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Uchikawa S, Kawaoka T, Murakami S, Miura R, Shirane Y, Johira Y, Kosaka M, Fujii Y, Fujino H, Ono A, Murakami E, Miki D, Hayes CN, Tsuge M, Oka S. Significance of changes in tumor markers in patients treated with durvalumab plus tremelimumab combination therapy as a surrogate marker for tumor response to unresectable hepatocellular carcinoma. Hepatol Res 2024. [PMID: 39152708 DOI: 10.1111/hepr.14104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/19/2024]
Abstract
AIM When evaluating response to immune checkpoint inhibitor therapy, the tumor sometimes initially swells before shrinking and ultimately responding, also called pseudo-progression. In this study, we analyzed whether tumor markers were useful for reflecting the treatment response. METHODS Thirty-three patients who were treated with durvalumab plus tremelimumab combination therapy (Dur + Tre) were enrolled. Their functional reserve was Child-Pugh grade A. Their tumor markers α-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), or AFP-Lectin 3 fraction (AFP-L3) were positive. Tumor markers were evaluated before treatment and at 1, 4, and 8 weeks after the start of treatment. The first radiological evaluation was carried out at 4 weeks and the second evaluation at 8-12 weeks. The responders included those with complete response and partial response and the nonresponders included those with stable disease (SD) and progression disease at best response evaluated by Response Evaluation Criteria in Solid Tumors. RESULTS In the responder group, the change ratio of AFP, DCP, and AFP-L3 specifically decreased at 8 weeks. In the nonresponder group, the change ratio of DCP specifically increased at 4 weeks. The optimal cut-off value to divide responders and nonresponders at 4 weeks was approximately -40%. The ratio of responders was 72.7% in the patients whose AFP or DCP decreased over 40% at 4 weeks. CONCLUSIONS The change in tumor markers is a more useful predicter of tumor response to Dur + Tre than imaging evaluation alone.
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Affiliation(s)
- Shinsuke Uchikawa
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Serami Murakami
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryoichi Miura
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Shirane
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yusuke Johira
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masanari Kosaka
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Clinical Oncology, Hiroshima University Hospital, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Uchikawa S, Kawaoka T, Fujino H, Ono A, Nakahara T, Murakami E, Yamauchi M, Miki D, Imamura M, Aikata H. Evaluation of atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma using contrast-enhanced ultrasonography. J Med Ultrason (2001) 2023; 50:57-62. [PMID: 36169740 PMCID: PMC10912139 DOI: 10.1007/s10396-022-01260-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/19/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev. METHODS A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included. RESULTS Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3. CONCLUSION The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3.
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Affiliation(s)
- Shinsuke Uchikawa
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Hatsue Fujino
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Medicine and Molecular Science, Division of Frontier Medical Science Programs for Biomedical Research Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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Application and Impact of Antiviral Therapy for Patients with HBV-Related Hepatocellular Carcinoma Receiving Sorafenib and Lenvatinib Treatment. Viruses 2022; 14:v14112355. [PMID: 36366452 PMCID: PMC9692815 DOI: 10.3390/v14112355] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/24/2022] [Indexed: 02/01/2023] Open
Abstract
Overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) has improved in the era of multi-line sequential therapy. The application of antiviral therapy and its impact on survival for patients with HBV-related HCC needs to be reassessed. The aim of this study was to evaluate the application and impact of antiviral therapy on survival for patients with HBV-related HCC receiving tyrosine kinase inhibitor (TKI) therapy. Patients with advanced HBV-related HCC treated with sorafenib or lenvatinib as first-line therapy with (n = 377) and without (n = 182) nucleos(t)ide analogue (NUC) therapy were retrospectively enrolled. Prognostic factors of OS were evaluated. Secular trends in the increased application of NUC therapy and improved survival were observed in the last decade. The HBV reactivation rate in patients without NUC therapy was 6.6%. By multivariate analysis, baseline low HBV viral load, achieving undetectable HBV DNA after TKI therapy, and ability to receive second-line therapy were found to be independent predictors of OS. In subgroup patients with NUC therapy, starting NUC before TKI was associated with a better OS. In conclusion, the application of antiviral therapy for patients with HBV-related HCC receiving TKI therapy has increased over time. Achieving complete virological suppression may contribute to a better OS in patients with advanced HBV-related HCC.
