G. Abou-Alfa, Tim Meyer, Richard K. G. Do, S. Piha-Paul, Joseph S Light, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, James J. Harding, Raed Al-Rajabi, Crystal S. Denlinger, Pablo Cano, Albert S. Cornelius, Eileen M. O’Reilly, D. Diprimeo, L. Eli, John D. Gordan, D. Solit
Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mTOR inhibitors (compassionate-use program) in patients with FLC. Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% CI 0–21.8) and the disease control rate was 13.3% (95% CI 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.
简介纤维母细胞瘤（FLC）表现出包括HER2在内的多种癌基因上调和多种免疫抑制机制。我们研究了泛HER酪氨酸激酶抑制剂奈拉替尼作为单药（SUMMIT 2期篮子研究）或与免疫检查点和/或mTOR抑制剂（compassionate-use计划）一起用于FLC患者的疗效和安全性：在SUMMIT研究中，患者口服奈拉替尼240毫克/天，或与pembrolizumab 2毫克/千克静脉注射每3周一次、nivolumab 240毫克静脉注射每2周一次、依维莫司7.5毫克/天口服或舒尼替尼37.5毫克/天口服进行双联用或三联用。SUMMIT的主要终点是客观反应率，安全性是次要终点：15名FLC患者在SUMMIT中接受了奈拉替尼单药治疗。客观反应率为5%（95% CI 0-21.8），疾病控制率为13.3%（95% CI 1.7-40.5）。病情恶化后，有五名患者在使用或不使用依维莫司或舒尼替尼的情况下加用了免疫检查点抑制剂。另有两名患者在SUMMIT之外接受了基于奈拉替尼的联合治疗，总共有17名患者接受了奈拉替尼治疗。其中一名接受了奈拉替尼加pembrolizumab治疗的患者确诊为部分应答，一名接受了奈拉替尼加依维莫司治疗的患者病情稳定了6个月，一名接受了奈拉替尼加pembrolizumab加舒尼替尼治疗的患者病情稳定了16个月。接受奈拉替尼单药治疗的患者中，分别有10人（66.7%）和2人（13.3%）出现了3/4级不良事件。奈拉替尼联合疗法的3级不良事件为高血糖（n = 1；奈拉替尼加pembrolizumab）、肝功能衰竭和过敏性休克（各n = 1，奈拉替尼加pembrolizumab加依维莫司）。联合疗法未出现4级不良事件：结论：在FLC患者中，单药奈拉替尼的疗效有限，但奈拉替尼与免疫疗法和/或mTOR靶向药物联合使用可观察到临床获益。
{"title":"Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without mTOR Inhibitors in Patients with Fibrolamellar Carcinoma","authors":"G. Abou-Alfa, Tim Meyer, Richard K. G. Do, S. Piha-Paul, Joseph S Light, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, James J. Harding, Raed Al-Rajabi, Crystal S. Denlinger, Pablo Cano, Albert S. Cornelius, Eileen M. O’Reilly, D. Diprimeo, L. Eli, John D. Gordan, D. Solit","doi":"10.1159/000540290","DOIUrl":"https://doi.org/10.1159/000540290","url":null,"abstract":"Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mTOR inhibitors (compassionate-use program) in patients with FLC.\u0000Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint.\u0000Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% CI 0–21.8) and the disease control rate was 13.3% (95% CI 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy.\u0000Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":11.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sungeun Park, Boyeon Koo, B. Jeong, Sang Hyun Choi, Jeong Min Lee
Introduction The Liver Imaging Reporting and Data System (LI-RADS) categorization has been proposed as a potential prognostic indicator for primary liver neoplasms in patients with liver cirrhosis or chronic hepatitis B. This multicenter study aimed to determine whether LI-RADS categorization can offer additional post-surgical prognostic value for intrahepatic cholangiocarcinoma (ICCA) when used in conjunction with the American Joint Committee on Cancer (AJCC) guidelines. Methods Patients with high risk for hepatocellular carcinoma, surgically confirmed ICCAs, and available preoperative MRI were enrolled. LI-RADS categorization of ICCAs was performed using MRI features, and multivariate analyses were conducted incorporating LI-RADS category, AJCC staging, and clinicopathologic factors to evaluate their predictive value for postoperative recurrence-free survival (RFS) and overall survival (OS). In patients with early recurrence (<2-years), the percentages of AJCC stage I and LR-M