Ignite Creation Date:
2024-05-06 @ 12:30 PM
Last Modification Date:
2024-10-26 @ 12:59 PM
Study NCT ID:
NCT03775863
Status:
COMPLETED
Last Update Posted:
2018-12-19
First Post:
2018-12-12
Brief Title:
AFP Model and Liver Transplantation
Sponsor:
Austral University Argentina
Organization:
Austral University Argentina
Study Overview
Official Title:
Evaluation of the AFP Model in Predicting Recurrence of Hepatocellular Carcinoma After Liver Transplantation in Patients Without Microvascular Invasion
Status:
COMPLETED
Status Verified Date:
2018-12
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 Aim Presence of microvascular invasion mvi in the explanted liver defines a higher risk of recurrence of hepatocellular carcinoma HCC after liver transplantation LT The aim of this study is to evaluate pre LT selection models of HCC recurrence specifically in patients without mvi in the explanted liver
Methods Three multicenter cohorts are going to be included a Latin American a French and an Italian cohort of consecutive adult patients with HCC a first LT performed during two different periods 2005-2011 and 2012-2016 AFP model is going to be compared against Milan and San Francisco criteria according to each models accuracy and prediction of HCC recurrence among patients without microvascular invasion in the explanted liver considering these candidates as Low-risk patients Multivariate Cox regression analysis with hazard ratios HR and 95 confidence intervals CI for 5-year recurrence is going to be done with Competing Risk Regression analysis and corresponding Subhazard Ratios SHR
Methods Three multicenter cohorts are going to be included a Latin American a French and an Italian cohort of consecutive adult patients with HCC a first LT performed during two different periods 2005-2011 and 2012-2016 AFP model is going to be compared against Milan and San Francisco criteria according to each models accuracy and prediction of HCC recurrence among patients without microvascular invasion in the explanted liver considering these candidates as Low-risk patients Multivariate Cox regression analysis with hazard ratios HR and 95 confidence intervals CI for 5-year recurrence is going to be done with Competing Risk Regression analysis and corresponding Subhazard Ratios SHR
Detailed Description:
Introduction Recurrence of hepatocellular carcinoma HCC after liver transplantation LT is a catastrophic event with limited therapeutics and poor survival 1 Prior to 1990s transplantation for HCC was a limited option with high recurrence and poor recipient survival largely because of a lack of accurate selection of transplant candidates and a late diagnosis
The Milan criteria have remained as the gold standard selection criteria with post-transplant 5-year recurrence less than 15 and 5-year survival over 70 2 These criteria do not contemplate a relevant histological variable and a risk marker of recurrence microvascular invasion mvi Presence of mvi in the explanted liver has been identified as an independent variable related to recurrence that categorizes patients with low and high risk of HCC recurrence 3 That is why other selection criteria beyond Milan criteria have tried to find pre-transplant surrogate markers of mvi or other related risk factors for recurrence 4-6
Serum alpha-fetoprotein AFP is a marker of renewed interest as a selection criterion which has been identified as an independent risk variable associated with recurrence and as a surrogate marker of mvi 4578 Evaluation of mvi before LT by a tumor biopsy has many caveats on the one hand the risk of tumor seeding bleeding and other complications and on the other hand the absence of it does not exclude of its presence in the explanted liver analysis
Consequently while it is known that the presence of mvi defines a greater risk its absence generates uncertainty regarding the risk of recurrence in this population The Up-to 7 criteria showed that the occurrence of mvi at any size and tumor number was paralleled by a significant lower patient survival and higher recurrence 3 However the Metroticket calculator excluded important pre transplant variables such as serum AFP and tumor treatment or progression while on the waitlist 9 A recently predicting model the RETREAT score showed that when considering pre and post transplant variables the AFP at different cut-offs presence of mvi and the sum of the largest tumor diameter and tumor number were associated with HCC recurrence 7 While it has been published earlier in Italian and French cohorts that the prevalence of mvi is 24 411 in another Latin American validation cohort of the AFP model the prevalence of mvi was 222 10
Our objective therefore is to evaluate the AFP model against Milan and San Francisco criteria UCSF in the prediction of HCC recurrence and patient survival specifically in patients without mvi in the explanted liver and evaluate if the AFP model can assure and identify good candidates for LT that are beyond Milan and UCSF in this subgroup of patients
