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Stefanini B, Manfredi GF, D’Alessio A, Fulgenzi CA, Awosika N, Celsa C, Pirisi M, Rigamonti C, Burlone M, Vincenzi F, Minisini R, Gennari A, Yip V, Slater S, El-Shakankery K, Jain A, Tovoli F, Piscaglia F, Spalding D, Pai M, Pinato DJ. Delivering adjuvant and neoadjuvant treatments in the early stages of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:647-660. [PMID: 39435480 PMCID: PMC11601036 DOI: 10.1080/17474124.2024.2419519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. AREAS COVERED This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. EXPERT OPINION Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC.While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice.
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Affiliation(s)
- Bernardo Stefanini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia F. Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Claudia A.M. Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Nichola Awosika
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Mario Pirisi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Cristina Rigamonti
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Michela Burlone
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Vincent Yip
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Sarah Slater
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Karim El-Shakankery
- Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - Ananya Jain
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Duncan Spalding
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Madhava Pai
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Kokudo N, Kokudo T, Song P, Tang W. Role of liver resection in the era of advanced systemic therapy for hepatocellular carcinoma. Glob Health Med 2024; 6:170-173. [PMID: 38947413 PMCID: PMC11197156 DOI: 10.35772/ghm.2024.01002] [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: 01/09/2024] [Accepted: 01/29/2024] [Indexed: 07/02/2024]
Abstract
The recent dramatic progress in systemic therapy for hepatocellular carcinoma (HCC) provides the possibility of a combination of surgery and systemic therapy including adjuvant, neoadjuvant, or conversion settings. Since the turn of the century, at least three negative studies have tested adjuvant therapies after curative resection or ablation, including uracil-tegafur, which is an oral chemotherapeutic drug, sorafenib, and peretinoin, which a synthetic retinoid that may induce the apoptosis and differentiation of liver cancer cells. Using more potent immuno-checkpoint inhibitors (ICIs), at least 4 phase III trials of adjuvant immunotherapy are ongoing: nivolumab, durvalumab/ bevacizumab, pembrolizumab, and atezolizumab+bevacizumab. Very recently, the last trial indicated a significantly better recurrence-free survival (RFS) for adjuvant atezolizumab+bevacizumab. Another promising combination of surgery and systemic therapy is neoadjuvant therapy for potentially resectable cases or a conversion strategy for oncologically unresectable cases. There are 2 neoadjuvant trials for technically or oncologically unresectable HCCs ongoing in Japan: the LENS-HCC trial using lenvatinib and the RACB study using atezolizumab+bevacizumab. A longer follow-up may be needed, but the overall survival (OS) in resected cases seems much higher than that in unresectable cases. Recently, the Japan Liver Cancer Association (JLCA) and the Japanese Society of HPB Surgery (JSHPBS) created a joint working group on "so-called borderline resectable HCC". They obtained a Japanese consensus on this issue that has been published on the websites of JLCA and JSHPBS. The definition of resectability or borderline resectability provides a common language regarding advanced HCC for investigators and is a useful tool for future clinical trials.
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Affiliation(s)
- Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Takashi Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Peipei Song
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Wei Tang
- National Center for Global Health and Medicine, Tokyo, Japan
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Moriguchi M, Kataoka S, Itoh Y. Evolution of Systemic Treatment for Hepatocellular Carcinoma: Changing Treatment Strategies and Concepts. Cancers (Basel) 2024; 16:2387. [PMID: 39001448 PMCID: PMC11240810 DOI: 10.3390/cancers16132387] [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: 05/25/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has undergone substantial advancements. With the advent of atezolizumab plus bevacizumab (ATZ/BEV) combination therapy, followed by durvalumab plus tremelimumab, the era of immunotherapy for HCC has commenced. The emergence of systemic treatment with high response rates has led to improvements in overall survival while enabling conversion to radical surgical resection in some patients with HCC. In patients with intermediate-stage HCC, new treatment strategies combining systemic treatment and transcatheter arterial chemoembolization (TACE) are under development in clinical trials. Moreover, the addition of local therapies, such as TACE, to systemic treatment according to the treatment effect could achieve a certain percentage of complete response. In the IMbrave050 trial, the efficacy of ATZ/BEV combination therapy was validated in patients predicted to have a high risk of recurrence, especially in those who had undergone radical surgery or radiofrequency ablation for HCC. Therefore, systemic treatment for HCC is entering a new phase for all disease stages. The objective of this review is to organize the current position of systemic therapy for each HCC stage and discuss the development of new treatment methods and strategies, with a focus on regimens incorporating immune checkpoint inhibitors, along with future prospects.
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Affiliation(s)
- Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan; (S.K.); (Y.I.)
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Li L, Li ZZ, Pan LX, Su JY, Huang S, Ma L, Zhong JH. Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions. J Clin Transl Hepatol 2024; 12:525-533. [PMID: 38779519 PMCID: PMC11106350 DOI: 10.14218/jcth.2024.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/31/2024] [Accepted: 04/09/2024] [Indexed: 05/25/2024] Open
Abstract
Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.
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Affiliation(s)
- Le Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Guangxi Academy of Medical Sciences, Emergency Department, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Zhen-Zhen Li
- Pathology Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Li-Xin Pan
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jia-Yong Su
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Shan Huang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi, China
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Du JS, Hsu SH, Wang SN. The Current and Prospective Adjuvant Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1422. [PMID: 38611100 PMCID: PMC11011082 DOI: 10.3390/cancers16071422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer and is highly invasive and easily recurs. For HCC, chemotherapy shows limited effect. The gold standard for HCC treatment includes curative surgical resection or liver transplantation. However, the recurrence rate at 5 years after liver resection is estimated at approximately 70% and even at 5 years after liver transplantation, it is 20%. Therefore, improving survival outcomes after curative surgical resection of liver cancer is crucial. This review highlights the importance of identifying risk factors for HCC recurrence following radical surgical resection and adjuvant therapy options that may reduce the recurrence risk and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization and radiotherapy), adjuvant systemic therapy (e.g., small molecule targeted therapy and immunotherapy), and other adjuvant therapies (e.g., chemotherapy). However, further research is needed to refine the use of these therapies and optimize their effectiveness in preventing HCC recurrence.
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Affiliation(s)
- Jeng-Shiun Du
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shen-Nien Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Wen Y, Lu L, Mei J, Ling Y, Guan R, Lin W, Wei W, Guo R. Hepatic Arterial Infusion Chemotherapy vs Transcatheter Arterial Chemoembolization as Adjuvant Therapy Following Surgery for MVI-Positive Hepatocellular Carcinoma: A Multicenter Propensity Score Matching Analysis. J Hepatocell Carcinoma 2024; 11:665-678. [PMID: 38596593 PMCID: PMC11001557 DOI: 10.2147/jhc.s453250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/17/2024] [Indexed: 04/11/2024] Open
Abstract
Background Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors. Methods Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared. Results In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P<0.05). The a-HAIC group show significantly better 1-, 3-, and 5-year OS rates compared to the a-TACE and control groups (96.3%, 80.0%, 72.8% vs 84.4%, 57.0%, 29.8% vs 84.5%, 62.8%, 53.4%, P<0.05). But the OS rates of a-TACE and control groups showed no significant difference (P=0.279). Multivariate analysis identified a-HAIC (HR=0.449, P=0.000) and a-TACE (HR=0.633, P=0.007) as independent protective factors. For OS, a-HAIC (HR=0.388, P=0.003) was identified as an independent protective factor, too. Conclusion Compared to a-TACE and the control group, a-HAIC demonstrated greater benefits in preventing tumor recurrence and improving survival in HCC patients with MVI.
