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Chen SC, Ho HL, Liu CA, Hung YP, Chiang NJ, Chen MH, Chao Y, Yang MH. PIVKA-II as a surrogate biomarker for therapeutic response in Non-AFP-secreting hepatocellular carcinoma. BMC Cancer 2025; 25:199. [PMID: 39905360 PMCID: PMC11792300 DOI: 10.1186/s12885-025-13568-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Alpha-fetoprotein (AFP) is a key biomarker for hepatocellular carcinoma (HCC), but 30-40% of cases are AFP-negative. Prothrombin induced by vitamin K absence II (PIVKA-II) is more sensitive for HCC detection, though its role in systemic therapy remains underexplored. This study aimed to evaluate PIVKA-II in non-AFP-secreting HCC treated with systemic therapy. METHODS Patients with unresectable HCC undergoing systemic therapy were enrolled. Baseline imaging and PIVKA-II levels were recorded. After 8-12 weeks of treatment, response was evaluated through imaging and repeat PIVKA-II measurements. RESULTS A total of 116 treatment assessments from 61 cases were analyzed. Baseline PIVKA-II levels correlated with tumor size, but not tumor number or liver function. PIVKA-II regression (≥ 50% reduction) and progression (≥ 50% increase) were defined using ROC analysis. Imaging showed 71.0% objective response in the regression group, 50.0% stable disease in the stable group, and 83.7% progressive disease in the progression group (p < 0.001). This association held for targeted therapies, immune checkpoint inhibitors, and chemotherapy. Progression-free survival (PFS) for the regression, stable, and progression groups was non-reached, 6.7, and 3.2 months (p = 0.0002), and overall survival (OS) was non-reached, non-reached, and 18.5 months (p = 0.02). CONCLUSIONS This study is the first to establish the "50-50 rule" for PIVKA-II response in non-AFP-secreting HCC treated with systemic therapy, highlighting its value as a surrogate marker for radiological outcomes and prognosis.
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Affiliation(s)
- San-Chi Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-An Liu
- Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ping Hung
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Nai-Jung Chiang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Huang Chen
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- Department of Internal Medicine, Central Clinical & Hospital, Taipei, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 201 Shipai Road, Sec. 2, Taipei, Taiwan.
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
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Saeki I, Shimose S, Tomonari T, Ito T, Tani J, Takeuchi Y, Yoshioka N, Naito T, Takeuchi M, Kakizaki S, Hatanaka T, Sasaki K, Yasunaka T, Sakata M, Iwamoto H, Itano S, Shirono T, Tanabe N, Yamamoto T, Kanayama Y, Naganuma A, Nishina S, Otsuka M, Kobara H, Kawashima H, Takayama T, Kawaguchi T, Yamasaki T, Takami T, Hepatology InVestigator Experts in Japan (HIVE-J) Study Group. Alpha-fetoprotein and des-gamma-carboxy prothrombin can predict the objective response of patients with hepatocellular carcinoma receiving durvalumab plus tremelimumab therapy. PLoS One 2024; 19:e0311084. [PMID: 39321197 PMCID: PMC11423983 DOI: 10.1371/journal.pone.0311084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/12/2024] [Indexed: 09/27/2024] Open
Abstract
Durvalumab plus tremelimumab (Durva/Treme) combined immunotherapy is the first-line therapy recommended for unresectable hepatocellular carcinoma (HCC). Since sequential therapy is more effective in improving prognosis, tumor markers have been used as predictive biomarkers for response to systemic therapy. This study aimed to investigate the predictive ability of objective response (OR) by tumor markers for Durva/Treme therapy against HCC. In this multicenter study, 110 patients with HCC who received Durva/Treme therapy were retrospectively enrolled. The OR rate was 15.5%. To aid early decision-making regarding OR, we evaluated the predictors contributing to OR in two steps: before (first step) and 4 weeks after (second step) treatment induction. Changes in tumor markers (alpha-fetoprotein [AFP] and des-gamma-carboxy prothrombin [DCP]) from baseline to 4 weeks after treatment (ΔAFP/ΔDCP) were included as the input factors. In the first step, multivariable analysis identified only the baseline AFP level (odds ratio 3.497, p = 0.029) as a predictor of OR. Patients with AFP ≥ 400 ng/mL had a significantly higher OR rate than those with < 400 ng/mL (28.2 vs. 8.5%, p = 0.011), and there was no significant difference in progression-free survival (PFS) between the two groups. When AFP/DCP response was defined as a ≥10% reduction from baseline, multivariable analysis showed that AFP response (odds ratio 6.023, p = 0.042) and DCP response (odds ratio 11.657, p = 0.006) were both independent predictors of OR in the second step. The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy.
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Affiliation(s)
- Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Kagawa, Japan
| | - Yasuto Takeuchi
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Naoki Yoshioka
- Department of Gastroenterology and Hepatology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi, Japan
| | - Takehito Naito
- Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan
| | - Mamiko Takeuchi
- Department of Gastroenterology, Anjo Kosei Hospital, Anjo, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, NHO Takasaki General Medical Center, Takasaki, Gunma, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Kyo Sasaki
- Department of Gastroenterology and Hepatology, Kawasaki Medical School, Kurashiki, Japan
| | - Tetsuya Yasunaka
- Department of Gastroenterology, Fukuyama City Hospital, Okayama, Japan
| | - Masahiro Sakata
- Department of Gastroenterology, NHO Fukuyama Medical Center, Fukuyama, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Iwamoto Internal Medical Clinic, Kitakyusyu, Japan
| | - Satoshi Itano
- Department of Gastroenterology and Hepatology, Kurume Central Hospital, Kurume, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Norikazu Tanabe
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
- Division of Laboratory, Yamaguchi University Hospital, Yamaguchi, Japan
| | - Takafumi Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yuki Kanayama
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, NHO Takasaki General Medical Center, Takasaki, Gunma, Japan
| | - Sohji Nishina
- Department of Gastroenterology and Hepatology, Kawasaki Medical School, Kurashiki, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Kagawa, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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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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Kuzuya T, Kawabe N, Muto H, Wada Y, Komura G, Nakano T, Tanaka H, Nakaoka K, Ohno E, Funasaka K, Nagasaka M, Miyahara R, Hirooka Y. Early Changes in Alpha-Fetoprotein and Des-γ-Carboxy Prothrombin Are Useful Predictors of Antitumor Response to Durvalumab Plus Tremelimumab Therapy for Advanced Hepatocellular Carcinoma. Curr Oncol 2024; 31:4225-4240. [PMID: 39195298 PMCID: PMC11353012 DOI: 10.3390/curroncol31080315] [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: 06/26/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
The relationship between antitumor response and tumor marker changes was evaluated in patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab (Dur/Tre). Forty patients were enrolled in this retrospective evaluation of treatment outcomes. According to the Response Evaluation Criteria for Solid Tumors version 1.1 at 8 weeks, the objective response (OR) rate was 25% and the disease control (DC) rate was 57.5%. The median alpha-fetoprotein (AFP) ratio at 4 weeks was 0.39 in patients who achieved OR at 8 weeks (8W-OR group), significantly lower than the 1.08 in the non-8W-OR group (p = 0.0068); however, it was 1.22 in patients who did not achieve DC at 8 weeks (non-8W-DC group), significantly higher than the 0.53 in the 8W-DC group (p = 0.0006). Similarly, the median des-γ-carboxy-prothrombin (DCP) ratio at 4 weeks was 0.15 in the 8W-OR group, significantly lower than the 1.46 in the non-8W-OR group (p < 0.0001); however, it was 1.23 in the non-8W-DC group, significantly higher than the 0.49 in the 8W-DC group (p = 0.0215). Early changes in tumor markers after Dur/Tre initiation were associated with antitumor response. In particular, changes in AFP and DCP at 4 weeks may offer useful biomarkers for early prediction of both response and progressive disease following Dur/Tre.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake 470-1192, Japan; (N.K.); (H.M.); (Y.W.); (G.K.); (T.N.); (H.T.); (K.N.); (E.O.); (K.F.); (M.N.); (R.M.); (Y.H.)
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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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Colloca GA, Venturino A. Radiographic and serologic response in patients with unresectable hepatocellular carcinoma receiving systemic antineoplastic treatments: A trial-level analysis. Cancer 2024; 130:1773-1783. [PMID: 38231887 DOI: 10.1002/cncr.35199] [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: 10/08/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND In a disease like unresectable hepatocellular carcinoma, overall survival is an inadequate outcome measure for evaluating the effectiveness of treatments given the high risk of death from liver failure. There is an unmet need for reliable alternative end points for clinical trials and daily clinical practice. To evaluate treatment response in patients with unresectable or metastatic hepatocellular carcinoma (mHCC), imaging-related end points are often used, whereas serologic end points have been developed for patients with serum alpha-fetoprotein levels >20 ng/mL. The objective of this study was to evaluate clinical trials that report concomitant assessment of radiographic and serologic response in patients with mHCC. METHODS After a systematic review, studies that evaluated response according to radiographic and serologic criteria were selected. A correlation between progression-free survival (PFS) and overall survival (OS) was performed, and a linear regression of each response-related outcome measure with OS was reported. Finally, the effect of eight baseline variables on OS and response-related measures was evaluated. RESULTS Twenty-six studies were included, including 16 first-line studies and 10 second-line studies. PFS and response rates demonstrated a significant relationship with OS, whereas disease control rates did not. The responses were correlated with OS, particularly in the first-line setting, after targeted therapy, and whenever assessment was early. Among the baseline variables, only performance status had a prognostic role, whereas hepatitis B virus-related liver disease was associated with higher radiographic response rates. CONCLUSIONS PFS and radiographic and serologic response rates appear to be reliable intermediate end points in patients with mHCC who are undergoing systemic antineoplastic therapy. However, the serologic response is available earlier.