or LR tumor-in-vein (TIV) were calculated, respectively. Results Among the 166 ICCAs analyzed, 13.3% (22/166) were classified as LR-4/5, 77.7% (129/166) as LR-M, and 9.0% (15/166) as LR TIV. Classifications according to the 8th AJCC guidelines for patients with available post-surgical pathologic data and follow-up imaging were 40.6% (63/155) stage I tumors, 23.9% (37/155) stage II, and 35.5% (55/155) stage III. Multivariate analysis revealed that LI-RADS category (LR-M or LR-TIV) was a significant factor for predicting both RFS (hazard ratio [HR]=2.86, p=.02) and OS (HR=3.18, p=.03). Additionally, AJCC staging (II or III) was a significant factor for RFS (HR=3.90, p<.001) and OS (HR=3.29, p<.001), male sex was a significant factor for RFS (HR=1.89, p=.006) and OS (HR=2.23, p=.002), and positive resection margin was a significant factor for OS (HR=1.91, p=.03). Among the 80 patients with early recurrence, 97.5% displayed LR-M or LR-TIV features, while 11.3% were AJCC stage I patients. Conclusion The MRI-based preoperative LI-RADS categorization of ICCA provides additional post-surgical prognostic value beyond the AJCC guidelines, with significant implications for both RFS and OS.
导言：肝脏成像报告和数据系统（LI-RADS）分类已被提出作为肝硬化或慢性乙型肝炎患者原发性肝肿瘤的潜在预后指标。这项多中心研究旨在确定当与美国癌症联合委员会（AJCC）指南结合使用时，LI-RADS分类是否能为肝内胆管癌（ICCA）提供额外的术后预后价值。方法 选取肝细胞癌高风险、经手术确诊为 ICCA 且可进行术前 MRI 检查的患者作为研究对象。利用磁共振成像特征对ICCA进行LI-RADS分类，并结合LI-RADS分类、AJCC分期和临床病理因素进行多变量分析，以评估它们对术后无复发生存期（RFS）和总生存期（OS）的预测价值。结果 在分析的 166 例 ICCA 中，13.3%（22/166）被归类为 LR-4/5，77.7%（129/166）被归类为 LR-M，9.0%（15/166）被归类为 LR TIV。根据第 8 版 AJCC 指南，有术后病理数据和随访影像学资料的患者的肿瘤分期为：40.6%（63/155）为 I 期，23.9%（37/155）为 II 期，35.5%（55/155）为 III 期。多变量分析显示，LI-RADS分类（LR-M或LR-TIV）是预测RFS（危险比[HR]=2.86，P=.02）和OS（HR=3.18，P=.03）的重要因素。此外，AJCC分期（II或III）是预测RFS（HR=3.90，p<.001）和OS（HR=3.29，p<.001）的重要因素，男性是预测RFS（HR=1.89，p=.006）和OS（HR=2.23，p=.002）的重要因素，切除边缘阳性是预测OS（HR=1.91，p=.03）的重要因素。在80例早期复发患者中，97.5%具有LR-M或LR-TIV特征，11.3%为AJCC I期患者。
{"title":"LI-RADS category can be a post-surgical prognostic factor for intrahepatic cholangiocarcinoma in patients with liver cirrhosis or chronic hepatitis B","authors":"Sungeun Park, Boyeon Koo, B. Jeong, Sang Hyun Choi, Jeong Min Lee","doi":"10.1159/000539794","DOIUrl":"https://doi.org/10.1159/000539794","url":null,"abstract":"Introduction The Liver Imaging Reporting and Data System (LI-RADS) categorization has been proposed as a potential prognostic indicator for primary liver neoplasms in patients with liver cirrhosis or chronic hepatitis B. This multicenter study aimed to determine whether LI-RADS categorization can offer additional post-surgical prognostic value for intrahepatic cholangiocarcinoma (ICCA) when used in conjunction with the American Joint Committee on Cancer (AJCC) guidelines. \u0000Methods Patients with high risk for hepatocellular carcinoma, surgically confirmed ICCAs, and available preoperative MRI were enrolled. LI-RADS categorization of ICCAs was performed using MRI features, and multivariate analyses were conducted incorporating LI-RADS category, AJCC staging, and clinicopathologic factors to evaluate their predictive value for postoperative recurrence-free survival (RFS) and overall survival (OS). In patients with early recurrence (<2-years), the percentages of AJCC stage I and LR-M or LR tumor-in-vein (TIV) were calculated, respectively.