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Affiliation(s)
- Yuhua Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Lianghe Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Jie Mei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Yihong Ling
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Pathology of Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Renguo Guan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Wenping Lin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Wei Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
| | - Rongping Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China
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Vogel A, Grant RC, Meyer T, Sapisochin G, O'Kane GM, Saborowski A. Adjuvant and neoadjuvant therapies for hepatocellular carcinoma. Hepatology 2023:01515467-990000000-00690. [PMID: 38108634 DOI: 10.1097/hep.0000000000000726] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, London, UK
- Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Department of Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Grainne M O'Kane
- Trinity St. James's Cancer Institute, St. James's Hospital, Dublin, Ireland
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
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Ye Y, Wang Y, Xu H, Yi F. Network meta-analysis of adjuvant treatments for patients with hepatocellular carcinoma after curative resection. BMC Gastroenterol 2023; 23:320. [PMID: 37730533 PMCID: PMC10510134 DOI: 10.1186/s12876-023-02955-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023] Open
Abstract
PURPOSE The prevention of recurrence for patients with hepatocellular carcinoma after curative resection is still a great challenge in clinical practice. There are numerous studies that trying to search for favorable strategies to decrease the recurrence and prolong life span for these patients, whereas no consensus is reached till now. Herein, we aim to compare the efficacy between different reported treatments by network meta-analysis(NMA). METHODS We searched Pubmed, Web of Science and Cochrane Library for abstracts and full-text articles published from database inception through February 2023. All of the random controlled trials(RCTs) were evaluated and collected as eligible studies. The primary outcome was the prevention of recurrence between different procedures. The second outcomes were one-year survival, three-year survival and five-year survival. RESULTS Thirty-two RCTs including 5783 patients were selected, and 12 treatments were classified. Most of the studies were high quality with low bias. Thirty-one studies including 5629 patients were recruited for recurrence analysis. The network meta-analysis showed benefits from transarterial chemoembolization(TACE) + portal vein chemotherapy(PVC)[OR, 2.84 (1.15,6.99)] and internal radiotherapy(IRT) [OR, 2.63 (1.41,4.91)] compared to non-adjuvant(NA) treatment when considering prevention of recurrence. Seventeen studies including 2047 patients were collected for one-year survival analysis. The network meta-analysis showed benefit from TACE[OR, 0.33 (0.14,0.75)] when considering one-year survival. Twenty-one studies including 2463 patients were collected for three-year survival analysis. The network meta-analysis showed TACE [OR, 0.51 (0.30,0.86)], IRT[OR, 0.41 (0.20,0.83)] and dendritic cell(DC) [OR, 0.09 (0.01,0.98)] were better than NA when considering three-year survival. Sixteen studies including 1915 patients were collected for five-year survival analysis. The network meta-analysis didn't show any benefit from different treatments when considering five-year survival. Other strategies including external radiotherapy(ERT), branched-chain amino acids(BCAA), hepatic artery infusion chemotherapy(HAIC), cytokine-induced killer(CIK), adoptive immunotherapy(AIT), Huaier, interferon(IFN), oral chemotherapy(OCT) and sorafenib(SOR) didn't show significant benefit regardless of prevention of recurrence or short-, long- time survival. CONCLUSION This NMA found that TACE + PVC and IRT were considered as the procedures to decrease HCC recurrence rate. TACE, IRT and DC were preferred when considering the extending of life span for post-operative patients with HCC. Large scale of RCTs are needed to verify it.
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Affiliation(s)
- Yanyan Ye
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
| | - Ying Wang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China
| | - Haoqian Xu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China
| | - Fengming Yi
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. of China.
- JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, 330006, P.R. of China.
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Yang YQ, Wen ZY, Liu XY, Ma ZH, Liu YE, Cao XY, Hou L, Xie H. Current status and prospect of treatments for recurrent hepatocellular carcinoma. World J Hepatol 2023; 15:129-150. [PMID: 36926237 PMCID: PMC10011906 DOI: 10.4254/wjh.v15.i2.129] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/13/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023] Open
Abstract
Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.
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Affiliation(s)
- Yu-Qing Yang
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Zhen-Yu Wen
- Department of Occupational and Environmental Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Yan Liu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Zhen-Hu Ma
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yan-E Liu
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Xue-Ying Cao
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Li Hou
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Hui Xie
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Zeng ZM, Mo N, Zeng J, Ma FC, Jiang YF, Huang HS, Liao XW, Zhu GZ, Ma J, Peng T. Advances in postoperative adjuvant therapy for primary liver cancer. World J Gastrointest Oncol 2022; 14:1604-1621. [PMID: 36187393 PMCID: PMC9516643 DOI: 10.4251/wjgo.v14.i9.1604] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/13/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.
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Affiliation(s)
- Zhi-Ming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ning Mo
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Chao Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Feng Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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11
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Abstract
Liver resection is the standard curative treatment for liver cancer. Advances in surgical techniques over the last 30 years, including the preoperative assessment of the future liver remnant, have improved the safety of liver resection. In addition, advances in nonsurgical multidisciplinary treatment have increased the opportunities for tumor downstaging. Consequently, the indications for resection of more advanced liver cancer have expanded. Laparoscopic and robot-assisted liver resections have also gradually become more widespread. These techniques should be performed in stages, depending on the difficulty of the procedure. Advances in preoperative simulation and intraoperative navigation technology may have also lowered the threshold for their performance and may have promoted their widespread use. New insights and experiences gained from laparoscopic surgery may be applicable in open surgery. Liver transplantation, which is usually indicated for patients with poor liver function, has also become safer with advances in perioperative management. The indications for liver transplantation in liver cancer are also expanding. Although the coronavirus disease 2019 pandemic has forced the postponement of liver resection and transplantation procedures, liver surgeons should appropriately tailor the surgical plan to the individual patient as part of multidisciplinary treatment. This review may provide an entry point for future clinical research by identifying currently unresolved issues regarding liver cancer, and particularly hepatocellular carcinoma.
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Affiliation(s)
- Harufumi Maki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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12
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A Rare Cause of Haemorrhagic Shock: Rupture of Gastric Wall Seeding of Hepatocellular Carcinoma. Case Reports Hepatol 2022; 2022:6560834. [PMID: 35313555 PMCID: PMC8934241 DOI: 10.1155/2022/6560834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 01/10/2023] Open
Abstract
Ruptured hepatocellular carcinoma (HCC) can lead to peritoneal dissemination. However, gastric wall seeding from HCC is exceedingly rare, and little is known about its clinical course. Herein, we report a case of an 88-year-old man who presented with a four-hour history of nausea, vomiting, and upper abdominal pain. He has a history of ruptured HCC during surgery. The patient underwent an emergency laparotomy on account of haemorrhagic shock, which confirmed the diagnosis of ruptured HCC with gastric wall seeding. The findings from this study showed that the ruptured HCC can seed into the stomach wall, and the implanted lesions may rupture and lead to life-threatening haemorrhagic shock. Surgery is an effective treatment for bleeding from the implanted lesions.
