Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021). CONCLUSION PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.
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Affiliation(s)
- Katsuaki Ogushi
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - Satoshi Moriya
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara
| | - Masaki Kondo
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
- Department of Gastroenterology, Yokohama City University Hospital, Yokohama
| | - Manabu Morimoto
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital, Yokohama
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9
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Monteiro AR, Conde RS, Basto R, Sclafani F, Deleporte A, Hendlisz A, Dal Lago L. Targeted agents in older patients with gastrointestinal cancers - An overview. J Geriatr Oncol 2021; 12:1240-1252. [PMID: 34226158 DOI: 10.1016/j.jgo.2021.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/12/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022]
Abstract
Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.
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Affiliation(s)
- Ana Raquel Monteiro
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Rita Saúde Conde
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Department of Medical Oncology, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
| | - Raquel Basto
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Francesco Sclafani
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Amélie Deleporte
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Alain Hendlisz
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Lissandra Dal Lago
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
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10
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Cammarota A, D'Alessio A, Pressiani T, Rimassa L, Personeni N. Systemic Treatment for Older Patients with Unresectable Hepatocellular Carcinoma. Drugs Aging 2021; 38:579-591. [PMID: 34152589 DOI: 10.1007/s40266-021-00871-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2021] [Indexed: 12/25/2022]
Abstract
The incidence rate of hepatocellular carcinoma is growing and age at diagnosis is increasing; however, despite the unprecedented wealth of therapeutic options for advanced HCC, its optimal management in some categories, such as older adults, is yet to be defined. Even though age is not an exclusion criterion per se, most of the landmark trials enrolled a limited number of senior patients, raising some concerns on the potential benefit of active treatments in this group. The identification of more vulnerable patients remains a crucial issue in clinical practice. In fact, the suitability assessment for systemic therapy through performance status metrics might underestimate or conversely overestimate the fitness of older patients, failing to detect other relevant impairments. Thus, the assessment of frailty through geriatric screening scales is largely necessary. In addition, most of the available data relate to the use of sorafenib, while very little is known about the most recent therapeutic agents. Age subgroup analyses provided by many of the pivotal trials did not find significant efficacy or safety differences across ages; however, the most widely used cut-off age of 65 years may not be very informative for the current older population. Regarding immunotherapy, the clinical benefit reported with immune checkpoint inhibitors reassures their safe use in senior patients and supports further investigations to assess their efficacy in this population.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy. .,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy.
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, Milan, Italy
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11
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Systemic treatment of HCC in special populations. J Hepatol 2021; 74:931-943. [PMID: 33248171 DOI: 10.1016/j.jhep.2020.11.026] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/05/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Recent years have seen significant progress in the systemic treatment of hepatocellular carcinoma (HCC), including the advent of immunotherapy. While several large phase III trials have provided the evidence for a multi-line treatment paradigm, they have focused on a highly selected group of patients by excluding potentially confounding comorbidities. As a result, high quality evidence for the systemic treatment of HCC in patients with various comorbidities is missing. This review summarises current knowledge on the use of approved medicines in patients with HIV, autoimmune disease, cardiovascular disease, diabetes, fibrolamellar HCC, mixed HCC-cholangiocarcinoma, decompensated cirrhosis (Child-Pugh B and C), a significant bleeding history, vascular invasion or portal vein thrombosis, as well as the elderly, those on haemodialysis, and those after solid organ transplantation. The article highlights relevant knowledge gaps and current clinical challenges. To improve the safety and efficacy of HCC treatment in these subgroups, future trials should be designed to specifically include patients with comorbidities.
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12
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Marta GN, da Fonseca LG, Braghiroli MI, Moura F, Hoff PM, Sabbaga J. Efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma. Clinics (Sao Paulo) 2021; 76:e2498. [PMID: 33503195 PMCID: PMC7811833 DOI: 10.6061/clinics/2021/e2498] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals <70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34-9.3) and Group B (9.0 months, 95%CI 5.38-12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39-3.60) and Group B (3.0 months, 95%CI 1.68-4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC.
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Affiliation(s)
- Guilherme Nader Marta
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Leonardo G. da Fonseca
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Maria Ignez Braghiroli
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Fernando Moura
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Paulo M. Hoff
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Jorge Sabbaga
- Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
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13
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Hajiev S, Allara E, Motedayеn Aval L, Arizumi T, Bettinger D, Pirisi M, Rimassa L, Pressiani T, Personeni N, Giordano L, Kudo M, Thimme R, Park JW, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Sharma R. Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study. Br J Cancer 2021; 124:407-413. [PMID: 33071284 PMCID: PMC7852559 DOI: 10.1038/s41416-020-01116-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/15/2020] [Accepted: 09/25/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly. METHODS In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models. RESULTS Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib. CONCLUSIONS Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
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Affiliation(s)
- Saur Hajiev
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Elias Allara
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Leila Motedayеn Aval
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Tadaaki Arizumi
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Dominik Bettinger
- Department of Medicine II, University Medical Center, Freiburg, Germany
- Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
| | - Laura Giordano
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS, Rozzano (Milan), Italy
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Robert Thimme
- Department of Medicine II, University Medical Center, Freiburg, Germany
| | | | - Tamar H Taddei
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - David E Kaplan
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ramya Ramaswami
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - David J Pinato
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Rohini Sharma
- Division of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
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14
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Kudo M. Recent Advances in Systemic Therapy for Hepatocellular Carcinoma in an Aging Society: 2020 Update. Liver Cancer 2020; 9:640-662. [PMID: 33442538 PMCID: PMC7768150 DOI: 10.1159/000511001] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/17/2020] [Indexed: 02/04/2023] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib increased the available treatment options for patients with extrahepatic spread and vascular invasion and improved survival in patients with advanced HCC; however, various shortcomings such as low response rates and relatively high toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at developing new molecular targeted agents to provide more treatment options and second-line agents for patients with disease progression or intolerance to sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all first-line and second-line clinical trials conducted during this period failed. However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in quick succession from clinical trials and became available for clinical use. In addition, nivolumab and pembrolizumab were approved as second-line agents after sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety profiles to those in the general population.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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15
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Mantovani S, Varchetta S, Mele D, Donadon M, Torzilli G, Soldani C, Franceschini B, Porta C, Chiellino S, Pedrazzoli P, Santambrogio R, Barabino M, Cigala C, Piccolo G, Opocher E, Maestri M, Sangiovanni A, Bernuzzi S, Lhospice F, Kraiem M, Mondelli MU, Oliviero B. An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:3583. [PMID: 33266137 PMCID: PMC7761065 DOI: 10.3390/cancers12123583] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 12/29/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.