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Kudo M. Urgent Global Need for PIVKA-II and AFP-L3 Measurements for Surveillance and Management of Hepatocellular Carcinoma. Liver Cancer 2024; 13:113-118. [PMID: 38751558 PMCID: PMC11095620 DOI: 10.1159/000537897] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/31/2024] [Indexed: 05/18/2024] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Higashiosaka, Japan
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McEneaney LJ, Vithayathil M, Khan S. Screening, Surveillance, and Prevention of Hepatocellular Carcinoma. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:271-290. [DOI: 10.1002/9781119756422.ch16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Tai Y, Morita Y, Makino M, Ida S, Muraki R, Kitajima R, Takeda M, Kikuchi H, Hiramatsu Y, Takeuchi H. A Case of Giant Hepatocellular Carcinoma Successfully Treated with Lenvatinib Followed by Parenchymal-Sparing Hepatectomy. THE JAPANESE JOURNAL OF GASTROENTEROLOGICAL SURGERY 2023; 56:547-559. [DOI: 10.5833/jjgs.2022.0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Yuta Tai
- Department of Surgery, Shizuoka City Shimizu Hospital
| | | | | | - Shinya Ida
- Department of Surgery, Hamamatsu University School of Medicine
| | - Ryuta Muraki
- Department of Surgery, Hamamatsu University School of Medicine
| | - Ryo Kitajima
- Department of Surgery, Hamamatsu University School of Medicine
| | - Makoto Takeda
- Department of Surgery, Hamamatsu University School of Medicine
| | | | - Yoshihiro Hiramatsu
- Department of Surgery, Hamamatsu University School of Medicine
- Department of Perioperative Functioning Care and Support, Hamamatsu University School of Medicine
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine
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Tanabe N, Saeki I, Aibe Y, Matsuda T, Hanazono T, Nishi M, Hidaka I, Kuwashiro S, Shiratsuki S, Matsuura K, Egusa M, Nishiyama N, Fujioka T, Kawamoto D, Sasaki R, Nishimura T, Oono T, Hisanaga T, Matsumoto T, Ishikawa T, Yamasaki T, Takami T. Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:2927. [PMID: 37296889 PMCID: PMC10251947 DOI: 10.3390/cancers15112927] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.
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Affiliation(s)
- Norikazu Tanabe
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Yamaguchi, Japan; (N.T.); (T.Y.)
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Yuki Aibe
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Kokura Memorial Hospital, Kitakyushu 802-8555, Fukuoka, Japan
| | - Takashi Matsuda
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Shimonoseki Medical Center, Shimonoseki 750-0061, Yamaguchi, Japan
| | - Tadasuke Hanazono
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Saiseikai Shimonoseki General Hospital, Shimonoseki 759-6603, Yamaguchi, Japan
| | - Maiko Nishi
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Yamaguchi Rosai Hospital, Sanyo-Onoda 756-0095, Yamaguchi, Japan
| | - Isao Hidaka
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Saiseikai Yamaguchi General Hospital, Yamaguchi 753-0078, Yamaguchi, Japan
| | - Shinya Kuwashiro
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Yamaguchi Prefectural Grand Medical Center, Hofu 747-8511, Yamaguchi, Japan
| | - Shogo Shiratsuki
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Tokuyama Central Hospital, Syunan 745-8522, Yamaguchi, Japan
| | - Keiji Matsuura
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Gastroenterology, Shuto General Hospital, Yanai 742-0032, Yamaguchi, Japan
| | - Maho Egusa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Natsuko Nishiyama
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Tsuyoshi Fujioka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Daiki Kawamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Ryo Sasaki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Tatsuro Nishimura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Takashi Oono
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Takuro Hisanaga
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Toshihiko Matsumoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
| | - Takahiro Yamasaki
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Yamaguchi, Japan; (N.T.); (T.Y.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan; (M.E.); (N.N.); (T.F.); (D.K.); (R.S.); (T.N.); (T.O.); (T.H.); (T.M.); (T.I.); (T.T.)
- Yamaguchi Clinical Research Group—Hepatology (YCR-H), Ube 755-8505, Yamaguchi, Japan (M.N.); (I.H.); (S.K.)
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11
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Kinami T, Amioka K, Kawaoka T, Uchikawa S, Yamasaki S, Kosaka M, Johira Y, Yano S, Naruto K, Ando Y, Yamaoka K, Fujii Y, Fujino H, Nakahara T, Ono A, Murakami E, Okamoto W, Yamauchi M, Miki D, Tsuge M, Imamura M, Aikata H, Oka S. Evaluation of Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma Using the Combination of Response Evaluation Criteria in Solid Tumors and Alpha-Fetoprotein. Cancers (Basel) 2023; 15:cancers15082304. [PMID: 37190231 DOI: 10.3390/cancers15082304] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is currently positioned as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). It may be difficult to decide whether to continue this treatment if radiological response is assessed as stable disease (SD). Therefore, the relationship between radiological response and prognosis was analyzed. A total of 109 patients with u-HCC and Child-Pugh Score of 5-7 received this treatment. Radiological response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at the first and second evaluations. Of SD patients (n = 71) at the first RECIST evaluation, partial response, SD, and progressive disease (PD) were seen in 10, 55, and 6 patients, respectively, at the second evaluation. On multivariate analysis, in patients with SD at the first RECIST evaluation, a 25% or greater increase in the alpha-fetoprotein (AFP) value from initiation of treatment (odds ratio, 7.38; p = 0.037) was the independent factor for PD at the second evaluation. In patients with SD (n = 59) at the second RECIST evaluation, decreased AFP from initiation of treatment (hazard ratio, 0.46; p = 0.022) was the independent factor related to progression-free survival on multivariate analysis. AFP trends could help decide the Atezo + Beva treatment strategy.
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Affiliation(s)
- Takahiro Kinami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kei Amioka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shintaro Yamasaki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Masanari Kosaka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yusuke Johira
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Shigeki Yano
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kensuke Naruto
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yuwa Ando
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Kenji Yamaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Wataru Okamoto
- Department of Clinical Oncology, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology, Hiroshima Prefectural Hospital, Hiroshima 734-8530, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
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12
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Wang H, Zhang G, Yang X, Lu Z, Zhao H. Lenvatinib plus immune checkpoint inhibitors or locoregional therapy in unresectable hepatocellular carcinoma: Lessons learned and moving forwards. Biochim Biophys Acta Rev Cancer 2023; 1878:188841. [PMID: 36423747 DOI: 10.1016/j.bbcan.2022.188841] [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: 01/17/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma is one of the deadliest neoplasms around the world, and a major proportion of patients are diagnosed in an advanced state not amenable to curative treatment. Lenvatinib, a promising first-line targeted therapy, has shown antitumour activity in both preclinical studies and clinical trials. Emerging evidence indicates that a combination of lenvatinib plus anti-PD-1 inhibitors or locoregional therapies exerts a stronger antitumour effect than monotherapy and even offers the possibility of long-term survival while maintaining acceptable tolerability. Several studies have also shown the superiority of lenvatinib over sorafenib in combination strategies. This review addresses the rationale behind lenvatinib-based combination therapies and comprehensively summarizes various clinical studies investigating lenvatinib in combination with immune checkpoint inhibitors (ICIs), locoregional therapies, and other systemic treatments. We discuss the unsatisfactory search for suitable biomarkers and key ongoing trials in this field.
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Affiliation(s)
- Huaiyuan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease. Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730 Beijing, China
| | - Ge Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease. Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730 Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease. Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730 Beijing, China
| | - Zhenhui Lu
- Hepatobiliary and Pancreatic Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Guangdong, China.
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Disease. Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 100730 Beijing, China.