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13
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Association between chemotherapy and prognostic factors of survival in hepatocellular carcinoma: a SEER population-based cohort study. Sci Rep 2021; 11:23754. [PMID: 34887446 PMCID: PMC8660869 DOI: 10.1038/s41598-021-02698-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatectomy and transplantation are the main surgical therapies for HCC patients, and radiotherapy or chemotherapy is often used as adjuvant treatment. Researches have evaluated the independent predictors of HCC, but evidence for factors predicting the efficacy of chemotherapy is rare. Patients diagnosed with HCC between 2010 and 2015 from the SEER database were included and randomly divided into non-chemotherapy and chemotherapy groups. The predictors of CSS and OS were analyzed with the Cox proportional-hazards regression model and Fine and Gray’s competing risk model. Although there was no significant difference in survival analysis between the chemotherapy and non-chemotherapy groups, the cumulative cancer-specific mortality of most HCC patients was decreased in the chemotherapy group. AJCC stage, tumor size, grade, surgery and radiotherapy were predictors of OS and CSS in the non-chemotherapy group, while AJCC stage, tumor size, AFP, grade and surgery in the chemotherapy group. Surgery combined with chemotherapy was applicable to all AJCC stage patients. Surgery was the major treatment option for patients in AJCC I and AJCC II stage, and chemotherapy in AJCC III and AJCC IV stage. In conclusion, the study provided population-based estimates of the prognostic factors in HCC patients with or without chemotherapy.
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14
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Liu Y, Wang Y, Guo X, He Y, Zhou J, Lv Q, Huang X, Li X. Comparative Effectiveness of Adjuvant Treatment for Resected Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis. Front Oncol 2021; 11:709278. [PMID: 34540675 PMCID: PMC8445365 DOI: 10.3389/fonc.2021.709278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
Background It is controversial whether adjuvant treatment could be recommended for hepatocellular carcinoma (HCC) after curative hepatectomy. Thus, we performed a network meta-analysis (NMA) to assess adjuvant treatment’s benefit and determine the optimal adjuvant regimen. Methods We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing adjuvant therapy versus no active treatment after curative hepatectomy among patients with HCC. Pooled data on recurrence and overall survival (OS) were analyzed within pairwise meta-analysis and NMA. Results Twenty-three eligible trials (3,940 patients) reporting eight treatments were included. The direct meta-analysis showed that adjuvant therapy prevented the recurrence (OR = 0.65; 95% CI: 0.55, 0.77; P = 0.177; I2 = 21.7%) and contributed to OS (HR = 0.63; 95% CI: 0.54, 0.73; P = 0.087; I2 = 31.1%) in comparison to the observation. In the NMA, internal radiotherapy (IRT; OR = 0.55; 95% CI: 0.39, 0.77; SUCRA = 87.7%) followed by hepatic artery infusion chemotherapy (HAIC; OR = 0.6; 95% CI: 0.36, 0.97; SUCRA = 77.8%), and HAIC (HR = 0.44; 95% CI: 0.21, 0.87; SUCRA = 82.6%) followed by IRT (HR 0.54; 95% CI:0.36, 0.81; SUCRA = 69.7%) were ranked superior to other treatments in terms of preventing recurrence and providing survival benefit, respectively. Conclusions The addition of adjuvant therapy lowers the risk of recurrence and provide survival benefit after surgical resection for HCC. HAIC and IRT are likely to be the two most effective adjuvant regimens. Systematic Review Registration https://inplasy.com/inplasy-2020-11-0039/.
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Affiliation(s)
- Ying Liu
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuzhu Wang
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xinkun Guo
- Deparment of Hepatic Oncology, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Yifeng He
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qianzhou Lv
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaowu Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xiaoyu Li
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
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15
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Zhang W, Zhang B, Chen XP. Adjuvant treatment strategy after curative resection for hepatocellular carcinoma. Front Med 2021; 15:155-169. [PMID: 33754281 DOI: 10.1007/s11684-021-0848-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/20/2021] [Indexed: 01/27/2023]
Abstract
Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.
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Affiliation(s)
- Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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16
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The Management of Recurrence of Hepatocellular Carcinoma Occurring Within 6 Months After Hepatic Resection: A Comparative Study Using a Propensity Score Matching Analysis. J Gastrointest Cancer 2021; 53:272-281. [PMID: 33471258 DOI: 10.1007/s12029-021-00585-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial. METHODS Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses. RESULTS Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups. CONCLUSION Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.
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17
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Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma. Molecules 2021; 26:molecules26020295. [PMID: 33435572 PMCID: PMC7827668 DOI: 10.3390/molecules26020295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/06/2021] [Accepted: 01/06/2021] [Indexed: 01/01/2023] Open
Abstract
The high rates of hepatocellular carcinoma (HCC) recurrence after initially successful curative therapy emphasize ongoing unmet needs to prevent or reduce HCC recurrence. Retinoid acid (RA), a metabolite of vitamin A and its related analogues (termed retinoids) has been suggested as a promising chemotherapeutic agent in cancer treatment. The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use.
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18
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Four gene intrahepatic metastasis-risk signature predicts hepatocellular carcinoma malignant potential and early recurrence from intrahepatic metastasis. Surgery 2020; 169:903-910. [PMID: 33160638 DOI: 10.1016/j.surg.2020.09.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 09/16/2020] [Accepted: 09/30/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatocellular carcinoma has a high recurrence rate even after curative surgery, and hepatocellular carcinoma risk-predictive biomarkers will enable identification of patients who most need close monitoring and cancer-preventive intervention. Hepatocellular carcinoma has 2 different recurrence patterns-a multicentric recurrence and an intrahepatic metastasis. We have reported that the molecular gene signature from the gene expression of adjacent liver can be used to predict multicentric recurrence of hepatocellular carcinoma, but the signature to predict recurrence from intrahepatic metastasis has not been established. We aimed to identify the recurrence from intrahepatic metastasis gene signature from the gene expression of tumor to predict recurrence from intrahepatic metastasis. METHODS The intrahepatic metastasis-risk signature was created based on the exhaustive analysis using a microarray transcriptome database of hepatocellular carcinoma. The intrahepatic metastasis-risk signature was measured in a cohort of 80 hepatocellular carcinoma patients, and the correlation with hepatocellular carcinoma recurrence and overall survival and each gene signature were analyzed and validated. RESULTS The gene signature assay classified the patients into high- (n = 20), intermediate- (n = 40), and low-risk (n = 20) groups. The high-risk prediction was independently associated with higher early hepatocellular carcinoma recurrence (hazard ratio = 3.7, P = .03) in multivariable modeling adjusted by tumor size, tumor number, and microvascular invasion. Gene set enrichment analysis demonstrates that the gene sets associated with "cell cycle" or "histone modulation" are highly enriched in the high intrahepatic metastasis gene signature group CONCLUSION: The intrahepatic metastasis gene signature predicts early recurrence and is associated with malignant potential related to the promoted cell cycle.
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19
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Kokudo T, Kokudo N. What liver surgeons have achieved in the recent decade for patients with hepatocellular carcinoma? Glob Health Med 2020; 2:265-268. [PMID: 33330819 DOI: 10.35772/ghm.2020.01086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022]
Abstract
In the past decade, there has been remarkable progress in surgical treatment for hepatocellular carcinoma (HCC) based on evidence created by epoch-making prospective trials or national registry big data analysis. A head-to-head randomized controlled trial comparing liver resection and local ablation for small oligo HCCs (SURF trial) demonstrated comparable recurrence-free survival provided both modalities are feasible. Survival benefit of liver resection for HCC with vascular invasion was demonstrated by two propensity scored matched analyses based on Japanese national data. Furthermore, expanded HCC criteria for living donor liver transplantation were developed based on Japanese national data, and this "5-5-500 rule" was accepted by the social insurance system in Japan. The recent remarkable progress in promising new anti-HCC agents may open the door for effective neoadjuvant or adjuvant treatment in combination with surgery.
