Ignite Creation Date:
2024-05-06 @ 3:13 PM
Last Modification Date:
2024-10-26 @ 1:45 PM
Study NCT ID:
NCT04555265
Status:
COMPLETED
Last Update Posted:
2023-08-31
First Post:
2020-09-11
Brief Title:
Cytokine Change in Hepatocellular Carcinoma Treated by Thermal Ablation
Sponsor:
Chinese University of Hong Kong
Organization:
Chinese University of Hong Kong
Study Overview
Official Title:
Investigation of Cytokine Change and Its Prognostic Value in Patients With Hepatocellular Carcinoma Treated by Thermal Ablation
Status:
COMPLETED
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Hepatocellular carcinoma HCC is the most common primary liver cancer with aggressive tumor behavior Radiofrequency ablation RFA or microwave ablation MWA is an effective curative treatment for early stage HCC This thermal ablation of liver tumor induces host immune response with changes in serum concentration of various cytokines It is not clear whether this host immune response correlates with tumor recurrence and long-term patient survival
Objective This prospective study is to investigate the change of cytokines level following RFA or MWA for HCC and its clinical correlation with tumor recurrence and patients long-term survival data
Hypothesis Thermal ablation of HCC creates tumor antigen source for the generation of antitumor immunity and enhances host immune responses The resulting inflammation and changes in cytokines may augment tumor cell death by increasing neutrophil infiltration and oxidative burst mechanisms On the other hand there may be negative effects via the production of growth factors which could stimulate tumor cell growth within the sub-lethal margin Therefore the ultimate clinical consequences would be significantly affected by these immune responses
Study design This is a prospective study on the measurement of changes of serum cytokines in patients with HCC undergone RFA or MWA using the commercially available kit MILLIPEX Human cytokinechemokine magnetic bead panel - Immunology Multiplex Assay which measure 10 cytokines including IL-1β IL-6 IL-10 IL-12 p40 IL-12 p70 TNF-α CXCL8 CXCL9 CXCL10 CCL2 CCL5 Statistical correlation will be performed between the cytokine change and long-term patients clinical outcome using the prospectively collected database
Subjects Patients with HCC undergone RFA or MWA in the Department of Surgery The Chinese University of Hong Kong will be recruited Exclusion criteria were evidence of extrahepatic metastasis patients receiving combined hepatectomy and other local ablative therapy and patients with decompensated liver function that preclude local ablative treatment
Intervention RFA or MWA will be performed for patients with HCC The serum samples of all consecutive recruited patients will be collected prospectively during the intervention The measurement of cytokines level will be performed in the Laboratory of Department of Chemical Pathology The Chinese University of Hong Kong under the standard protocol
Main outcome measures Primary outcome measure is early intrahepatic tumor recurrence within one year after thermal ablation Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Data analysis All data will be prospectively collected by a research assistant and computerized in a database Statistical analysis will be performed by Chi-square test or Fishers exact test where appropriate to compare discrete variables and Mann-Whitney U test to compare continuous variables Cumulative survival will be computed by the Kaplan-Meier method and compared by Log-rank test Multivariable analysis using logistic regression model will be done to identify the independent prognostic factors affecting early tumor recurrence
Expected results Understanding the relationship between the cytokines change during thermal ablation and post-treatment tumor recurrence helps to identify high risk patients for the possible adjuvant therapy in future study
Objective This prospective study is to investigate the change of cytokines level following RFA or MWA for HCC and its clinical correlation with tumor recurrence and patients long-term survival data
Hypothesis Thermal ablation of HCC creates tumor antigen source for the generation of antitumor immunity and enhances host immune responses The resulting inflammation and changes in cytokines may augment tumor cell death by increasing neutrophil infiltration and oxidative burst mechanisms On the other hand there may be negative effects via the production of growth factors which could stimulate tumor cell growth within the sub-lethal margin Therefore the ultimate clinical consequences would be significantly affected by these immune responses
Study design This is a prospective study on the measurement of changes of serum cytokines in patients with HCC undergone RFA or MWA using the commercially available kit MILLIPEX Human cytokinechemokine magnetic bead panel - Immunology Multiplex Assay which measure 10 cytokines including IL-1β IL-6 IL-10 IL-12 p40 IL-12 p70 TNF-α CXCL8 CXCL9 CXCL10 CCL2 CCL5 Statistical correlation will be performed between the cytokine change and long-term patients clinical outcome using the prospectively collected database
Subjects Patients with HCC undergone RFA or MWA in the Department of Surgery The Chinese University of Hong Kong will be recruited Exclusion criteria were evidence of extrahepatic metastasis patients receiving combined hepatectomy and other local ablative therapy and patients with decompensated liver function that preclude local ablative treatment
Intervention RFA or MWA will be performed for patients with HCC The serum samples of all consecutive recruited patients will be collected prospectively during the intervention The measurement of cytokines level will be performed in the Laboratory of Department of Chemical Pathology The Chinese University of Hong Kong under the standard protocol