\u0000Results Among the 166 ICCAs analyzed, 13.3% (22/166) were classified as LR-4/5, 77.7% (129/166) as LR-M, and 9.0% (15/166) as LR TIV. Classifications according to the 8th AJCC guidelines for patients with available post-surgical pathologic data and follow-up imaging were 40.6% (63/155) stage I tumors, 23.9% (37/155) stage II, and 35.5% (55/155) stage III. Multivariate analysis revealed that LI-RADS category (LR-M or LR-TIV) was a significant factor for predicting both RFS (hazard ratio [HR]=2.86, p=.02) and OS (HR=3.18, p=.03). Additionally, AJCC staging (II or III) was a significant factor for RFS (HR=3.90, p<.001) and OS (HR=3.29, p<.001), male sex was a significant factor for RFS (HR=1.89, p=.006) and OS (HR=2.23, p=.002), and positive resection margin was a significant factor for OS (HR=1.91, p=.03). Among the 80 patients with early recurrence, 97.5% displayed LR-M or LR-TIV features, while 11.3% were AJCC stage I patients.\u0000Conclusion The MRI-based preoperative LI-RADS categorization of ICCA provides additional post-surgical prognostic value beyond the AJCC guidelines, with significant implications for both RFS and OS. ","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141341262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kyu-pyo Kim, Kang Mo Kim, B. Ryoo, Won-Mook Choi, Won Chul Cha, Mira Kang, Dongjoo Sinn, M. Goh, Do Young Kim, Min Ji Lee, Subin Lim, DongKyu Kim, Kyoungdae Baek, Joohyun Kim, Eui Jun Choi, Doik Lee, Jung-Ae Kim, Ki-Hun Kim
Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the Albumin-Bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database. Methods: The Liver Cancer IN Korea (LINK) research network, a multi-center initiative, retrospectively collected electronic medical records from three academic hospitals in South Korea, encompassing HCC patients diagnosed between 2015 and 2020. Inclusion criteria mandated at least one HCC treatment and excluded patients with other primary cancer diagnoses. The study followed patients until death, the last visit, or June 2021, employing standardized data processing and rule-based algorithms for data consistency. The prognostic efficacy of ALBI scores and CP scores was compared through time-dependent receiver operating characteristic (ROC) curves and the inverse probability censoring weighting method. Results: From 25,248 newly diagnosed patients, 10,297 were included, with 65.82% having hepatitis B etiology and a median follow-up of 27.49 months. Patients’ classification by modified ALBI (mALBI) grade at diagnosis revealed: grade 1 (48.87%), 2a (20.50%), 2b (24.54%), and 3 (5.17%), with a minimal percentage missing (0.92%). Transarterial therapy (54.07%) and tyrosine kinase inhibitors (84.14% as the first-line systemic therapy) were predominant treatments. The ALBI score demonstrated greater prognostic efficacy than the CP score in long-term outcomes, with time-dependent area under the ROC curve analysis showing a score of 0.71 for ALBI versus 0.67 for CP at 60 months. Furthermore, higher mALBI grades were significantly associated with poorer survival outcomes, as indicated by both univariate and multivariate Cox proportional regression model analyses (p < 0.001). Conclusions: The study confirmed the ALBI score’s superior prognostic ability over the CP score, especially evident in long-term outcomes, suggesting a shift towards more nuanced liver function assessment tools in real-world clinical practice.