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Affiliation(s)
- Takashi Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
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20
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Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis 2020; 7:359-369. [PMID: 32884990 PMCID: PMC7452398 DOI: 10.1016/j.gendis.2020.02.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 02/20/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor recurrence rate after surgery or ablation of hepatocellular carcinoma (HCC) is as high as 70%. However, there are no widely accepted adjuvant therapies; therefore, no treatment has been recommended by guidelines from the American Association for the Study of Liver Disease or the European Association for the Study of the Liver. All the registered trials failed to find any treatment to prolong recurrence-free survival, which is the primary outcome in most studies, including sorafenib. Some investigator-initiated studies revealed that anti-hepatitis B virus agents, interferon-α, transcatheter chemoembolization, chemokine-induced killer cells, and other treatments prolonged patient recurrence-free survival or overall survival after curative therapies. In this review, we summarize the current status of adjuvant treatments for HCC and explain the challenges associated with designing a clinical trial for adjuvant therapy. Promising new treatments being used as adjuvant therapy, especially anti-PD-1 antibodies, are also discussed.
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Key Words
- Adjuvant therapy
- Anti-PD-1 antibody
- CIK, chemokine-induced killer cells
- CR, complete response
- Clinical trial
- HCC, hepatocellular carcinoma
- Hepatocellular carcinoma
- ICI, immune checkpoint inhibitor
- Molecular targeted therapy
- ORR, objective response rate
- OS, overall survival
- PD-1, program death-1
- PD-L1, program death-1 ligand
- PR, partial response
- RCT, randomized clinical trial
- RECIST, Response Evaluation Criteria in Solid Tumors
- RFS, recurrence-free survival
- Recurrence-free survival
- TACE, transcatheter chemoembolization
- TKI, tyrosine kinase inhibitor
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Affiliation(s)
- Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kang-Shuai Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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21
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Safety and Long-Term Outcome of Intratumoral Injection of OK432-Stimulated Dendritic Cells for Hepatocellular Carcinomas After Radiofrequency Ablation. Transl Oncol 2020; 13:100777. [PMID: 32413834 PMCID: PMC7226894 DOI: 10.1016/j.tranon.2020.100777] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/18/2022] Open
Abstract
Dendritic cell (DC)–based immunotherapies are believed to help eradicate residual tumor cells, including hepatocellular carcinoma (HCC). Here, we assessed the safety and clinical response to OK432-stimulated monocyte-derived DCs (MoDCs) in treating HCC after radiofrequency ablation (RFA). MoDCs were derived from 30 HCC patients in the presence of interleukin-4 and granulocyte-macrophage colony stimulating factor for 5 days and then cultured for 2 more days in the medium (basic protocol) or stimulated with OK432. On day 7, DCs were harvested and percutaneously injected into HCC tumors after RFA. We observed no grade 3 or 4 National Cancer Institute Common Toxicity Criteria adverse events. Kaplan-Meier analysis indicated that patients treated with RFA + OK432-stimulated DCs transfer had longer recurrence-free survival than those treated with RFA + basic-protocol DCs (median: 24.8 vs 13.0 months; P = .003). RFA with DC infusion can enhance various tumor-associated antigen (TAA)–specific T-cell responses. Additionally, the 5-year RFS rate for patients with significantly increased TAA-specific T-cell responses was much higher than for other patients (50.0% vs. 7.7%; P = .030). Our study provides useful information for development of HCC immunotherapies (trial registration: UMIN000001701).
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22
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Lu SD, Li L, Liang XM, Chen W, Chen FL, Fan LL, Ahir BK, Zhang WG, Zhong JH. Updates and advancements in the management of hepatocellular carcinoma patients after hepatectomy. Expert Rev Gastroenterol Hepatol 2019; 13:1077-1088. [PMID: 31648568 DOI: 10.1080/17474124.2019.1684898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The 5-year recurrence rate of hepatocellular carcinoma (HCC) after hepatic resection or local ablation is up to 70%. Adjuvant therapies to prevent HCC recurrence have been reported but are not currently recommended by EASL or AASLD guidelines. This review examined evidence from randomized controlled trials, meta-analyses and systematic reviews on the safety and efficacy of adjuvant therapies and chemotherapies in HCC patients after resection or local ablation.Areas covered: PubMed was searched through 15 June 2019. Available evidence was assessed based on the GRADE system.Expert commentary: Transarterial chemoembolization is the best adjuvant therapy for HCC patients at high risk of recurrence, antiviral therapy with nucleoside analogs is effective for preventing recurrence of HBV-related HCC, and interferon-α is effective for preventing recurrence of HCV-related HCC. Further studies are needed to clarify the efficacy of adjuvant immune checkpoint inhibitors. Adjuvant sorafenib appears to offer negligible clinical benefit and high risk of adverse effects.
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Affiliation(s)
- Shi-Dong Lu
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin-Min Liang
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Wu Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Fu-Li Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Lang-Lin Fan
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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23
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Wen T, Jin C, Facciorusso A, Donadon M, Han HS, Mao Y, Dai C, Cheng S, Zhang B, Peng B, Du S, Jia C, Xu F, Shi J, Sun J, Zhu P, Nara S, Millis JM. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus. Hepatobiliary Surg Nutr 2018; 7:353-371. [PMID: 30498711 DOI: 10.21037/hbsn.2018.08.01] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes.
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Affiliation(s)
- Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chen Jin
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Matteo Donadon
- Department of Hepatobiliary & General Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy
| | - Ho-Seong Han
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Baogang Peng
- Department of Liver Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Changjun Jia
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
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Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017; 11:317-370. [PMID: 28620797 PMCID: PMC5491694 DOI: 10.1007/s12072-017-9799-9] [Citation(s) in RCA: 1612] [Impact Index Per Article: 201.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 05/02/2017] [Indexed: 02/06/2023]
Abstract
There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia-Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments.
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Affiliation(s)
- Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-city, Yamanashi, Japan.
- The University of Tokyo, Tokyo, Japan.