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13
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Persano M, Casadei-Gardini A, Burgio V, Scartozzi M, Cascinu S, Rimini M. Five years of lenvatinib in hepatocellular carcinoma: are there any predictive and/or prognostic factors? Expert Rev Anticancer Ther 2023; 23:19-27. [PMID: 36472371 DOI: 10.1080/14737140.2023.2156340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Lenvatinib was the first drug approved in 2017 for first-line treatment of hepatocarcinoma (HCC) after 10 years of Sorafenib as exclusive standard of care. The therapeutic armamentarium has recently expanded following the approval of atezolizumab plus bevacizumab. AREAS COVERED Numerous studies have been conducted during the past 5 years on Lenvatinib use in real-world settings in an effort to determine prognostic and predictive factors of Lenvatinib efficacy. In order to choose the most effective therapeutic approach, it may be helpful to summarize these results in this review. EXPERT OPINION A subgroup that appears to benefit most from Lenvatinib therapy are patients with non-viral cirrhosis. This aspect is of great importance today considering the increase in NASH prevalence. Also, a significant proportion of BCLC B patients appear to respond well to Lenvatinib therapy. The biological heterogeneity highlighted in HCC patients, along with the growing number of therapeutic options, makes the identification of stratification tools able to define which patients are more likely to respond to a treatment rather than another one of crucial interest. Further investigation deepening the biological pathways underlying HCC carcinogenesis are of particular interest in order to pave the way for precision medicine even for HCC patients.
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Affiliation(s)
- Mara Persano
- Medical Oncology, University Hospital of Cagliari, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Valentina Burgio
- IRCCS San Raffaele Scientific Institute Hospital, Department of Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology, University Hospital of Cagliari, Milan, Italy
| | - Stefano Cascinu
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- IRCCS San Raffaele Scientific Institute Hospital, Department of Oncology, Vita-Salute San Raffaele University, Milan, Italy
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14
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Li Q, Su T, Zhang X, Pan Y, Ma S, Zhang L, Zhang X, Gao X. A Real-World Study of Optimal Treatment with Anlotinib First-Line Therapy in Advanced Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:3037-3046. [PMID: 36275784 PMCID: PMC9580834 DOI: 10.2147/cmar.s379911] [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: 06/24/2022] [Accepted: 09/29/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment. Patients and Methods Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety. Results Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88–8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥3 AEs was 38.7%. Conclusion Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.
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Affiliation(s)
- Qingqing Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Tong Su
- Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Xu Zhang
- Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China
| | - Yanfeng Pan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China,Correspondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email
| | - Shengli Ma
- Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China
| | - Lu Zhang
- Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China
| | - Xianqiang Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
| | - Xiaojuan Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China
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15
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Laface C, Fedele P, Maselli FM, Ambrogio F, Foti C, Molinari P, Ammendola M, Lioce M, Ranieri G. Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities. Cancers (Basel) 2022; 14:4028. [PMID: 36011021 PMCID: PMC9406380 DOI: 10.3390/cancers14164028] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, BR, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, BR, Italy
| | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | | | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
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16
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Lim DH, Casadei-Gardini A, Lee MA, Lonardi S, Kim JW, Masi G, Chon HJ, Rimini M, Kim I, Cheon J, Hwang JE, Kang JH, Lim HY, Yoo C. Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib. Future Oncol 2022; 18:3021-3030. [PMID: 35903991 DOI: 10.2217/fon-2022-0524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.
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Affiliation(s)
- Dong-Hoon Lim
- University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Andrea Casadei-Gardini
- Vita-Salute San Raffaele University School of Medicine, Milan, 20132, Italy.,Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Myung Ah Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, 06591, South Korea
| | - Sara Lonardi
- Oncology Unit 3, Veneto Institute of Oncology IOV-IRCCS, Padua, 35128, Italy
| | - Jin Won Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Gianluca Masi
- Department of Translational Research & New Technologies in Medicine & Surgery, University of Pisa, Pisa, 56126, Italy
| | - Hong Jae Chon
- Division of Hematology-Oncology, Department of Internal Medicine, Bundang CHA Hospital, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Margherita Rimini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Ilhwan Kim
- Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, 48108, South Korea
| | - Jaekyung Cheon
- Division of Hematology-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 44033, South Korea
| | - Jun-Eul Hwang
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea
| | - Jung Hun Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University, Jinju, 52727, South Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
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17
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Kaneko S, Kurosaki M, Tsuchiya K, Yasui Y, Hayakawa Y, Inada K, Tanaka Y, Ishido S, Kirino S, Yamashita K, Nobusawa T, Matsumoto H, Kakegawa T, Higuchi M, Takaura K, Tanaka S, Maeyashiki C, Tamaki N, Takahashi Y, Nakanishi H, Izumi N. Clinical evaluation of Elecsys PIVKA-II for patients with advanced hepatocellular carcinoma. PLoS One 2022; 17:e0265235. [PMID: 35271670 PMCID: PMC8912231 DOI: 10.1371/journal.pone.0265235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/23/2022] [Indexed: 02/08/2023] Open
Abstract
Background Prothrombin induced by vitamin K absence-II (PIVKA-II) was reported as a diagnosis and prognosis marker for hepatocellular carcinoma (HCC). Although the development of systemic therapies for advanced HCC has been remarkable, the role of PIVKA-II is unclear. This prospective study aimed to verify Elecsys PIVKA-II compared with Lumipulse PIVKA-II in a cohort with advanced HCC undergoing systemic therapy. Methods A total of 62 HCC patients who were treated with atezolizumab and bevacizumab (ATZ+BEV) and molecular targeted agents (MTAs) were prospectively enrolled at Musashino Red Cross Hospital from January 2020 to December 2020. A total of 208 serum samples from 52 patients were tested using Elecsys PIVKA-II and Lumipulse PIVKA-II assays. Furthermore, the relationship of Elecsys PIVKA-II and progression-free survival (PFS) was investigated with 48 patients (24 ATZ+BEV and 24 MTAs) whose Lumipulse PIVKA-II levels were >40 mAU/mL. Results In the test accuracy analysis, the Elecsys assay has a correlation coefficient (R) of 0.92 compared with that of the Lumipulse assay (ATZ+BEV, 0.95; MTAs, 0.91). In the PFS analysis, the number of patients who received ATZ+BEV and MTAs as first- and late-line therapy were 9 and 13, and 15 and 11, respectively. The PIVKA-II response was defined for patients who had a reduction in the Elecsys PIVKA-II level on the first month of treatment evaluation. The PFS of patients with Elecsys PIVKA-II response was significantly longer than that of nonresponse patients (5.8 months vs 3.8 months, p = 0.0205). Conclusion The Elecsys PIVKA-II was not only as useful as the Lumipulse PIVKA-II but also for stratifying the PFS of patients with advanced HCC.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuki Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Ishido
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tsubasa Nobusawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroaki Matsumoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tatsuya Kakegawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shohei Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- * E-mail: , ,
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18
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Liu B, Shang X, Shi JY, Cui GZ, Li X, Wang NY. Early Alpha-Fetoprotein Response Is Associated With Survival in Patients With HBV-Related Hepatocellular Carcinoma Receiving Lenvatinib. Front Oncol 2022; 12:807189. [PMID: 35251977 PMCID: PMC8893311 DOI: 10.3389/fonc.2022.807189] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/26/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND/PURPOSE Lenvatinib is a first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes with lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels. METHODS This retrospective analysis included patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for >1 month between November 2018 and May 2021. Early AFP response was defined as a >20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. Radiological response (Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival, and overall survival were assessed in AFP responders and non-responders. RESULTS Of the 46 patients analyzed, 30 (65.2%) were early AFP responders and 16 (34.8%) were non-responders. Compared to the non-responders, early AFP responders had a significantly higher objective response rate (34.5% vs 6.3%, p=0.0349), disease control rate (82.8% vs 50.0%; p=0.0203) and longer median progression-free survival (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p=0.028). A subsequent multivariate analysis confirmed that early AFP response (HR, 0.387; 95% CI, 0.183-0.992; p=0.0154), Eastern Cooperative Oncology Group Performance Status of 0 (HR, 0.890; 95% CI, 0.811-0.976; p=0.0132) and Albumin-Bilirubin grade 1 (HR, 0.457; 95% CI, 0.269-0.963; p=0.0327) were independent prognostic factors for longer progression-free survival. CONCLUSION AFP is an important prognostic factor and a predictive biomarker for survival benefit with lenvatinib treatment in patients with HBV-related uHCC.
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Affiliation(s)
| | | | | | | | | | - Nan-Ya Wang
- The Cancer Center, First Hospital of Jilin University, Changchun, China
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19
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Cammarota A, Zanuso V, D'Alessio A, Pressiani T, Bozzarelli S, Personeni N, Rimassa L. The dual checkpoint blockade in unresectable hepatocellular carcinoma: Opportunities emerging in clinical trials. Expert Opin Investig Drugs 2022; 31:425-435. [PMID: 35152830 DOI: 10.1080/13543784.2022.2042253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION To prevent damage from an immune response against autoantigens and toxins originating from the gut, the liver promotes an immune-tolerant milieu providing fertile ground for immune escape of cancer cells. Therefore, the use and evaluation of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) is a treatment rationale. AREA COVERED In this article, we discuss the role of the dual ICIs blockade in advanced HCC, covering the biological basis for their combination, their mechanism of action, and the results of the early phase studies testing nivolumab plus ipilimumab and durvalumab plus tremelimumab. Furthermore, we provide the results of the phase III HIMALAYA trial and an overview of the ongoing trials investigating the dual ICIs in different disease stages. EXPERT OPINION The potential approval of the dual ICIs blockade strategies for advanced HCC will set the entry of antiangiogenic-free options, expanding the proportion of patients eligible for a first-line treatment. However, it will pose a series of clinical challenges with a sizeable proportion of patients, namely Child-Pugh B, elderly, and immunocompromised patients, still marginalized. Also, given the rate of disease progression, identifying reliable predictive biomarkers is crucial to inform treatment choice and sequences. Finally, the compelling response rate of such combinations is paving the way for their evaluation in earlier stages.
