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Hendi M, Mou Y, Lv J, Zhang B, Cai X. Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Hepatocellular Carcinoma: A New Update. Gastrointest Tumors 2021; 8:145-152. [PMID: 34722467 DOI: 10.1159/000516405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background Hepatic arterial infusion chemotherapy (HAIC) is one option for treating massive tumors and unresectable hepatocellular carcinoma (HCC). However, there is a lack of remedial treatment after these treatments are ineffective or failed. Summary Some studies have discovered that HAIC has greater survival in patients with advanced HCC. A previous study has shown that HAIC is effective in the treatment of advanced HCC, and the data on randomized clinical trials are limited and unclear. Key Message More clinical trials and research are needed in order to make HAIC a standard and recommended therapy for advanced HCC. Our review focuses on the clinical applications of hepatic artery infusion treatment.
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Affiliation(s)
- Maher Hendi
- Department of Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiping Mou
- Department of Surgery, Zhejiang Provincial Peoples Hospital, Hangzhou, China
| | - Jiemin Lv
- Department of Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zhang
- Department of Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiujun Cai
- Department of Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Kondo M, Morimoto M, Kobayashi S, Ohkawa S, Hidaka H, Nakazawa T, Aikata H, Hatanaka T, Takizawa D, Matsunaga K, Okuse C, Suzuki M, Taguri M, Ishibashi T, Numata K, Maeda S, Tanaka K. Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial. BMC Cancer 2019; 19:954. [PMID: 31615466 PMCID: PMC6794885 DOI: 10.1186/s12885-019-6198-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
Background The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. Methods Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. Results For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0–18.8) in the HAIC group and 15.2 months (95% CI, 8.2–19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7–5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3–6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. Conclusions Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. Trial registration UMIN ID 000006147, registration data: August 11, 2011.
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Affiliation(s)
- Masaaki Kondo
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan. .,Department of Gastroenterology, Yokohama City University Hospital; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
| | - Manabu Morimoto
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan.,Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Satoshi Kobayashi
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital; 1-1-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-0815, Japan
| | - Hisashi Hidaka
- Gastroenterology Division of Internal Medicine, Kitasato University Hospital; 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0329, Japan
| | - Takahide Nakazawa
- Gastroenterology Division of Internal Medicine, Kitasato University Hospital; 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0329, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University; 1-2-3, Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Takeshi Hatanaka
- Department of Internal Medicine, Isesaki Municipal Hospital; 12-1, Tsunatorihonmachi, Isesaki, Gunma, 372-0817, Japan
| | - Daichi Takizawa
- Department of Internal Medicine, Isesaki Municipal Hospital; 12-1, Tsunatorihonmachi, Isesaki, Gunma, 372-0817, Japan
| | - Kotaro Matsunaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine; 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital; 1-30-37, Shukugawara, Tama-ku, Kawasaki, Kanagawa, 214-8525, Japan
| | - Michihiro Suzuki
- Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital; 1-30-37, Shukugawara, Tama-ku, Kawasaki, Kanagawa, 214-8525, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Takako Ishibashi
- Yokohama City University Center for Novel and Exploratory Clinical trials; 1-1-1, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital; 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Katsuaki Tanaka
- Gastroenterological Center, Yokohama City University Medical Center 4-57, Urafune-cho, Minami-ku, Yokohama, Kanagawa, 232-0024, Japan.,Gastroenterology Division, Hadano Red Cross Hospital; 1-1-1, Tatenodai, Hadano, Kanagawa, 257-0017, Japan
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Sato T, Tanaka T, Nishiofuku H, Fukuoka Y, Masada T, Tatsumoto S, Marugami N, Morita K, Obayashi C, Hori S, Kaneko M, Kijima A, Kichikawa K. Superabsorbent Polymer Microspheres Prepared with Hypertonic Saline to Reduce Microsphere Expansion. Cardiovasc Intervent Radiol 2018; 41:1412-1418. [DOI: 10.1007/s00270-018-1990-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 05/19/2018] [Indexed: 01/01/2023]