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Affiliation(s)
- Stefania Mantovani
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Stefania Varchetta
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Dalila Mele
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Camillo Porta
- Department of Medical Sciences and Human Oncology, “Aldo Moro” University of Bari and Policlinico Consorziale, 70124 Bari, Italy;
| | - Silvia Chiellino
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | - Paolo Pedrazzoli
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | | | - Matteo Barabino
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Claudia Cigala
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Gaetano Piccolo
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Enrico Opocher
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Marcello Maestri
- Division of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, CRC “A. M. and A. Migliavacca” Center for Liver Disease, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Stefano Bernuzzi
- Immunohematology and Transfusion Service, Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | | | - Manel Kraiem
- Innate Pharma, 13009 Marseille, France; (F.L.); (M.K.)
| | - Mario Umberto Mondelli
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Barbara Oliviero
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
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16
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Shimose S, Iwamoto H, Niizeki T, Shirono T, Noda Y, Kamachi N, Okamura S, Nakano M, Suga H, Kuromatsu R, Yamaguchi T, Kawaguchi T, Tanaka M, Noguchi K, Koga H, Torimura T. Clinical Significance of Adverse Events for Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study. Cancers (Basel) 2020; 12:cancers12071867. [PMID: 32664489 PMCID: PMC7408786 DOI: 10.3390/cancers12071867] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/05/2020] [Accepted: 07/09/2020] [Indexed: 12/14/2022] Open
Abstract
We sought to investigate the clinical profile(s) associated with the discontinuation of lenvatinib (LEN) due to severe adverse events (DLSAE) in patients with unresectable hepatocellular carcinoma (HCC). This retrospective study enrolled 177 patients with HCC treated with LEN. Independent factors associated with DLSAE were advanced age, albumin-bilirubin (ALBI) grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2. The overall survival (OS) in the group that did not require DLSAE was significantly longer compared to the group that did require DLSAE (median survival time (MST): not reached vs. 12.8 months, p < 0.001). Moreover, advanced age was the most important variable for DLSAE in a decision tree analysis. Hypertension and hand-foot-skin-reaction (HFSR) were also significantly associated with longer survival, and the occurrence of hypertension was the earliest predictor for improved prognosis, while appetite loss and development of grade ≥ 3 fatigue were predictive of a poor prognosis. We concluded that the appearance of hypertension has potential as an early surrogate marker to predict improved prognosis. Moreover, careful management to avoid discontinuation of treatment leads to longer survival in patients receiving LEN.
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Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
- Correspondence: (S.S.); (H.I.)
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
- Iwamoto Internal Medical Clinic, Kitakyusyu 802-0832, Japan;
- Correspondence: (S.S.); (H.I.)
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Hideya Suga
- Department of Gastroenterology and Hepatology, Yanagawa Hospital, Fukuoka 832-0077, Japan;
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Taizo Yamaguchi
- Iwamoto Internal Medical Clinic, Kitakyusyu 802-0832, Japan;
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Masatoshi Tanaka
- Department of Gastroenterology and Hepatology, Miyama, Fukuoka 839-0295, Japan;
| | - Kazunori Noguchi
- Department of Gastroenterology and Hepatology, Omuta City Hospital, Fukuoka 836-8567, Japan;
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.N.); (T.S.); (Y.N.); (N.K.); (S.O.); (M.N.); (R.K.); (T.K.); (H.K.); (T.T.)
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17
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Taniguchi M, Mizuno S, Yoshikawa T, Fujinami N, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Nakatsura T. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis. Cancer Sci 2020; 111:2747-2759. [PMID: 32449239 PMCID: PMC7419030 DOI: 10.1111/cas.14497] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 12/20/2022] Open
Abstract
There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long‐term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican‐3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease‐free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1‐y recurrence rate after surgery was reduced by approximately 15%, and the 5‐y and 8‐y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5‐y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long‐term prognosis.
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Affiliation(s)
- Masatake Taniguchi
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Motokazu Sugimoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinichiro Takahashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaru Konishi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoto Gotohda
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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18
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Cho E, Cho HA, Jun CH, Kim HJ, Cho SB, Choi SK. A Review of Hepatocellular Carcinoma in Elderly Patients Focused on Management and Outcomes. In Vivo 2020; 33:1411-1420. [PMID: 31471386 DOI: 10.21873/invivo.11618] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 02/07/2023]
Abstract
Recent studies report a significant age-specific increase in hepatocellular carcinoma (HCC) development among persons over 75 years old. Therefore, there is an urgent need to determine the optimal treatment strategy in elderly patients with HCC. This systemic review examines the clinical characteristics, efficacy, and safety of first-line treatment modalities. The literature was searched regarding epidemiology and clinical outcomes in elderly patients (age ≥75 years) undergoing first-line treatment for HCC. Causative or comorbid conditions of HCC in elderly patients differed from those in younger patients. Radiofrequency ablation may be effective and safe in early stages. Surgical resection may also be feasible in the early stages for selected patients. Transarterial chemoembolization may be safe and effective for intermediate HCC, and sorafenib may be feasible in elderly patients with advanced HCC. Prospective randomized trials are needed to establish the treatment strategy for elderly patients with HCC.
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Affiliation(s)
- Eunae Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonnam National University Medical School, Gwanjgu, Republic of Korea
| | - Hyun A Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonnam National University Medical School, Gwanjgu, Republic of Korea
| | - Chung Hwan Jun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonnam National University Medical School, Gwanjgu, Republic of Korea
| | - Hee Joon Kim
- Department Surgery, Chonnam National University Medical School, Gwanjgu, Republic of Korea
| | - Sung Bum Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonnam National University Medical School, Gwanjgu, Republic of Korea
| | - Sung Kyu Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonnam National University Medical School, Gwanjgu, Republic of Korea
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19
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Bioactivity Evaluation of a Novel Formulated Curcumin. Nutrients 2019; 11:nu11122982. [PMID: 31817577 PMCID: PMC6950821 DOI: 10.3390/nu11122982] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/14/2019] [Accepted: 11/19/2019] [Indexed: 12/20/2022] Open
Abstract
Curcumin has been used as a traditional medicine and/or functional food in several cultures because of its health benefits including anticancer properties. However, poor oral bioavailability of curcumin has limited its oral usage as a food supplement and medical food. Here we formulated curcumin pellets using a solid dispersion technique. The pellets had the advantages of reduced particle size, improved water solubility, and particle porosity. This pellet form led to an improvement in curcumin's oral bioavailability. Additionally, we used the C-Map and Library of Integrated Network-Based Cellular Signatures (LINCS) Unified Environment (CLUE) gene expression database to determine the potential biological functions of formulated curcumin. The results indicated that, similar to conventional curcumin, the formulated curcumin acted as an NF-κB pathway inhibitor. Moreover, ConsensusPathDB database analysis was used to predict possible targets and it revealed that both forms of curcumin exhibit similar biological functions, including apoptosis. Biochemical characterization revealed that both the forms indeed induced apoptosis of hepatocellular carcinoma (HCC) cell lines. We concluded that the formulated curcumin increases the oral bioavailability in animals, and, as expected, retains characteristics similar to conventional curcumin at the cellular level. Our screening platform using big data not only confirms that both the forms of curcumin have similar mechanisms but also predicts the novel mechanism of the formulated curcumin.
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20
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Haaker L, De Meue E, Wildiers H, Verbiest A, Dumez H, Lerut E, Pans S, Albersen M, Beuselinck B. Bone metastases and age are associated with earlier dose reductions in metastatic clear-cell renal cell carcinoma patients treated with angiogenesis inhibitors. Acta Clin Belg 2019; 74:414-423. [PMID: 30497350 DOI: 10.1080/17843286.2018.1551744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Background: Metastatic clear-cell renal cell carcinoma (m-ccRCC) patients with bone metastases (BM) treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) have a poorer outcome compared to patients without BM. We aimed to investigate whether an increased incidence of VEGFR-TKI treatment interruptions and/or dose reductions in patients with BM could explain this difference in outcome. Patients and methods: Retrospective study on m-ccRCC patients treated in first-line with VEGFR-TKI. Analysis of the incidence of treatment interruptions and dose reductions and time-to-event analysis. Study of the correlation with the presence of BM at start of first-line VEGFR-TKIs. Results: Two-hundred-and-five patients were included. In patients with BM, median time-to-dose-reduction was significantly shorter (3 versus 5 cycles; p = 0.005) than in patients without BM. 63% of the total number of cycles was administered at reduced dose, compared to 41% in patients without BM. Age at start of VEGFR-TKI (≤ versus >70 years) was significantly associated with median time-to-dose-reduction (5 versus 3 cycles; p = 0.007). On multivariate analysis, the presence of BM (p = 0.004; HR 1.82, 95%CI 1.21-2.73) and age at start of VEGFR-TKIs (p = 0.017; HR 1.65, 95%CI 1.10-2.50) were independently associated with time-to-dose-reduction. Conclusion: In m-ccRCC patients treated with VEGFR-TKIs, dose reductions occurred earlier in patients with BM compared to patients without BM and in elderly patients.