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Affiliation(s)
- Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Valentina Zanuso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, W120HS, United Kingdom
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
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20
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Dong D, Shi JY, Shang X, Liu B, Xu WL, Cui GZ, Wang NY. Prognostic significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib: A retrospective analysis. Medicine (Baltimore) 2022; 101:e28680. [PMID: 35119010 PMCID: PMC8812594 DOI: 10.1097/md.0000000000028680] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 01/04/2022] [Indexed: 02/07/2023] Open
Abstract
Our study investigated the correlation between sarcopenia and clinical outcomes in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. We retrospectively evaluated 40 consecutive patients with unresectable HCC receiving lenvatinib between November 2018 and May 2020 at the First Hospital of Jilin University. Skeletal muscle mass was measured before treatment initiation. Prognostic significance was assessed with univariate and multivariate Cox proportional hazards models. Overall survival (OS) and progression-free survival (PFS) were evaluated for patients with and without sarcopenia. Sarcopenia was present in 23/40 patients (57.5%). After a median follow-up of 9.2 months, patients with sarcopenia had significantly worse OS and PFS compared with those without sarcopenia (OS: 8.4 months [m] vs 14.7 m, P = .02; PFS: 4.2 m vs 9.0 m, P = .04). Multivariate Cox proportional hazards models identified presence of sarcopenia as an independent risk factor for shorter OS (hazard ratio [HR], 0.257; 95% confidence interval [CI], 0.083-0.794; P = .02). In subgroup analysis, sarcopenia was associated with worse survival than non-sarcopenic patients, irrespective of age, Barcelona clinic liver cancer stage, or albumin-bilirubin grade. Our results show sarcopenia may be a predictor of poor prognosis in patients with HCC receiving lenvatinib. Management of sarcopenia is a vital factor for improving survival outcomes in patients with HCC.
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Affiliation(s)
- Dong Dong
- Department of Radiology, First Hospital of Jilin University, Changchun, China
| | - Jin-Yu Shi
- Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Xiao Shang
- Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Bo Liu
- Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Wei-Ling Xu
- Department of Radiology, First Hospital of Jilin University, Changchun, China
| | - Guo-Zhen Cui
- Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Nan-Ya Wang
- Cancer Center, First Hospital of Jilin University, Changchun, China
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21
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Naganuma A, Suzuki Y, Hoshino T, Yasuoka H, Tamura Y, Naruse H, Tanaka H, Hirai K, Sakamoto I, Ogawa T, Hatanaka T, Kakizaki S. A case of conversion hepatectomy for huge ruptured hepatocellular carcinoma after transarterial embolization and lenvatinib therapy. Clin J Gastroenterol 2022; 15:177-184. [PMID: 34811701 DOI: 10.1007/s12328-021-01558-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/10/2021] [Indexed: 12/09/2022]
Abstract
We herein report a successfully treated case of huge ruptured hepatocellular carcinoma (HCC) by conversion hepatectomy after transarterial embolization (TAE) and lenvatinib therapy. A 33-year-old male patient with right hypochondralgia and liver tumor was referred to our hospital. He had a history of surgery for heart malformation. The tumor at the right lobe was 15 cm in diameter with bloody ascites. Right atrial thrombus 4.5 cm in diameter and marked cardiac dilatation were observed. TAE with ethanol suspended in lipiodol and gelatin sponge achieved hemostasis of the ruptured HCC. Although viable HCC remained after TAE, surgical treatment was abandoned because of abdominal wall invasion and his heart function. Lenvatinib and rivaroxaban were then initiated for HCC and atrial thrombus, respectively. Lenvatinib treatment resulted in a reduction in tumor marker levels and the tumor size. First, we planned conversion hepatectomy after 5 months of lenvatinib. However, recurrence of atrial thrombus prompted us to put off the surgery, and lenvatinib was re-administered. After improvement of atrial thrombus, we finally performed conversion hepatectomy 10 months after starting lenvatinib administration. The tumor was completely removed by combined resection of the diaphragm, and the patient has been doing well without any signs of recurrence.
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Affiliation(s)
- Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Yuhei Suzuki
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Hidetoshi Yasuoka
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Yuki Tamura
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Hiroaki Naruse
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Hiroshi Tanaka
- Department of Surgery, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Keitaro Hirai
- Department of Surgery, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Ichiro Sakamoto
- Department of Surgery, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Tetsushi Ogawa
- Department of Surgery, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma, 371-0821, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan.
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma, 370-0829, Japan.
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22
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Cucarull B, Tutusaus A, Rider P, Hernáez-Alsina T, Cuño C, García de Frutos P, Colell A, Marí M, Morales A. Hepatocellular Carcinoma: Molecular Pathogenesis and Therapeutic Advances. Cancers (Basel) 2022; 14:cancers14030621. [PMID: 35158892 PMCID: PMC8833604 DOI: 10.3390/cancers14030621] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be a serious medical problem with poor prognosis, without major therapeutic improvement for years and increasing incidence. Fortunately, advances in systemic treatment options are finally arriving for HCC patients. After a decade of sorafenib as a standard therapy for advanced HCC, several tyrosine kinase inhibitors (TKIs), antiangiogenic antibodies, and immune checkpoint inhibitors have reached the clinic. Although infections by hepatitis B virus and hepatitis C virus remain principal factors for HCC development, the rise of non- alcoholic steatohepatitis from diabetes mellitus or metabolic syndrome is impeding HCC decline. Knowledge of specific molecular mechanisms, based on the etiology and the HCC microenvironment that influence tumor growth and immune control, will be crucial for physician decision-making among a variety of drugs to prescribe. In addition, markers of treatment efficacy are needed to speed the movement of patients towards other potentially effective treatments. Consequently, research to provide scientific data for the evidence-based management of liver cancer is guaranteed in the coming years and discussed here.
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Affiliation(s)
- Blanca Cucarull
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | | | - Carlos Cuño
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Unidad Asociada (IMIM), IIBB-CSIC, CIBERCV, IDIBAPS, 08036 Barcelona, Spain
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08036 Barcelona, Spain
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, 08036 Barcelona, Spain; (B.C.); (A.T.); (P.R.); (C.C.); (P.G.d.F.); (A.C.)
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, CIBEREHD, IDIBAPS, 08036 Barcelona, Spain
- Correspondence: (M.M.); (A.M.); Tel.: +34-932558314 (M.M. & A.M.)