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Orsi F. HCC. LOCOREGIONAL TUMOR THERAPY 2018:43-82. [DOI: 10.1007/978-3-319-69947-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol 2017; 48:103-114. [DOI: 10.1093/jjco/hyx180] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/24/2017] [Indexed: 12/12/2022] Open
Affiliation(s)
- Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
| | - Makoto Ueno
- Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
| | - Hiroshi Ishii
- Clinical Research Center, Shikoku Cancer Center, Matsuyama
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan
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Ma KW, Cheung TT. Surgical resection of localized hepatocellular carcinoma: patient selection and special consideration. J Hepatocell Carcinoma 2016; 4:1-9. [PMID: 28097107 PMCID: PMC5207474 DOI: 10.2147/jhc.s96085] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Localized hepatocellular carcinoma (HCC) refers to a solitary or few tumors located within either the left or right hemiliver without evidence of bilobar or extrahepatic spread. This term encompasses a heterogeneous morphology with no regard to stage of prognosis of the disease. Surgical resection remains the mainstay of curative treatment for the localized HCC. Various biochemical and radiological tests constitute an indispensible part of preoperative assessment. Emergence of laparoscopic hepatectomy has brought liver resection into a new era. Improved understanding of the pathophysiology of HCC allows more aggressive surgical resection without compromising outcomes. New insights into the management of special situations, such as ruptured HCC, pyogenic transformation of HCC, and HCC with portal vein tumor thrombus, rekindle the hopes of curative resection in these terminal events. Amalgamating salvage liver transplantation into the surgical management of resectable HCC has revolutionized the treatment paradigm of this deadly disease.
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Affiliation(s)
- Ka Wing Ma
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong
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Hatanaka T, Kakizaki S, Shimada Y, Takizawa D, Katakai K, Yamazaki Y, Sato K, Kusano M, Yamada M. Early Decreases in α-Fetoprotein and Des-γ-carboxy Prothrombin Predict the Antitumor Effects of Hepatic Transarterial Infusion Chemotherapy with Cisplatin (CDDP) Powder in Patients with Advanced Hepatocellular Carcinoma. Intern Med 2016; 55:2163-2171. [PMID: 27522991 DOI: 10.2169/internalmedicine.55.6688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective We retrospectively investigated the relationship between the tumor response and serial changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) during hepatic arterial infusion of a cisplatin powder formulation (CDDP powder) in patients with advanced hepatocellular carcinoma (HCC). Methods Seventy-six advanced HCC patients were analyzed. All HCC patients received high-concentration cisplatin (1.43 mg/mL) via the haptic artery at a dose of 65 mg/m(2). AFP and DCP were measured at baseline and four to eight weeks after treatment, and the antitumor responses were evaluated according to the response evaluation criteria in solid tumours (RECIST) criteria after one or two courses of treatment. The patients were classified into two groups, a decreased group and a non-decreased group, according to the change in the serum levels of AFP and DCP at four to eight weeks compared to baseline. Results The response to treatment of the decreased group (n=16) and non-decreased group (n=60) was complete response/partial response/stable disease/progressive disease (CR/PR/SD/PD) in 4/4/5/3 and 1/11/8/40 patients, respectively. The response rate and disease control rate of the decreased group were significantly higher than those of the non-decreased group (p=0.016 and p<0.001, respectively). The median survival time (MST) of the decreased/non-decreased groups were 25.9/10.6 months, respectively. The cumulative survival rates for the decreased group were significantly higher than those of the non-decreased group (p=0.042). In the multivariate analysis, vascular invasion and the decreased group were significant factors that affected the therapeutic efficacy. Conclusion A decrease in the levels of AFP and DCP after the first treatment with CDDP powder is a good predictor for the antitumor effect and the prognosis.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Internal Medicine, Isesaki Municipal Hospital, Japan
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Yamamoto Y, Ikoma H, Morimura R, Shoda K, Konishi H, Murayama Y, Komatsu S, Shiozaki A, Kuriu Y, Kubota T, Nakanishi M, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C, Ochiai T, Otsuji E. Post-hepatectomy survival in advanced hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol 2015; 21:246-253. [PMID: 25574098 PMCID: PMC4284342 DOI: 10.3748/wjg.v21.i1.246] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 06/07/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) using the tumor-node-metastasis (TNM) staging system.
