A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma
Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods:...
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Elsevier
2024-02-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923003130 |
| _version_ | 1827355889313513472 |
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| author | Lorenz Balcar Bernhard Scheiner Claudia Angela Maria Fulgenzi Antonio D’Alessio Katharina Pomej Marta Bofill Roig Elias Laurin Meyer Jaekyung Che Naoshi Nishida Pei-Chang Lee Linda Wu Celina Ang Anja Krall Anwaar Saeed Bernardo Stefanini Antonella Cammarota Tiziana Pressiani Yehia I. Abugabal Shadi Chamseddine Brooke Wietharn Alessandro Parisi Yi-Hsiang Huang Samuel Phen Caterina Vivaldi Francesca Salani Gianluca Masi Dominik Bettinger Arndt Vogel Johann von Felden Kornelius Schulze Marianna Silletta Michael Trauner Adel Samson Henning Wege Fabio Piscaglia Peter R. Galle Rudolf Stauber Masatoshi Kudo Amit G. Singal Aleena Itani Susanna V. Ulahannan Neehar D. Parikh Alessio Cortellini Ahmed Kaseb Lorenza Rimassa Hong Jae Chon David J. Pinato Matthias Pinter |
| author_facet | Lorenz Balcar Bernhard Scheiner Claudia Angela Maria Fulgenzi Antonio D’Alessio Katharina Pomej Marta Bofill Roig Elias Laurin Meyer Jaekyung Che Naoshi Nishida Pei-Chang Lee Linda Wu Celina Ang Anja Krall Anwaar Saeed Bernardo Stefanini Antonella Cammarota Tiziana Pressiani Yehia I. Abugabal Shadi Chamseddine Brooke Wietharn Alessandro Parisi Yi-Hsiang Huang Samuel Phen Caterina Vivaldi Francesca Salani Gianluca Masi Dominik Bettinger Arndt Vogel Johann von Felden Kornelius Schulze Marianna Silletta Michael Trauner Adel Samson Henning Wege Fabio Piscaglia Peter R. Galle Rudolf Stauber Masatoshi Kudo Amit G. Singal Aleena Itani Susanna V. Ulahannan Neehar D. Parikh Alessio Cortellini Ahmed Kaseb Lorenza Rimassa Hong Jae Chon David J. Pinato Matthias Pinter |
| author_sort | Lorenz Balcar |
| collection | DOAJ |
| description | Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625. |
| first_indexed | 2024-03-08T04:50:52Z |
| format | Article |
| id | doaj.art-a0a6b9404c43458295dafe7f3cb32ed2 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-08T04:50:52Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-a0a6b9404c43458295dafe7f3cb32ed22024-02-08T05:13:41ZengElsevierJHEP Reports2589-55592024-02-0162100982A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinomaLorenz Balcar0Bernhard Scheiner1Claudia Angela Maria Fulgenzi2Antonio D’Alessio3Katharina Pomej4Marta Bofill Roig5Elias Laurin Meyer6Jaekyung Che7Naoshi Nishida8Pei-Chang Lee9Linda Wu10Celina Ang11Anja Krall12Anwaar Saeed13Bernardo Stefanini14Antonella Cammarota15Tiziana Pressiani16Yehia I. Abugabal17Shadi Chamseddine18Brooke Wietharn19Alessandro Parisi20Yi-Hsiang Huang21Samuel Phen22Caterina Vivaldi23Francesca Salani24Gianluca Masi25Dominik Bettinger26Arndt Vogel27Johann von Felden28Kornelius Schulze29Marianna Silletta30Michael Trauner31Adel Samson32Henning Wege33Fabio Piscaglia34Peter R. Galle35Rudolf Stauber36Masatoshi Kudo37Amit G. Singal38Aleena Itani39Susanna V. Ulahannan40Neehar D. Parikh41Alessio Cortellini42Ahmed Kaseb43Lorenza Rimassa44Hong Jae Chon45David J. Pinato46Matthias Pinter47Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United KingdomDivision of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, ItalyDivision of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, ItalyDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaSection for Medical Statistics, Center for Medical Data Science, Medical University of Vienna, Vienna, AustriaSection for Medical Statistics, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria; Berry Consultants, Vienna, AustriaMedical Oncology, Department of Internal Medicine, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of KoreaDepartment of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, JapanDivision of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USADepartment of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, AustriaDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh (UPMC), Pittsburgh, PA, USADivision of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDrug Development Unit, Sarah Cannon Research Institute UK, London, UK; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), ItalyMedical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), ItalyDept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADivision of Medical Oncology, Department of Medicine, University of Kansas Cancer Center, Westwood, KS, USADepartment of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, ItalyInstitute of Clinical Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan; Healthcare and Services Center, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USAUnit of Medical Oncology 2, University Hospital of Pisa, Pisa, ItalyDepartment of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyDepartment of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyDepartment of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Centre, Freiburg, GermanyDepartment of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyI. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, GermanyI. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, GermanyOperative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, ItalyDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaLeeds Institute of Medical Research at St. James's (LIMR), School of Medicine, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Leeds, UKI. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, GermanyDivision of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyI. Medical Department, University Medical Centre Mainz, Mainz, GermanyDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, AustriaDepartment of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, JapanDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USAStephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAStephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USADepartment of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USADivision of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200 - 00128 Roma, ItalyDept of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), ItalyMedical Oncology, Department of Internal Medicine, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of KoreaDivision of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel.: +43 1 40400 47440, fax: +43 1 40400 47350. (M. Pinter), or Division of Cancer, Department of Surgery and Cancer, Imperial College London, Du Cane Road, W12 0HS, London, UK. (D.J. Pinato)Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Corresponding authors. Addresses: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Tel.: +43 1 40400 47440, fax: +43 1 40400 47350. (M. Pinter), or Division of Cancer, Department of Surgery and Cancer, Imperial College London, Du Cane Road, W12 0HS, London, UK. (D.J. Pinato)Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73–0.86) but not in female (pooled HR 0.85; 95% CI 0.70–1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59–1.04; 1.02, 95% CI 0.80–1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.http://www.sciencedirect.com/science/article/pii/S2589555923003130genderliver cancergender medicineimmunotherapysex |
| spellingShingle | Lorenz Balcar Bernhard Scheiner Claudia Angela Maria Fulgenzi Antonio D’Alessio Katharina Pomej Marta Bofill Roig Elias Laurin Meyer Jaekyung Che Naoshi Nishida Pei-Chang Lee Linda Wu Celina Ang Anja Krall Anwaar Saeed Bernardo Stefanini Antonella Cammarota Tiziana Pressiani Yehia I. Abugabal Shadi Chamseddine Brooke Wietharn Alessandro Parisi Yi-Hsiang Huang Samuel Phen Caterina Vivaldi Francesca Salani Gianluca Masi Dominik Bettinger Arndt Vogel Johann von Felden Kornelius Schulze Marianna Silletta Michael Trauner Adel Samson Henning Wege Fabio Piscaglia Peter R. Galle Rudolf Stauber Masatoshi Kudo Amit G. Singal Aleena Itani Susanna V. Ulahannan Neehar D. Parikh Alessio Cortellini Ahmed Kaseb Lorenza Rimassa Hong Jae Chon David J. Pinato Matthias Pinter A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma JHEP Reports gender liver cancer gender medicine immunotherapy sex |
| title | A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| title_full | A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| title_fullStr | A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| title_full_unstemmed | A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| title_short | A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| title_sort | meta analysis and real world cohort study on the sex related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma |
| topic | gender liver cancer gender medicine immunotherapy sex |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923003130 |
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metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma AT ahmedkaseb metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma AT lorenzarimassa metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma AT hongjaechon metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma AT davidjpinato metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma AT matthiaspinter metaanalysisandrealworldcohortstudyonthesexrelateddifferencesinefficacyandsafetyofimmunotherapyforhepatocellularcarcinoma |