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":"43 1","pages":"0"},"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":"60 1","pages":"0"},"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":"39 1","pages":"0"},"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}
Chi Leung Chiang, Francis Ann Shing Lee, Kenneth Sik Kwan Chan, Venus Wan Yan Lee, Keith Wan Hang Chiu, Ryan Lok Man Ho, John Ka Shun Fong, Natalie Sean Man Wong, Winnie Wing Ling Yip, Cynthia Sin Yu Yeung, Vince Wing Hang Lau, Man Kwan, Feng-Ming Spring Kong, Albert Chi Yan Chan
Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6–18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.
{"title":"Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-alone in Unresectable Hepatocellular Carcinoma (HCC)","authors":"Chi Leung Chiang, Francis Ann Shing Lee, Kenneth Sik Kwan Chan, Venus Wan Yan Lee, Keith Wan Hang Chiu, Ryan Lok Man Ho, John Ka Shun Fong, Natalie Sean Man Wong, Winnie Wing Ling Yip, Cynthia Sin Yu Yeung, Vince Wing Hang Lau, Man Kwan, Feng-Ming Spring Kong, Albert Chi Yan Chan","doi":"10.1159/000533425","DOIUrl":"https://doi.org/10.1159/000533425","url":null,"abstract":"<b><i>Introduction:</i></b> While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. <b><i>Results:</i></b> The median tumor size was 7.3 cm (range, 2.6–18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (<i>p</i> = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (<i>p</i> = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, <i>p</i> = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (<i>p</i> = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (<i>n</i> = 2 hepatitis, <i>n</i> = 1 dermatitis) leading to permanent treatment discontinuation. <b><i>Conclusion:</i></b> Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135660816","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}
G. Abou-Alfa, Peter R. Galle, Yee Chao, Joseph Erinjeri, Jeong Heo, M. Borad, Angelo Luca, James M. Burke, Adina Pelusio, Delphine Agathon, Monika Lusky, C. Breitbach, S. Qin, Edward Gane
Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.
简介对肝细胞癌（HCC）患者进行pexa-vec（pexastimogene devacirepvec）（一种溶瘤和免疫治疗疫苗病毒）瘤内给药，可产生局部和远处肿瘤反应。我们假设，随后使用索拉非尼治疗可显示出更优越的疗效。研究方法这项随机III期开放标签研究评估了晚期HCC患者使用pexa-vec后再使用索拉非尼与索拉非尼进行序贯治疗的疗效比较。主要终点是总生存期（OS）。主要次要终点包括进展时间（TTP）、无进展生存期、总反应率（ORR）和疾病控制率（DCR）。对所有接受≥1次研究治疗的患者进行安全性评估。研究结果该研究在16个国家的142个地点进行。从2015年12月30日到2019年8月2日的中期分析，459名患者被随机分配（pexa-vec加索拉非尼：234人，索拉非尼：225人）。在中期分析中，pexa-vec 加索拉非尼治疗组的中位 OS 为 12.7 个月（95% CI：9.89，14.95），索拉非尼治疗组的中位 OS 为 14.0 个月（95% CI：11.01，18.00）。这导致研究提前结束。佩沙韦克加索拉非尼治疗组和索拉非尼治疗组的中位TTP分别为2.0个月（95% CI：1.77，2.96）和4.2个月（95% CI：2.92，4.63）；ORR分别为19.2%（45例患者）和20.9%（47例患者）；DCR分别为50.0%（117例患者）和57.3%（129例患者）。pexa-vec加索拉非尼治疗组和索拉非尼治疗组分别有117例（53.7%）和77例（35.5%）患者报告了严重不良事件。肝功能衰竭是两组中最常见的不良反应。结论pexa-vec联合索拉非尼的序贯治疗并没有增加晚期HCC的临床获益，而且与单独使用索拉非尼相比效果更差。检查点抑制剂附加价值的出现应指导溶瘤病毒治疗策略的进一步发展。
{"title":"PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential Treatment with Pexa-Vec (JX-594) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma","authors":"G. Abou-Alfa, Peter R. Galle, Yee Chao, Joseph Erinjeri, Jeong Heo, M. Borad, Angelo Luca, James M. Burke, Adina Pelusio, Delphine Agathon, Monika Lusky, C. Breitbach, S. Qin, Edward Gane","doi":"10.1159/000533650","DOIUrl":"https://doi.org/10.1159/000533650","url":null,"abstract":"Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"57 1","pages":""},"PeriodicalIF":13.8,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139333543","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: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients’ survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23–21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08–4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40–4.61, p = 0.002), and platelets <150,000/μL (OR: 2.47; 95% CI: 1.35–4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.