{"title":"Prognostic Efficacy of the Albumin-Bilirubin Score and Treatment Outcomes in Hepatocellular Carcinoma: A Large-Scale, Multi-Center Real-World Database Study","authors":"Kyu-pyo Kim, Kang Mo Kim, B. Ryoo, Won-Mook Choi, Won Chul Cha, Mira Kang, Dongjoo Sinn, M. Goh, Do Young Kim, Min Ji Lee, Subin Lim, DongKyu Kim, Kyoungdae Baek, Joohyun Kim, Eui Jun Choi, Doik Lee, Jung-Ae Kim, Ki-Hun Kim","doi":"10.1159/000539724","DOIUrl":"https://doi.org/10.1159/000539724","url":null,"abstract":"Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the Albumin-Bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database.\u0000\u0000Methods: The Liver Cancer IN Korea (LINK) research network, a multi-center initiative, retrospectively collected electronic medical records from three academic hospitals in South Korea, encompassing HCC patients diagnosed between 2015 and 2020. Inclusion criteria mandated at least one HCC treatment and excluded patients with other primary cancer diagnoses. The study followed patients until death, the last visit, or June 2021, employing standardized data processing and rule-based algorithms for data consistency. The prognostic efficacy of ALBI scores and CP scores was compared through time-dependent receiver operating characteristic (ROC) curves and the inverse probability censoring weighting method.\u0000\u0000Results: From 25,248 newly diagnosed patients, 10,297 were included, with 65.82% having hepatitis B etiology and a median follow-up of 27.49 months. Patients’ classification by modified ALBI (mALBI) grade at diagnosis revealed: grade 1 (48.87%), 2a (20.50%), 2b (24.54%), and 3 (5.17%), with a minimal percentage missing (0.92%). Transarterial therapy (54.07%) and tyrosine kinase inhibitors (84.14% as the first-line systemic therapy) were predominant treatments. The ALBI score demonstrated greater prognostic efficacy than the CP score in long-term outcomes, with time-dependent area under the ROC curve analysis showing a score of 0.71 for ALBI versus 0.67 for CP at 60 months. Furthermore, higher mALBI grades were significantly associated with poorer survival outcomes, as indicated by both univariate and multivariate Cox proportional regression model analyses (p < 0.001).\u0000\u0000Conclusions: The study confirmed the ALBI score’s superior prognostic ability over the CP score, especially evident in long-term outcomes, suggesting a shift towards more nuanced liver function assessment tools in real-world clinical practice.\u0000","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141339267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Masanori Inoue, S. Ogasawara, Kazufumi Kobayashi, T. Okubo, N. Itokawa, Masamichi Obu, Kentaro Fujimoto, Hidemi Unozawa, S. Yumita, K. Fujiwara, Miyuki Nakagawa, Hiroaki Kanzaki, K. Koroki, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Shingo Nakamoto, Kengo Nagashima, E. Itobayashi, M. Atsukawa, Yoshihiro Koma, R. Azemoto, Naoya Kato
Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.
{"title":"Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy","authors":"Masanori Inoue, S. Ogasawara, Kazufumi Kobayashi, T. Okubo, N. Itokawa, Masamichi Obu, Kentaro Fujimoto, Hidemi Unozawa, S. Yumita, K. Fujiwara, Miyuki Nakagawa, Hiroaki Kanzaki, K. Koroki, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Shingo Nakamoto, Kengo Nagashima, E. Itobayashi, M. Atsukawa, Yoshihiro Koma, R. Azemoto, Naoya Kato","doi":"10.1159/000539380","DOIUrl":"https://doi.org/10.1159/000539380","url":null,"abstract":"Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. \u0000Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD.\u0000Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498).\u0000Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.\u0000\u0000","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141116673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Hatanaka, Atsushi Hiraoka, Toshifumi Tada, Satoru Kakizaki
{"title":"Letter regarding ‘Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 study’","authors":"T. Hatanaka, Atsushi Hiraoka, Toshifumi Tada, Satoru Kakizaki","doi":"10.1159/000538580","DOIUrl":"https://doi.org/10.1159/000538580","url":null,"abstract":"","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140374959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Finn, Shukui Qin, Fabio Piscaglia, Thomas R Jeffry Evans, Jennifer J. Knox, C. López López, Z. Ramji, Min Ren, K. Mody, Arndt Vogel, Masatoshi Kudo
Introduction: In REFLECT, lenvatinib was noninferior to sorafenib in terms of overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC; median 13.6 vs 12.3 months; HR 0.92, 95% CI 0.79-1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per Response Evaluation Criteria in Solid tumors version 1.1 (RECIST v1.1); per modified RECIST (mRECIST), the ORR was 40.6%. We sought to further characterize these tumor responses and explore ORR’s importance among outcomes for patients with HCC. Methods: Efficacy assessments included all patients randomized to receive lenvatinib treatment (body weight ≥60 kg, 12 mg/day; <60 kg, 8 mg/day). Time to first objective response (TTR) and duration of response (DOR) included patients who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Results: 478 Patients were randomized to receive lenvatinib. By IIR, 90 patients (18.8%) achieved an objective response per RECIST v1.1 and 194 (40.6%) had an objective response per mRECIST. Median TTR/DOR were 2.8 months/7.4 months in responders per RECIST v1.1, and 1.9 months/7.3 months in responders per mRECIST, respectively. Per baseline disease characteristics, ORRs by Child-Pugh score (A5/A6) were 21.2%/11.2% per RECIST v1.1 and 42.9%/33.6% per mRECIST, respectively. By baseline alpha-fetoprotein (AFP) level (<400/≥400 ng/mL), ORRs were: 21.4%/15.4% per RECIST v1.1 and 45.6%/33.8% per mRECIST, respectively. Incidences of treatment-related treatment-emergent adverse events were 98.9% in responders per RECIST v1.1 and 97.9% in responders per mRECIST. Conclusions: Responses were seen even in those patients with more severe disease at baseline. Tumor responses occurred early and were durable.