Main outcome measures Primary outcome measure is early intrahepatic tumor recurrence within one year after thermal ablation Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Data analysis All data will be prospectively collected by a research assistant and computerized in a database Statistical analysis will be performed by Chi-square test or Fishers exact test where appropriate to compare discrete variables and Mann-Whitney U test to compare continuous variables Cumulative survival will be computed by the Kaplan-Meier method and compared by Log-rank test Multivariable analysis using logistic regression model will be done to identify the independent prognostic factors affecting early tumor recurrence
Expected results Understanding the relationship between the cytokines change during thermal ablation and post-treatment tumor recurrence helps to identify high risk patients for the possible adjuvant therapy in future study
Detailed Description:
Background Liver cancer is the sixth most common malignancy in the world It is the fourth leading cause of cancer-related deaths and has a global incidence of more than 840000 new cases in 20181 Hepatocellular carcinoma HCC accounts for 75 - 85 of primary liver cancer Hepatectomy radiofrequency ablation RFA and orthotopic liver transplantation are the main treatment options for patients with early stage HCC2 Hepatectomy is only indicated in patients with early stage HCC and preserved liver function whereas the application of liver transplantation is limited globally because of organ shortage RFA is therefore the most effective treatment in patients with HCC and borderline liver function due to cirrhotic liver especially in Asia-Pacific region where hepatitis B infection is prevalent
Thermal ablation kills tumors via direct thermal denaturation and coagulation of tumor proteins3 The retention of devitalized and damaged tumor cells within the body stimulates a robust inflammatory response It has also been reported that thermal ablation creates a tumor antigen source for the generation of antitumor immunity and enhances host immune responses4 Activated platelets release interleukin IL -1 tumor necrosis factor TNF and transforming growth factor which increase vascular permeability and promote chemotaxis Neutrophils are attracted to the ablation site and perform debris scavenging by releasing free radicals via oxidative burst mechanisms aimed at destroying inciting agents Macrophage migration ensues transitioning to the proliferative stage during which macrophages secrete growth factors including TNF vascular endothelial growth factor VEGF and basic fibroblast growth factor5 The level of proliferative activity of macrophages and lymphocytes is mediated by IL-6 positively and IL-10 negatively6 7 In the event of an incomplete ablation or nearly complete ablation viable tumor cells in the sub-lethal ablation zone may be affected positively or negatively by the concomitant inflammatory response including increased levels of cytokines and growth factors Inflammation following ablation may have negative effects via the production of growth factors and cytokines by macrophages and lymphocytes which could stimulate tumor cell growth within the sub-lethal zone8 Human and animal studies using immunohistochemical staining of tissues enzyme-linked immunosorbent assay of tissue lysates and enzyme-linked immunosorbent assay of plasma have shown significant increase in specific inflammatory and immunomodulatory mediators after RFA9 10 The principle investigator has previously reported the inflammatory responses of RFA using the porcine liver model that the level of systemic inflammatory markers TNF and IL-1 was significantly elevated after RFA when compared with hepatectomy11 Although pre-clinical studies on inflammatory responses of thermal ablation for liver tumor are substantial clinical correlation of these micro-environmental reaction is limited in the literature Erinjeri et al12 reported that the ablation type and primary diagnosis predicted the change of IL-6 and patient age predicted the change of IL-10 after thermal ablation of tumors IL-6 may act as surrogates for immunogenic cell death and the combination of immunogenic death-inducing procedures with immune check-point inhibitor may be beneficial to prolong patient survival after RFA13 At the cellular level RFA has proven to enhance tumor-associated antigen-specific T cell response and this contributes to the HCC recurrence-free survival of patients14 Nonetheless it is still not clear about the possible relationship between RFA-induced cytokines change and its prognostic value on tumor recurrence and long-term patient survival
The principle investigator has reported the results of 209 patients receiving RFA as the sole treatment for HCC15 The overall tumor recurrence rate was up to 80 with median follow-up of 26 months Hence identification of high-risk patients who might develop early recurrence using surrogate biomarkers eg cytokines carries an important clinical implication on the use of adjuvant treatment eg immune check-point inhibitor
Therefore the investigators propose this single-center prospective study to analysis the change in serum cytokines level in patients with HCC treated by RFA or MWA The result will be used to correlate the clinical outcome of patients especially tumor recurrence and long-term survival outcome This proposed clinical trial is of clinical importance in establishing the potential role of immune response as surrogate biomarkers to predict long-term patient outcome It establishes the platform for future study of adjuvant treatment using immune check-point inhibitor for patients with HCC treated by RFA or other thermal ablative therapy The investigators center is a tertiary referral center in Hong Kong managing patients with complicated hepatobiliary and pancreatic diseases The number of new cases of patients with HCC managed in the investigators center is around 200 every year and the number of patients with HCC undergoing hepatectomy is around 80 every year All the investigators are experts with vast experience in clinical and basic researches of patients with HCC The investigators have conducted and published several randomized trials on management of HCC and other aspects of hepatobiliary surgery in international journals16-19