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Affiliation(s)
- Lorenz Haaker
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Elisabeth De Meue
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Hans Wildiers
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Annelies Verbiest
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Herlinde Dumez
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Evelyne Lerut
- Department of Pathology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Steven Pans
- Department of Radiology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Maarten Albersen
- Department of Urology, University Hospitals Leuven, KULeuven, Leuven, Belgium
| | - Benoit Beuselinck
- Department of General Medical Oncology, University Hospitals Leuven, KULeuven, Leuven, Belgium
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21
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Kondo M, Morimoto M, Kobayashi S, Ohkawa S, Hidaka H, Nakazawa T, Aikata H, Hatanaka T, Takizawa D, Matsunaga K, Okuse C, Suzuki M, Taguri M, Ishibashi T, Numata K, Maeda S, Tanaka K. Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial. BMC Cancer 2019; 19:954. [PMID: 31615466 PMCID: PMC6794885 DOI: 10.1186/s12885-019-6198-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
Background The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. Methods Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. Results For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0–18.8) in the HAIC group and 15.2 months (95% CI, 8.2–19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7–5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3–6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. Conclusions Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. Trial registration UMIN ID 000006147, registration data: August 11, 2011.
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Affiliation(s)
- Masaaki Kondo
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan. .,Department of Gastroenterology, Yokohama City University Hospital; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
| | - Manabu Morimoto
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan.,Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Satoshi Kobayashi
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Hisashi Hidaka
- Gastroenterology Division of Internal Medicine, Kitasato University Hospital; 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0329, Japan
| | - Takahide Nakazawa
- Gastroenterology Division of Internal Medicine, Kitasato University Hospital; 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0329, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University; 1-2-3, Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Takeshi Hatanaka
- Department of Internal Medicine, Isesaki Municipal Hospital; 12-1, Tsunatorihonmachi, Isesaki, Gunma, 372-0817, Japan
| | - Daichi Takizawa
- Department of Internal Medicine, Isesaki Municipal Hospital; 12-1, Tsunatorihonmachi, Isesaki, Gunma, 372-0817, Japan
| | - Kotaro Matsunaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine; 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital; 1-30-37, Shukugawara, Tama-ku, Kawasaki, Kanagawa, 214-8525, Japan
| | - Michihiro Suzuki
- Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital; 1-30-37, Shukugawara, Tama-ku, Kawasaki, Kanagawa, 214-8525, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Takako Ishibashi
- Yokohama City University Center for Novel and Exploratory Clinical trials; 1-1-1, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Katsuaki Tanaka
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan.,Gastroenterology Division, Hadano Red Cross Hospital; 1-1-1, Tatenodai, Hadano, Kanagawa, 257-0017, Japan
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22
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Tada T, Kumada T, Toyoda H, Tsuji K, Hiraoka A, Michitaka K, Deguchi A, Ishikawa T, Imai M, Ochi H, Joko K, Shimada N, Tajiri K, Hirooka M, Koizumi Y, Hiasa Y, Tanaka J. Impact of albumin-bilirubin grade on survival in patients with hepatocellular carcinoma who received sorafenib: An analysis using time-dependent receiver operating characteristic. J Gastroenterol Hepatol 2019; 34:1066-1073. [PMID: 30549320 DOI: 10.1111/jgh.14564] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/20/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Albumin-bilirubin (ALBI) grade was developed as a new method to assess hepatic function. Sorafenib has been confirmed to be effective in improving survival in patients with advanced hepatocellular carcinoma (HCC). In this study, we investigated the impact of ALBI grade versus Child-Pugh classification on survival in HCC patients who received sorafenib. METHODS A total of 567 patients with advanced HCC who received sorafenib were included. We analyzed survival based on Child-Pugh classification or score and ALBI grade or score. We also compared the ability of ALBI and Child-Pugh scores to predict survival using time-dependent receiver operating characteristic analysis. RESULTS Cumulative survival rates at 90, 180, 360, and 720 days were 84.1%, 66.6%, 47.0%, and 23.3%, respectively. Median survival was 316 days (95% confidence interval, 279-377). Both Child-Pugh classification and ALBI grade were independently associated with overall survival in multivariate analyses. In addition, overall survival differed significantly between patients with ALBI grades 1 and 2 (hazard ratio, 1.44; 95% confidence interval, 1.09-1.92, P = 0.011) among patients with a Child-Pugh score of 5. Time-dependent receiver operating characteristic analysis showed that ALBI score predicted overall survival better than Child-Pugh score. CONCLUSIONS Albumin-bilirubin grade is a better predictor of survival in patients with advanced HCC who received sorafenib therapy than Child-Pugh classification.
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Affiliation(s)
- Toshifumi Tada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Kunihiko Tsuji
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa-Rosai Hospital, Marugame, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan
| | - Michitaka Imai
- Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan
| | - Hironori Ochi
- Hepato-Biliary Center, Matsuyama Red-Cross Hospital, Matsuyama, Japan
| | - Koji Joko
- Hepato-Biliary Center, Matsuyama Red-Cross Hospital, Matsuyama, Japan
| | - Noritomo Shimada
- Department of Gastroenterology, Otakanomori Hospital, Kashiwa, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
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23
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Akazawa Y, Suzuki T, Yoshikawa T, Mizuno S, Nakamoto Y, Nakatsura T. Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma. World J Meta-Anal 2019; 7:80-95. [DOI: 10.13105/wjma.v7.i3.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/12/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease, with a poor clinical prognosis. Many standard therapies are often considered for HCC treatment today; however, these conventional therapies often fail to achieve sufficiently effective clinical results. Today, HCC therapy is set to undergo a major revolution, owing to rapid developments in cancer immunotherapy, particularly immune checkpoint inhibitor therapy. Cancer immunotherapy is a novel and promising treatment strategy that differs significantly from conventional therapies in its approach to achieve antitumor effects. In fact, many cancer immunotherapies have been tested worldwide and shown to be effective against various types of cancer; HCC is no exception to this trend. For example, we identified a specific cancer antigen called glypican-3 (GPC3) and performed clinical trials of GPC3-targeted peptide vaccine immunotherapy in patients with HCC. Here, we present an overview of the immune mechanisms for development and progression of HCC, our GPC3-based immunotherapy, and immune checkpoint inhibitor therapy against HCC. Finally, we discuss the future prospects of cancer immunotherapy against HCC. We believe that this review and discussion of cancer immunotherapy against HCC could stimulate more interest in this promising strategy for cancer therapy and help in its further development.
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Affiliation(s)
- Yu Akazawa
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Toshihiro Suzuki
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
| | | | | | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
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24
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Hosseinzadeh F, Verdi J, Ai J, Hajighasemlou S, Seyhoun I, Parvizpour F, Hosseinzadeh F, Iranikhah A, Shirian S. Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: a review. Cancer Cell Int 2018; 18:133. [PMID: 30214375 PMCID: PMC6131874 DOI: 10.1186/s12935-018-0624-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Background High prevalence of hepatocellular carcinoma (HCC) and typically poor prognosis of this disease that lead to late stage diagnosis when potentially curative therapies are least effective; therefore, development of an effective and systematic treatment is an urgent requirement. Main body In this review, several current treatments for HCC patients and their advantages or disadvantages were summarized. Moreover, various recent preclinical and clinical studies about the performances of "two efficient agents, sorafenib or natural killer (NK) cells", against HCC cells were investigated. In addition, the focus this review was on the chemo-immunotherapy approach, correlation between sorafenib and NK cells and their effects on the performance of each other for better suppression of HCC. Conclusion It was concluded that combinational therapy with sorafenib and NK cells might improve the outcome of applied therapeutic approaches for HCC patients. Finally, it was also concluded that interaction between sorafenib and NK cells is dose and time dependent, therefore, a careful dose and time optimizing is necessary for development of a combinational immune-cell therapy.