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23
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Kuzuya T, Kawabe N, Hashimoto S, Miyahara R, Sawaki A, Nakano T, Nakaoka K, Tanaka H, Miyachi Y, Mii A, Kamejima S, Takahara T, Kato Y, Sugioka A, Hirooka Y. Early Changes in Alpha-Fetoprotein Are a Useful Predictor of Efficacy of Atezolizumab plus Bevacizumab Treatment in Patients with Advanced Hepatocellular Carcinoma. Oncology 2021; 100:12-21. [PMID: 34731863 DOI: 10.1159/000519448] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/02/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION The aim of this study was to investigate the early changes in alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab and to evaluate the relationship between changes in these tumor markers and treatment efficacy. METHODS Of 58 consecutive patients who started atezolizumab plus bevacizumab at our institution, 50 patients with information on antitumor response obtained at 6 weeks after therapy were enrolled in this study and their treatment outcomes were retrospectively evaluated. RESULTS According to the Response Evaluation Criteria in Solid Tumors at 6 weeks, the objective response (OR) rate was 22.0% and the disease control (DC) rate was 78.0%. In patients who achieved OR at 6 weeks, median AFP and DCP ratios at weeks 1, 2, 3, and 6 were significantly lower than those in patients who did not achieve OR. AFP ratios in patients who did not achieve DC at 6 weeks (Non-6W-DC group) were significantly higher than in those who achieved DC at week 6 (6W-DC group). Median overall survival in the Non-6W-DC group was significantly shorter than in the 6W-DC group (156 days vs. not reached, p = 0.0008). An AFP ratio of 1.4 or higher at 3 weeks had a specificity of 88.0% and a sensitivity of 88.9% for predicting Non-6W-DC. Median progression-free survival was significantly shorter in patients with an AFP ratio of 1.4 or higher at 3 weeks than in those with an AFP ratio of <1.4 (42 days vs. 210 days, p = 0.0003). CONCLUSION Early changes in AFP might be useful for predicting the antitumor efficacy of atezolizumab plus bevacizumab in patients with advanced HCC. An AFP ratio of 1.4 or higher at 3 weeks might be an early predictor of refractoriness to atezolizumab plus bevacizumab therapy.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Naoto Kawabe
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Senju Hashimoto
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Akira Sawaki
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Takuji Nakano
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Kazunori Nakaoka
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Hiroyuki Tanaka
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Yohei Miyachi
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Arisa Mii
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Sayaka Kamejima
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | | | - Yutaro Kato
- Department of Surgery, Fujita Health University, Toyoake, Japan
| | - Atsushi Sugioka
- Department of Surgery, Fujita Health University, Toyoake, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
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24
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Hayakawa Y, Tsuchiya K, Kurosaki M, Yasui Y, Kaneko S, Tanaka Y, Ishido S, Inada K, Kirino S, Yamashita K, Nobusawa T, Matsumoto H, Kakegawa T, Higuchi M, Takaura K, Tanaka S, Maeyashiki C, Tamaki N, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Okamoto R, Izumi N. Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice. Invest New Drugs 2021; 40:392-402. [PMID: 34586531 DOI: 10.1007/s10637-021-01185-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/21/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND We aimed to investigate the efficacy and safety of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (u-HCC) based on whether they had previously received systemic therapy, as well as the association of atezolizumab plus bevacizumab with early alpha-fetoprotein (AFP) response in real-world practice. METHODS A total of 52 patients with u-HCC were treated with atezolizumab plus bevacizumab between October 2020 and April 2021. The Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were used to evaluate radiological responses. RESULTS The patients received atezolizumab plus bevacizumab as 1st-line (n = 23), 2nd-line (n = 16), 3rd-line (n = 6), 4th-line (n = 3), 5th-line (n = 3), or 6th-line (n = 1) therapy. According to RECIST, the objective response rate (ORR) and disease control rate (DCR) in all patients were 15.4% and 57.7%. In the 1st-line patients, ORR and DCR based on RECIST 1.1 were 27.3% and 81.8%. The median time to progression (TTP) assessed by RECIST was significantly longer among patients receiving atezolizumab plus bevacizumab as 1st-line therapy than in patients receiving atezolizumab plus bevacizumab as later-line therapy (P < 0.001). Patients with an AFP response (reduction ≥ 20% from baseline) at 6 weeks had a significantly longer TTP assessed by RECIST than those without an AFP response (P = 0.02). CONCLUSION Patients who received atezolizumab plus bevacizumab as 1st-line therapy had better clinical outcome than those who received atezolizumab plus bevacizumab in later lines. The AFP response at 6 weeks could be a predictor of disease progression.
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Affiliation(s)
- Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan. .,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yuki Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Shun Ishido
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Tsubasa Nobusawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hiroaki Matsumoto
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Tatsuya Kakegawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Shohei Tanaka
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.,Division of Gastroenterology and Hepatology, Department of Medicine, NAFLD Research Center, University of California San Diego, La Jolla, CA92093, USA
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1, Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
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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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Reductions in AFP and PIVKA-II can predict the efficiency of anti-PD-1 immunotherapy in HCC patients. BMC Cancer 2021; 21:775. [PMID: 34218801 PMCID: PMC8254996 DOI: 10.1186/s12885-021-08428-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 05/27/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Few biomarkers can predict the efficiency of PD-1 blockade in patients with hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic role of AFP and PIVKA-II in HCC patients receiving anti-PD-1 immunotherapy. METHODS A total of 235 HCC patients treated with PD-1 blockade were enrolled. Serum AFP and PIVKA-II levels were collected before and after treatments. The patients were divided into groups based on the reduction in AFP and PIVKA-II: AFP reduction ≤50% vs AFP reduction > 50% and PIVKA-II reduction ≤50% vs PIVKA-II reduction > 50%. The primary endpoints included objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Binary logistic regression analyses were used to explore the related factors of ORR. A Cox proportional hazards model was employed to identify the potential prognostic factors of PFS and OS. RESULTS Among all the patients, 34.9% (82/235) achieved a complete or partial response. There was a positive correlation between AFP reduction > 50% or PIVKA-II reduction> 50% and the ORR of PD-1 blockade (P < 0.001 and = 0.003). PFS was significantly improved in patients with AFP reduction > 50% and PIVKA-II reduction > 50% (p < 0.001 and = 0.021). In addition, AFP reduction > 50% and PIVKA-II reduction> 50% were positively correlated with longer OS (p = 0.003 and 0.006). CONCLUSION Early reductions in AFP and PIVKA-II can be predictors of the efficacy of PD-1 blockade in HCC patients.
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27
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D'Alessio A, Cammarota A, Prete MG, Pressiani T, Rimassa L. The evolving treatment paradigm of advanced hepatocellular carcinoma: putting all the pieces back together. Curr Opin Oncol 2021; 33:386-394. [PMID: 33867478 DOI: 10.1097/cco.0000000000000744] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The therapeutic landscape of advanced hepatocellular carcinoma (HCC) has become notably complex in recent years. With this review, we aimed to put the most recent findings in perspective and tried to delineate the rapidly changing treatment algorithm. RECENT FINDINGS The combination of atezolizumab and bevacizumab has become the new first-line standard of care treatment for unresectable HCC after the positive results of the phase 3 IMbrave150 study. Nivolumab monotherapy failed to demonstrate advantage versus sorafenib in the CheckMate 459 trial, while two different therapeutic strategies (sintilimab and bevacizumab biosimilar and donafenib) outperformed sorafenib in two phase 2/3 studies conducted in the Chinese population. Several immunotherapy combinations are currently under study in large phase 3 trials after promising results in earlier phase studies. About further lines of treatment, the combination of ipilimumab and nivolumab was approved for sorafenib-pretreated patients after the positive results of the phase 1/2 CheckMate 040 study and apatinib was proven effective in the Chinese population in a phase 2/3 study, while pembrolizumab as monotherapy did not show statistically significant superiority when compared with placebo in the KEYNOTE-240 study. SUMMARY Because of the growing complexity of advanced HCC treatment, the implementation of predictive biomarkers of response is eagerly needed.
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Affiliation(s)
- Antonio D'Alessio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Antonella Cammarota
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Giuseppina Prete
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Fujii Y, Ono A, Hayes CN, Aikata H, Yamauchi M, Uchikawa S, Kodama K, Teraoka Y, Fujino H, Nakahara T, Murakami E, Miki D, Okamoto W, Kawaoka T, Tsuge M, Imamura M, Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:215. [PMID: 34174931 PMCID: PMC8235843 DOI: 10.1186/s13046-021-02016-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02016-3.
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Affiliation(s)
- Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Wataru Okamoto
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. .,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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29
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Yamaoka K, Kodama K, Hiramatsu A, Ando Y, Kosaka Y, Suehiro Y, Fujii Y, Uchikawa S, Morio K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Imamura M, Takahashi S, Chayama K, Aikata H. Extracellular water to total body water ratio obtained by bioelectrical impedance analysis determines the dose intensity of lenvatinib for the treatment of patients with advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2021; 36:1685-1693. [PMID: 33326154 DOI: 10.1111/jgh.15377] [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: 01/15/2020] [Revised: 10/29/2020] [Accepted: 12/05/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The aim of this study was to identify the factors that contribute to the maintenance of relative dose intensity (RDI) of lenvatinib in hepatocellular carcinoma (HCC) patients. METHODS Thirty-two patients with advanced HCC treated with lenvatinib were enrolled. We evaluated the relationship between maintenance of RDI and various clinical data, parameters obtained by body composition measurements with bioelectrical impedance analysis (BIA) and grip strength at the start of lenvatinib treatment. RESULTS Multivariate analysis showed that only the extracellular water to total body water ratio (ECW/TBW) ≤ 0.400 at initiation of treatment was associated with RDI ≥ 50% (odds ratio, 6.94; 95% confidence interval [CI], 1.00-48.00; P = 0.049). When the RDI was compared between ECW/TBW ≤ 0.400 group and ECW/TBW > 0.400 group, the RDI was significantly higher in the ECW/TBW ≤ 0.400 group at each of 0-4W, 4-6W, and 6-8W points. The P value at each point was 0.003, 0.003, and 0.005, respectively. On the other hand, multivariate analysis showed that only the ECW/TBW ≤ 0.400 at initiation of treatment was associated with the extension of duration until reduction or withdrawal of lenvatinib (hazard ratio, 4.86; 95% CI, 1.52-15.50; P = 0.007). CONCLUSION The extracellular water to total body water ratio, a parameter of body composition measurement by BIA, was significantly associated with the maintenance of RDI and the duration until reduction or withdrawal of lenvatinib in HCC patients. In addition to standard predictors such as Child-Pugh score and modified albumin-bilirubin grade that have been used to date, ECW/TBW might be a new predictor of RDI in HCC patients treated with lenvatinib.