| | - Ann-Lii Cheng
- Department of Oncology and Internal Medicine, National Taiwan University Hospital, National Taiwan University Cancer Center and Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osaka-Sayama, Osaka, Japan
| | - Jeong Min Lee
- Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jidong Jia
- Beijing Key Laboratory of Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoghesh K Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University and Hospital, Karachi, Pakistan
| | | | - Takamasa Ohki
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Cosmas Rinaldi A Lesmana
- Digestive Disease and GI Oncology Center, Medistra Hospital, University of Indonesia, Jakarta, Indonesia
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Laurentius A Lesmana
- Digestive Disease and GI Oncology Center, Medistra Hospital, University of Indonesia, Jakarta, Indonesia
| | - Rino A Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Shuntaro Obi
- Third Department of Internal Medicine, Teikyo University School of Medicine, Chiba, Japan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Kobayashi T, Aikata H, Kobayashi T, Ohdan H, Arihiro K, Chayama K. Patients with early recurrence of hepatocellular carcinoma have poor prognosis. Hepatobiliary Pancreat Dis Int 2017; 16:279-288. [PMID: 28603096 DOI: 10.1016/s1499-3872(16)60181-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Early recurrence (ER) after hepatic resection (HR) is a poor prognostic factor for patients with hepatocellular carcinoma (HCC). This study aimed to identify the clinicopathological features, outcomes, and risk factors for ER after HR for small HCC in order to clarify the reasons why ER is a worse recurrence pattern. METHODS We retrospectively examined 130 patients who underwent HR for small HCC (≤30 mm). Recurrence was classified into ER (<2 years) and late recurrence (LR) (≥2 years). The clinicopathological features, outcomes, and risk factors for ER were analyzed by multivariate analysis. RESULTS ER was observed in 39 patients (30.0%). The survival rate of the ER group was significantly lower than that of the LR group (P<0.005), and ER was an independent prognostic factor for poor survival (P=0.0001). The ER group had a significantly higher frequency (P=0.0039) and shorter interval (P=0.027) of development to carcinoma beyond the Milan criteria (DBMC) compared with the LR group, and ER was an independent risk factor for DBMC (P<0.0001). Multi-nodularity, non-simple nodular type, and microvascular invasion were independent predictors for ER (P=0.012, 0.010, and 0.019, respectively). CONCLUSIONS ER was a highly malignant recurrence pattern associated with DBMC and subsequent poor survival after HR for small HCC. Multi-nodularity, non-simple nodular type, and microvascular invasion predict ER, and taking these factors into consideration may be useful for the decision of the treatment strategy for small HCC after HR.
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Affiliation(s)
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan.
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26
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Ishizuka M, Kubota K, Nemoto T, Shimoda M, Kato M, Iso Y, Tago K. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: A randomized controlled trial. Asian J Surg 2016; 39:149-54. [PMID: 26123137 DOI: 10.1016/j.asjsur.2015.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 03/16/2015] [Accepted: 04/01/2015] [Indexed: 12/15/2022] Open
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Zhu GQ, Shi KQ, Yu HJ, He SY, Braddock M, Zhou MT, Chen YP, Zheng MH. Optimal adjuvant therapy for resected hepatocellular carcinoma: a systematic review with network meta-analysis. Oncotarget 2015; 6:18151-18161. [PMID: 26061709 PMCID: PMC4627241 DOI: 10.18632/oncotarget.4098] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 05/26/2015] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Major adjuvant therapies (ATs) for resected hepatocellular carcinoma (HCC) include chemotherapy, internal radiation therapy (IRT), interferon therapy (IFNT) and immunotherapy but the optimum regimen remains inconclusive. We aim to compare these therapies in terms of patient survival and recurrence rates. METHODS We searched PubMed, EMBASE and Cochrane library databases for randomized trials comparing the above four therapies until 31 March 2014. We estimated the HRs for survival and ORs for overall recurrence among different therapies. Toxic effects were also evaluated. RESULTS Fourteen eligible articles were included. IFNT improved 5-year survival greatly (HR 1.81, 95% CI 1.01-3.81, P = 0.034), whereas chemotherapy (HR 0.33, 95% CI 0.03-2.02), IRT (HR 0.31, 95% CI 0.02-3.33) and immunotherapy (HR 0.73, 95% CI 0.05-9.12) all provided a poorer survival outcome after 1-year. Similarly, for 5-year survival rates, although differing, IRT did not provide a significant improvement in survival (HR 1.38, 95% CI 0.34-5.19) compared with IFNT. Chemotherapy (HR 0.49, 95% CI 0.18-1.14) and immunotherapy (HR 0.56, 95% CI 0.17-1.59) did not appear to provide benefit over IFNT. Chemotherapy was ranked the worst in overall recurrence (OR 0.99, 95% CI 0.18-5.38) and most likely to cause toxic effects. CONCLUSIONS IFNT was the most efficacious AT regimen both for short and long term survivals. Immunotherapy and IFNT were the most two effective in preventing overall relapse for resected HCC.
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Affiliation(s)
- Gui-Qi Zhu
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ke-Qing Shi
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
| | - Hua-Jian Yu
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Sun-Yue He
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Martin Braddock
- Global Medicines Development, AstraZeneca R&D, Loughborough, United Kingdom
| | - Meng-Tao Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong-Ping Chen
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
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Affiliation(s)
- Kazuhiro Nouso
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan,
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29
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Jeng WJ, Lin CC, Chen WT, Sheen IS, Lin CY, Lin SM. Adjuvant therapy for hepatocellular carcinoma after curative treatment. Dig Dis 2014; 32:747-54. [PMID: 25376293 DOI: 10.1159/000368017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy in the world. Although resection and various locoregional therapies can achieve eradication or complete ablation of small HCC, HCC recurrence after these therapies is still common. Although candidates for medical ablation usually exhibit compensated hepatic functional status, the frequent recurrence of HCC after successful ablation contributes to short survival. Therefore, attempts to prevent HCC recurrence are essential to prolong survival. Efforts in preventing HCC recurrence after curative therapies include prevention of early recurrence by improving liver immunity and eliminating microscopic tumor foci or micrometastases, and prevention of late recurrence by reducing the hepatitis activity and using antiviral therapies based on viral suppression/eradication. In HCC with vascular invasion, adjuvant transcatheter arterial chemoembolization should be considered to provide better control. Whether the adjuvant use of sorafenib may suppress microscopic tumor foci or micrometastases may be unveiled in the near future. This review article will update the algorithms, novel medication or study drugs in the prevention of HCC after curative therapies.
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Affiliation(s)
- Wen-Juei Jeng
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taipei, Taiwan, ROC
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Zhong JH, Zhong QL, Li LQ, Li H. Adjuvant and chemopreventive therapies for resectable hepatocellular carcinoma: a literature review. Tumour Biol 2014; 35:9459-9468. [PMID: 25119592 DOI: 10.1007/s13277-014-2443-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 08/04/2014] [Indexed: 01/27/2023] Open
Abstract
The recurrence rate of hepatocellular carcinoma (HCC) after potentially curative hepatic resection (HR) is very high. Many clinical trials have explored the efficacy of several treatment modalities to prevent recurrence, including adjuvant and chemopreventive therapy, but they have often reported contradictory findings. As a result, most liver guidelines and liver seminars do not unequivocally endorse adjuvant or chemopreventive therapy for HCC patients after potentially curative HR. To examine the available evidence on this question, we comprehensively searched PubMed for controlled studies that included a supportive care or placebo control arm, and we used the GRADE system to classify and assess the results.
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Affiliation(s)
- Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
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31
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Chau GY. Resection of hepatitis B virus-related hepatocellular carcinoma: Evolving strategies and emerging therapies to improve outcome. World J Gastroenterol 2014; 20:12473-12484. [PMID: 25253947 PMCID: PMC4168080 DOI: 10.3748/wjg.v20.i35.12473] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 01/28/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, largely due to hepatitis B virus (HBV), hepatitis C virus and liver cirrhosis. Chronic HBV infection is estimated to cause 55%-60% of the cases of HCC worldwide and over 70% in Asian countries. Liver resection is currently the mainstay of treatment due to the low surgical mortality, a wider treatment indication, and simplicity of post-treatment follow-up. There is an ever-increasing demand on surgeons to perform curative liver resection in HCC, with the hope of avoiding tumor recurrences. Hepatitis B-related-HCC has distinct clinicopathological features, which should be considered when treating the disease. The author presents a review of the recently evolving strategies and emerging therapies to improve HCC postresectional outcomes and focus on perioperative measures to improve patient outcome, with particular reference to the current status of adjuvant therapies in HCC patients after liver resection.