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Affiliation(s)
- Faezeh Hosseinzadeh
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jafar Ai
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saieh Hajighasemlou
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Iran Food and Drug Administration, Tehran, Iran
| | - Iman Seyhoun
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Frzad Parvizpour
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abolfazl Iranikhah
- 4Department of Gastroenterology, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Sadegh Shirian
- 5Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.,6Shiraz Molecular Pathology Research Center, Dr. Daneshbod Lab, Shiraz, Iran
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25
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Takada H, Kurosaki M, Nakanishi H, Takahashi Y, Itakura J, Tsuchiya K, Yasui Y, Tamaki N, Takaura K, Komiyama Y, Higuchi M, Kubota Y, Wang W, Okada M, Enomoto N, Izumi N. Impact of pre-sarcopenia in sorafenib treatment for advanced hepatocellular carcinoma. PLoS One 2018; 13:e0198812. [PMID: 29912922 PMCID: PMC6005492 DOI: 10.1371/journal.pone.0198812] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 05/27/2018] [Indexed: 12/12/2022] Open
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 cm2/m2 for men and 38 cm2/m2 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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Affiliation(s)
- Hitomi Takada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuyuki Komiyama
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Youhei Kubota
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wann Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- * E-mail:
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26
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Clinical Response after Sorafenib for Hepatocellular Carcinoma in Elderly Patients: A Report of Two Cases. TUMORI JOURNAL 2018; 98:53e-56e. [DOI: 10.1177/030089161209800224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Among primary liver cancers occurring worldwide, hepatocellular carcinoma (HCC) is the major histological type accounting for 70–85% of all cases. Phase III trials in patients with advanced HCC treated with sorafenib (SO), a multitargeted tyrosine kinase inhibitor, showed significant improvements in both overall and progression-free survival. We report the cases of two elderly patients with advanced HCC who had prolonged stable disease following treatment with SO (400 mg bid). Patient 1 was treated with SO for a period of 16 months until evidence of right sacral metastases was noted. Patient 2 received SO 400 mg bid from January 2009 to October 2009 until radiological evidence of disease progression was noted. Both patients experienced minimal toxicity, suggesting that SO can be safely administered to elderly patients.
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27
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Du J, Mao Y, Liu M, Tie Y, Huang H, Zhao J, Xiang Z, Luo D. Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 2017; 8:102413-102419. [PMID: 29254256 PMCID: PMC5731966 DOI: 10.18632/oncotarget.22061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 09/20/2017] [Indexed: 02/05/2023] Open
Abstract
Currently, whether the impact of age on efficacy of molecular targeted agents (MTAs) in the treatment of hepatocellular carcinoma (HCC) patients remains undetermined. We searched databases and abstracts presented at ASCO meeting to identify relevant studies. The endpoints were overall survival (OS) and progression-free survival (PFS). Data were examined using age cutoffs of 65 years. A total of 4,231 HCC patients from eight RCTs were included for analysis, with 1,607 patients aged ≥ 65 years and 2,624 patients aged < 65 years. The pooled results demonstrated that the use of MTAs in patients < 65 years significantly improved PFS (HR 0.69, 95% CI: 0.51–0.95, p = 0.023) and OS (HR 0.79, 95% CI: 0.69–0.89, p < 0.001) when compared to controls. For HCC patients aged ≥ 65 years, the use of MTAs significantly improved PFS (HR 0.66, 95% CI: 0.53–0.84, p = 0.001) but not for OS (HR 0.94, 95% CI: 0.81 –1.09, p = 0.41). No publication bias was detected by Begg's and Egger's tests for OS. Therefore, the treatment effect of MTAs on OS might be different in younger and older HCC patients undergoing first-line or second-line treatment, but not for PFS benefit.
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Affiliation(s)
- Jing Du
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Mao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Liu
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Tie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hai Huang
- West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Zhao
- West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Zhongzheng Xiang
- West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Di Luo
- West China Medical School, West China Hospital, Sichuan University, Chengdu, China
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28
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Williet N, Clavel L, Bourmaud A, Verot C, Bouarioua N, Roblin X, Merle P, Phelip JM. Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma. Dig Liver Dis 2017; 49:1043-1049. [PMID: 28712860 DOI: 10.1016/j.dld.2017.06.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/10/2017] [Accepted: 06/12/2017] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). METHODS This was a bicentric retrospective study including all patients ≥75years and treated with sorafenib for advanced HCC between January 2010 and March 2014. RESULTS Of the 51 patients included (median age: 78 years, range: 75-92; performance status (PS) 0-1: 98%; cirrhosis: 88.2%; Child-Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3-4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p=0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p=0.01), or other cardiovascular histories (OR: 30.9; p=0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p<0.0001). CONCLUSION Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.
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Affiliation(s)
- Nicolas Williet
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France.
| | - Léa Clavel
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Aurélie Bourmaud
- Department of Public Health, Hygée Center, Saint Priest en Jarez, France; Inserm, Clinical Investigation Center 1408, Saint-Etienne, France
| | - Céline Verot
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Nadia Bouarioua
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Xavier Roblin
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Philippe Merle
- Hepatology Unit, Hospital Group of North Lyon, Civic Hospice of Lyon, Claude Bernard Lyon 1 University, Research center for oncology of Lyon; INSERM 1052, Lyon Cedex 03, France
| | - Jean-Marc Phelip
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France; University Jean Monnet, LINA EA 4624, France
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29
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Tsuchiya N, Yoshikawa T, Fujinami N, Saito K, Mizuno S, Sawada Y, Endo I, Nakatsura T. Immunological efficacy of glypican-3 peptide vaccine in patients with advanced hepatocellular carcinoma. Oncoimmunology 2017; 6:e1346764. [PMID: 29123959 PMCID: PMC5665076 DOI: 10.1080/2162402x.2017.1346764] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 06/19/2017] [Accepted: 06/21/2017] [Indexed: 02/08/2023] Open
Abstract
We have previously conducted a phase I trial to test the efficacy of a glypican-3 (GPC3) peptide vaccine in patients with advanced hepatocellular carcinoma (HCC); however, its immunological mechanism of action remains unclear. Here, we report a pilot study conducted to evaluate the immunological mechanisms of action of this GPC3 peptide vaccine (UMIN-CTR number 000005093). Eleven patients with advanced HCC were vaccinated with the GPC3 peptide in this trial. The primary end point was GPC3 peptide-specific immune response induced by the GPC3 peptide vaccination. The secondary endpoints were clinical and biologic outcomes. We demonstrated that the present vaccine induced GPC3 peptide-specific cytotoxic T lymphocytes (CTLs), which were found to infiltrate into the tumor. Moreover, we established GPC3 peptide-specific CTL clones from a biopsy specimen: these cells exhibited GPC3 peptide-specific cytokine secretion and cell cytotoxicity. The plasma GPC3 level tended to decrease temporarily at least once during the follow-up period. The GPC3-specific CTL frequency after vaccination was correlated with overall survival. The degree of skin reactions at the injection site correlated with the GPC3 peptide-specific CTLs. Furthermore, we sequenced the T cell receptors (TCRs) of tumor-infiltrating lymphocyte (TIL) clones, and confirmed the existence of this TCR repertoire in both tumor tissue and PBMCs. In response to these data, we are developing TCR-engineered T cell therapy using TCR sequences obtained from GPC3 peptide-specific CTL clones for improved efficacy in patients with advanced HCC.