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Affiliation(s)
- Kenji Yamaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yosuke Suehiro
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Wei F, Huang Q, He J, Luo L, Zeng Y. Lenvatinib Plus Camrelizumab versus Lenvatinib Monotherapy as Post-Progression Treatment for Advanced Hepatocellular Carcinoma: A Short-Term Prognostic Study. Cancer Manag Res 2021; 13:4233-4240. [PMID: 34079375 PMCID: PMC8166816 DOI: 10.2147/cmar.s304820] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/10/2021] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Compared the outcomes between lenvatinib plus camrelizumab therapy and lenvatinib monotherapy as post-progression treatment for advanced hepatocellular carcinoma (HCC) with progressive disease (PD). PATIENTS AND METHODS A total of 48 advanced HCC patients were included in this retrospective study between June 2019 and March 2020. The patients were divided into the lenvatinib plus camrelizumab group (n=21) and the lenvatinib group (n=27). Primary endpoints were overall survival (OS) and progression-free survival (PFS), and secondary endpoints were the objective response rate (ORR) and adverse events (AEs). RESULTS The median follow-up time was 8.4 months. The median OS was not obtained. The median PFS of lenvatinib plus camrelizumab group was significantly longer than that of lenvatinib group (8.0 months vs 4.0 months, p=0.011). Compared with lenvatinib group, lenvatinib plus camrelizumab group had higher ORR (28.57% vs 7.41%) and disease control rate (DCR) (71.43% vs 51.85%). The most common adverse events (AEs) included hand-foot skin reaction, hypertensions and abnormal hepatic function damage. Overall, 23.81% and 25.93% of patients experienced grade ≥3AEs in the lenvatinib plus camrelizumab group and the lenvatinib group, respectively. CONCLUSION Lenvatinib plus camrelizumab as post-progression treatment is effective and safe for advanced hepatocellular carcinoma with PD.
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Affiliation(s)
- Fuqun Wei
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Qizhen Huang
- Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Jian He
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Liuping Luo
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
| | - Yongyi Zeng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China
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31
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Ando Y, Kawaoka T, Amioka K, Naruto K, Ogawa Y, Yoshikawa Y, Kikukawa C, Kosaka Y, Uchikawa S, Morio K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Fukuhara T, Mori N, Takaki S, Tsuji K, Nonaka M, Hyogo H, Aisaka Y, Masaki K, Honda Y, Moriya T, Naeshiro N, Takahashi S, Imamura M, Chayama K, Aikata H. Efficacy and Safety of Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy for Patients with Intermediate-Stage Hepatocellular Carcinoma. Oncology 2021; 99:507-517. [PMID: 33946070 DOI: 10.1159/000515865] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/13/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). METHODS Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. RESULTS After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. CONCLUSION For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.
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Affiliation(s)
- Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Amioka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kensuke Naruto
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yutaro Ogawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Yoshikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chihiro Kikukawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Michihiro Nonaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Yoji Honda
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Takashi Moriya
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Noriaki Naeshiro
- Department of Gastroenterology, National Hospital Organization Higashihiroshima Medical Center, Hiroshima, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Takahashi K, Kim J, Takahashi A, Hashimoto S, Doi M, Furuya K, Hashimoto R, Owada Y, Ogawa K, Ohara Y, Akashi Y, Hisakura K, Enomoto T, Shimomura O, Noguchi M, Oda T. Conversion hepatectomy for hepatocellular carcinoma with main portal vein tumour thrombus after lenvatinib treatment: A case report. World J Hepatol 2021; 13:384-392. [PMID: 33815680 PMCID: PMC8006080 DOI: 10.4254/wjh.v13.i3.384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/31/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accompanied by portal vein tumour thrombus (PVTT) presents an aggressive disease course, worsening liver function reserve, and a high recurrence rate. Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion. However, to achieve longer survival in these patients, the treatment strategy should be concluded with removal of the tumour by locoregional therapy. We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment. CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up. Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches. With the diagnosis of unresectable HCC with Vp4 (main trunk/contralateral branch) PVTT, lenvatinib was started at 12 mg/d. The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT, which had retreated to the contralateral first-order portal branch. He tolerated the full dose without major adverse effects. With cessation of lenvatinib for 7 d, radical left lobectomy and PVTT thrombectomy were conducted. The patient's postoperative course was uneventful. Microscopically, the primary lesion showed fibrotic changes, with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas. The majority of the PVTT showed necrosis. He was alive without recurrence for 8 mo. CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.
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Affiliation(s)
- Kazuhiro Takahashi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan.
| | - Jaejeong Kim
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Amane Takahashi
- Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama 3620806, Saitama, Japan
| | - Shinji Hashimoto
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Manami Doi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Kinji Furuya
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Ryosuke Hashimoto
- Department of Diagnostic Pathology, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yohei Owada
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Koichi Ogawa
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yusuke Ohara
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Yoshimasa Akashi
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Katsuji Hisakura
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Tsuyoshi Enomoto
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Osamu Shimomura
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Masayuki Noguchi
- Department of Diagnostic Pathology, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Tatsuya Oda
- Department of Gastrointestinal and Hepatobiliary Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
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Amioka K, Kawaoka T, Ogawa Y, Kikukawa C, Naruto K, Yoshikawa Y, Ando Y, Kosaka Y, Uchikawa S, Morio K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Imamura M, Fukuhara T, Mori N, Takaki S, Tsuji K, Masaki K, Honda Y, Kouno H, Kohno H, Chayama K, Aikata H. Comparison of the Clinical Outcome of Ramucirumab for Unresectable Hepatocellular Carcinoma with That of Prior Tyrosine Kinase Inhibitor Therapy. Oncology 2021; 99:327-335. [PMID: 33677453 DOI: 10.1159/000514315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/05/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. METHODS Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. RESULTS The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. CONCLUSION The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.
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Affiliation(s)
- Kei Amioka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yutaro Ogawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chihiro Kikukawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kensuke Naruto
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Yoshikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Yoji Honda
- Department of Gastroenterology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Hirotaka Kouno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Hiroshi Kohno
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,
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Kasuya K, Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Kajiwara A, Iritani S, Fujiyama S, Hosaka T, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ikeda K, Arase Y, Eguchi Y, Hashimoto M, Kumada H. Efficacy and Safety of Ramucirumab in Patients with Unresectable Hepatocellular Carcinoma with Progression after Treatment with Lenvatinib. Intern Med 2021; 60:345-351. [PMID: 32963154 PMCID: PMC7925279 DOI: 10.2169/internalmedicine.5185-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/29/2020] [Indexed: 12/16/2022] Open
Abstract
Objective A survival benefit was demonstrated for ramucirumab (RAM) in patients with unresectable hepatocellular carcinoma (uHCC) and α-fetoprotein (AFP) concentrations ≥400 ng/mL who had previously received sorafenib (SOR). However, it is unclear whether RAM has a similar efficacy in patients with uHCC that progresses after lenvatinib (LEN) treatment. This study aimed to evaluate the early anti-tumor response to RAM as a second-line treatment for advanced uHCC after LEN treatment. Methods We retrospectively assessed the efficacy and safety of RAM at 6 weeks after initiation. The therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients We evaluated 7 patients with uHCC who received RAM as a second- or third-line treatment after LEN failure. Results The disease control rate (DCR) was 28.6% (2 of 7 patients). After the initiation of RAM, a rapid disease progression resulted in 1 patient death after 19 days. The median progression-free survival (PFS) was 41 days. There were no grade 3 or 4 treatment-related adverse events. At 6 weeks, there was no deterioration in the modified albumin-bilirubin (mALBI) grade. In patients with an imaging response of stable disease (SD), the rate of AFP production decreased from the baseline. Conclusion RAM may have a therapeutic potential for the suppression of uHCC progression in patients previously treated with LEN, as well as for maintaining the liver function during treatment. Evaluating the AFP trends may therefore be useful for predicting RAM effectiveness.