METHODS: We retrospectively analyzed 372 patients with HCC who underwent hepatectomy between 1980 and 2009. We studied the outcomes of HCC patients with PVTT to evaluate the American Joint Committee on Cancer TNM staging system (7th edition) for stratifying and predicting the prognosis of a large cohort of HCC patients after hepatectomy in a single-center. Portal vein invasion (vp) 1 was defined as an invasion or tumor thrombus distal to the second branch of the portal vein, vp2 as an invasion or tumor thrombus in the second branch of the portal vein, vp3 as an invasion or tumor thrombus in the first branch of the portal vein, and vp4 as an invasion or tumor thrombus in the portal trunk or extending to a branch on the contralateral side.
RESULTS: The cumulative 5-year overall survival (5yrOS) and 5-year disease-free survival (5yrDFS) rates of the 372 patients were 58.3% and 31.3%, respectively. The 5yrDFS and 5yrOS of vp3-4 patients (n = 10) were 20.0%, and 30.0%, respectively, which was comparable with the corresponding survival rates of vp1-2 patients (P = 0.466 and 0.586, respectively). In the subgroup analysis of patients with macroscopic PVTT (vp2-4), the OS of the patients who underwent preoperative transarterial chemoembolization was comparable to that of patients who did not (P = 0.747). There was a significant difference in the DFS between patients with stage I HCC and those with stage II HCC (5yrDFS 39.2% vs 23.1%, P < 0.001); however, the DFS for stage II was similar to that for stage III (5yrDFS 23.1% vs 13.8%, P = 0.330). In the subgroup analysis of stage II-III HCC (n = 148), only alpha-fetoprotein (AFP) > 100 mg/dL was independently associated with DFS.
CONCLUSION: Hepatectomy for vp3-4 HCC results in a survival rate similar to hepatectomy for vp1-2. AFP stratified the stage II-III HCC patients according to prognosis.
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Takaki H, Yamakado K, Tsurusaki M, Yasumoto T, Baba Y, Narimatsu Y, Shimohira M, Yamaguchi M, Matsuo K, Inaba Y, Mikami K, Watanabe R, Nishida N, Anai H, Kakizawa H, Hirota S. Hepatic arterial infusion chemotherapy with fine-powder cisplatin and iodized-oil suspension in patients with intermediate-stage and advanced-stage (Barcelona Clinic Liver Cancer stage-B or stage-C) hepatocellular carcinoma: multicenter phase-II clinical study. Int J Clin Oncol 2014; 20:745-54. [PMID: 25432660 DOI: 10.1007/s10147-014-0773-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 11/16/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE This single-arm, multicenter, phase-II trial evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) using fine-powder cisplatin and iodized-oil suspension in patients with intermediate- and advanced-stage [Barcelona Clinic Liver Cancer (BCLC) stage-B and stage-C] hepatocellular carcinomas (HCCs). METHODS The Institutional Review Board approved this study and patients provided written informed consent. Thirty-five patients (24 men and 11 women, mean 74 ± 6 years [range 60-87 years]) with BCLC stage-B (57 %, 20/35) or stage-C (43 %, 15/35) HCCs who were not candidates for other locoregional treatments were enrolled. HAIC was performed using a suspension of fine-powder cisplatin with a maximum dose of 65 mg/m(2) and iodized oil on demand. The primary endpoint was the response rate evaluated based on Response Evaluation Criteria in Solid Tumor (RECIST) and modified RECIST (mRECIST). Secondary endpoints were overall survival, progression-free survival, and safety. RESULTS The initial and best overall response rates at 4 weeks and 3 months, respectively, were 14 and 17 % based on RECIST, and 57 and 23 % based on mRECIST. The median overall and progression-free survival times were 18 and 4 months, respectively. The most frequent grade-3 or grade-4 adverse events were elevation of serum alanine (23 %) and aspartate aminotransferase (20 %), and thrombocytopenia (17 %). CONCLUSION This HAIC provides promising therapeutic effects with acceptable safety to patients with intermediate-stage and advanced-stage HCCs.