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Affiliation(s)
- Nobuhiro Tsuchiya
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan.,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Huku-ura, Kanazawa-ku, Yokohama, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan
| | - Keigo Saito
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan
| | - Yu Sawada
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan.,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Huku-ura, Kanazawa-ku, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Huku-ura, Kanazawa-ku, Yokohama, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwanoha, Kashiwa, Chiba, Japan
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30
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Parsons HM, Chu Q, Karlitz JJ, Stevens JL, Harlan LC. Adoption of Sorafenib for the Treatment of Advanced-Stage Hepatocellular Carcinoma in Oncology Practices in the United States. Liver Cancer 2017; 6:216-226. [PMID: 29234628 PMCID: PMC5704716 DOI: 10.1159/000473862] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. We examined sorafenib use since Food and Drug Administration (FDA) approval in 2007 and associated survival for individuals diagnosed with advanced HCC, conducting a population-based evaluation of treatment patterns and outcomes for this newly approved drug in the US over time. METHODS We identified individuals diagnosed with Barcelona Clinic Liver Cancer Stage C from the 2007 and 2012 National Cancer Institute Patterns of Care study. We examined trends in use as well as patient and clinical factors associated with receiving sorafenib using multivariate logistic regression analysis. We then evaluated the association between sorafenib use and overall hazard of death using multivariate Cox proportional hazards regression. RESULTS Among 550 individuals diagnosed with advanced HCC, we found no significant increase in the proportion of patients treated with sorafenib from 2007 to 2012 (26.3 vs. 30.4%). After adjusting for patient and clinical characteristics, non-Hispanic Blacks (compared to non-Hispanic Whites) and those with a lower Child-Pugh score remained more likely to receive sorafenib. Individuals receiving systemic chemotherapy only, radiation therapy only, or no treatment at all experienced a higher risk of death than those treated with sorafenib, while those receiving a transplant experienced a lower risk of death. CONCLUSIONS Sorafenib has not been widely adopted into oncology practice since FDA approval for advanced HCC. Few factors apart from Child-Pugh score and race/ethnicity predict sorafenib use in clinical practice, although sorafenib treatment is associated with a lower risk of death.
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Affiliation(s)
- Helen M. Parsons
- Division of Health Policy and Management, University of Minnesota, Minneapolis, MN
| | - Quyen Chu
- LSU-Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Jordan J. Karlitz
- Division of Gastroenterology, Tulane University School of Medicine, New Orleans, LA, USA
| | | | - Linda C. Harlan
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA
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31
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Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: age is not a problem. Eur J Gastroenterol Hepatol 2017; 29:48-55. [PMID: 27623000 DOI: 10.1097/meg.0000000000000739] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive. METHODS All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated. RESULTS Data from 190 patients (157 men), median age 66 (26-87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5-8.7) vs. 10.4 (6.5-14.3) months, P=0.360 and 4.2 (2.3-6.2) vs. 5.6 (3.1-8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child-Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24-3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55-8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child-Pugh A (P=0.004 and P<0.001, respectively). CONCLUSION Elderly patients with advanced HCC, when treated with sorafenib, have an equivalent clinical outcome with similar toxicity rates as their younger counterparts. Age alone should not be a discriminating factor for the management of advanced HCC with sorafenib.
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32
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Li S, Wu L, Feng J, Li J, Liu T, Zhang R, Xu S, Cheng K, Zhou Y, Zhou S, Kong R, Chen K, Wang F, Xia Y, Lu J, Zhou Y, Dai W, Guo C. In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity. Sci Rep 2016; 6:28479. [PMID: 27349173 PMCID: PMC4923908 DOI: 10.1038/srep28479] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 06/03/2016] [Indexed: 12/21/2022] Open
Abstract
Glycolysis, as an altered cancer cell-intrinsic metabolism, is an essential hallmark of cancer. Phosphofructokinase (PFK) is a metabolic sensor in the glycolytic pathway, and restricting the substrate availability for this enzyme has been researched extensively as a target for chemotherapy. In the present study, we investigated that the effects of epigallocatechin-3-gallate (EGCG), an active component of green tea, on inhibiting cell growth and inducing apoptosis by promoting a metabolic shift away from glycolysis in aerobic glycolytic hepatocellular carcinoma (HCC) cells. EGCG modulated the oligomeric structure of PFK, potentially leading to metabolic stress associated apoptosis and suggesting that EGCG acts by directly suppressing PFK activity. A PFK activity inhibitor enhanced the effect, while the allosteric activator reversed EGCG-induced HCC cell death. PFK siRNA knockdown-induced apoptosis was not reversed by the activator. EGCG enhanced the effect of sorafenib on cell growth inhibition in both aerobic glycolytic HCC cells and in a xenograft mouse model. The present study suggests a potential role for EGCG as an adjuvant in cancer therapy, which merits further investigation at the clinical level.
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Affiliation(s)
- Sainan Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rong Zhang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The Shanghai Tenth Hospital School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, China
| | - Shizan Xu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The Shanghai Tenth Hospital School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, China
| | - Keran Cheng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The School of Medicine of Soochow University, Suzhou 215006, China
| | - Yuqing Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The School of Medicine of Soochow University, Suzhou 215006, China
| | - Shunfeng Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The School of Medicine of Soochow University, Suzhou 215006, China
| | - Rui Kong
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
- The School of Medicine of Soochow University, Suzhou 215006, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
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Brunot A, Le Sourd S, Pracht M, Edeline J. Hepatocellular carcinoma in elderly patients: challenges and solutions. J Hepatocell Carcinoma 2016; 3:9-18. [PMID: 27574587 PMCID: PMC4994800 DOI: 10.2147/jhc.s101448] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most common cause of death by cancer in the world. Due to the delayed HCC development in hepatitis C carriers and nonalcoholic fatty liver disease, the incidence of HCC in the elderly is increasing and is becoming a global health issue. Elderly patients with HCC should be assessed through proper oncologic approach, namely, screening tools for frailty (Geriatric-8 or Vulnerable Elders Survey-13) and comprehensive geriatric assessment. This review of the literature supports the same treatment options for elderly patients as for younger patients, in elderly patients selected as fit following proper oncogeriatric assessment. Unfit patients should be managed through a multidisciplinary team involving both oncological and geriatrician professionals. Specific studies and recommendations for HCC in the elderly should be encouraged.
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Affiliation(s)
- Angélique Brunot
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Samuel Le Sourd
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Marc Pracht
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
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Kinoshita A, Koike K, Nishino H. Clinical features and prognosis of elderly patients with hepatocellular carcinoma not indicated for surgical resection. Geriatr Gerontol Int 2016; 17:189-201. [PMID: 26847184 DOI: 10.1111/ggi.12747] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2015] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide. The average life expectancy during the 20th century has increased in many parts of the world, and therefore the opportunities to examine elderly HCC patients have significantly increased worldwide. Many elderly patients develop HCC with intermediate to advanced stages of disease at the initial diagnosis, and have more comorbidities and compromised liver regeneration compared with younger patients. These circumstances show that elderly patients with HCC are poorer candidates for surgical resection or transplantation. The aim of the present review was to focus on the clinical features and prognosis of elderly HCC patients not indicated for surgical resection including multimodal treatment. Although the chronological age of 60 or 65 years as the definition of an elderly person is accepted in most countries, many studies in our review article define elderly as those aged 75 years or older. Geriatr Gerontol Int 2017; 17: 189-201.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
| | - Kazuhiko Koike
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
| | - Hirokazu Nishino
- Division of Gastroenterology and Hepatology, the Jikei University Daisan Hospital, Tokyo, Japan
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Chao TI, Tai WT, Hung MH, Tsai MH, Chen MH, Chang MJ, Shiau CW, Chen KF. A combination of sorafenib and SC-43 is a synergistic SHP-1 agonist duo to advance hepatocellular carcinoma therapy. Cancer Lett 2015; 371:205-13. [PMID: 26679051 DOI: 10.1016/j.canlet.2015.11.039] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/21/2015] [Accepted: 11/30/2015] [Indexed: 12/11/2022]
Abstract
Sorafenib is the first and currently the only standard treatment for advanced hepatocellular carcinoma (HCC). We previously developed a sorafenib derivative SC-43, which exhibits much more enhanced anti-HCC activity than sorafenib and also promotes apoptosis in sorafenib-resistant HCC cells. Herein, a novel "sorafenib plus" combination therapy was developed by coupling sorafenib treatment with SC-43. Both sorafenib and SC-43 are proven Src homology region 2 domain containing phosphatase 1 (SHP-1) agonists. The combined actions of sorafenib and SC-43 enhanced SHP-1 activity, which was associated with diminished STAT3-related signals and stronger expression of apoptotic genes above that of either drug alone, culminating in increased cell death. Decreased p-STAT3 signaling and tumor size, as well as increased SHP-1 activity were observed in mice receiving the combination therapy in a subcutaneous HCC model. More reduced orthotopic HCC tumor size and prolonged survival were also observed in mice in the combination treatment arm compared to mice in either of the monotherapy arms. These results in the preclinical setting pave the way for further clinical studies to treat unresectable HCC.