{"title":"Characterization of Tumor Responses in Patients With Unresectable Hepatocellular Carcinoma Treated With Lenvatinib in the Phase 3 Randomized Trial, REFLECT","authors":"R. Finn, Shukui Qin, Fabio Piscaglia, Thomas R Jeffry Evans, Jennifer J. Knox, C. López López, Z. Ramji, Min Ren, K. Mody, Arndt Vogel, Masatoshi Kudo","doi":"10.1159/000537947","DOIUrl":"https://doi.org/10.1159/000537947","url":null,"abstract":"Introduction: In REFLECT, lenvatinib was noninferior to sorafenib in terms of overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC; median 13.6 vs 12.3 months; HR 0.92, 95% CI 0.79-1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per Response Evaluation Criteria in Solid tumors version 1.1 (RECIST v1.1); per modified RECIST (mRECIST), the ORR was 40.6%. We sought to further characterize these tumor responses and explore ORR’s importance among outcomes for patients with HCC.\u0000\u0000Methods: Efficacy assessments included all patients randomized to receive lenvatinib treatment (body weight ≥60 kg, 12 mg/day; <60 kg, 8 mg/day). Time to first objective response (TTR) and duration of response (DOR) included patients who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. \u0000\u0000Results: 478 Patients were randomized to receive lenvatinib. By IIR, 90 patients (18.8%) achieved an objective response per RECIST v1.1 and 194 (40.6%) had an objective response per mRECIST. Median TTR/DOR were 2.8 months/7.4 months in responders per RECIST v1.1, and 1.9 months/7.3 months in responders per mRECIST, respectively. Per baseline disease characteristics, ORRs by Child-Pugh score (A5/A6) were 21.2%/11.2% per RECIST v1.1 and 42.9%/33.6% per mRECIST, respectively. By baseline alpha-fetoprotein (AFP) level (<400/≥400 ng/mL), ORRs were: 21.4%/15.4% per RECIST v1.1 and 45.6%/33.8% per mRECIST, respectively. Incidences of treatment-related treatment-emergent adverse events were 98.9% in responders per RECIST v1.1 and 97.9% in responders per mRECIST.\u0000\u0000Conclusions: Responses were seen even in those patients with more severe disease at baseline. Tumor responses occurred early and were durable.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140430290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Finn, Masatoshi Kudo, Gisoo Barnes, Tim Meyer, F. Boisserie, R. Abdrashitov, Yaxi Chen, Songzi Li, Andrew X. Zhu, Shukui Qin, Arndt Vogel
Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy–naive adults with HCC were randomized 1:1 to receive tislelizumab n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change differences in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR, 0.68; 95% CI, 0.49-0.94), QLQ-C30 physical functioning (HR, 0.46; 95% CI, 0.33-0.64) and fatigue (HR, 0.48; 95% CI, 0.37-0.63), QLQ-HCC18 symptom index (HR, 0.53; 95% CI, 0.34-0.81), and HCC-specific fatigue (HR, 0.60; 95% CI, 0.46-0.80). For pain, both arms had similar risk of deterioration (HR, 0.78; 95% CI, 0.56-1.09). At cycle 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had better HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.