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MESH Headings
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/secondary
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/virology
- Chemotherapy, Adjuvant
- Hepatectomy/adverse effects
- Hepatectomy/methods
- Hepatectomy/mortality
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/mortality
- Humans
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Liver Neoplasms/virology
- Neoplasm Recurrence, Local
- Neoplasm Staging
- Neoplasm, Residual
- Treatment Outcome
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32
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Kobayashi S, Nagano H, Sakai D, Eguchi H, Hatano E, Kanai M, Seo S, Taura K, Fujiwara Y, Ajiki T, Takemura S, Kubo S, Yanagimoto H, Toyokawa H, Tsuji A, Terajima H, Morita S, Ioka T. Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study. Cancer Chemother Pharmacol 2014; 74:699-709. [DOI: 10.1007/s00280-014-2543-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 07/11/2014] [Indexed: 12/21/2022]
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Zhong J, Xiang B, Ma L, Li L. Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: A systematic review. Mol Clin Oncol 2014; 2:1091-1096. [PMID: 25279203 DOI: 10.3892/mco.2014.337] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 06/30/2014] [Indexed: 01/27/2023] Open
Abstract
The findings of randomized clinical trials (RCTs) regarding the efficacy of adjuvant conventional oral systemic chemotherapy (COSC) for patients with hepatocellular carcinoma (HCC) following curative hepatic resection (HR) are contradictory. Therefore, a systematic review of RCTs is required to evaluate the clinical efficacy of adjuvant COSC. Sources such as Medline, Embase and the Cochrane Library were systematically searched and all the RCTs comparing curative HR alone to HR plus COSC for HCC were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. No treatment-related mortality was reported by the included RCTs and the adverse effects of COSC were generally mild. However, adjuvant COSC did not achieve a statistically significant improvement in the 1-, 3- and 5-year overall survival (OR=1.43, 95% CI: 0.58-3.56, P=0.44; OR=1.39, 95% CI: 0.75-2.55, P=0.29; and OR=1.20, 95% CI: 0.46-3.16, P=0.71, respectively). In addition, adjuvant COSC did not achieve a statistically significant decrease in the incidence of 1-, 3- and 5-year tumor recurrence, with pooled ORs of 0.92 (95% CI: 0.26-1.35, P=0.66); 0.82 (95% CI: 0.66-1.01, P=0.06); and 0.84 (95% CI: 0.71-1.01, P=0.06), respectively. Narrative reviews offer no evidence supporting the use of COSC. Adjuvant COSC has provided marginal benefits for HCC patients following curative HR. Considering the efficacy of sorafenib for advanced HCC and the results of this systematic review, no further trials should be performed to assess the efficacy of adjuvant COSC.
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Affiliation(s)
- Jianhong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Abstract
Hepatocellular carcinoma (HCC) is associated with poor prognosis and often recurs even after curative hepatic resection (HR) or radiofrequency ablation (RFA). In fact, recurrence is the most frequent cause of postoperative death in patients with HCC; it can arise through intrahepatic metastasis by the primary tumor or through the emergence of de novo tumors. Even though studies have examined numerous adjuvant therapies and chemotherapies for their ability to prevent recurrence, no consensus recommendations exist about their clinical application. To gain a comprehensive picture of clinical options, we identified 39 randomized controlled trials, involving 4113 participants, which explore the efficacy of adjuvant or chemotherapies to prevent HCC recurrence after potentially curative HR or RFA. The available evidence suggests a significant improvement in recurrence-free survival and overall survival when transarterial chemoembolization is used for patients who are at high risk for recurrence, lamivudine for patients with hepatitis B virus (HBV)-related HCC (>500 copies of HBV DNA/ml), and interferon-α for patients with hepatitis C virus (HCV)-infected HCC. In contrast, available evidence does not definitively establish clinical benefits of interferon-β for patients with HCV-related HCC, interferon-α for patients with HBV-related HCC, or any of the following therapies for patients with HCC: iodine-125 brachytherapy, autologous tumor vaccination, adoptive immunotherapy, or therapy involving acyclic retinoid, vitamin K2 analog, iodine-131-labeled lipiodol, sorafenib, heparanase inhibitor PI-88, or capecitabine. Though the findings of our review should be interpreted with caution because of clinical heterogeneity and small sample size in the included trials, they highlight gaps in the evidence base, and therefore, may guide future research.
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Affiliation(s)
- Jian-Hong Zhong
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University , Nanning 530021 , PR China
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35
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A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:351-63. [PMID: 23781519 DOI: 10.1155/2013/417894] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The high recurrence rate of hepatocellular carcinoma (HCC) after potentially curative treatment determines the long-term prognosis. OBJECTIVE To evaluate the efficacy and safety of adjuvant therapies in patients with HCC who have undergone hepatic resection, transplantation or locoregional ablation therapy. METHODS Several databases were searched to identify randomized controlled trials (RCTs) fulfilling the predefined selection criteria. Meta-analyses were performed to estimate the effects of adjuvant therapies of any modality on recurrence-free survival (RFS) and overall survival (OS). RESULTS Eight adjuvant modalities were identified from 27 eligible RCTs conducted predominantly in Asian populations comparing adjuvant with no adjuvant therapy. Adjuvant chemotherapy, internal radiation and heparanase inhibitor PI-88 therapy failed to improve RFS or OS, while interferon (IFN) therapy yielded significant survival results. The findings of adjuvant vitamin analogue therapy required further examination. Adjuvant adoptive immunotherapy conferred significant benefit for RFS but not for OS. Although cancer vaccine therapy and radioimmunotherapy may improve survival after radical surgery, the results were from single, small-scale trials. Severe side effects were observed in the studies of adjuvant chemotherapy and of IFN therapy. CONCLUSIONS Adjuvant IFN therapy can improve both RFS and OS; however, the benefits of using this agent should be weighed against its side effects. Combination of systemic and transhepatic arterial chemotherapy is not recommended for HCC after potentially curative treatment. Other adjuvant therapies produce limited success for survival. Additional RCTs with proper design are required to establish the role of adjuvant therapies for HCC.
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Hasegawa K, Aoki T, Yamamoto S, Takemura N, Sakamoto Y, Sugawara Y, Norihiro K. [Liver cancer: progress in diagnosis and treatments. Topics: VI. Progress in treatments of liver cancer; 1. Liver resection for hepatocellular carcinoma]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2014; 103:70-77. [PMID: 24605493 DOI: 10.2169/naika.103.70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Taku Aoki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Satoshi Yamamoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Nobuyuki Takemura
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Yasuhiko Sugawara
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
| | - Kokudo Norihiro
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan
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37
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Jia WD, Liu WB. Comprehensive treatment for hepatocellular carcinoma in patients at a high risk of recurrence after hepatectomy. Shijie Huaren Xiaohua Zazhi 2013; 21:3183-3189. [DOI: 10.11569/wcjd.v21.i30.3183] [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] [Indexed: 02/06/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is high in China. Hepatectomy is the first choice for some HCC patients at a high risk of recurrence; however, the rate of postoperative recurrence in these patients remains high. Since single postoperative treatment trying to avoid recurrence often does not work effectively, more than one means are needed to reduce the recurrence on the basis of understanding the effectiveness of different therapeutic methods. In this paper, we will discuss the origin and molecular mechanisms of recurrence as well as the related treatments for HCC at a high risk of recurrence, with an aim to explore more effective and reasonable comprehensive treatments to prevent recurrence in HCC patients at a high risk of recurrence after hepatectomy.
