Objectives:The combination of atezolizumab plus bevacizumab(A+B)represents one of the standards first-line treatments for unresectable hepatocellular carcinoma(HCC).Metformin has garnered attention for its potential a...Objectives:The combination of atezolizumab plus bevacizumab(A+B)represents one of the standards first-line treatments for unresectable hepatocellular carcinoma(HCC).Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control.This study aimed to assess metformin’s impact in patients with type 2 diabetes mellitus(T2DM)receiving A+B therapy.Methods:This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE(Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma)dataset across 18 Italian centres(May 2020-January 2024).We evaluated objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS),and time to progression(TTP)using Cox regression analysis and Inverse Probability of Treatment Weighting(IPTW)to address confounding.Results:Among 523 patients,341(65.2%)did not have diabetes and 182(34.8%)had T2DM.In the overall population,metformin showed no significant benefit for PFS(HR=1.15,95%CI[0.88-1.50],p=0.316)or OS(HR=1.28,95%CI[0.94-1.74],p=0.124).In the subgroup with T2DM(N=180),metformin showed no significant benefit for PFS(HR=1.41,95%CI[0.97-2.05],p=0.069),OS(HR=1.23,95%CI[0.81-1.86],p=0.333),or TTP(HR=0.82,95%CI[0.53-1.26],p=0.363).IPTW analysis confirmed these negative findings.Conclusion:This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy.Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.展开更多
The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in th...The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in the diagnostic algorithm for this tumor,histology is currently relegated to controversial cases.Furthermore,the risk of complications,such as tumor seeding and bleeding,as well as inadequate sampling have further limited the use of liver biopsy for HCC management.However,there is growing evidence of prognostic and therapeutic information available from microscopic and molecular analysis of HCC and,as the information content of the tissue sample increases,the advantages of liver biopsy might modify the current risk/benefit ratio.We herein review the role and potentiality of liver biopsy in the diagnosis and management of HCC.As the potentiality of precision medicine comes to the management of HCC,it will be crucial to have rapid pathways to define prognosis,and even treatment,by identifying the patients who could most benefit from target-driven therapies.All of the above reasons suggest that the current role of liver biopsy in the management of HCC needs substantial reconsideration.展开更多
Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different mult...Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.展开更多
Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC)from other tumors,mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatment...Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC)from other tumors,mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments,in order to improve the success rate of experimental therapies.Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies.Recently,clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients.Due to their frail status and sometimes fast-progressing disease,the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly,preventing their enrollment in clinical trials.However,the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients,and solid networks between research centers and referring institutions.An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials.Ultimately,institution of multidisciplinary teams can optimize treatment choice,biopsy timing,and quick enrollment of patients in clinical trials,before their performance status deteriorates.展开更多
BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontin...BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.展开更多
Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not...Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.展开更多
In the current era of immunotherapy, the treatment of hepatobiliary cancers is rapidly evolving. The use of immunotherapeutic approaches, which include peptide-based vaccines, checkpoint inhibitors and antibodies, par...In the current era of immunotherapy, the treatment of hepatobiliary cancers is rapidly evolving. The use of immunotherapeutic approaches, which include peptide-based vaccines, checkpoint inhibitors and antibodies, particularly applies to advanced hepatobiliary cancers, for which the availability of limited therapeutic options encourages the adoption of alternative strategies. Thanks to the published/presented, although conflicting, results of some of the clinical trials on this topic together with the incoming results of some other trials, clinicians involved in the cure of hepatobiliary cancer patients need to understand the basic and advanced applications of immunotherapies (1-6).展开更多
Over the past years,important progresses have been made in the treatment of patients with colorectal liver metastases(CLM).Now,5-year overall survival rate may exceed 50%by using the combination of multimodality thera...Over the past years,important progresses have been made in the treatment of patients with colorectal liver metastases(CLM).Now,5-year overall survival rate may exceed 50%by using the combination of multimodality therapies among which modern systemic chemotherapy,with or without monoclonal antibodies,and hepatic resection are the cornerstones(1,2).In such multimodality,hepatic artery infusion(HAI)has been proposed since many years with the rationale of increasing the concentration of chemotherapy agents in the liver(3).However,HAI still remains infrequently used,in particular in the adjuvant setting mainly because of the requirement of a multidisciplinary team to manage therapy,and the more widespread use of systemic chemotherapy-in particular following the perioperative“sandwich”schema(4).展开更多
According to its etymology,the English word“liver”is related to the verb“to live”,and indeed there are few domains of oncology research as lively as liver cancer.The therapeutic landscape of hepatocellular carcino...According to its etymology,the English word“liver”is related to the verb“to live”,and indeed there are few domains of oncology research as lively as liver cancer.The therapeutic landscape of hepatocellular carcinoma(HCC)has been rapidly changing over the last years,after the successful introduction of immune checkpoint inhibitors(ICIs)as standard of care for the treatment of unresectable or metastatic HCC(uHCC).Following more than a decade of tyrosine kinase inhibitors(TKIs)as the only available treatment for advanced HCC,in 2020 the results of the IMbrave150 trial radically changed the therapeutic algorithm(1,2).The combination of the anti-programmed death ligand 1(PD-L1)monoclonal antibody(mAb)atezolizumab and the anti-vascular endothelial growth factor(VEGF)mAb bevacizumab outperformed sorafenib in terms of overall survival(OS)and progression-free survival(PFS),meeting both its co-primary endpoints.The combination has been recognised as the new first-line standard of care by all major scientific societies,and it has been approved by regulatory agencies worldwide(3).展开更多
文摘Objectives:The combination of atezolizumab plus bevacizumab(A+B)represents one of the standards first-line treatments for unresectable hepatocellular carcinoma(HCC).Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control.This study aimed to assess metformin’s impact in patients with type 2 diabetes mellitus(T2DM)receiving A+B therapy.Methods:This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE(Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma)dataset across 18 Italian centres(May 2020-January 2024).We evaluated objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS),and time to progression(TTP)using Cox regression analysis and Inverse Probability of Treatment Weighting(IPTW)to address confounding.Results:Among 523 patients,341(65.2%)did not have diabetes and 182(34.8%)had T2DM.In the overall population,metformin showed no significant benefit for PFS(HR=1.15,95%CI[0.88-1.50],p=0.316)or OS(HR=1.28,95%CI[0.94-1.74],p=0.124).In the subgroup with T2DM(N=180),metformin showed no significant benefit for PFS(HR=1.41,95%CI[0.97-2.05],p=0.069),OS(HR=1.23,95%CI[0.81-1.86],p=0.333),or TTP(HR=0.82,95%CI[0.53-1.26],p=0.363).IPTW analysis confirmed these negative findings.Conclusion:This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy.Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.