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Affiliation(s)
- Kayoko Kasuya
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
- Graduate School of Medical Science, Saga University, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Junichi Shindoh
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
- Hepatobiliary-pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Japan
| | - Yuta Kobayashi
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
- Hepatobiliary-pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Japan
| | - Akira Kajiwara
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Soichi Iritani
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
| | - Yuichiro Eguchi
- Liver Center, Saga University Hospital, Saga University, Japan
| | - Masaji Hashimoto
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
- Hepatobiliary-pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Japan
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Hatanaka T, Naganuma A, Kakizaki S. Lenvatinib for Hepatocellular Carcinoma: A Literature Review. Pharmaceuticals (Basel) 2021; 14:36. [PMID: 33418941 PMCID: PMC7825021 DOI: 10.3390/ph14010036] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/01/2021] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, Gunma 371-0821, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsucho, Takasaki, Gunma 370-0829, Japan;
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi, Gunma 371-8511, Japan
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Kaneko S, Tsuchiya K, Yasui Y, Inada K, Kirino S, Yamashita K, Osawa L, Hayakawa Y, Sekiguchi S, Higuchi M, Takaura K, Maeyashiki C, Tamaki N, Takeguchi T, Takeguchi Y, Nakanishi H, Itakura J, Takahashi Y, Himeno Y, Kurosaki M, Izumi N. Early radiological response evaluation with response evaluation criteria in solid tumors 1.1 stratifies survival in hepatocellular carcinoma patients treated with lenvatinib. JGH Open 2020; 4:1183-1190. [PMID: 33319054 PMCID: PMC7731835 DOI: 10.1002/jgh3.12420] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/20/2020] [Accepted: 09/05/2020] [Indexed: 12/29/2022]
Abstract
Background and Aim Lenvatinib (LEN) has an antitumor effect with an early reduction in contrast enhancement for unresectable hepatocellular carcinoma (HCC). The aim of this study was to reveal the most useful radiological response evaluation for overall survival (OS) in patients treated with LEN. Methods Patients receiving LEN therapy (n = 80) were retrospectively recruited from April 2018 to January 2020. Enhanced computed tomography scans were performed at baseline and every 4-8 weeks. OS and radiological response were evaluated using response evaluation criteria in solid tumors (RECIST 1.1), modified RECIST (mRECIST), and Choi criteria. To be eligible for study, a minimal cumulative duration of LEN was 4 weeks. A total of 62 patients were included in the analysis. Results The median OS was 469 days. The RECIST 1.1, mRECIST, and Choi criteria identified 14 (22.5%), 30 (48.3%), and 33 (53.2%) patients with an objective response, respectively. In the univariate analysis, Child-Pugh class B, major vascular invasion, and high alpha-fetoprotein (>200) were statistically significant poor prognostic factors. Radiological response was a significantly better prognostic factor in each criterion (RECIST, mRECIST, and Choi). In the multivariate analysis, radiological response evaluated by RECIST (hazard ratio, 0.259; 95% confidence interval, 0.0723-0.928; P = 0.038) was an independent factor. Furthermore, only RECIST significantly stratified prognosis (P = 0.041) when limited to the first evaluation. Conclusion RECIST 1.1 was useful even as early therapeutic evaluation for HCC patients treated with LEN. Understanding the characteristics of radiological response over time may contribute to improving the prognosis of patients with HCC.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yutaka Yasui
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kento Inada
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Sakura Kirino
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Koji Yamashita
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Leona Osawa
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yuka Hayakawa
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Mayu Higuchi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Kenta Takaura
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Nobuharu Tamaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | | | - Yuko Takeguchi
- Department of RadiologyMusashino Red Cross HospitalTokyoJapan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Jun Itakura
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yuka Takahashi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Yoshiro Himeno
- Department of RadiologyMusashino Red Cross HospitalTokyoJapan
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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Hatanaka T, Naganuma A, Shibasaki M, Kohga T, Arai Y, Nagashima T, Ueno T, Namikawa M, Saito S, Hoshino T, Takizawa D, Arai H, Makita F, Kakizaki S, Harimoto N, Shirabe K, Uraoka T. The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: A Real-World Study. Oncology 2020; 99:203-214. [PMID: 33279908 DOI: 10.1159/000511734] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 09/21/2020] [Indexed: 01/27/2023]
Abstract
AIM The aim of this retrospective study was to investigate the efficacy and safety of ramucirumab treatment under real-world conditions and to clarify the role of albumin-bilirubin (ALBI) score in predicting outcomes. METHODS Between June 2019 and May 2020, a total of 16 patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab in Gunma Saiseikai Maebashi Hospital and its affiliated hospitals was included. RESULTS The median age was 71 (interquartile range [IQR] 65-74) years old, and 12 patients (75.0%) were male. The modified ALBI (mALBI) grade was 1, 2a, and 2b at baseline in 4 (25.0%), 3 (18.8%), and 9 patients (56.3%), respectively. The Barcelona Clinic Liver Cancer stage was intermediate and advanced stage in 1 (6.3%) and 15 patients (93.8%), respectively. The serum α-fetoprotein at baseline was 4,911 (IQR 2,091-17,377) ng/mL. The disease control rate in patients with mALBI grade1 + 2a was significantly higher than in those with mALBI grade 2b (100 vs. 28.6%, p = 0.028). The patients with mALBI grade 1 + 2a had a significantly better overall survival (OS) and longer progression-free survival (PFS) than those with mALBI grade 2b (median OS 6.7 vs. 3.0 months; p = 0.036, median PFS 7.5 vs. 1.4 months; p = 0.002). The number of cycles of ramucirumab treatment was significantly correlated with the ALBI score (r = -0.452, p = 0.030). The patients with mALBI grade 1 + 2a showed a low incidence of adverse events (AEs) and discontinuation due to AEs. CONCLUSIONS Advanced HCC patients with mALBI grade 1 + 2a may be a good indication for ramucirumab treatment.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan,
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | | | - Tatsuya Kohga
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Yosuke Arai
- Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Shuichi Saito
- Department of Gastroenterology, Tomioka General Hospital, Tomioka, Japan
| | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Fujio Makita
- Department of Gastrointestinal Surgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
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Ando Y, Kawaoka T, Suehiro Y, Yamaoka K, Kosaka Y, Uchikawa S, Kodama K, Morio K, Fujino H, Nakahara T, Murakami E, Yamauchi M, Tsuge M, Hiramatsu A, Fukuhara T, Mori N, Takaki S, Tsuji K, Nonaka M, Hyogo H, Aisaka Y, Masaki K, Honda Y, Moriya T, Naeshiro N, Azakami T, Takahashi S, Imamura M, Chayama K, Aikata H. Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib. Oncology 2020; 98:787-797. [PMID: 32882687 DOI: 10.1159/000509387] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 06/11/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. METHODS Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. RESULTS One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465-18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099-0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07-0.592, p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12-0.746, p = 0.01) were significant prognostic factors. CONCLUSION Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.
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Affiliation(s)
- Yuwa Ando
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yosuke Suehiro
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenji Yamaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yumi Kosaka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Michihiro Nonaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Yasuyuki Aisaka
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Yoji Honda
- Department of Gastroenterology, Hiroshima City Asa Hospital, Hiroshima, Japan
| | - Takashi Moriya
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Noriaki Naeshiro
- Department of Gastroenterology, National Hospital Organization Higashihiroshima Medical Center, Hiroshima, Japan
| | - Takahiro Azakami
- Department of Gastroenterology, Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
- Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan,
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Kunimoto H, Shakado S, Tanaka T, Takata K, Yamauchi R, Fukuda H, Tsuchiya N, Yokoyama K, Morihara D, Takeyama Y, Hirai F, Sakisaka S. Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma. Oncology 2020; 98:779-786. [PMID: 32877911 DOI: 10.1159/000509005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/27/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIMS Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks. PATIENTS AND METHODS Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines. RESULTS At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation. CONCLUSION Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.
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Affiliation(s)
- Hideo Kunimoto
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan, .,Department of Hepatology, Nagano Municipal Hospital, Nagano, Japan,
| | - Satoshi Shakado
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hiromi Fukuda
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Naoaki Tsuchiya
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Daisuke Morihara
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
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Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther 2020; 5:146. [PMID: 32782275 PMCID: PMC7419547 DOI: 10.1038/s41392-020-00264-x] [Citation(s) in RCA: 472] [Impact Index Per Article: 94.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
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Affiliation(s)
- Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Yuan Chung
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
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Komiyama S, Numata K, Moriya S, Fukuda H, Chuma M, Maeda S. Lenvatinib for large hepatocellular carcinomas with portal trunk invasion: Two case reports. World J Clin Cases 2020; 8:2574-2584. [PMID: 32607334 PMCID: PMC7322437 DOI: 10.12998/wjcc.v8.i12.2574] [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: 03/19/2020] [Revised: 04/24/2020] [Accepted: 06/03/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma (uHCC), the drug proved non-inferior to sorafenib in terms of the overall survival, but offered better progression-free survival. However, the effects of lenvatinib in uHCC patients with a tumor thrombus in the main portal vein and/or a high tumor burden (tumor occupancy more than 50% of the total liver volume), remain unclear, because these were set as exclusion criteria in the aforementioned trial.
CASE SUMMARY A 53-year-old man (case 1) and 66-year-old woman (case 2) with uHCC presented to us with a tumor thrombus in both the main portal vein and inferior vena cava, a high tumor burden accompanied by a tumor diameter greater than > 100 mm, and distant metastasis, with the residual liver function classified as grade 2A according to the modified Albumin–Bilirubin grading. We started both patients on lenvatinib. The therapeutic effect, as evaluated by the modified Response Evaluation Criteria in Solid Tumors, was rated as partial response in both case 1 and case 2 (at 8 wk and 4 wk after the start of lenvatinib administration, respectively). The therapeutic effect was sustained for 6 mo in case 1 and 20 mo in case 2. Fever occurred as an adverse event in both case 1 and 2, and hyperthyroidism and thrombocytopenia in only case 2, neither of which, however, necessitated treatment discontinuation.