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Shimose S, Hiraoka A, Tanaka M, Iwamoto H, Tanaka T, Noguchi K, Aino H, Yamaguchi T, Itano S, Suga H, Niizeki T, Moriyama E, Shirono T, Noda Y, Kamachi N, Okamura S, Nakano M, Kawaguchi T, Kuromatsu R, Koga H, Torimura T. Deterioration of liver function and aging disturb sequential systemic therapy for unresectable hepatocellular carcinoma. Sci Rep 2022; 12:17018. [PMID: 36220865 PMCID: PMC9554046 DOI: 10.1038/s41598-022-21528-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/28/2022] [Indexed: 12/29/2022] Open
Abstract
This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy.
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Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, 790-0024, Japan
| | - Masatoshi Tanaka
- Clinical Research Center, Yokokura Hospital, Miyama, Fukuoka, 839-0295, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
- Iwamoto Internal Medical Clinic, Kitakyusyu, 802-0832, Japan
| | - Takaaki Tanaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, 790-0024, Japan
| | - Kazunori Noguchi
- Department of Gastroenterology, Omuta City Hospital, Omuta, 836-0861, Japan
| | - Hajime Aino
- Division of Gastroenterology, Department of Medicine, Social Insurance Tagawa Hospital, Tagawa, 826-0023, Japan
| | - Taizo Yamaguchi
- Iwamoto Internal Medical Clinic, Kitakyusyu, 802-0832, Japan
| | - Satoshi Itano
- Department of Gastroenterology, Kurume Central Hospital, Kurume, 830-0001, Japan
| | - Hideya Suga
- Department of Gastroenterology and Hepatology, Yanagawa Hospital, Yanagawa, 832-0077, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Etsuko Moriyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Shusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
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Yuan M, Chen TY, Chen XR, Lu YF, Shi J, Zhang WS, Ye C, Tang BZ, Yang ZG. Identification of predictive factors for post-transarterial chemoembolization liver failure in hepatocellular carcinoma patients: A retrospective study. World J Clin Cases 2022; 10:8535-8546. [PMID: 36157824 PMCID: PMC9453355 DOI: 10.12998/wjcc.v10.i24.8535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/09/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Post-transarterial chemoembolization (TACE) liver failure occurs frequently in hepatocellular carcinoma (HCC) patients. The identification of predictors for post-TACE liver failure is of great importance for clinical decision-making in this population.
AIM To investigate the occurrence rate and predictive factors of post-TACE liver failure in this retrospective study to provide clues for decision-making regarding TACE procedures in HCC patients.
METHODS The clinical records of HCC patients treated with TACE therapy were reviewed. Baseline clinical characteristics and laboratory parameters of these patients were extracted. Logistic models were used to identify candidates to predict post-TACE liver failure.
RESULTS A total of 199 HCC patients were enrolled in this study, and 70 patients (35.2%) developed post-TACE liver failure. Univariate and multivariate logistic models indicated that microspheres plus gelatin embolization and main tumor size > 5 cm were risk predictors for post-TACE liver failure [odds ratio (OR): 4.4, 95% confidence interval (CI): 1.2-16.3, P = 0.027; OR: 2.3, 95%CI: 1.05-5.3, P = 0.039, respectively]. Conversely, HCC patients who underwent tumor resection surgery before the TACE procedure had a lower risk for post-TACE liver failure (OR: 0.4, 95%CI: 0.2-0.95, P = 0.039).
CONCLUSION Microspheres plus gelatin embolization and main tumor size might be risk factors for post-TACE liver failure in HCC patients, while prior tumor resection could be a favorable factor reducing the risk of post-TACE liver failure.
