A. Ichida, J. Arita, E. Hatano, S. Eguchi, A. Saiura, Hiroaki Nagano, J. Shindoh, Masaji Hashimoto, Nobuyuki Takemura, K. Taura, Y. Sakamoto, Yu Takahashi, Y. Seyama, Yasuharu Sasaki, Kohei Uemura, N. Kokudo, Kiyoshi Hasegawa
Introduction: The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC. Methods: In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 minutes as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057). Results: Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months. Conclusions: The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC.
{"title":"A Multicenter Phase 2 Trial Evaluating the Efficacy and Safety of Preoperative Lenvatinib Therapy for Patients with Advanced Hepatocellular Carcinoma (LENS-HCC Trial)","authors":"A. Ichida, J. Arita, E. Hatano, S. Eguchi, A. Saiura, Hiroaki Nagano, J. Shindoh, Masaji Hashimoto, Nobuyuki Takemura, K. Taura, Y. Sakamoto, Yu Takahashi, Y. Seyama, Yasuharu Sasaki, Kohei Uemura, N. Kokudo, Kiyoshi Hasegawa","doi":"10.1159/000535514","DOIUrl":"https://doi.org/10.1159/000535514","url":null,"abstract":"Introduction: The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC. Methods: In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 minutes as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057). Results: Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months. Conclusions: The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139224239","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}
Masatoshi Kudo, Kaoru Tsuchiya, Y. Shao, R. Finn, Peter R. Galle, Michel Ducreux, Ann-Lii Cheng, Tatsuya Yamashita, Hironori Koga, R. Take, Kyoko Yamada, T. Asakawa, Yuki Nakagawa, Masafumi Ikeda
Introduction: The Phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs A-2). PFS was evaluated per independent review facility (IRF)–assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 vs A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs 9.7 months) per IRF-HCC mRECIST for group A-1 vs A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.
{"title":"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":"Masatoshi Kudo, Kaoru Tsuchiya, Y. Shao, R. Finn, Peter R. Galle, Michel Ducreux, Ann-Lii Cheng, Tatsuya Yamashita, Hironori Koga, R. Take, Kyoko Yamada, T. Asakawa, Yuki Nakagawa, Masafumi Ikeda","doi":"10.1159/000535501","DOIUrl":"https://doi.org/10.1159/000535501","url":null,"abstract":"Introduction: The Phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs A-2). PFS was evaluated per independent review facility (IRF)–assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 vs A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs 9.7 months) per IRF-HCC mRECIST for group A-1 vs A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139217114","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}
Sang Youn Hwang, Sangjune L. Lee, Hongqun Liu, Samuel S. Lee
Background: Immune check point inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKI) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue. Summary: Therefore, at present most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials. Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression, vascular invasion, etc. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options.
{"title":"Second-Line Treatment after Failure of Immune Check Point Inhibitors in Hepatocellular Carcinoma: Tyrosine Kinase Inhibitor, Retrial of Immunotherapy, or Locoregional Therapy?","authors":"Sang Youn Hwang, Sangjune L. Lee, Hongqun Liu, Samuel S. Lee","doi":"10.1159/000534303","DOIUrl":"https://doi.org/10.1159/000534303","url":null,"abstract":"Background: Immune check point inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKI) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue. Summary: Therefore, at present most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials. Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression, vascular invasion, etc. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282218","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}
Masatoshi Kudo, Richard S. Finn, Masafumi Ikeda, Max W. Sung, Ari D. Baron, Takuji Okusaka, Masahiro Kobayashi, Hiromitsu Kumada, Shuichi Kaneko, Marc Pracht, Tim Meyer, Satoshi Nagao, Kenichi Saito, Kalgi Mody, Zahra Ramji, Leonid Dubrovsky, Josep M. Llovet
Background: Treatment with lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). Objective: This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time. Methods: 100 Patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS) and investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020). Results: ORR was 43.0% (95% CI 33.1% to 53.3%) and median DOR was 17.1 months (95% CI 6.9 to 19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4 to 9.8 months) and 20.4 months (95% CI 14.4 to 25.9 months), respectively. No treatment-emergent ADAs were detected. Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.