Hypothesis RFA or MWA for HCC might induce inflammatory immune response with resulting change in cytokines level This micro-environmental reaction might positively or negatively regulate the residual tumor cells leading to the significant changes in tumor recurrence and long-term patient survival
Aim of study This prospective study aims to investigate the change of cytokines level following RFA or MWA for HCC and its clinical correlation with tumor recurrence and patients long-term survival data Primary outcome measure is early tumor recurrence within one year after RFA Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Primary outcome measure is early intrahepatic tumor recurrence within one year after RFA and MWA Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Analysis of cytokines level using studied patient serum samples
Analytes available
IL-1β IL-6 IL-10 IL-12 p40 IL-12 p70 TNF-α CXCL8 CXCL9 CXCL10 CCL2 CCL5
Commercially available kit
MILLIPLEX MAP Human CytokineChemokine Magnetic Bead Panel - Immunology Multiplex Assay
Application of kit
Simultaneously analyze multiple cytokine and chemokine biomarkers with MILLIPLEX MAP Human CytokineChemokine Magnetic Bead Panel - Immunology Multiplex Assay in human serum plasma and cell culture samples This is an overnight incubation assay
Expected time of study The investigators institution is a major tertiary referral center for HCC in Hong Kong The patient recruitment will be started once the approval from Institution Review Board is obtained The recruitment period is around 12 months to 18 months With the median follow-up period of around 18 months It is expected that the total period of study is three years
Sample size estimation Expected number of patients to be recruited is estimated at 60 according to the past patient number undergoing treatment under the department
Statistical analysis All data will be prospectively collected by a research assistant and computerized in a database Statistical analysis will be performed by Chi-square test or Fishers exact test where appropriate to compare discrete variables and Mann-Whitney U test to compare continuous variables Cumulative survival will be computed by the Kaplan-Meier method and compared by Log-rank test Multivariable analysis using logistic regression model will be done to identify the independent prognostic factors affecting early tumor recurrence
Ethical Consideration This study will be carried out in accordance with the Declaration of Helsinki of the World Medical Association and the International Conference on Harmonization - Good Clinical Practice
Consent Written voluntary consent will be obtained after full explanation of the trial to the patient before operation and randomization
Relevance to clinical applications
This study carries significant clinical influence on the surgical management of patient with HCC Since hepatitis B infection is still endemic in Asia-Pacific area like Hong Kong hepatitis B related HCC is still a burden among the whole pool of cancer patients This study aims to establish the potential role of immune response as surrogate biomarkers to predict long-term patient outcome It enhances the development of the platform for future study of adjuvant treatment using immune check-point inhibitor for patients with HCC treated by thermal ablative therapy
Thermal ablation kills tumors via direct thermal denaturation and coagulation of tumor proteins3 The retention of devitalized and damaged tumor cells within the body stimulates a robust inflammatory response It has also been reported that thermal ablation creates a tumor antigen source for the generation of antitumor immunity and enhances host immune responses4 Activated platelets release interleukin IL -1 tumor necrosis factor TNF and transforming growth factor which increase vascular permeability and promote chemotaxis Neutrophils are attracted to the ablation site and perform debris scavenging by releasing free radicals via oxidative burst mechanisms aimed at destroying inciting agents Macrophage migration ensues transitioning to the proliferative stage during which macrophages secrete growth factors including TNF vascular endothelial growth factor VEGF and basic fibroblast growth factor5 The level of proliferative activity of macrophages and lymphocytes is mediated by IL-6 positively and IL-10 negatively6 7 In the event of an incomplete ablation or nearly complete ablation viable tumor cells in the sub-lethal ablation zone may be affected positively or negatively by the concomitant inflammatory response including increased levels of cytokines and growth factors Inflammation following ablation may have negative effects via the production of growth factors and cytokines by macrophages and lymphocytes which could stimulate tumor cell growth within the sub-lethal zone8 Human and animal studies using immunohistochemical staining of tissues enzyme-linked immunosorbent assay of tissue lysates and enzyme-linked immunosorbent assay of plasma have shown significant increase in specific inflammatory and immunomodulatory mediators after RFA9 10 The principle investigator has previously reported the inflammatory responses of RFA using the porcine liver model that the level of systemic inflammatory markers TNF and IL-1 was significantly elevated after RFA when compared with hepatectomy11 Although pre-clinical studies on inflammatory responses of thermal ablation for liver tumor are substantial clinical correlation of these micro-environmental reaction is limited in the literature Erinjeri et al12 reported that the ablation type and primary diagnosis predicted the change of IL-6 and patient age predicted the change of IL-10 after thermal ablation of tumors IL-6 may act as surrogates for immunogenic cell death and the combination of immunogenic death-inducing procedures with immune check-point inhibitor may be beneficial to prolong patient survival after RFA13 At the cellular level RFA has proven to enhance tumor-associated antigen-specific T cell response and this contributes to the HCC recurrence-free survival of patients14 Nonetheless it is still not clear about the possible relationship between RFA-induced cytokines change and its prognostic value on tumor recurrence and long-term patient survival