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Affiliation(s)
- Min Yuan
- Department of Interventional Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Tian-You Chen
- Department of Interventional Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Xiao-Rong Chen
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yun-Fei Lu
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Jia Shi
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Wen-Si Zhang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Chen Ye
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Bo-Zong Tang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Department of Internal Medicine of Traditional Chinese Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 201200, China
| | - Zong-Guo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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Sho T, Morikawa K, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Kimura M, Nakai M, Suda G, Natsuizaka M, Ogawa K, Sakamoto N. Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy. World J Gastrointest Oncol 2021; 13:2076-2087. [PMID: 35070043 PMCID: PMC8713309 DOI: 10.4251/wjgo.v13.i12.2076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/08/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
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Affiliation(s)
- Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mugumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo 060-8638, Hokkaido, Japan
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Ochi H, Tani J, Tomonari T, Taniguchi T, Koizumi Y, Hirose A, Ogawa C, Hiraoka A, Morishita A, Moriya A, Hirooka M, Deguchi A, Symple Study Group. Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis. Hepatol Res 2021; 51:1219-1228. [PMID: 34534398 DOI: 10.1111/hepr.13713] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/06/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022]
Abstract
AIM Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation. METHODS This retrospective, multicenter study involved 51 patients treated with regorafenib after sorafenib-refractory treatment for u-HCC at seven institutions before March 2021. RESULTS Fourteen, 13, and 24 patients were classified based on modified albumin-bilirubin (mALBI) grade 1, 2a, and 2b, respectively. The median survival time and progression-free survival were 16.7 and 3.3 months, respectively. Only mALBI grade 2b or 3 was significantly associated with survival rate (hazard ratio, 2.13; 95% confidence interval, 1.01-4.49; p = 0.047). A comparison of median ALBI scores at the initiation of regorafenib (-2.35) with those at 4 weeks (-1.93) revealed a significant relative change (p = 0.0001). After 4 weeks, grade 1 or 2a persisted in 15 patients (Group 1); grade 1 or 2a deteriorated to 2b in 12 patients (Group 2); grade 2b or 3 before regorafenib administration was present in 22 patients (Group 3); and MST was 33.3, 12.8, and 11.3 months in the three groups, respectively (p = 0.05). Patients treated with lenvatinib (LEN) (n = 27, MST = 23.4 months) after regorafenib had a significantly longer survival time from regorafenib initiation than those not treated with LEN (n = 24, 11.8 months; p = 0.043). CONCLUSIONS Hepatic functional reserve significantly declined after regorafenib administration. During regorafenib treatment, favorable hepatic functional reserve before administration and maintenance of favorable hepatic reserve after administration lead to prolonged prognosis.
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Affiliation(s)
- Hironori Ochi
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University Graduate School of Medicine, Miki-cho, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medicine, Institute of Biomedical Sciences, Tokushima, Japan
| | - Tatsuya Taniguchi
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medicine, Institute of Biomedical Sciences, Tokushima, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akira Hirose
- Department of Gastroenterology and Hepatology, Kochi University Graduate School of Medicine, Kōchi, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Akihiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University Graduate School of Medicine, Miki-cho, Japan
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kannonji, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Marugame, Japan
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8
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Ricke J, Schinner R, Seidensticker M, Gasbarrini A, van Delden OM, Amthauer H, Peynircioglu B, Bargellini I, Iezzi R, De Toni EN, Malfertheiner P, Pech M, Sangro B. Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma. J Hepatol 2021; 75:1387-1396. [PMID: 34454995 DOI: 10.1016/j.jhep.2021.07.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/09/2021] [Accepted: 07/29/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. METHODS The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. ≥65 years-old, Child-Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol- vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. RESULTS ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years-old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age ≥65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). CONCLUSION SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. CLINICAL TRIAL NUMBER EudraCT 2009-012576-27, NCT01126645 LAY SUMMARY: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.
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Affiliation(s)
- Jens Ricke
- Department of Radiology, Ludwig Maximilan University Munich, München, Germany.
| | - Regina Schinner
- Department of Radiology, Ludwig Maximilan University Munich, München, Germany
| | - Max Seidensticker
- Department of Radiology, Ludwig Maximilan University Munich, München, Germany
| | - Antonio Gasbarrini
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Medicina interna e gastroenterologia, Roma, Italy
| | - Otto M van Delden
- Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | | | - Irene Bargellini
- Department of Vascular and Interventional Radiology, University Hospital of Pisa, Pisa, Italy
| | - Roberto Iezzi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC di Radiologia, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Roma, Italy
| | - Enrico N De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Peter Malfertheiner
- Department of Radiology and Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Maciej Pech
- Departments of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
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Ando Y, Kawaoka T, Kosaka M, Shirane Y, Johira Y, Miura R, Murakami S, Yano S, Amioka K, Naruto K, Kosaka Y, Uchikawa S, Kodama K, Fujino H, Nakahara T, Ono A, Murakami E, Yamauchi M, Okamoto W, Takahashi S, Imamura M, Chayama K, Aikata H. Early Tumor Response and Safety of Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma in Real-World Practice. Cancers (Basel) 2021; 13:3958. [PMID: 34439111 PMCID: PMC8394131 DOI: 10.3390/cancers13163958] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37-649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.
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Affiliation(s)
- Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Masanari Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Yuki Shirane
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Yusuke Johira
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Ryoichi Miura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Serami Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Shigeki Yano
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Kei Amioka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Kensuke Naruto
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
- Department of Clinical Oncology, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Wataru Okamoto
- Department of Clinical Oncology, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima 734-8551, Japan;
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima 734-8551, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (Y.A.); (T.K.); (M.K.); (Y.S.); (Y.J.); (R.M.); (S.M.); (S.Y.); (K.A.); (K.N.); (Y.K.); (S.U.); (K.K.); (H.F.); (T.N.); (A.O.); (E.M.); (M.Y.); (S.T.); (M.I.)
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