背景:lenvatinib治疗(体重≥60kg的患者剂量为12mg /天;在开放标签1b期研究116/KEYNOTE-524(主要分析数据截止日期:2019年10月31日)中，体重60 kg的患者，剂量为8mg /天)加派姆单抗200mg每3周一次，在一线不可切除的肝细胞癌(uHCC)患者中显示出抗肿瘤活性和可控的安全性。中位随访:10.6个月)。目的:该分析(更新数据截止日期:2021年3月31日)报告了17个月额外随访时间的疗效结果。方法:100例uHCC患者纳入初步分析(中位随访时间:27.6个月)。终点包括总生存期(OS)和研究者评估的无进展生存期(PFS)、客观缓解率(ORR)和反应持续时间(DOR)。通过3个月和9个月的最佳反应进行OS的里程碑式分析。还测量了派姆单抗抗药抗体(ADAs)和浓度(截止日期:2020年8月7日)。结果:ORR为43.0% (95% CI 33.1% ~ 53.3%)，中位DOR为17.1个月(95% CI 6.9 ~ 19.3个月)。中位PFS和OS分别为9.3个月(95% CI为7.4至9.8个月)和20.4个月(95% CI为14.4至25.9个月)。未检测到治疗后出现的ADAs。结论:结果显示lenvatinib + pembrolizumab在一线治疗uHCC患者具有持续的治疗效果。
{"title":"A Phase 1b Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma: Extended Analysis of Study 116","authors":"Masatoshi Kudo, Richard S. Finn, Masafumi Ikeda, Max W. Sung, Ari D. Baron, Takuji Okusaka, Masahiro Kobayashi, Hiromitsu Kumada, Shuichi Kaneko, Marc Pracht, Tim Meyer, Satoshi Nagao, Kenichi Saito, Kalgi Mody, Zahra Ramji, Leonid Dubrovsky, Josep M. Llovet","doi":"10.1159/000535154","DOIUrl":"https://doi.org/10.1159/000535154","url":null,"abstract":"Background: Treatment with lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). Objective: This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time. Methods: 100 Patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS) and investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020). Results: ORR was 43.0% (95% CI 33.1% to 53.3%) and median DOR was 17.1 months (95% CI 6.9 to 19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4 to 9.8 months) and 20.4 months (95% CI 14.4 to 25.9 months), respectively. No treatment-emergent ADAs were detected. Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136282546","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}
Introduction: Cirrhosis is deemed to be a contributing factor to the postoperative recurrence of hepatocellular carcinoma (HCC), however, the precise impact of liver fibrosis on both cancer-specific prognosis remains unclear. This investigation sought to elucidate the effect of liver fibrosis severity on the cancer-specific prognosis. Methods: A total of 524 consecutive patients were included. Recurrence-free survival (RFS) and disease-specific survival (DSS) were compared according to fibrosis stage. Moreover, postoperative outcomes were subjected to analysis in cohorts of patients with F0 and F1-3, as well as in those with F1-3 and F4, who were carefully matched for background factors. Results: The five-year RFS exhibited a significantly worse outcome in the F4 group compared to other stages of fibrosis [5-year RFS: F0 (46.6%), F1-3 (33.1%) and F4 (23.5%), P=0.03 (F0 vs. F1-3) and P<0.01 (F1-3 vs. F4)]. Additionally, the five-year DSS also presented a significantly worse prognosis in the F4 group (5-year DSS: F0 (82.9%), F1-3 (73.6%) and F4 (57.4%), P=0.04 (F0 vs. F1-3) and P<0.01 (F1-3 vs. F4)]. In multivariate analysis, fibrosis 1, 2, 3, and 4 stage (compared with F0) (HR: 1.70, 1.81, 1.89, and 3.99, 95 % CI: 1.10–1.99, 1.39–2.22, 1.41–2.55, and 2.25–5.01, P=0.022, P=0.008, P<0.001, and P<0.001, respectively) was independent risk factor for RFS. After matched analysis, both RFS and DSS exhibited significantly worse prognoses in the presence of more advanced fibrosis. There was a significantly higher incidence of multiple recurrences in the F4 group than the F1–3 group, and a number of recurrences were observed both in the same hepatic segment as the resected side and in the contralateral lobe in F4 group. Discussion/Conclusion: The hazard and recurrence pattern of HCC signifies that the prognosis could potentially be poor, as the hepatic fibrosis likely owing to a higher hepatocarcinogenic potential, even in the absence of progression to cirrhotic condition. The risk of de novo recurrence may also increase with the progression of this fibrosis.
