Pub Date : 2022-08-25eCollection Date: 2023-02-01DOI: 10.1159/000525499
Chiun Hsu, Michel Ducreux, Andrew X Zhu, Shukui Qin, Masafumi Ikeda, Tae-You Kim, Peter R Galle, Richard S Finn, Ethan Chen, Ning Ma, Youyou Hu, Lindong Li, Ann-Lii Cheng
Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib.
Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation.
Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab.
Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.
{"title":"Hepatic Events and Viral Kinetics in Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab.","authors":"Chiun Hsu, Michel Ducreux, Andrew X Zhu, Shukui Qin, Masafumi Ikeda, Tae-You Kim, Peter R Galle, Richard S Finn, Ethan Chen, Ning Ma, Youyou Hu, Lindong Li, Ann-Lii Cheng","doi":"10.1159/000525499","DOIUrl":"10.1159/000525499","url":null,"abstract":"<p><strong>Introduction: </strong>In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib.</p><p><strong>Methods: </strong>Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation.</p><p><strong>Results: </strong>Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab.</p><p><strong>Conclusions: </strong>Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 1","pages":"44-56"},"PeriodicalIF":11.6,"publicationDate":"2022-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/82/3c/lic-0012-0044.PMC9982337.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10847173","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}
Pub Date : 2022-08-23eCollection Date: 2023-02-01DOI: 10.1159/000526639
Khi Yung Fong, Joseph Jonathan Zhao, Rehena Sultana, Joycelyn Jie Xin Lee, Suat Ying Lee, Stephen Lam Chan, Thomas Yau, David Wai Meng Tai, Raghav Sundar, Chow Wei Too
Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation.
Methods: A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores.
Results: Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53-0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66-0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (I2 = 0%) and inconsistency (Cochran's Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS.
Conclusion: This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.
{"title":"First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis.","authors":"Khi Yung Fong, Joseph Jonathan Zhao, Rehena Sultana, Joycelyn Jie Xin Lee, Suat Ying Lee, Stephen Lam Chan, Thomas Yau, David Wai Meng Tai, Raghav Sundar, Chow Wei Too","doi":"10.1159/000526639","DOIUrl":"10.1159/000526639","url":null,"abstract":"<p><strong>Introduction: </strong>Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation.</p><p><strong>Methods: </strong>A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using <i>p</i> scores.</p><p><strong>Results: </strong>Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53-0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66-0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (<i>I</i><sup>2</sup> = 0%) and inconsistency (Cochran's <i>Q</i> = 0.52, <i>p</i> = 0.773) was observed. <i>p</i> scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS.</p><p><strong>Conclusion: </strong>This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 1","pages":"7-18"},"PeriodicalIF":11.6,"publicationDate":"2022-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/76/47/lic-0012-0007.PMC9982345.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10847176","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}
Pub Date : 2022-07-27eCollection Date: 2022-09-01DOI: 10.1159/000526163
Masatoshi Kudo
{"title":"Atezolizumab plus Bevacizumab Followed by Curative Conversion (ABC Conversion) in Patients with Unresectable, TACE-Unsuitable Intermediate-Stage Hepatocellular Carcinoma.","authors":"Masatoshi Kudo","doi":"10.1159/000526163","DOIUrl":"10.1159/000526163","url":null,"abstract":"","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 5","pages":"399-406"},"PeriodicalIF":11.6,"publicationDate":"2022-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/41/f5/lic-0011-0399.PMC9485978.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33484711","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}
Pub Date : 2022-07-13eCollection Date: 2022-12-01DOI: 10.1159/000525375
Marco Y W Zaki, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves
Introduction: Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME.
Methods: In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting.
Results: We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, p = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance.
Conclusion: SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.
{"title":"Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?","authors":"Marco Y W Zaki, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves","doi":"10.1159/000525375","DOIUrl":"10.1159/000525375","url":null,"abstract":"<p><strong>Introduction: </strong>Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME.</p><p><strong>Methods: </strong>In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting.</p><p><strong>Results: </strong>We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, <i>p</i> = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance.</p><p><strong>Conclusion: </strong>SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 6","pages":"540-557"},"PeriodicalIF":13.8,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10852619","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}
Pub Date : 2022-07-13eCollection Date: 2022-12-01DOI: 10.1159/000526003
Ka Shing Cheung, Wai K Leung
{"title":"Response to the Article on Antibiotics and Immune Checkpoint Inhibitors by Lin et al.","authors":"Ka Shing Cheung, Wai K Leung","doi":"10.1159/000526003","DOIUrl":"10.1159/000526003","url":null,"abstract":"","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 6","pages":"578-580"},"PeriodicalIF":11.6,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8c/fe/lic-0011-0578.PMC9801173.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10458349","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}
Pub Date : 2022-07-11eCollection Date: 2022-12-01DOI: 10.1159/000525145
Andrea Casadei-Gardini, Margherita Rimini, Masatoshi Kudo, Shigeo Shimose, Toshifumi Tada, Goki Suda, Myung Ji Goh, Andre Jefremow, Mario Scartozzi, Giuseppe Cabibbo, Claudia Campani, Emiliano Tamburini, Francesco Tovoli, Kazuomi Ueshima, Tomoko Aoki, Hideki Iwamoto, Takuji Torimura, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Ei Itobayashi, Hidenori Toyoda, Naoya Sakamoto, Takuya Sho, Wonseok Kang, Jürgen Siebler, Markus Friedrich Neurath, Valentina Burgio, Stefano Cascinu
Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes.
Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries.
Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months).
Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.
{"title":"Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study.","authors":"Andrea Casadei-Gardini, Margherita Rimini, Masatoshi Kudo, Shigeo Shimose, Toshifumi Tada, Goki Suda, Myung Ji Goh, Andre Jefremow, Mario Scartozzi, Giuseppe Cabibbo, Claudia Campani, Emiliano Tamburini, Francesco Tovoli, Kazuomi Ueshima, Tomoko Aoki, Hideki Iwamoto, Takuji Torimura, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Ei Itobayashi, Hidenori Toyoda, Naoya Sakamoto, Takuya Sho, Wonseok Kang, Jürgen Siebler, Markus Friedrich Neurath, Valentina Burgio, Stefano Cascinu","doi":"10.1159/000525145","DOIUrl":"10.1159/000525145","url":null,"abstract":"<p><strong>Introduction: </strong>In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes.</p><p><strong>Methods: </strong>The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries.</p><p><strong>Results: </strong>We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months).</p><p><strong>Conclusions: </strong>Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 6","pages":"527-539"},"PeriodicalIF":11.6,"publicationDate":"2022-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dd/11/lic-0011-0527.PMC9801178.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10458341","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}
Pub Date : 2022-07-08eCollection Date: 2023-02-01DOI: 10.1159/000525911
Haonan Lu, Jacob George, Mohammed Eslam, Augusto Villanueva, Luigi Bolondi, Helen L Reeves, Misti McCain, Edward Chambers, Caroline Ward, Dewi Sartika, Caroline Sands, Lynn Maslen, Matthew R Lewis, Ramya Ramaswami, Rohini Sharma
Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC.
Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC.
Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, p < 0.01).
Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.
{"title":"Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease.","authors":"Haonan Lu, Jacob George, Mohammed Eslam, Augusto Villanueva, Luigi Bolondi, Helen L Reeves, Misti McCain, Edward Chambers, Caroline Ward, Dewi Sartika, Caroline Sands, Lynn Maslen, Matthew R Lewis, Ramya Ramaswami, Rohini Sharma","doi":"10.1159/000525911","DOIUrl":"10.1159/000525911","url":null,"abstract":"<p><strong>Introduction: </strong>The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC.</p><p><strong>Methods: </strong>We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (<i>n</i> = 113) and MAFLD-associated HCC (<i>n</i> = 144) from six different centers. Regression models were used to identify a predictive model of HCC.</p><p><strong>Results: </strong>Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (<i>p</i> < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, <i>p</i> < 0.01).</p><p><strong>Conclusion: </strong>These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 1","pages":"19-31"},"PeriodicalIF":13.8,"publicationDate":"2022-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/aa/fc/lic-0012-0019.PMC9982340.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10853161","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}
This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.
{"title":"Liver Cancer Study Group of Japan Clinical Practice Guidelines for Intrahepatic Cholangiocarcinoma.","authors":"Shoji Kubo, Hiroji Shinkawa, Yoshinari Asaoka, Tatsuya Ioka, Hiroshi Igaki, Namiki Izumi, Takao Itoi, Michiaki Unno, Masayuki Ohtsuka, Takuji Okusaka, Masumi Kadoya, Masatoshi Kudo, Takashi Kumada, Norihiro Kokudo, Michiie Sakamoto, Yoshihiro Sakamoto, Hideyuki Sakurai, Tadatoshi Takayama, Osamu Nakashima, Yasushi Nagata, Etsuro Hatano, Kenichi Harada, Takamichi Murakami, Masakazu Yamamoto","doi":"10.1159/000522403","DOIUrl":"https://doi.org/10.1159/000522403","url":null,"abstract":"<p><p>This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"11 4","pages":"290-314"},"PeriodicalIF":13.8,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/3d/lic-0011-0290.PMC9294959.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9359193","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}