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Shindoh J, Kaseb A, Vauthey JN. Surgical strategy for liver cancers in the era of effective chemotherapy. Liver Cancer 2013; 2:47-54. [PMID: 24159596 PMCID: PMC3747536 DOI: 10.1159/000346222] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Systemic chemotherapy is the only option for advanced and/or disseminated disease in patients with hepatocellular carcinoma (HCC). For decades, various systemic therapies have been explored for the treatment of advanced HCC. Nevertheless, no satisfactory results have been obtained in cytotoxic chemotherapy so far. However, with the recent introduction of effective chemotherapy agents including sorafenib, the role of systemic therapy for the treatment of HCC is changing. The goals of systemic therapy include prolongation of survival with stabilization of disease progression and, in selected patients, downsizing of primarily unresectable tumors. In the era of effective chemotherapy, patients with advanced HCC should be managed with individualized approaches to optimize outcome.
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Affiliation(s)
- Junichi Shindoh
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA,*Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Boulevard, Unit 1484, Houston, TX 77030 (USA), E-Mail
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Kobayashi T, Ishiyama K, Ohdan H. Prevention of recurrence after curative treatment for hepatocellular carcinoma. Surg Today 2012; 43:1347-54. [PMID: 23271667 DOI: 10.1007/s00595-012-0473-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 10/26/2012] [Indexed: 12/22/2022]
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Ochiai T, Ikoma H, Okamoto K, Kokuba Y, Sonoyama T, Otsuji E. Clinicopathologic features and risk factors for extrahepatic recurrences of hepatocellular carcinoma after curative resection. World J Surg 2012; 36:136-43. [PMID: 22051887 DOI: 10.1007/s00268-011-1317-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The aim of this study was to clarify the clinicopathologic features of hepatocellular carcinoma (HCC) patients with extrahepatic metastasis after the removal of primary HCC, and the risk factors of extrahepatic recurrence. METHODS Clinicopathologic data were available for 264 HCC patients who underwent an R0 resection for HCC. Twenty-six patients who developed extrahepatic recurrence during the follow-up period (EXT group) were compared with patients who remained free from recurrence for at least 5 years after resection (n = 46) (No R group) or had only intrahepatic recurrences (n = 193) (INT group). We also estimated the risk factors of extrahepatic recurrence and survival in these 26 patients. RESULTS There were significant differences in primary tumor size, patient's age, findings in the noncancerous portion, macroscopic type, ductal invasion, intrahepatic metastasis, hepatic involvement and curability of primary tumor, treatment for recurrent tumor, and prognosis between the EXT group and the other groups. Extrahepatic recurrence was significantly associated with six factors by univariate analyses: age, indocyanine green (ICG) 15-min retention rate, tumor size, hepatic involvement of primary tumor, type of hepatectomy, and TNM stage, of which tumor size was an independent risk factor. Resection of recurrent tumor was the only independent favorable factor for survival of patients with extrahepatic recurrence. CONCLUSIONS HCC patients with extrahepatic recurrence had advanced primary tumors and poor prognosis. HCC patients with primary tumors larger than 60 mm were predicted to develop extrahepatic recurrence. Resection of recurrent tumor can improve the prognosis of HCC patients with extrahepatic recurrence.
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Affiliation(s)
- Toshiya Ochiai
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-Kawaramachi, Kamigyo-ku, Kyoto 602-8566, Japan.
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Jia WD. Adjuvant sorafenib after radical liver resection for the treatment of hepatocellular carcinoma: Recent research advances. Shijie Huaren Xiaohua Zazhi 2012; 20:2019-2023. [DOI: 10.11569/wcjd.v20.i22.2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Radical liver resection is still the major treatment for hepatocellular carcinoma (HCC) in recent years. However, postoperative recurrence and metastasis are major obstacles that lead to poor therapeutic benefits. Treatments to prevent recurrence are important for effectively prolonging the survival of HCC patients. Currently, various treatment options, such as transcatheter hepatic arterial chemoembolization, have been comprehensively assessed in clinical practice; however, evidence from large multicenter, randomized controlled trials is still lacking. The emergence of sorafenib, a molecular targeted drug, has opened a new avenue for improving the prognosis of HCC prognosis. Sorafenib might be an effective adjuvant treatment for HCC patients who received curative liver resection.
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Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, Liu JY, Xiang BD, Wu GB. Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2012; 38:286-295. [PMID: 22281155 DOI: 10.1016/j.ejso.2012.01.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 12/28/2011] [Accepted: 01/05/2012] [Indexed: 01/27/2023]
Abstract
AIMS Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies. METHODS MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73-0.97, P = 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07-1.22, P < 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28-1.27, P = 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00-1.05, P = 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients. CONCLUSIONS Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment.
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Affiliation(s)
- J-H Zhong
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning 530021, PR China
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Abstract
Hepatocellular carcinoma (HCC) has characteristic features of the coexistence of two life-threatening conditions, cancer and cirrhosis, which makes prognostic assessment difficult. In addition, the high rate of intrahepatic recurrence is a key feature that correlates with poor prognosis and its prevention is an issue for urgent investigation. Gene expression in the tumor and adjacent liver tissue for the prediction of intrahepatic recurrence of HCC has been extensively investigated. Among them, the expression of progenitor cell feature markers in the cancer cells such as epidermal cell adhesion molecule (EpCAM), cytokeratin 19 (CK19) and CD 133 have been shown to be associated with intrahepatic recurrence of HCC. Gene expression patterns from adjacent tissues were shown to predict early and overall recurrence in patients with HCC. Insulin resistance should be included in the analysis for the prevention of recurrence. To suppress or eradicate the replication of hepatitis B and C virus must be the most important issue for prevention. Supplementation by branched chain amino acid-enrichment and administration of vitamin K, acyclic retinoid and chemotherapeutic agents have been examined. There is an urgent need to develop a predictive tool and an effective treatment for prevention. It would be extremely valuable to find a useful biomarker for prediction and to develop new molecular targeting agents for the prevention of HCC recurrence in the near future.
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Affiliation(s)
- Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red-Cross Hospital, Musashinoshi, Tokyo, Japan
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Sansonno D, Lauletta G, Russi S, Conteduca V, Sansonno L, Dammacco F. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist 2012; 17:359-66. [PMID: 22334456 DOI: 10.1634/theoncologist.2011-0313] [Citation(s) in RCA: 125] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical or ablative treatments. The aim of this prospective, single-center, placebo-controlled, randomized, double-blind clinical study was to evaluate the effectiveness of transarterial chemoembolization (TACE) combined with sorafenib as a sequential treatment regimen in delaying time to progression (TTP) of intermediate-stage HCC in patients with chronic hepatitis C virus (HCV) infection. MATERIAL AND METHODS Between October, 2007 and January, 2011, 80 HCV-infected patients with Barcelona Clinic Liver Cancer stage B HCC underwent the TACE procedure. All had Child-Pugh class A disease. They were randomized 1:1 to receive sorafenib at a dose of 400 mg twice daily or placebo. Endpoints were the TTP and the rates of adverse events and toxicity. RESULTS Sixty-two of 80 patients (77%), 31 in the sorafenib group and 31 in the control group, completed the study. The median TTP was 9.2 months in the sorafenib group and 4.9 months in the placebo group (hazard ratio, 2.5; 95% confidence interval, 1.66-7.56; p < .001). Metachronous, multicentric HCC progression occurred less frequently in sorafenib-treated patients (p < .05). Adverse reactions to sorafenib caused withdrawal from the study of 9 (22%) patients. CONCLUSION A conventional TACE procedure followed by sorafenib treatment resulted in a significantly longer TTP in patients with intermediate-stage HCV-related HCC, with no unexpected side effects.