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Affiliation(s)
- Haruyuki Takaki
- Department of Radiology, Mie University School of Medicine, Mie, Japan,
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Onishi H, Nouso K, Nakamura S, Katsui K, Wada N, Morimoto Y, Miyahara K, Takeuchi Y, Kuwaki K, Yasunaka T, Miyake Y, Shiraha H, Takaki A, Kobayashi Y, Sakaguchi K, Kanazawa S, Yamamoto K. Efficacy of hepatic arterial infusion chemotherapy in combination with irradiation for advanced hepatocellular carcinoma with portal vein invasion. Hepatol Int 2014; 9:105-12. [PMID: 25788384 DOI: 10.1007/s12072-014-9592-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 10/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients. METHODS We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT). RESULTS Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p < 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18%, p < 0.01) and PVTT (45 vs. 18%, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively). CONCLUSIONS CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT.
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Affiliation(s)
- Hideki Onishi
- Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City, Okayama, 700-8558, Japan,
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Miyahara K, Nouso K, Yamamoto K. Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age. World J Gastroenterol 2014; 20:4151-9. [PMID: 24764653 PMCID: PMC3989951 DOI: 10.3748/wjg.v20.i15.4151] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 01/02/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma (HCC). After development of sorafenib and its introduction as a therapeutic agent used in the clinic, several critical questions have been raised. Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated. Although it is difficult to know the responders in advance using conventional characteristics of patients, there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib. Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists. In addition, effectiveness of the expanded application of sorafenib is still controversial, although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC. Recently, over 50 relevant drugs have been developed and are currently under investigation. The efficacy of some of these drugs has been extensively examined, but none have demonstrated any superiority over sorafenib, so far. However, there are several drugs that have shown efficacy for treatment after sorafenib failure, and these are proceeding to further studies. To address these issues and questions, we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib.
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Kimura O, Kondo Y, Kogure T, Kakazu E, Ninomiya M, Iwata T, Morosawa T, Shimosegawa T. Expression of EpCAM increases in the hepatitis B related and the treatment-resistant hepatocellular carcinoma. BIOMED RESEARCH INTERNATIONAL 2014; 2014:172913. [PMID: 24696843 PMCID: PMC3947853 DOI: 10.1155/2014/172913] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 01/06/2014] [Accepted: 01/06/2014] [Indexed: 12/26/2022]
Abstract
Increasing evidence supports the important role of cancer stem cells (CSCs). Many reports suggest that epithelial cell adhesion molecule (EpCAM) is a useful marker for cancer stem cells in hepatocellular carcinoma (HCC). To elucidate the mechanisms of cancer stem cells, the development of specific molecular targeted drugs has become very important. In the present study, we examined the EpCAM expression pattern and its characteristic expression in resected HCC. We studied the drug resistance of EpCAM expression cells. EpCAM expression was detected significantly more frequently with hepatitis B virus (HBV) than with other etiologies. In HCC resection patients who had received prior treatment (transcatheter arterial embolization or hepatic arterial infusion chemotherapy), EpCAM was strongly expressed. In particular, very strong expression was observed after hepatic arterial infusion chemotherapy. The PLC/PRF/5 human HCC cell line expressed bimodal EpCAM, and EpCAM-positive cells had CSC cell potency. The EpCAM expression in EpCAM-positive cells increased significantly by treatment with cisplatin. EpCAM-positive cells showed better viability than EpCAM-negative cells when treated with ciplatin. Collectively, our results suggest that cancer stem cells are highly expressed in hepatitis B and have potential anticancer drug resistance.