肝硬化被认为是肝细胞癌(HCC)术后复发的一个促进因素，然而，肝纤维化对两种癌症特异性预后的确切影响尚不清楚。本研究旨在阐明肝纤维化严重程度对癌症特异性预后的影响。方法:共纳入524例连续患者。根据纤维化分期比较无复发生存期(RFS)和疾病特异性生存期(DSS)。此外，对F0和F1-3组患者以及F1-3和F4组患者的术后结果进行分析，并仔细匹配背景因素。结果:F4组5年RFS预后明显差于其他纤维化分期[5年RFS: F0 (46.6%)， F1-3 (33.1%)， F4 (23.5%)， P=0.03 (F0 vs. F1-3)， P<0.01 (F1-3 vs. F4)]。此外，F4组5年DSS预后也明显较差(5年DSS: F0(82.9%)、F1-3(73.6%)、F4 (57.4%)， P=0.04 (F0 vs. F1-3)、P<0.01 (F1-3 vs. F4))。在多因素分析中，纤维化1、2、3和4期(与F0期相比)(HR: 1.70、1.81、1.89和3.99,95% CI: 1.10-1.99、1.39-2.22、1.41-2.55和2.25-5.01,P=0.022, P=0.008, P<0.001和P<0.001)是RFS的独立危险因素。在匹配分析后，RFS和DSS在存在更晚期纤维化时表现出明显更差的预后。F4组多发复发发生率明显高于F1-3组，且F4组与切除侧同一肝段及对侧肝叶均有多发复发。讨论/结论:HCC的危险和复发模式表明其预后可能很差，因为肝纤维化可能是由于较高的肝癌潜在致癌性，即使在没有肝硬化进展的情况下。新发复发的风险也可能随着纤维化的进展而增加。
{"title":"Impact of liver fibrosis severity on oncological prognosis in hepatocellular carcinoma","authors":"Koya Yasukawa, Akira Shimizu, Koji Kubota, Tsuyoshi Notake, Kiyotaka Hosoda, Hikaru Hayashi, Yuji Soejima","doi":"10.1159/000533857","DOIUrl":"https://doi.org/10.1159/000533857","url":null,"abstract":"Introduction: Cirrhosis is deemed to be a contributing factor to the postoperative recurrence of hepatocellular carcinoma (HCC), however, the precise impact of liver fibrosis on both cancer-specific prognosis remains unclear. This investigation sought to elucidate the effect of liver fibrosis severity on the cancer-specific prognosis. Methods: A total of 524 consecutive patients were included. Recurrence-free survival (RFS) and disease-specific survival (DSS) were compared according to fibrosis stage. Moreover, postoperative outcomes were subjected to analysis in cohorts of patients with F0 and F1-3, as well as in those with F1-3 and F4, who were carefully matched for background factors. Results: The five-year RFS exhibited a significantly worse outcome in the F4 group compared to other stages of fibrosis [5-year RFS: F0 (46.6%), F1-3 (33.1%) and F4 (23.5%), P=0.03 (F0 vs. F1-3) and P<0.01 (F1-3 vs. F4)]. Additionally, the five-year DSS also presented a significantly worse prognosis in the F4 group (5-year DSS: F0 (82.9%), F1-3 (73.6%) and F4 (57.4%), P=0.04 (F0 vs. F1-3) and P<0.01 (F1-3 vs. F4)]. In multivariate analysis, fibrosis 1, 2, 3, and 4 stage (compared with F0) (HR: 1.70, 1.81, 1.89, and 3.99, 95 % CI: 1.10–1.99, 1.39–2.22, 1.41–2.55, and 2.25–5.01, P=0.022, P=0.008, P<0.001, and P<0.001, respectively) was independent risk factor for RFS. After matched analysis, both RFS and DSS exhibited significantly worse prognoses in the presence of more advanced fibrosis. There was a significantly higher incidence of multiple recurrences in the F4 group than the F1–3 group, and a number of recurrences were observed both in the same hepatic segment as the resected side and in the contralateral lobe in F4 group. Discussion/Conclusion: The hazard and recurrence pattern of HCC signifies that the prognosis could potentially be poor, as the hepatic fibrosis likely owing to a higher hepatocarcinogenic potential, even in the absence of progression to cirrhotic condition. The risk of de novo recurrence may also increase with the progression of this fibrosis.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135808406","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}
Background Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness for advanced hepatocellular carcinoma (HCC). However, the discrepancy in the efficacy of ICIs in HCC patients with distinct etiologies has not been systematically validated. Methods PubMed, MEDLINE, EMBASE, clinicaltrials.gov and abstracts from ASCO and ESMO conferences were searched for eligible trials that explored the impact of etiology factor on the ICI treatment in HCC patients. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio (OR) of objective response rate (ORR) were calculated with stratification of hepatitis B virus (HBV), hepatitis C virus (HCV) and nonviral subgroup, and the heterogeneity between different etiological subgroup were assessed by using an interaction test. Results Eight eligible studies with a total of 5646 patients were identified from searching published articles and conference abstracts. ICI therapies were associated with significantly prolonged OS with the pooled HRs of 0.78 (95%CI 0.73-0.84, p < 0.001), 0.71 (95%CI 0.65-0.79, p < 0.001), 0.80 (95%CI 0.69-0.93, p = 0.003) and 0.87 (95%CI 0.77-0.97, p = 0.011) for the whole population, HBV subgroup, HCV subgroup and non-viral subgroup, respectively. In addition, this analysis reported a significant PFS improvement with ICI therapies