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Affiliation(s)
- Domenico Sansonno
- Liver Unit, Department of Internal Medicine and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy.
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Yoshida H, Shiratori Y, Kudo M, Shiina S, Mizuta T, Kojiro M, Yamamoto K, Koike Y, Saito K, Koyanagi N, Kawabe T, Kawazoe S, Kobashi H, Kasugai H, Osaki Y, Araki Y, Izumi N, Oka H, Tsuji K, Toyota J, Seki T, Osawa T, Masaki N, Ichinose M, Seike M, Ishikawa A, Ueno Y, Tagawa K, Kuromatsu R, Sakisaka S, Ikeda H, Kuroda H, Kokuryu H, Yamashita T, Sakaida I, Katamoto T, Kikuchi K, Nomoto M, Omata M. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011; 54:532-540. [PMID: 21574174 DOI: 10.1002/hep.24430] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2010] [Accepted: 05/03/2011] [Indexed: 02/07/2023]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.
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Affiliation(s)
- Haruhiko Yoshida
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, and Department of Gastroenterology and Hepatology, Kanto Central Hospital, Tokyo, Japan.
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Metronomic S-1 chemotherapy and vandetanib: an efficacious and nontoxic treatment for hepatocellular carcinoma. Neoplasia 2011; 13:187-97. [PMID: 21390182 DOI: 10.1593/neo.101186] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 12/06/2010] [Accepted: 12/08/2010] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC). METHODS We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot. RESULTS Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib. CONCLUSION Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.
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Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy of the liver and occurs most often in the setting of chronic liver disease. The most common acquired causes for this are chronic viral hepatitis infections (mostly HBV and HCV), and alcohol. Other causes include nonalcoholic fatty liver disease-related nonalcoholic steatohepatitis, autoimmune liver disease, and biliary diseases. In addition, certain heritable diseases like hemochromatosis and α-1-antitrypsin deficiency can also lead to HCC. Therefore, prevention of HCC can be achieved by preventing and controlling these problems. For treatment, curative modalities are surgical resection and liver transplantation. However, most patients are not candidates for these surgical maneuvers, and outcomes are poor. New therapeutic developments have brought some improvement with both local and systemic disease control.
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Affiliation(s)
- Davendra P S Sohal
- Department of Medicine, Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
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Hayashi M, Shimizu T, Hirokawa F, Inoue Y, Komeda K, Asakuma M, Miyamoto Y, Takeshita A, Shibayama Y, Tanigawa N. Clinicopathological Risk Factors for Recurrence within One Year after Initial Hepatectomy for Hepatocellular Carcinoma. Am Surg 2011. [DOI: 10.1177/000313481107700516] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) shows a high rate of recurrence after hepatectomy; predictive factors for early recurrence would help determine optimal therapeutic and management strategies. Among 163 patients with HCC undergoing hepatectomy with curative intent, 46 patients developed recurrence within 1 year. Clinicopathological data were retrospectively analyzed to identify predictive parameters for early recurrence. Survival rates in cases of recurrence within 1 year were worse than those of no recurrence within 1 year or recurrence after 1 year. Protein induced by vitamin K absence/antagonist II (PIVKA-II) greater than 150, positive fucosylated alpha-fetoprotein (L3-AFP), and deviancy from Milan criteria (MC) on preoperative imaging were associated with high risk of early recurrence and total number of these three risk factors predicted the survival. With multivariate analysis, 1) preoperatively, positive factors of two or more among three items of PIVKA-II, L3-AFP, and deviancy from MC; 2) and postoperatively, pathological cancer spread (microscopic vascular invasion and/or intrahepatic metastasis) both represented risks for early recurrence. A combination of three preoperative factors, PIVKA-II, L3-AFP, and MC status, in conjunction with the postoperative factor of cancer spread status represents a significant indicator for recurrence within 1 year. Improving the prognosis of patients with HCC would depend on how to adequately treat those at high risk of early recurrence.
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Affiliation(s)
- Michihiro Hayashi
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Tetsunosuke Shimizu
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Fumitoshi Hirokawa
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Yoshihiro Inoue
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Koji Komeda
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Mitsuhiro Asakuma
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Yoshiharu Miyamoto
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Atsushi Takeshita
- Departments of Pathology, Osaka Medical College Hospital, Osaka, Japan
| | - Yuro Shibayama
- Departments of Pathology, Osaka Medical College Hospital, Osaka, Japan
| | - Nobuhiko Tanigawa
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
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Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia 2011; 12:928-40. [PMID: 21076618 DOI: 10.1593/neo.10804] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 07/06/2010] [Accepted: 07/07/2010] [Indexed: 11/18/2022] Open
Abstract
Acquired resistance to antiangiogenic drugs, such as sorafenib, is a major clinical problem. We studied development of a resistance to sorafenib in new preclinical models of human hepatocellular carcinoma (HCC) along with a strategy to delay such resistance--combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficient mice, and an orthotopic transplant in nude mice. The complementary DNA for the β-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allow recovery from toxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g., >42 days) at doses of 30 to 60 mg/kg. Transplantation of cell lines established from progressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance.
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Xia Y, Qiu Y, Li J, Shi L, Wang K, Xi T, Shen F, Yan Z, Wu M. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17:3137-44. [PMID: 20602260 DOI: 10.1245/s10434-010-1148-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Postoperative recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical resection. To date, adjuvant chemotherapy or other adjuvant modalities have not been proven effective in preventing or delaying recurrence. The aim of this prospective randomized study was to evaluate the effectiveness of capecitabine as a postoperative adjuvant regimen in inhibiting the recurrence of HCC. MATERIALS AND METHODS Between August 2003 and January 2005, 60 HCC patients who underwent curative resection were randomized into a capecitabine (n = 30) or a control (n = 30) group. The capecitabine group received 4-6 episodes of capecitabine treatment plus routine supportive care. Each episode consisted of 2 weeks of capecitabine followed by 1-week rest. The control group received routine supportive care only. The follow-up was 4-65 months (median: 47.5 months). RESULTS Cancer recurred in 16 patients (53.3%) in the capecitabine group and in 23 patients (76.7%) in the control group. The median time to recurrence (TTR) was 40.0 months (95% confidence interval [95% CI], 31.0-49.2 months) and 20.0 months (95% CI, 12.8-27.2 months) in the capecitabine and control groups, respectively (P = 0.046). The 5-year overall survival rate was 62.5% and 39.8% in the capecitabine group and control group, respectively (P = .216). Adverse reactions to capecitabine were generally mild and included nausea, vomiting, diarrhea, and decreased white blood cell and/or platelet counts. CONCLUSION Postoperative adjuvant therapy with capecitabine is well tolerated, postpones the recurrence of HCC, and reduces the risk of tumor recurrence. In addition, it is likely to improve postoperative survival.
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Affiliation(s)
- Yong Xia
- The First Department of Comprehensive Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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