{"title":"Tislelizumab vs sorafenib in first-line treatment of unresectable hepatocellular carcinoma: impact on health-related quality of life in RATIONALE-301 study","authors":"R. Finn, Masatoshi Kudo, Gisoo Barnes, Tim Meyer, F. Boisserie, R. Abdrashitov, Yaxi Chen, Songzi Li, Andrew X. Zhu, Shukui Qin, Arndt Vogel","doi":"10.1159/000537966","DOIUrl":"https://doi.org/10.1159/000537966","url":null,"abstract":"Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms.\u0000Methods: Systemic therapy–naive adults with HCC were randomized 1:1 to receive tislelizumab n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints.\u0000Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change differences in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR, 0.68; 95% CI, 0.49-0.94), QLQ-C30 physical functioning (HR, 0.46; 95% CI, 0.33-0.64) and fatigue (HR, 0.48; 95% CI, 0.37-0.63), QLQ-HCC18 symptom index (HR, 0.53; 95% CI, 0.34-0.81), and HCC-specific fatigue (HR, 0.60; 95% CI, 0.46-0.80). For pain, both arms had similar risk of deterioration (HR, 0.78; 95% CI, 0.56-1.09). At cycle 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. \u0000\u0000Conclusion: Patients with 1L HCC treated with tislelizumab had better HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.\u0000","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140444906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Urgent Global Need for PIVKA-II and AFP-L3 Measurements for Surveillance and Management of Hepatocellular Carcinoma","authors":"Masatoshi Kudo","doi":"10.1159/000537897","DOIUrl":"https://doi.org/10.1159/000537897","url":null,"abstract":"<jats:p>NA</jats:p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140447079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuki Kunimune, Yutaka Suehiro, I. Saeki, Yurika Yamauchi, N. Tanabe, Toshihiko Matsumoto, S. Higaki, Ikuei Fujii, Chieko Suzuki, N. Okayama, Mitsuaki Nishioka, Kiyoshi Ichihara, Hiroaki Nagano, Isao Sakaida, T. Takami, Takahiro Yamasaki
Introduction: Patients with hepatitis virus-related hepatocellular carcinoma (viral HCC) are decreasing as hepatitis control improves, but those with non-viral-related HCC (non-viral HCC) are increasing in Japan. No established surveillance system exists for patients with non-viral HCC, so they are often diagnosed at an advanced stage. To address this, we performed this study. Methods: We collected serum samples from 516 participants (154 healthy subjects, 93 chronic liver disease [CLD] patients without HCC, and 269 HCC patients). Participants were divided into a control group comprising healthy subjects and patients with CLD and an HCC group. We evaluated serum methylated HOXA1 (m-HOXA1) copy numbers using modified combined restriction digital PCR (CORD) assay (1-step CORD assay). We assessed diagnostic performance of m-HOXA1 compared to HCC tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) and created a novel index to improve HCC prediction. Results: Serum m-HOXA1 level was significantly higher in each HCC stage group versus the control group. Its sensitivity was 69.1% and specificity was 78.5% for diagnosing HCC. The area under the curve (AUC) of m-HOXA1 was superior to that of AFP and equal to that of DCP. Multivariate logistic regression analysis revealed independent contributions of m-HOXA1, DCP, and AFP, in that order of strength, to diagnose HCC after adjustment for age and sex. We designated the predictive probability of HCC based on the regression model as the ASDAm-H1 (Age, Sex, DCP, AFP, and m-HOXA1) index. Its diagnostic accuracy was 0.96 by AUC with a sensitivity of 86.2% and specificity of 93.9%. Sensitivity was identical for viral and non-viral HCCs. When limited to early-stage HCC, sensitivity of the ASDAm-H1 index was 76.3%. Conclusions: We showed distinguished performance of the ASDAm-H1 index to detect viral and non-viral HCC, even at an early stage. This index might have potential as a non-viral HCC surveillance system.