Patients and Methods Study design setting and participating centers This study is going to include three multicenter cohorts of consecutive adult patients 17 years of age who underwent a first LT between January 1 2005 and December 31 2016 41011 Participating centers will appoint a study coordinator responsible for data collection In cases of conflicting or missing data central revision and resubmission were requested All the requested variables are going to be included in a written CRF
Eligibility criteria and study variables Criteria for inclusion required patients to be adult cirrhotic or non-cirrhotic recipients with confirmed HCC in the explanted liver Patients are going to be excluded if 1 other tumors than HCC are confirmed in the explanted liver or 2 there are missing relevant information 3 extrahepatic or macrovascular tumor invasion were observed during pre transplant evaluation or in the explanted liver 4 incidental HCC 5 had a previous liver transplant and 6 patients with microvascular invasion in the explanted liver this latter criteria is going to be assessed for the final inclusion criteria
Recipient characteristics pre-transplant tumor characteristics and serum α-fetoprotein AFP levels are going to be recorded at listing and at last pre-LT evaluation Subjects with HCC diagnosis prior to transplant based on imaging criteria are going to be classified according to Milan MC and University of California San Francisco UCSF 12 and the AFP model 4 depending on size and number of lesions detected on pre-LT computerized tomography CT or magnetic resonance images MRI and on serum pre-LT AFP levels ngml including the following cut-offs values 100 ngml 101-1000 ngml and 1000 ngml 4
Tumor treatment before transplantation is going to be recorded date and type of treatments performed including trans-arterial chemoembolization TACE radiofrequency ablation RFA percutaneous ethanol injection PEI and liver resection LR
Explanted liver findings will include macroscopic and microscopic evaluation of each nodule number and diameter cm of each presence of mvi and degree of tumor differentiation according to Edmonson-Steiner grading system Nodules of largest diameter are going to be identified as the major nodule Necrotic nodules are going to be also measured including necrotic and viable tumor diameter Finally Milan and Up-to seven criteria are going to also be applied to the explanted liver specimen
Study end-points Primary end-points analyzed are going to be 5-year patient survival and HCC recurrence Recurrence is going to be determined on the basis of imaging criteria plus serum AFP or by biopsy Time to recurrence TTR is going to be calculated considering it a robust clinical outcome measure and calculated as the time in months elapsed between transplantation and diagnosis of recurrence
Secondary aims include the development of tumor progression while on the waitlist according to RECIST 11 criteria
Statistical Analysis Categorical data were compared using Fishers exact test or Chi-Square Χ2 test 2-tailed Continuous variables were compared with Students T test or Wilcoxon rank-sum test according to their distribution respectively First of all in order to evaluate if microvascular invasion in the explant is an independent risk variable for recurrence a multivariate Cox regression analysis with hazard ratios HR and 95 confidence intervals 95 CI for identifying explanted liver risk variables for 5-year recurrence is going to be carried out evaluating potential confounding variables After calculation of each adjusted HR separately in each overall cohort French Italian and LATAM cumulative incidence of recurrence by a competing risk regression analysis with death is going to be compared among patients with or without mvi high and low risk patients respectively
Second after evaluating the effect of mvi as a selection criteria of low and high risk patients the following analysis is going to be done after excluding patients with mvi in each cohort in order to evaluate the performance of the AFP model in these low-risk patients
A multivariate Cox regression analysis HR 95 CI is going to be done in order to identify the effect of each pre-LT model on prediction of HCC 5-year recurrence adjusted with potential confounding variables Variables with a P value 005 after the univariate analysis are going to be included in the multivariate model generated by stepwise forward elimination evaluating P values Wald test and considering adjusted HR with confounding variables 20 of change in crude HR For each multivariate model 1 variable per 10 events were included Adjustment of each final model is going to be evaluated with proportional hazards through graphic and statistical evaluation Schoenfeld residual test Calibration is going to be assessed by comparison of observed and predicted curves and evaluation of the goodness of fit of the model by Harrells c-statistic index