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Affiliation(s)
- Osamu Kimura
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tatsuki Morosawa
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
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Katagiri S, Yamamoto M. Multidisciplinary treatments for hepatocellular carcinoma with major portal vein tumor thrombus. Surg Today 2014; 44:219-26. [PMID: 23591833 PMCID: PMC3898334 DOI: 10.1007/s00595-013-0585-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 01/23/2013] [Indexed: 02/07/2023]
Abstract
In recent years, various treatment options have become available for patients with hepatocellular carcinoma (HCC) according to the degree of background liver damage, tumor diameter and other factors associated with disease progression. Therapy has also shifted toward evidence-based treatment. Policies for the management of HCC with portal vein tumor thrombus, which has been considered an intractable condition, have not been established. Surgical resection was previously positioned as the treatment of choice, but the outcomes after resection alone were found to be disappointing. At present, multiple interdisciplinary treatments, combining resection with intra-arterial chemotherapy, radiotherapy, systemic chemotherapy and/or immunotherapy, are used on a trial-and-error basis since no standard regimens have been developed. Clinical trials of surgery combined with transarterial chemoembolization, hepatic arterial infusion of chemotherapy and radiation have obtained improved 5-year survival rates of 21.5-56 %. The safety of surgical resection in HCC with major portal vein tumor thrombus has improved, but the optimal type(s) and timing of auxiliary therapy to use in combination with resection remain to be defined.
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Affiliation(s)
- Satoshi Katagiri
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan,
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Miyaki D, Aikata H, Kan H, Fujino H, Urabe A, Masaki K, Fukuhara T, Kobayashi T, Naeshiro N, Nakahara T, Kawaoka T, Hiramatsu A, Takahashi S, Ishikawa M, Kakizawa H, Awai K, Chayama K. Clinical outcome of sorafenib treatment in patients with advanced hepatocellular carcinoma refractory to hepatic arterial infusion chemotherapy. J Gastroenterol Hepatol 2013; 28:1834-41. [PMID: 23808713 DOI: 10.1111/jgh.12311] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/17/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM It has been reported about poor prognosis in patients with advanced hepatocellular carcinoma (HCC) refractory to hepatic arterial infusion chemotherapy (HAIC). We assessed the survival benefits of sorafenib therapy for advanced HCC in HAIC refractory patients. METHODS The study subjects were 191 patients with advanced HCC who had been treated with HAIC. Sorafenib was used in 27 patients who finally failed to respond to HAIC (HAIC/sorafenib group). Clinical outcome was compared between HAIC/sorafenib and HAIC alone groups. RESULTS There were no significant differences in clinical characteristics and response rate of HAIC between the two groups (response rate: 25.9%, HAIC/sorafenib group; 30.4%, HAIC alone group). The median survival time (MST) for all patients was 11.0 months. The survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group (MST 22.2 vs 8.7 months, P = 0.017). From administration sorafenib, the disease control rate was 51.8% with MST of 10.4 months. Among HAIC non-responders, the survival rate was significantly higher in the HAIC/sorafenib group than HAIC alone group. Multivariate analysis identified additional therapy with sorafenib as significant and independent determinant of overall survival in all patients and HAIC non-responders. CONCLUSION Additional therapy with sorafenib could probably improve the prognosis of HAIC refractory patients.