The principle investigator has reported the results of 209 patients receiving RFA as the sole treatment for HCC15 The overall tumor recurrence rate was up to 80 with median follow-up of 26 months Hence identification of high-risk patients who might develop early recurrence using surrogate biomarkers eg cytokines carries an important clinical implication on the use of adjuvant treatment eg immune check-point inhibitor
Therefore the investigators propose this single-center prospective study to analysis the change in serum cytokines level in patients with HCC treated by RFA or MWA The result will be used to correlate the clinical outcome of patients especially tumor recurrence and long-term survival outcome This proposed clinical trial is of clinical importance in establishing the potential role of immune response as surrogate biomarkers to predict long-term patient outcome It establishes the platform for future study of adjuvant treatment using immune check-point inhibitor for patients with HCC treated by RFA or other thermal ablative therapy The investigators center is a tertiary referral center in Hong Kong managing patients with complicated hepatobiliary and pancreatic diseases The number of new cases of patients with HCC managed in the investigators center is around 200 every year and the number of patients with HCC undergoing hepatectomy is around 80 every year All the investigators are experts with vast experience in clinical and basic researches of patients with HCC The investigators have conducted and published several randomized trials on management of HCC and other aspects of hepatobiliary surgery in international journals16-19
Hypothesis RFA or MWA for HCC might induce inflammatory immune response with resulting change in cytokines level This micro-environmental reaction might positively or negatively regulate the residual tumor cells leading to the significant changes in tumor recurrence and long-term patient survival
Aim of study This prospective study aims to investigate the change of cytokines level following RFA or MWA for HCC and its clinical correlation with tumor recurrence and patients long-term survival data Primary outcome measure is early tumor recurrence within one year after RFA Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Primary outcome measure is early intrahepatic tumor recurrence within one year after RFA and MWA Secondary outcome measures are other tumor recurrence pattern late intrahepatic recurrence and extrahepatic metastasis overall survival and recurrence-free survival
Analysis of cytokines level using studied patient serum samples
Analytes available
IL-1β IL-6 IL-10 IL-12 p40 IL-12 p70 TNF-α CXCL8 CXCL9 CXCL10 CCL2 CCL5
Commercially available kit
MILLIPLEX MAP Human CytokineChemokine Magnetic Bead Panel - Immunology Multiplex Assay
Application of kit
Simultaneously analyze multiple cytokine and chemokine biomarkers with MILLIPLEX MAP Human CytokineChemokine Magnetic Bead Panel - Immunology Multiplex Assay in human serum plasma and cell culture samples This is an overnight incubation assay
Expected time of study The investigators institution is a major tertiary referral center for HCC in Hong Kong The patient recruitment will be started once the approval from Institution Review Board is obtained The recruitment period is around 12 months to 18 months With the median follow-up period of around 18 months It is expected that the total period of study is three years
Sample size estimation Expected number of patients to be recruited is estimated at 60 according to the past patient number undergoing treatment under the department
Statistical analysis All data will be prospectively collected by a research assistant and computerized in a database Statistical analysis will be performed by Chi-square test or Fishers exact test where appropriate to compare discrete variables and Mann-Whitney U test to compare continuous variables Cumulative survival will be computed by the Kaplan-Meier method and compared by Log-rank test Multivariable analysis using logistic regression model will be done to identify the independent prognostic factors affecting early tumor recurrence
Ethical Consideration This study will be carried out in accordance with the Declaration of Helsinki of the World Medical Association and the International Conference on Harmonization - Good Clinical Practice
Consent Written voluntary consent will be obtained after full explanation of the trial to the patient before operation and randomization
Relevance to clinical applications
This study carries significant clinical influence on the surgical management of patient with HCC Since hepatitis B infection is still endemic in Asia-Pacific area like Hong Kong hepatitis B related HCC is still a burden among the whole pool of cancer patients This study aims to establish the potential role of immune response as surrogate biomarkers to predict long-term patient outcome It enhances the development of the platform for future study of adjuvant treatment using immune check-point inhibitor for patients with HCC treated by thermal ablative therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None