Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma
Background & Aims: Immune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923000782 |
| _version_ | 1797819883812028416 |
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| author | David J. Pinato Xiaoxue Li Pallavi Mishra-Kalyani Antonio D’Alessio Claudia A.M. Fulgenzi Bernhard Scheiner Matthias Pinter Guo Wei Julie Schneider Donna R. Rivera Richard Pazdur Marc R. Theoret Sandra Casak Steven Lemery Lola Fashoyin-Aje Alessio Cortellini Lorraine Pelosof |
| author_facet | David J. Pinato Xiaoxue Li Pallavi Mishra-Kalyani Antonio D’Alessio Claudia A.M. Fulgenzi Bernhard Scheiner Matthias Pinter Guo Wei Julie Schneider Donna R. Rivera Richard Pazdur Marc R. Theoret Sandra Casak Steven Lemery Lola Fashoyin-Aje Alessio Cortellini Lorraine Pelosof |
| author_sort | David J. Pinato |
| collection | DOAJ |
| description | Background & Aims: Immune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains unclear. Methods: This study retrospectively analysed an FDA database including 4,098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or in combination (n = 584), tyrosine kinase inhibitor (TKI) (n = 1,968), vascular endothelial growth factor pathway inhibitors (n = 480), or placebo (n = 808) as part of nine international clinical trials. Exposure to ATB within 30 days before or after treatment initiation was correlated with overall survival (OS) and progression-free survival (PFS) across therapeutic modality before and after inverse probability of treatment weighting (IPTW). Results: Of 4,098 patients with unresectable/metastatic HCC, of which 39% were of hepatitis B aetiology and 21% were of hepatitis C aetiology, 83% were males with a median age of 64 years (range 18–88), a European Collaborative Oncology Group performance status of 0 (60%), and Child–Pugh A class (98%). Overall, ATB exposure (n = 620, 15%) was associated with shorter median PFS (3.6 months in ATB-exposed vs. 4.2 months; hazard ratio [HR] 1.29; 95% CI 1.22, 1.36) and OS (8.7 months in ATB-exposed vs. 10.6 months; HR 1.36; 95% CI 1.29, 1.43). In IPTW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52; 95% CI 1.34, 1.73), TKI (HR 1.29; 95% CI 1.19, 1.39), and placebo (HR 1.23; 95% CI 1.11, 1.37). Similar results were observed in IPTW analyses of OS in patients treated with ICI (HR 1.22; 95% CI 1.08, 1.38), TKI (HR 1.40; 95% CI 1.30, 1.52), and placebo (HR 1.40; 95% CI 1.25, 1.57). Conclusions: Unlike other malignancies where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with worse outcomes in this study across different therapies for HCC including placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut–liver axis remains to be demonstrated in translational studies. Impact and Implications: A growing body of evidence suggests the host microbiome, frequently altered by antibiotic treatment, as an important outcome predictor in the context of immune checkpoint inhibitor therapy. In this study, we analysed the effects of early antibiotic exposure on outcomes in almost 4,100 patients with hepatocellular carcinoma treated within nine multicentre clinical trials. Interestingly, early exposure to antibiotic treatment was associated with worse outcomes not only in patients treated with immune checkpoint inhibitors but also in those treated with tyrosine kinase inhibitors and placebo. This is in contrast to data published in other malignancies, where the detrimental effect of antibiotic treatment may be more prominent in immune checkpoint inhibitor recipients, highlighting the uniqueness of hepatocellular carcinoma given the complex interplay between cirrhosis, cancer, risk of infection, and the pleiotropic effect of molecular therapies for this disease. |
| first_indexed | 2024-03-13T09:29:11Z |
| format | Article |
| id | doaj.art-6927577eae4849a9b007d6bf4469b648 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-13T09:29:11Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-6927577eae4849a9b007d6bf4469b6482023-05-26T04:22:02ZengElsevierJHEP Reports2589-55592023-06-0156100747Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinomaDavid J. Pinato0Xiaoxue Li1Pallavi Mishra-Kalyani2Antonio D’Alessio3Claudia A.M. Fulgenzi4Bernhard Scheiner5Matthias Pinter6Guo Wei7Julie Schneider8Donna R. Rivera9Richard Pazdur10Marc R. Theoret11Sandra Casak12Steven Lemery13Lola Fashoyin-Aje14Alessio Cortellini15Lorraine Pelosof16Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Corresponding authors. Addresses: Imperial College London Hammersmith Campus, Du Cane Road, W12 0HS, London, UK. Tel.: +44-20-83833720.Office of Biostatistics, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USAOffice of Biostatistics, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USADepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Department of Biomedical Sciences, Humanitas University, Milan, ItalyDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Department of Medical Oncology, University Campus Bio-Medico of Rome, Rome, ItalyDepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; 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, AustriaOncology Center of Excellence, US FDA, Silver