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Affiliation(s)
- Tzu-I Chao
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Tien Tai
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Man-Hsin Hung
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Program in Molecular Medicine, School of Life Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Hsien Tsai
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Min-Hsuan Chen
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Mao-Ju Chang
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Chung-Wai Shiau
- Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Kuen-Feng Chen
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
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Shimada M, Okawa H, Kondo Y, Maejima T, Kataoka Y, Hisamichi K, Maekawa M, Matsuura M, Jin Y, Mori M, Suzuki H, Shimosegawa T, Mano N. Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma. TOHOKU J EXP MED 2015; 237:173-182. [PMID: 26477611 DOI: 10.1620/tjem.237.173] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC(sorafenib) and AUC(N-oxide), respectively). Inter-group comparison revealed that AUC(N-oxide) and AUC ratio (AUC(N-oxide)/AUC(sorafenib)) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC(N-oxide) and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC(N-oxide:) 2.0 μg ∙ day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) ≤ 2.0 μg ∙ day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.
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Affiliation(s)
- Miki Shimada
- Department of Pharmaceutical Sciences, Tohoku University Hospital
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Tsuchiya N, Sawada Y, Endo I, Uemura Y, Nakatsura T. Potentiality of immunotherapy against hepatocellular carcinoma. World J Gastroenterol 2015; 21:10314-10326. [PMID: 26420958 PMCID: PMC4579878 DOI: 10.3748/wjg.v21.i36.10314] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/21/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future.
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Sayem MA, Tomita Y, Yuno A, Hirayama M, Irie A, Tsukamoto H, Senju S, Yuba E, Yoshikawa T, Kono K, Nakatsura T, Nishimura Y. Identification of glypican-3-derived long peptides activating both CD8 + and CD4 + T cells; prolonged overall survival in cancer patients with Th cell response. Oncoimmunology 2015; 5:e1062209. [PMID: 26942076 PMCID: PMC4760284 DOI: 10.1080/2162402x.2015.1062209] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/01/2015] [Accepted: 06/10/2015] [Indexed: 12/26/2022] Open
Abstract
In a recent phase I clinical trial, a vaccine consisting of glypican-3 (GPC3)-derived CTL epitopes was found to be safe and induced measurable immune and clinical responses in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify GPC3-derived long peptides (GPC3-LPs) carrying promiscuous HLA class II-restricted T helper (Th) cell epitopes. Using a computer algorithm, we predicted GPC3-LPs that can bind to promiscuous HLA class II molecules. Their antigenicity for induction of specific CD4+ T cells in healthy donors or patients with HCC, before and after vaccination with GPC3-SPs, was proven by IFNγ enzyme-linked immunospot assays. Natural processing of these epitopes was confirmed by the immune response of helper T cells to dendritic cells (DCs) loaded with GPC3 proteins. Cross-presentation capacity was assessed in vitro using human DCs and LPs encapsulated in liposomes and in vivo in HLA-A2 transgenic mice (Tgm). All five LPs could induce Th1 cells and were presented by several frequently occurring HLA class II molecules in vitro. Four of them were likely to be naturally processed. One of the LPs encapsulated in liposomes was well cross-presented in vitro; it cross-primed CTLs in HLA-A2 Tgm. LP-specific and HLA class II-restricted CD4+ T-cell responses were observed in 14 of 20 HCC patients vaccinated with GPC3-SPs. Repeated vaccinations enhanced GPC3-LP-specific responses in 8 of 13 patients with HCC. Moreover, the presence of the specific Th cell was correlated with prolonged overall survival (OS). GPC3-LPs can be useful for cancer immunotherapy.
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Affiliation(s)
- Mohammad A Sayem
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Biotechnology and Genetic Engineering; Mawlana Bhashani Science and Technology University; Tangail, Bangladesh
| | - Yusuke Tomita
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Respiratory Medicine; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan
| | - Akira Yuno
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Oral and Maxillofacial Surgery; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan
| | - Masatoshi Hirayama
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Oral and Maxillofacial Surgery; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan
| | - Atsushi Irie
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan
| | - Hirotake Tsukamoto
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan
| | - Satoru Senju
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan
| | - Eiji Yuba
- Department of Applied Chemistry; Graduate School of Engineering; Osaka Prefecture University ; Sakai, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy; Exploratory Oncology Research and Clinical Trial Center; National Cancer Center ; Kashiwa, Japan
| | - Kenji Kono
- Department of Applied Chemistry; Graduate School of Engineering; Osaka Prefecture University ; Sakai, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy; Exploratory Oncology Research and Clinical Trial Center; National Cancer Center ; Kashiwa, Japan
| | - Yasuharu Nishimura
- Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan
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Dai W, Wang F, Lu J, Xia Y, He L, Chen K, Li J, Li S, Liu T, Zheng Y, Wang J, Lu W, Zhou Y, Yin Q, Abudumijiti H, Chen R, Zhang R, Zhou L, Zhou Z, Zhu R, Yang J, Wang C, Zhang H, Zhou Y, Xu L, Guo C. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. Oncotarget 2015; 6:13703-13717. [PMID: 25938543 PMCID: PMC4537043 DOI: 10.18632/oncotarget.3800] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cancer cells exhibit an altered metabolic phenotype known as the aerobic glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell glycolysis. Aerobic glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression.
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Affiliation(s)
- Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei He
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianrong Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Wenxia Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Yuqing Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qin Yin
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huerxidan Abudumijiti
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rongxia Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rong Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Li Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Zheng Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Rong Zhu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Jing Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huawei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ling Xu
- Department of Gastroenterology, Shanghai Tongren Hospital, Jiaotong University of Medicine, Shanghai, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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Kondo M, Morimoto M, Ishii T, Nozaki A, Fukuda H, Numata K, Kobayashi S, Ohkawa S, Hidaka H, Nakazawa T, Shibuya A, Okuse C, Suzuki M, Sakamaki K, Morita S, Maeda S, Tanaka K. Hepatic arterial infusion chemotherapy with cisplatin and sorafenib in hepatocellular carcinoma patients unresponsive to transarterial chemoembolization: a propensity score-based weighting. J Dig Dis 2015; 16:143-151. [PMID: 25495751 DOI: 10.1111/1751-2980.12221] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We aimed to evaluate the efficacy and tolerability of hepatic arterial infusion chemotherapy (HAIC) using cisplatin as an alternative to sorafenib for the treatment of hepatocellular carcinoma (HCC) patients who had not responded to transarterial chemoembolization (TACE). METHODS Medical records of 127 consecutive HCC patients without extrahepatic metastasis (cisplatin, n = 44; sorafenib, n = 83) who had not responded to prior TACE at four institutions were retrospectively reviewed. An inverse probability of treatment weighting using propensity scoring was used to adjust for the selection bias. RESULTS Severe adverse events accounting for treatment discontinuation occurred in 2.3% of the patients in the cisplatin group and 32.5% of those in the sorafenib group. The median overall survival (OS) period was 11.2 months (95% CI 4.8-17.7) in the cisplatin group and 10.2 months (95% CI 8.8-11.5) in the sorafenib group, respectively. After an inverse probability of treatment weighting adjustment, the survival outcome of the HAIC treatment group was not inferior to that of the sorafenib treatment group (hazard ratio 0.758; 95% CI 0.471-1.219, P = 0.253). CONCLUSION HAIC with cisplatin can be an alternative treatment for the selection of HCC patients who have not responded to prior TACE and cannot tolerate sorafenib.