CONCLUSION Even in hepatocellular carcinoma patients with poor prognostic factors, if the liver function is well-preserved, lenvatinib is effective and safe.
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Affiliation(s)
- Satoshi Komiyama
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 2320024, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 2320024, Japan
| | - Satoshi Moriya
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 2320024, Japan
| | - Hiroyuki Fukuda
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 2320024, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Kanagawa 2320024, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 2360004, Japan
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Kawamura Y, Kobayashi M, Shindoh J, Kobayashi Y, Kasuya K, Sano T, Fujiyama S, Hosaka T, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ikeda K, Arase Y, Hashimoto M, Kumada H. Pretreatment Heterogeneous Enhancement Pattern of Hepatocellular Carcinoma May Be a Useful New Predictor of Early Response to Lenvatinib and Overall Prognosis. Liver Cancer 2020; 9:275-292. [PMID: 32647631 PMCID: PMC7325131 DOI: 10.1159/000505190] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/03/2019] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE The aim of this study was to evaluate the performance of pretreatment computed tomography (CT) enhancement of hepatocellular carcinoma (HCC) as a potential predictor of response to lenvatinib and its relevance to survival outcomes. METHODS We evaluated 51 consecutive patients who received lenvatinib treatment for unresectable HCC. On imaging analysis, pretreatment arterial/portal phase dynamic CT images were classified as follows: type 2, homogeneous enhancement pattern with increased arterial blood flow; type 3, heterogeneous enhancement pattern with a septum-like structure; and type 4, heterogeneous enhancement pattern with irregularly shaped ring structures. Treatment response was evaluated using modified Response Evaluation Criteria in Solid Tumors at 2-12 weeks after initiation of lenvatinib, and the correlations between the CT enhancement patterns and response to lenvatinib or survival outcomes were investigated. RESULTS Of the 51 patients, 38 (75%) experienced an objective response (OR). ORs were significantly more common in heterogeneously enhanced HCC (types 3 and 4) than in homogeneous HCC (type 2) (83 vs. 53%, respectively; p = 0.037). Multivariate analysis revealed that pretreatment heterogeneous enhancement pattern is an independent predictor for response to lenvatinib (odds ratio, 4.75; p = 0.042). Presence of OR was associated with longer progression-free survival (PFS) (hazard ratio, 0.36; p = 0.017), and patients with oncologically aggressive type 3 and 4 tumors showed similar PFS to those harboring type 2 tumors (p = 0.455), reflecting that OR was more common in type 3 or 4 tumors compared with type 2 tumors. Although postprogression survival was extremely poor in patients with type 4 tumors (p = 0.064), overall survival after introduction of lenvatinib was not statistically different among the three groups of patients (p = 0.053). CONCLUSION The CT enhancement pattern of HCC may predict response to lenvatinib. OR seems to occur more frequently in HCC with oncologically aggressive features and may contribute to prolonged survival through a prolonged progression-free interval, even in an oncologically poor-risk group of patients.
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Affiliation(s)
- Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Junichi Shindoh
- Hepatobiliary-Pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yuta Kobayashi
- Hepatobiliary-Pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Kayoko Kasuya
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Tomoya Sano
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Masaji Hashimoto
- Hepatobiliary-Pancreatic Surgery Division, Department of Gastroenterological Surgery, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
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Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment. Cells 2020; 9:1370. [PMID: 32492896 PMCID: PMC7349517 DOI: 10.3390/cells9061370] [Citation(s) in RCA: 315] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina;
- Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
| | - Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina;
| | - Mário G. Pessôa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
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Kirino S, Tsuchiya K, Kurosaki M, Kaneko S, Inada K, Yamashita K, Osawa L, Hayakawa Y, Sekiguchi S, Okada M, Wang W, Higuchi M, Takaura K, Maeyashiki C, Tamaki N, Yasui Y, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Izumi N. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PLoS One 2020; 15:e0231828. [PMID: 32310967 PMCID: PMC7170221 DOI: 10.1371/journal.pone.0231828] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 04/01/2020] [Indexed: 01/26/2023] Open
Abstract
Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%–100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09–0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16–0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI <70% (91.7% vs. 54.2%, p = 0.008). A baseline albumin level >3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.
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Affiliation(s)
- Sakura Kirino
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shun Kaneko
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Koji Yamashita
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Leona Osawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Hayakawa
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Shuhei Sekiguchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mao Okada
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Wan Wang
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Mayu Higuchi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Kenta Takaura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroyuki Nakanishi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yuka Takahashi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
- * E-mail:
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Early Predictors of Objective Response in Patients with Hepatocellular Carcinoma Undergoing Lenvatinib Treatment. Cancers (Basel) 2020; 12:cancers12040779. [PMID: 32218295 PMCID: PMC7225985 DOI: 10.3390/cancers12040779] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 02/08/2023] Open
Abstract
There are limited reports regarding early predictors of objective response (OR) in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. This retrospective study including 70 patients aimed to investigate the efficacy of hepatic biochemical markers. Changes in tumor marker (alpha-fetoprotein (AFP)/des-gamma-carboxy prothrombin (DCP)) levels and albumin-bilirubin (ALBI) score between the baseline value and that estimated one month after treatment were evaluated. We identified several predictors of OR, including changes in tumor marker levels. The OR rate calculated using modified Response Evaluation Criteria in Solid Tumor (mRECIST) was 41.4%. Response was defined as a reduction in AFP and DCP levels of ≥40% from baseline. OR was significantly associated with AFP response, but not with DCP. Predictors of OR were evaluated in two groups (high-AFP group: baseline AFP ≥ 10 ng/mL; low-AFP group: remaining patients). A multivariate analysis identified AFP response (odds ratio, 51.389; p = 0.001) and ALBI score (odds ratio, 6.866; p = 0.039) as independent predictors of OR in the high-AFP and low-AFP groups, respectively. Changes in the ALBI score indicated deterioration in both responders and non-responders, with a significant difference in non-responders (p = 0.003). AFP response, baseline ALBI score, and change in the ALBI score were early predictors of OR in patients with HCC undergoing lenvatinib treatment.
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Takahashi A, Moriguchi M, Seko Y, Shima T, Mitsumoto Y, Takashima H, Kimura H, Fujii H, Ishikawa H, Yo T, Ishiba H, Morita A, Jo M, Nagao Y, Arai M, Hara T, Okajima A, Muramatsu A, Yoshinami N, Nakajima T, Mitsuyoshi H, Umemura A, Nishikawa T, Yamaguchi K, Okanoue T, Itoh Y. Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis. Cancers (Basel) 2020; 12:cancers12030754. [PMID: 32209994 PMCID: PMC7140019 DOI: 10.3390/cancers12030754] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/15/2020] [Accepted: 03/18/2020] [Indexed: 02/08/2023] Open
Abstract
We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions’ longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child–Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.
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Affiliation(s)
- Aya Takahashi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Correspondence: ; Tel.: +81-75-251-5519; Fax: +81-75-251-0710
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, Japan
| | - Yasuhide Mitsumoto
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, Japan
| | - Hidetaka Takashima
- Department of Gastroenterology, Osaka General Hospital of West Japan Railway Company, Osaka 545-0053, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan
| | - Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 605-0981, Japan
| | - Hiroki Ishikawa
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Omihachiman 523-0082, Japan
| | - Takaharu Yo
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Omihachiman 523-0082, Japan
| | - Hiroshi Ishiba
- Department of Gastroenterology and Hepatology, North Medical Center of Kyoto Prefectural University of Medicine, Yosagun 629-2261, Japan
| | - Atsuhiro Morita
- Department of Gastroenterology, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan
| | - Masayasu Jo
- Department of Gastroenterology, Otsu City Hospital, Otsu 520-0804, Japan
| | - Yasuyuki Nagao
- Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi 570-8540, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Kyoto Yamashiro General Medical Center, Kizugawa 619-0214, Japan
| | - Tasuku Hara
- Department of Gastroenterology, Fukuchiyama City Hospital, Fukuchiyama 620-8505, Japan
| | - Akira Okajima
- Department of Gastroenterology, Koseikai Takeda Hospital, Kyoto 600-8558, Japan
| | - Akira Muramatsu
- Department of Gastroenterology, Akashi City Hospital, Akashi 673-8501, Japan
| | - Naomi Yoshinami
- Department of Gastroenterology, Kyoto City Hospital, Kyoto 604-8845, Japan
| | - Tomoki Nakajima
- Department of Gastroenterology, Saiseikai Kyoto Hospital, Kyoto 617-0814, Japan
| | - Hironori Mitsuyoshi
- Department of Gastroenterology and Hepatology, Kyoto Chubu Medical Center, Kyoto 629-0197, Japan
| | - Atsushi Umemura
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Taichiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M. Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma. Hepatol Res 2020; 50:374-381. [PMID: 31721363 DOI: 10.1111/hepr.13452] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/22/2019] [Accepted: 11/01/2019] [Indexed: 02/08/2023]
Abstract
AIM We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. METHODS This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. RESULTS The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). CONCLUSIONS The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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