with HRs of 0.78 (p = 0.004), 0.53 (p < 0.001), 0.65 (p = 0.011) and 0.81 (p = 0.107) for whole population, HBV, HCV and nonviral subgroup, respectively. The HBV-related HCC patients showed the more distinctive HRs for OS and PFS than other etiology subgroups, and this difference was significant in PFS (p for heterogeneity = 0.001) and there was a tendency of significance in OS (p for heterogeneity = 0.079). Furthermore, the ORR advantages of ICI therapies over control were also confirmed with the pooled ORs of 3.62 (p < 0.001), 3.84 (p < 0.001), 3.05 (p < 0.001) and 2.99 (p < 0.001) for whole population, HBV, HCV and nonviral subgroup, respectively (p for heterogeneity = 0.743). Conclusions ICI therapies significantly improve OS, PFS and ORR for HCC patients with different etiologies. HBV-related HCC patients could be the highlighted population to benefit from ICI treatment.
{"title":"Hepatocellular Carcinoma Patients with Hepatitis B Virus Infection Exhibited Favorable Survival from Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis","authors":"Qi Du, Jia Yuan, Zhenggang Ren","doi":"10.1159/000534446","DOIUrl":"https://doi.org/10.1159/000534446","url":null,"abstract":"Background Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness for advanced hepatocellular carcinoma (HCC). However, the discrepancy in the efficacy of ICIs in HCC patients with distinct etiologies has not been systematically validated. Methods PubMed, MEDLINE, EMBASE, clinicaltrials.gov and abstracts from ASCO and ESMO conferences were searched for eligible trials that explored the impact of etiology factor on the ICI treatment in HCC patients. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio (OR) of objective response rate (ORR) were calculated with stratification of hepatitis B virus (HBV), hepatitis C virus (HCV) and nonviral subgroup, and the heterogeneity between different etiological subgroup were assessed by using an interaction test. Results Eight eligible studies with a total of 5646 patients were identified from searching published articles and conference abstracts. ICI therapies were associated with significantly prolonged OS with the pooled HRs of 0.78 (95%CI 0.73-0.84, p < 0.001), 0.71 (95%CI 0.65-0.79, p < 0.001), 0.80 (95%CI 0.69-0.93, p = 0.003) and 0.87 (95%CI 0.77-0.97, p = 0.011) for the whole population, HBV subgroup, HCV subgroup and non-viral subgroup, respectively. In addition, this analysis reported a significant PFS improvement with ICI therapies with HRs of 0.78 (p = 0.004), 0.53 (p < 0.001), 0.65 (p = 0.011) and 0.81 (p = 0.107) for whole population, HBV, HCV and nonviral subgroup, respectively. The HBV-related HCC patients showed the more distinctive HRs for OS and PFS than other etiology subgroups, and this difference was significant in PFS (p for heterogeneity = 0.001) and there was a tendency of significance in OS (p for heterogeneity = 0.079). Furthermore, the ORR advantages of ICI therapies over control were also confirmed with the pooled ORs of 3.62 (p < 0.001), 3.84 (p < 0.001), 3.05 (p < 0.001) and 2.99 (p < 0.001) for whole population, HBV, HCV and nonviral subgroup, respectively (p for heterogeneity = 0.743). Conclusions ICI therapies significantly improve OS, PFS and ORR for HCC patients with different etiologies. HBV-related HCC patients could be the highlighted population to benefit from ICI treatment.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136067994","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}
Andrea Pasta, Francesco Calabrese, Ariel Jaffe, Sara Labanca, Simona Marenco, Giulia Pieri, Maria Corina Plaz Torres, Mario Strazzabosco, Edoardo G. Giannini
Background: Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized. Objectives: In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis. Methods: We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available. Results: Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients (p = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21–0.90; p = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; p = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; p = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; p = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12–2.86; p = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01–11.1, p < 0.0001). Lastly, OS was longer in patients with ALBI grades 1–2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, p = 0.0008). Conclusions: Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade.