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Affiliation(s)
- Masaaki Kondo
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
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Morimoto M, Numata K, Kondo M, Kobayashi S, Ohkawa S, Hidaka H, Nakazawa T, Okuwaki Y, Okuse C, Matsunaga K, Suzuki M, Morita S, Taguri M, Tanaka K. Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis. Hepatol Res 2015; 45:279-87. [PMID: 24802232 DOI: 10.1111/hepr.12354] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/30/2014] [Accepted: 04/30/2014] [Indexed: 12/24/2022]
Abstract
AIM Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. METHODS We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity score-matching analysis was used to adjust for potential bias. RESULTS Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05-1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for propensity score matching. The incidence of grade 3-4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; full-dose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively). CONCLUSION Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age.
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Affiliation(s)
- Manabu Morimoto
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan; Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan
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Hu H, Duan Z, Long X, Hertzanu Y, Tong X, Xu X, Shi H, Liu S, Yang Z. Comparison of treatment safety and patient survival in elderly versus nonelderly patients with advanced hepatocellular carcinoma receiving sorafenib combined with transarterial chemoembolization: a propensity score matching study. PLoS One 2015; 10:e0117168. [PMID: 25689846 PMCID: PMC4331363 DOI: 10.1371/journal.pone.0117168] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 12/17/2014] [Indexed: 12/22/2022] Open
Abstract
AIMS This retrospective study was carried out to compare the outcomes between elderly (≥70 years of age) and nonelderly patients (<70 years of age) with advanced hepatocellular carcinoma (HCC) who received sorafenib combined with transarterial chemoembolization (TACE). METHODS 88 patients with a confirmed diagnosis of advanced HCC were enrolled in this study. Of these, 24 elderly patients were matched with 48 nonelderly patients at a 1:2 ratio using propensity score matching to minimize selection bias. The related adverse events and survival benefits were compared between the two groups. RESULTS Sorafenib combined with TACE was equally well tolerated in both age groups, and grade 3 or 4 adverse events were similarly observed in 54.2% of elderly and 50.0% of nonelderly patients (P = 0.739). There were no significant differences in survival time between the elderly and nonelderly patients (P = 0.876). Significant prognostic factors for overall survival as identified by multivariate analysis were the Child-Pugh score and portal vein invasion. CONCLUSIONS Sorafenib combined with TACE may be well tolerated and effective in elderly patients with advanced HCC. Age alone is not a parameter for the treatment of advanced HCC patients.
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Affiliation(s)
- Hao Hu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenhua Duan
- Chengdu Center for Disease Control and Prevention, Chengdu, China
| | - Xiaoran Long
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yancu Hertzanu
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Xiaoqiang Tong
- Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing, China
| | - Xiaoquan Xu
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haibin Shi
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhengqiang Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Sorafenib use in elderly patients with hepatocellular carcinoma: caution about use of platelet aggregation inhibitors. Cancer Chemother Pharmacol 2014; 75:215-9. [PMID: 25477009 DOI: 10.1007/s00280-014-2645-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 12/01/2014] [Indexed: 12/27/2022]
Abstract
PURPOSE Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). The peak incidence of HCC is around 70 years. We aimed to evaluate safety and efficacy of sorafenib in the elderly population. METHODS We retrospectively reviewed data from patients treated with sorafenib for HCC at our institution. We compared safety and efficacy data across different age groups. RESULTS Since 2005, 129 patients were treated, 78 (60.5 %) were <70 years old and 51 (39.5 %) were ≥70. The frequency of dose reduction was similar between the two groups (48.7 vs. 58.8 %), as was the occurrence of severe toxicities (41.0 vs. 51.0 %) and hospitalization due to toxicity (9.0 vs. 13.7 %). However, asthenia and bleeding were more frequent in the elderly. The higher frequency of bleeding was explained by concomitant antiplatelet treatments, and major asthenia was frequent in PS1 elderly patients. There was a trend toward less frequent interruption of treatment in the younger group (25.6 vs. 39.2 %) and significantly less frequent definitive discontinuation of treatment due to toxicity (24.4 vs. 45.1 %). Median progression-free survival was 5.6 months in both age groups, while median overall survival was 9.6 months in the younger age group and 12.6 months in the older age group. CONCLUSION Sorafenib showed similar results in terms of safety and efficacy in the elderly and younger HCC populations. Careful baseline evaluation is needed for patient's selection in the elderly population, including discussion about antiplatelet therapy discontinuation and caution in PS1 patients, as well as active management of toxicity.
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Jo M, Yasui K, Kirishima T, Shima T, Niimi T, Katayama T, Mori T, Funaki J, Sumida Y, Fujii H, Takami S, Kimura H, Mitsumoto Y, Minami M, Yamaguchi K, Yoshinami N, Mizuno M, Sendo R, Tanaka S, Shintani H, Kagawa K, Okanoue T, Itoh Y. Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma. Hepatol Res 2014; 44:1329-38. [PMID: 24528772 DOI: 10.1111/hepr.12308] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 01/16/2014] [Accepted: 01/29/2014] [Indexed: 12/24/2022]
Abstract
AIM Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC. METHODS In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups. RESULTS Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort. CONCLUSION Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years.
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Affiliation(s)
- Masayasu Jo
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Molecular Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of Medicine, Yosano, Japan
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Terashima T, Yamashita T, Arai K, Sunagozaka H, Kitahara M, Nakagawa H, Kagaya T, Mizukoshi E, Honda M, Kaneko S. Feasibility and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma after sorafenib. Hepatol Res 2014; 44:1179-85. [PMID: 24171787 DOI: 10.1111/hepr.12266] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 10/22/2013] [Accepted: 10/23/2013] [Indexed: 12/13/2022]
Abstract
AIM Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no proven therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy. METHODS We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m(2) per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5-fluorouracil (330 mg/m(2) per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon α-2b (1 μg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest. RESULTS The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatment-related deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively. CONCLUSIONS Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib.