Spring, MD, USAOncology Center of Excellence, US FDA, Silver Spring, MD, USAOncology Center of Excellence, US FDA, Silver Spring, MD, USAOncology Center of Excellence, US FDA, Silver Spring, MD, USA; Office of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USAOncology Center of Excellence, US FDA, Silver Spring, MD, USA; Office of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USAOffice of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USAOffice of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USAOffice of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USADepartment of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UKOffice of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US FDA, Silver Spring, MD, USA; Office of Oncologic Diseases, Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), 10903 New Hampshire Avenue, White Oak Building 22, Silver Spring, MD 20993, USA. Tel.: +1-240-402-6469.Background & Aims: Immune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains unclear. Methods: This study retrospectively analysed an FDA database including 4,098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or in combination (n = 584), tyrosine kinase inhibitor (TKI) (n = 1,968), vascular endothelial growth factor pathway inhibitors (n = 480), or placebo (n = 808) as part of nine international clinical trials. Exposure to ATB within 30 days before or after treatment initiation was correlated with overall survival (OS) and progression-free survival (PFS) across therapeutic modality before and after inverse probability of treatment weighting (IPTW). Results: Of 4,098 patients with unresectable/metastatic HCC, of which 39% were of hepatitis B aetiology and 21% were of hepatitis C aetiology, 83% were males with a median age of 64 years (range 18–88), a European Collaborative Oncology Group performance status of 0 (60%), and Child–Pugh A class (98%). Overall, ATB exposure (n = 620, 15%) was associated with shorter median PFS (3.6 months in ATB-exposed vs. 4.2 months; hazard ratio [HR] 1.29; 95% CI 1.22, 1.36) and OS (8.7 months in ATB-exposed vs. 10.6 months; HR 1.36; 95% CI 1.29, 1.43). In IPTW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52; 95% CI 1.34, 1.73), TKI (HR 1.29; 95% CI 1.19, 1.39), and placebo (HR 1.23; 95% CI 1.11, 1.37). Similar results were observed in IPTW analyses of OS in patients treated with ICI (HR 1.22; 95% CI 1.08, 1.38), TKI (HR 1.40; 95% CI 1.30, 1.52), and placebo (HR 1.40; 95% CI 1.25, 1.57). Conclusions: Unlike other malignancies where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with worse outcomes in this study across different therapies for HCC including placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut–liver axis remains to be demonstrated in translational studies. Impact and Implications: A growing body of evidence suggests the host microbiome, frequently altered by antibiotic treatment, as an important outcome predictor in the context of immune checkpoint inhibitor therapy. In this study, we analysed the effects of early antibiotic exposure on outcomes in almost 4,100 patients with hepatocellular carcinoma treated within nine multicentre clinical trials. Interestingly, early exposure to antibiotic treatment was associated with worse outcomes not only in patients treated with immune checkpoint inhibitors but also in those treated with tyrosine kinase inhibitors and placebo. This is in contrast to data published in other malignancies, where the detrimental effect of antibiotic treatment may be more prominent in immune checkpoint inhibitor recipients, highlighting the uniqueness of hepatocellular carcinoma given the complex interplay between cirrhosis, cancer, risk of infection, and the pleiotropic effect of molecular therapies for this disease.http://www.sciencedirect.com/science/article/pii/S2589555923000782AntibioticsCancer immunotherapyTargeted therapyImmune checkpoint inhibitorsHepatocellular carcinomaGut microbiota |
| spellingShingle | David J. Pinato Xiaoxue Li Pallavi Mishra-Kalyani Antonio D’Alessio Claudia A.M. Fulgenzi Bernhard Scheiner Matthias Pinter Guo Wei Julie Schneider Donna R. Rivera Richard Pazdur Marc R. Theoret Sandra Casak Steven Lemery Lola Fashoyin-Aje Alessio Cortellini Lorraine Pelosof Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma JHEP Reports Antibiotics Cancer immunotherapy Targeted therapy Immune checkpoint inhibitors Hepatocellular carcinoma Gut microbiota |
| title | Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma |
| title_full | Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma |
| title_fullStr | Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma |
| title_full_unstemmed | Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma |
| title_short | Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma |
| title_sort | association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune based therapy for hepatocellular carcinoma |
| topic | Antibiotics Cancer immunotherapy Targeted therapy Immune checkpoint inhibitors Hepatocellular carcinoma Gut microbiota |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923000782 |
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