文摘The role of liver biopsy in the diagnosis of hepatocellular carcinoma(HCC)has been challenged over time by the ability of imaging techniques to characterize liver lesions in patients with known cirrhosis.In fact,in the diagnostic algorithm for this tumor,histology is currently relegated to controversial cases.Furthermore,the risk of complications,such as tumor seeding and bleeding,as well as inadequate sampling have further limited the use of liver biopsy for HCC management.However,there is growing evidence of prognostic and therapeutic information available from microscopic and molecular analysis of HCC and,as the information content of the tissue sample increases,the advantages of liver biopsy might modify the current risk/benefit ratio.We herein review the role and potentiality of liver biopsy in the diagnosis and management of HCC.As the potentiality of precision medicine comes to the management of HCC,it will be crucial to have rapid pathways to define prognosis,and even treatment,by identifying the patients who could most benefit from target-driven therapies.All of the above reasons suggest that the current role of liver biopsy in the management of HCC needs substantial reconsideration.
文摘Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.
文摘Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC)from other tumors,mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments,in order to improve the success rate of experimental therapies.Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies.Recently,clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients.Due to their frail status and sometimes fast-progressing disease,the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly,preventing their enrollment in clinical trials.However,the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients,and solid networks between research centers and referring institutions.An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials.Ultimately,institution of multidisciplinary teams can optimize treatment choice,biopsy timing,and quick enrollment of patients in clinical trials,before their performance status deteriorates.
文摘BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.
文摘Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.
文摘In the current era of immunotherapy, the treatment of hepatobiliary cancers is rapidly evolving. The use of immunotherapeutic approaches, which include peptide-based vaccines, checkpoint inhibitors and antibodies, particularly applies to advanced hepatobiliary cancers, for which the availability of limited therapeutic options encourages the adoption of alternative strategies. Thanks to the published/presented, although conflicting, results of some of the clinical trials on this topic together with the incoming results of some other trials, clinicians involved in the cure of hepatobiliary cancer patients need to understand the basic and advanced applications of immunotherapies (1-6).
文摘Over the past years,important progresses have been made in the treatment of patients with colorectal liver metastases(CLM).Now,5-year overall survival rate may exceed 50%by using the combination of multimodality therapies among which modern systemic chemotherapy,with or without monoclonal antibodies,and hepatic resection are the cornerstones(1,2).In such multimodality,hepatic artery infusion(HAI)has been proposed since many years with the rationale of increasing the concentration of chemotherapy agents in the liver(3).However,HAI still remains infrequently used,in particular in the adjuvant setting mainly because of the requirement of a multidisciplinary team to manage therapy,and the more widespread use of systemic chemotherapy-in particular following the perioperative“sandwich”schema(4).
文摘According to its etymology,the English word“liver”is related to the verb“to live”,and indeed there are few domains of oncology research as lively as liver cancer.The therapeutic landscape of hepatocellular carcinoma(HCC)has been rapidly changing over the last years,after the successful introduction of immune checkpoint inhibitors(ICIs)as standard of care for the treatment of unresectable or metastatic HCC(uHCC).Following more than a decade of tyrosine kinase inhibitors(TKIs)as the only available treatment for advanced HCC,in 2020 the results of the IMbrave150 trial radically changed the therapeutic algorithm(1,2).The combination of the anti-programmed death ligand 1(PD-L1)monoclonal antibody(mAb)atezolizumab and the anti-vascular endothelial growth factor(VEGF)mAb bevacizumab outperformed sorafenib in terms of overall survival(OS)and progression-free survival(PFS),meeting both its co-primary endpoints.The combination has been recognised as the new first-line standard of care by all major scientific societies,and it has been approved by regulatory agencies worldwide(3).