{"title":"SAFETY AND EFFICACY OF ATEZOLIZUMAB/ BEVACIZUMAB IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AND IMPAIRED LIVER FUNCTION: A SYSTEMATIC REVIEW AND META-ANALYSIS","authors":"Andrea Pasta, Francesco Calabrese, Ariel Jaffe, Sara Labanca, Simona Marenco, Giulia Pieri, Maria Corina Plaz Torres, Mario Strazzabosco, Edoardo G. Giannini","doi":"10.1159/000533991","DOIUrl":"https://doi.org/10.1159/000533991","url":null,"abstract":"<b><i>Background:</i></b> Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized. <b><i>Objectives:</i></b> In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis. <b><i>Methods:</i></b> We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available. <b><i>Results:</i></b> Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients (<i>p</i> = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21–0.90; <i>p</i> = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; <i>p</i> = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; <i>p</i> = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; <i>p</i> = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12–2.86; <i>p</i> = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01–11.1, <i>p</i> &lt; 0.0001). Lastly, OS was longer in patients with ALBI grades 1–2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, <i>p</i> = 0.0008). <b><i>Conclusions:</i></b> Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135803622","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}
Introduction Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. Methods This study includes 152 resected HCCs; mutations in the catenin beta-1, adenomatous polyposis coli, or AXIN1, or AXIN2 genes were defined as Wnt/β-catenin mutations. With hierarchical cluster analyses, TME were classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME. Results Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule (EpCAM) and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells and MDSC activation and recognized as low enhancement nodule on Gd-EOB-DTPA-enhanced MRI. Conclusion Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1, both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway.
{"title":"Two distinct characteristics of immune microenvironment in human hepatocellular carcinoma with Wnt/β-catenin mutations","authors":"Tomoko Aoki, Naoshi Nishida, Yutaka Kurebayashi, Kazuko Sakai, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Yasunori Minami, Masakatsu Tsurusaki, Takuya Nakai, Michiie Sakamoto, Kazuto Nishio, Masatoshi Kudo","doi":"10.1159/000533818","DOIUrl":"https://doi.org/10.1159/000533818","url":null,"abstract":"Introduction Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations. Methods This study includes 152 resected HCCs; mutations in the catenin beta-1, adenomatous polyposis coli, or AXIN1, or AXIN2 genes were defined as Wnt/β-catenin mutations. With hierarchical cluster analyses, TME were classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME. Results Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule (EpCAM) and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells and MDSC activation and recognized as low enhancement nodule on Gd-EOB-DTPA-enhanced MRI. Conclusion Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1, both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135147252","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}
Yu Ki Sim, Ming Chuen Chong, Mihir Gandhi, Yogesh Mahadev Pokharkar, Yanan Zhu, Luming Shi, Li Lequn, Chien-Hung Chen, Masatoshi Kudo, Joon Hyeok Lee, Simone I Strasser, Rawisak Chanwat, Pierce K.H. Chow
Introduction: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. Methods: Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. Results: A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. Conclusion: The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient’s treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.
{"title":"Real-world Data on the Diagnosis, Treatment and Management of Hepatocellular Carcinoma in the Asia-Pacific: The INSIGHT study","authors":"Yu Ki Sim, Ming Chuen Chong, Mihir Gandhi, Yogesh Mahadev Pokharkar, Yanan Zhu, Luming Shi, Li Lequn, Chien-Hung Chen, Masatoshi Kudo, Joon Hyeok Lee, Simone I Strasser, Rawisak Chanwat, Pierce K.H. Chow","doi":"10.1159/000534513","DOIUrl":"https://doi.org/10.1159/000534513","url":null,"abstract":"<b><i>Introduction:</i></b> Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. <b><i>Methods:</i></b> Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. <b><i>Results:</i></b> A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. <b><i>Conclusion:</i></b> The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient’s treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146198","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}
Background Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy. Summary Reportedly, 9–36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machineries, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibiting suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for effective application of ICIs and molecular-targeted therapies. Key Messages Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.
{"title":"Genetic/epigenetic alteration and tumor immune microenvironment in intrahepatic cholangiocarcinoma: Transforming the immune microenvironment with molecular targeted agents","authors":"Naoshi Nishida, Masatoshi Kudo","doi":"10.1159/000534443","DOIUrl":"https://doi.org/10.1159/000534443","url":null,"abstract":"Background Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy. Summary Reportedly, 9–36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machineries, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibiting suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for effective application of ICIs and molecular-targeted therapies. Key Messages Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135647519","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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