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Affiliation(s)
- Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
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Nemoto T, Matsuda H, Nosaka T, Saito Y, Ozaki Y, Hayama R, Naito T, Takahashi K, Ofuji K, Ohtani M, Hiramatsu K, Suto H, Nakamoto Y. Comparison of hepatic arterial infusion chemotherapy and sorafenib in elderly patients with advanced hepatocellular carcinoma: A case series. Mol Clin Oncol 2014; 2:1028-1034. [PMID: 25279193 DOI: 10.3892/mco.2014.371] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 07/08/2014] [Indexed: 02/07/2023] Open
Abstract
Sorafenib and hepatic arterial infusion chemotherapy (HAIC) are both indicated for unresectable hepatocellular carcinoma (HCC). In this study, we compared the efficacy and safety of HAIC to that of sorafenib in elderly patients with HCC. Eligible patients included those aged ≥70 years, with histologically or clinically confirmed advanced HCC. A total of 12 patients received sorafenib (800 mg per day) and 8 patients received HAIC with 5-fluorouracil (300 mg/m2 on days 1-5 and 8-12) with or without cisplatin (20 mg/m2 on days 1 and 8), with interferon-α (3 times per week for 4 weeks). The response rate was significantly higher in patients treated with HAIC (37.5%) compared to that in patients treated with sorafenib (no response). The median overall survival (18.6 and 11.7 months) and progression-free survival (4.0 and 5.0 months) were similar between the sorafenib and HAIC groups, respectively. In the sorafenib group, 58.3% of the patients discontinued treatment compared to none in the HAIC group. The most frequent adverse event leading to discontinuation of sorafenib was anorexia. Similar to sorafenib, HAIC appears to be a feasible treatment and may also have the advantage of an adequate safety profile for elderly patients with advanced HCC. Further study of HAIC in a larger population of elderly patients is required to assess its potential as an alternative to sorafenib for HCC.
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Affiliation(s)
- Tomoyuki Nemoto
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Hidetaka Matsuda
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Takuto Nosaka
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Yasushi Saito
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Yoshihiko Ozaki
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Ryoko Hayama
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Tatsushi Naito
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Kazuto Takahashi
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Kazuya Ofuji
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Masahiro Ohtani
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Katsushi Hiramatsu
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Hiroyuki Suto
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Yasunari Nakamoto
- Division of Gastroenterology, Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
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Fukuda H, Numata K, Moriya S, Shimoyama Y, Ishii T, Nozaki A, Kondo M, Morimoto M, Maeda S, Sakamaki K, Morita S, Tanaka K. Hepatocellular carcinoma: concomitant sorafenib promotes necrosis after radiofrequency ablation--propensity score matching analysis. Radiology 2014; 272:598-604. [PMID: 24689883 DOI: 10.1148/radiol.14131640] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
PURPOSE To retrospectively compare radiofrequency ablation (RFA) combined with the multikinase inhibitor sorafenib (hereafter, sorafenib-RFA) and RFA alone in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Between January 2007 and December 2011, 16 patients (mean age, 72.8 years; age range 52-84 years; 10 men, six women) with HCC tumors less than 3 cm in diameter were included in the sorafenib-RFA group, and 136 patients (mean age, 72.1 years; age range, 51-86 years; 92 men, 44 women) with HCC tumors less than 3 cm in diameter were included in the RFA alone (control) group. Mean diameters of the greatest long-axis dimensions of HCC were 22.8 mm ± 4.6 (standard deviation) in the sorafenib-RFA group and 18.1 mm ± 4.4 in the control group. RFA was performed immediately after the 7-day administration of sorafenib. Propensity score matching analysis was used to adjust for potential biases. RESULTS Fifteen of the 16 patients in the sorafenib-RFA group and 30 of the 136 patients in the control group were selected during propensity score matching. No significant differences between the sorafenib-RFA group (n = 15) and the control group (n = 30) were observed with regard to age, sex, etiology, Child-Pugh class, tumor size, puncture number, needle size, location at the liver margin, or location adjacent to a main vessel. The respective mean diameters of the greatest long- and short-axis dimensions of the RFA-induced ablated area were 46.3 mm ± 10.3 and 33.0 mm ± 6.9 in the sorafenib-RFA group and 32.9 mm ± 7.6 and 25.6 mm ± 5.7 in the control group; both of these dimensions were significantly larger in the sorafenib-RFA group (both P < .001). CONCLUSION Sorafenib-RFA may be superior to standard RFA alone in the treatment of HCC tumors smaller than 3 cm in diameter.
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Affiliation(s)
- Hiroyuki Fukuda
- From the Gastroenterological Center (H.F., K.N., S. Moriya, Y.S., T.I., A.N., M.K., M.M., K.T.), Department of Gastroenterology (S. Maeda), Department of Biostatistics and Epidemiology (K.S., S. Morita), and Clinical Research Coordinating Center (K.S., S. Morita, K.T.), Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa 232-0024, Japan
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Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Worldwide progressive population aging demands consensus development for decision making when treating elderly patients. Age itself might not be a critical determinant for the selection of a therapeutic option. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated, and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control, have been demonstrated, leading to evaluation of the activity and toxicity of some of the new molecularly targeted agents. Sorafenib was demonstrated to significantly increase the survival of patients with advanced HCC in two prospective, randomized, placebo-controlled trials. Subsequently, a number of retrospective or prospective studies have indicated that the effectiveness of sorafenib therapy in the treatment of HCC is similar in elderly and non-elderly patients. The aim of this review is to describe the impact of age on the effects of sorafenib-targeted therapy in patients with HCC, and the next treatment options with new targeted agents (everolimus, tivantinib, linifanib, etc.).
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Nishikawa H, Takeda H, Tsuchiya K, Joko K, Ogawa C, Taniguchi H, Orito E, Uchida Y, Osaki Y, Izumi N. Sorafenib Therapy for BCLC Stage B/C Hepatocellular Carcinoma; Clinical Outcome and Safety in Aged Patients: A Multicenter Study in Japan. J Cancer 2014; 5:499-509. [PMID: 24963354 PMCID: PMC4067509 DOI: 10.7150/jca.9257] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 05/11/2014] [Indexed: 02/07/2023] Open
Abstract
Background and aims: We aimed to compare clinical outcomes and safety after sorafenib therapy between patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma (HCC) aged ≥75 years (aged group, n=179) and those with BCLC stage B or C HCC aged <75 years (control group, n=279). Patients and methods: We compared overall survival (OS), progression free survival (PFS), best treatment response and sorafenib related serious adverse events (SAEs) of grade 3 or more in the two groups. Furthermore, for reducing the selection bias, we compared clinical outcome of these two groups using propensity score matching analysis. Results: The median OS and PFS intervals were 9.7 and 3.8 months in the aged group and 8.2 and 3.3 months in the control group (P=0.641 for OS and P=0.068 for PFS). Disease control rates were 49.2% (88/179) in the aged group and 49.1% (137/279) in the control group (P>0.999). Objective response rates were 15.1% (27/179) in the aged group and 14.3% (40/279) in the control group (P=0.892). Treatment related SAEs of grade 3 or more were observed in 51 patients (28.5%) in the aged group and in 69 patients (24.7%) in the control group (P=0.385). In the propensity score matched cohort (132 pairs), no significant difference in the two groups was observed in terms of OS (P=0.898) and PFS (P=0.407). Conclusion: In BCLC stage B or C HCC patients treated with sorafenib, life expectancy, disease progression, treatment efficacy and SAEs are unaffected by age over 75 years.
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Affiliation(s)
- Hiroki Nishikawa
- 1. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital
| | - Haruhiko Takeda
- 1. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital
| | - Kaoru Tsuchiya
- 2. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Kouji Joko
- 3. Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital
| | - Chikara Ogawa
- 4. Department of Gastroenterology, Takamatsu Red Cross Hospital
| | | | - Etsuro Orito
- 6. Department of Gastroenterology and Hepatology Nagoya Daini Red Cross Hospital
| | - Yasushi Uchida
- 7. Department of Gastroenterology, Matsue Red Cross Hospital
| | - Yukio Osaki
- 1. Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital
| | - Namiki Izumi
- 2. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
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Fukudo M, Ito T, Mizuno T, Shinsako K, Hatano E, Uemoto S, Kamba T, Yamasaki T, Ogawa O, Seno H, Chiba T, Matsubara K. Exposure–Toxicity Relationship of Sorafenib in Japanese Patients with Renal Cell Carcinoma and Hepatocellular Carcinoma. Clin Pharmacokinet 2013; 53:185-96. [DOI: 10.1007/s40262-013-0108-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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