{"title":"Incidence and predictors of esophagogastric varices bleeding in patients with hepatocellular carcinoma in lenvatinib","authors":"Massimo Iavarone, Eleonora Alimenti, Toshifumi Tada, Shigeo Shimose, Goki Suda, Changhoon Yoo, Caterina Soldà, Fabio Piscaglia, Giulia Tosetti, Fabio Marra, Caterina Vivaldi, Fabio Conti, Marta Schirripa, Hideki Iwamoto, Takuya Sho, So Heun Lee, Mario Domenico Rizzato, Matteo Tonnini, Margherita Rimini, Claudia Campani, Gianluca Masi, Francesco Foschi, Mariangela Bruccoleri, Takumi Kawaguchi, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Shinya Fukunishi, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Takeshi Hatanaka, Satoru Kakizaki, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Atsushi Naganuma, Andrea Casadei-Gardini, Pietro Lampertico","doi":"10.1159/000534127","DOIUrl":"https://doi.org/10.1159/000534127","url":null,"abstract":"<b><i>Introduction:</i></b> Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. <b><i>Methods:</i></b> In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients’ survival. <b><i>Results:</i></b> 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23–21.57, <i>p</i> = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08–4.17, <i>p</i> = 0.03), nPVT (OR: 2.54; 95% CI: 1.40–4.61, <i>p</i> = 0.002), and platelets &lt;150,000/μL (OR: 2.47; 95% CI: 1.35–4.50, <i>p</i> = 0.003). <b><i>Conclusion:</i></b> In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134973088","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}
Angeles García-Criado, Jordi Rimola, Susana Seijo, Anna Darnell, Ernest Belmonte, Victor Sapena, Julián Moreno-Rojas, Valeria Pérez, Virginia Hernández-Gea, Carmen Ayuso, Maria Reig, Juan Carlos García-Pagán, Jordi Bruix
Introduction: The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. Methods: Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. Results: A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. Conclusions: Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign.
{"title":"MRI Using Gadoxetic Acid in the Work-Up of Liver Nodules Not Conclusively Benign in Budd-Chiari Syndrome: A Prospective Long-Term Follow-Up","authors":"Angeles García-Criado, Jordi Rimola, Susana Seijo, Anna Darnell, Ernest Belmonte, Victor Sapena, Julián Moreno-Rojas, Valeria Pérez, Virginia Hernández-Gea, Carmen Ayuso, Maria Reig, Juan Carlos García-Pagán, Jordi Bruix","doi":"10.1159/000533598","DOIUrl":"https://doi.org/10.1159/000533598","url":null,"abstract":"<b><i>Introduction:</i></b> The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. <b><i>Methods:</i></b> Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. <b><i>Results:</i></b> A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. <b><i>Conclusions:</i></b> Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136214853","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: Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC.
Methods: Sixty-four patients with Child-Pugh scores of 5-7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated.
Results: The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579-9.180; p = 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614-24.010; p = 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133-6.194; p = 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr).
Conclusion: Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.
{"title":"Risk Factors for Early Onset of Proteinuria in Patients Receiving Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.","authors":"Yuwa Ando, Tomokazu Kawaoka, Masanari Kosaka, Yuki Shirane, Yusuke Johira, Ryoichi Miura, Serami Murakami, Shigeki Yano, Kei Amioka, Kensuke Naruto, Yumi Kosaka, Shinsuke Uchikawa, Kenichiro Kodama, Hatsue Fujino, Takashi Nakahara, Atushi Ono, Eisuke Murakami, Masami Yamauchi, Wataru Okamoto, Shoichi Takahashi, Michio Imamura, Hiroshi Aikata","doi":"10.1159/000528145","DOIUrl":"https://doi.org/10.1159/000528145","url":null,"abstract":"<p><strong>Introduction: </strong>Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC.</p><p><strong>Methods: </strong>Sixty-four patients with Child-Pugh scores of 5-7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated.</p><p><strong>Results: </strong>The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579-9.180; <i>p</i> = 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614-24.010; <i>p</i> = 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133-6.194; <i>p</i> = 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr).</p><p><strong>Conclusion: </strong>Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 3","pages":"251-261"},"PeriodicalIF":13.8,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1f/7b/lic-0012-0251.PMC10433089.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10049724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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