{"title":"Combination Assay of Methylated HOXA1 with Tumor Markers Shows High Sensitivity for Detection of Early-Stage Hepatocellular Carcinoma","authors":"Yuki Kunimune, Yutaka Suehiro, I. Saeki, Yurika Yamauchi, N. Tanabe, Toshihiko Matsumoto, S. Higaki, Ikuei Fujii, Chieko Suzuki, N. Okayama, Mitsuaki Nishioka, Kiyoshi Ichihara, Hiroaki Nagano, Isao Sakaida, T. Takami, Takahiro Yamasaki","doi":"10.1159/000536211","DOIUrl":"https://doi.org/10.1159/000536211","url":null,"abstract":"<b><i>Introduction:</i></b> Patients with hepatitis virus-related hepatocellular carcinoma (viral HCC) are decreasing as hepatitis control improves, but those with non-viral-related HCC (non-viral HCC) are increasing in Japan. No established surveillance system exists for patients with non-viral HCC, so they are often diagnosed at an advanced stage. To address this, we performed this study. <b><i>Methods:</i></b> We collected serum samples from 516 participants (154 healthy subjects, 93 chronic liver disease [CLD] patients without HCC, and 269 HCC patients). Participants were divided into a control group comprising healthy subjects and patients with CLD and an HCC group. We evaluated serum methylated <i>HOXA1</i> (m-<i>HOXA1</i>) copy numbers using modified combined restriction digital PCR (CORD) assay (1-step CORD assay). We assessed diagnostic performance of m-<i>HOXA1</i> compared to HCC tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) and created a novel index to improve HCC prediction. <b><i>Results:</i></b> Serum m-<i>HOXA1</i> level was significantly higher in each HCC stage group versus the control group. Its sensitivity was 69.1% and specificity was 78.5% for diagnosing HCC. The area under the curve (AUC) of m-<i>HOXA1</i> was superior to that of AFP and equal to that of DCP. Multivariate logistic regression analysis revealed independent contributions of m-<i>HOXA1</i>, DCP, and AFP, in that order of strength, to diagnose HCC after adjustment for age and sex. We designated the predictive probability of HCC based on the regression model as the ASDAm-H1 (<underline>A</underline>ge, <underline>S</underline>ex, <underline>D</underline>CP, <underline>A</underline>FP, and <underline>m</underline><underline>-</underline><i><underline>H</underline>OXA<underline>1</underline></i>) index. Its diagnostic accuracy was 0.96 by AUC with a sensitivity of 86.2% and specificity of 93.9%. Sensitivity was identical for viral and non-viral HCCs. When limited to early-stage HCC, sensitivity of the ASDAm-H1 index was 76.3%. <b><i>Conclusions:</i></b> We showed distinguished performance of the ASDAm-H1 index to detect viral and non-viral HCC, even at an early stage. This index might have potential as a non-viral HCC surveillance system.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140456586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan established HCC management consensus guidelines in 2016 and updated them in 2023. Current recommendations focus on addressing critical issues in HCC management, including surveillance, diagnosis, systemic treatment, and posttreatment monitoring. For surveillance and diagnosis, we updated the guidelines to include the role of protein induced by vitamin K absence or antagonist II (PIVKA-II) and gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in detecting HCCs. For systemic treatment, the updated guidelines summarize the multiple choices available for targeted therapy, immune checkpoint inhibitors, and a combination of both, especially for those carcinomas refractory to or unsuitable for transarterial chemoembolization. We have added a new section, posttreatment monitoring, that describes the important roles of PIVKA-II and EOB-MRI after HCC therapy, including surgery, locoregional therapy, and systemic treatment. Through this update of the management consensus guidelines, patients with HCC may benefit from optimal diagnosis, therapeutic modalities, and posttreatment monitoring.
{"title":"Management Consensus Guidelines for Hepatocellular Carcinoma: 2023 Update on Surveillance, Diagnosis, Systemic Treatment, and Posttreatment Monitoring by the Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan","authors":"Wei Teng, Hung-Wei Wang, Shi-Ming Lin","doi":"10.1159/000537686","DOIUrl":"https://doi.org/10.1159/000537686","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan established HCC management consensus guidelines in 2016 and updated them in 2023. Current recommendations focus on addressing critical issues in HCC management, including surveillance, diagnosis, systemic treatment, and posttreatment monitoring. For surveillance and diagnosis, we updated the guidelines to include the role of protein induced by vitamin K absence or antagonist II (PIVKA-II) and gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in detecting HCCs. For systemic treatment, the updated guidelines summarize the multiple choices available for targeted therapy, immune checkpoint inhibitors, and a combination of both, especially for those carcinomas refractory to or unsuitable for transarterial chemoembolization. We have added a new section, posttreatment monitoring, that describes the important roles of PIVKA-II and EOB-MRI after HCC therapy, including surgery, locoregional therapy, and systemic treatment. Through this update of the management consensus guidelines, patients with HCC may benefit from optimal diagnosis, therapeutic modalities, and posttreatment monitoring.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140458144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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