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Affiliation(s)
- Daisuke Miyaki
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
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Ikeda M, Okusaka T, Furuse J, Mitsunaga S, Ueno H, Yamaura H, Inaba Y, Takeuchi Y, Satake M, Arai Y. A multi-institutional phase II trial of hepatic arterial infusion chemotherapy with cisplatin for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol 2013; 72:463-70. [PMID: 23812005 DOI: 10.1007/s00280-013-2222-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 06/16/2013] [Indexed: 12/13/2022]
Abstract
PURPOSE The objective of this study was to evaluate the response rate, survival, and adverse effects of hepatic arterial infusion chemotherapy (HAIC) using cisplatin in patients with advanced hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHODS Twenty-five patients of advanced HCC with PVTT in the main or first branch, having no prior history of chemotherapy, measurable lesions, adequate liver and renal function, and adequate bone marrow reserve, were enrolled. Cisplatin was administered at the dose of 65 mg/m(2) via the proper hepatic artery. Treatment was repeated every 4-6 weeks for a maximum of six courses until the appearance of evidence of tumor progression or unacceptable toxicity. RESULTS The median number of treatments was 3 (range 1-6). Among the 25 enrolled patients, complete response was achieved in 1 (4 %) patient and partial response in 6 (24 %), corresponding to a response rate of 28 % (95 % CI 12-49 %). The median progression-free and overall survival times and the 1-, 2-, and 3-year survival rates in the enrolled patients were 3.6 and 7.6 months and 40.3, 36.0, 20 %, respectively. Four of the seven patients who showed complete or partial response survived for more than 3 years. The main grade 3/4 non-hematological adverse events of this treatment were elevation of the serum aspartate aminotransferase (44 %) and alanine aminotransferase (24 %). CONCLUSION HAIC with cisplatin exerts moderate activity with mild toxicity in advanced HCC patients with PVTT. Especially, markedly prolonged survival can be expected in patients who respond to this treatment.
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Affiliation(s)
- Masafumi Ikeda
- Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
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Current chemotherapies for advanced hepatocellular carcinoma. Clin J Gastroenterol 2013; 6:89-93. [DOI: 10.1007/s12328-013-0363-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 01/18/2013] [Indexed: 10/27/2022]
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Nishiofuku H, Tanaka T, Matsuoka M, Otsuji T, Anai H, Sueyoshi S, Inaba Y, Koyama F, Sho M, Nakajima Y, Kichikawa K. Transcatheter arterial chemoembolization using cisplatin powder mixed with degradable starch microspheres for colorectal liver metastases after FOLFOX failure: results of a phase I/II study. J Vasc Interv Radiol 2012. [PMID: 23194749 DOI: 10.1016/j.jvir.2012.09.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
PURPOSE To report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol. MATERIALS AND METHODS A fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m(2), 65 mg/m(2), and 80 mg/m(2). In phase II, tumor response, toxicity, and survival times were assessed. RESULTS The study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m(2). In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval [CI], 4.06-13.5 mo) and 21.1 months (95% CI, 8.37-33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%). CONCLUSIONS This study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m(2) mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.
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Affiliation(s)
- Hideyuki Nishiofuku
- Department of Radiology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan.
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Ueda H, Fukuchi H, Tanaka C. Toxicity and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma (Review). Oncol Lett 2011; 3:259-263. [PMID: 22740891 DOI: 10.3892/ol.2011.469] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 09/29/2011] [Indexed: 12/22/2022] Open
Abstract
The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly for patients with portal vein tumor thrombosis. Chemotherapy is one of the most significant treatment options for patients with advanced HCC not indicated for hepatic resection, percutaneous ablation and transcatheter arterial chemoembolization. Systemic chemotherapy does not play a central role in the treatment of HCC due to the issue of low sensitivity for chemotherapeutic agents and the difficulties in administering a sufficient dose due to chronic liver dysfunction. Therefore, patients with advanced HCC are usually treated with hepatic arterial infusion chemotherapy (HAIC), which is increasingly used as an approach to advanced HCC in Japan. HAIC provides moderate therapeutic efficacy and survival benefit with substantially tolerable toxicity profiles in patients with advanced HCC.
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Affiliation(s)
- Hiroki Ueda
- Department of Chemotherapy, Wakayama Medical University Oncology Center, Wakayama City, Wakayama 641-8509, Japan
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