Finally a competing risk analysis with death and recurrence is going to be done with calculation of subharzard ratios SHR and 95 CI Kaplan Meier survival curves were compared using the log-rank test Mantel-Cox Collected data were analyzed with STATA 100
Agenda
1 Collection and analysis of data until 1-January-2018
2 Full statistical analysis and overall results until 1-January to February-2019
3 Submission of overall results to all co-authors included in the 3 cohorts March 2019
4 Manuscript figures and tables done March 2019
The Milan criteria have remained as the gold standard selection criteria with post-transplant 5-year recurrence less than 15 and 5-year survival over 70 2 These criteria do not contemplate a relevant histological variable and a risk marker of recurrence microvascular invasion mvi Presence of mvi in the explanted liver has been identified as an independent variable related to recurrence that categorizes patients with low and high risk of HCC recurrence 3 That is why other selection criteria beyond Milan criteria have tried to find pre-transplant surrogate markers of mvi or other related risk factors for recurrence 4-6
Serum alpha-fetoprotein AFP is a marker of renewed interest as a selection criterion which has been identified as an independent risk variable associated with recurrence and as a surrogate marker of mvi 4578 Evaluation of mvi before LT by a tumor biopsy has many caveats on the one hand the risk of tumor seeding bleeding and other complications and on the other hand the absence of it does not exclude of its presence in the explanted liver analysis
Consequently while it is known that the presence of mvi defines a greater risk its absence generates uncertainty regarding the risk of recurrence in this population The Up-to 7 criteria showed that the occurrence of mvi at any size and tumor number was paralleled by a significant lower patient survival and higher recurrence 3 However the Metroticket calculator excluded important pre transplant variables such as serum AFP and tumor treatment or progression while on the waitlist 9 A recently predicting model the RETREAT score showed that when considering pre and post transplant variables the AFP at different cut-offs presence of mvi and the sum of the largest tumor diameter and tumor number were associated with HCC recurrence 7 While it has been published earlier in Italian and French cohorts that the prevalence of mvi is 24 411 in another Latin American validation cohort of the AFP model the prevalence of mvi was 222 10
Our objective therefore is to evaluate the AFP model against Milan and San Francisco criteria UCSF in the prediction of HCC recurrence and patient survival specifically in patients without mvi in the explanted liver and evaluate if the AFP model can assure and identify good candidates for LT that are beyond Milan and UCSF in this subgroup of patients
Patients and Methods Study design setting and participating centers This study is going to include three multicenter cohorts of consecutive adult patients 17 years of age who underwent a first LT between January 1 2005 and December 31 2016 41011 Participating centers will appoint a study coordinator responsible for data collection In cases of conflicting or missing data central revision and resubmission were requested All the requested variables are going to be included in a written CRF
Eligibility criteria and study variables Criteria for inclusion required patients to be adult cirrhotic or non-cirrhotic recipients with confirmed HCC in the explanted liver Patients are going to be excluded if 1 other tumors than HCC are confirmed in the explanted liver or 2 there are missing relevant information 3 extrahepatic or macrovascular tumor invasion were observed during pre transplant evaluation or in the explanted liver 4 incidental HCC 5 had a previous liver transplant and 6 patients with microvascular invasion in the explanted liver this latter criteria is going to be assessed for the final inclusion criteria
Recipient characteristics pre-transplant tumor characteristics and serum α-fetoprotein AFP levels are going to be recorded at listing and at last pre-LT evaluation Subjects with HCC diagnosis prior to transplant based on imaging criteria are going to be classified according to Milan MC and University of California San Francisco UCSF 12 and the AFP model 4 depending on size and number of lesions detected on pre-LT computerized tomography CT or magnetic resonance images MRI and on serum pre-LT AFP levels ngml including the following cut-offs values 100 ngml 101-1000 ngml and 1000 ngml 4
Tumor treatment before transplantation is going to be recorded date and type of treatments performed including trans-arterial chemoembolization TACE radiofrequency ablation RFA percutaneous ethanol injection PEI and liver resection LR
Explanted liver findings will include macroscopic and microscopic evaluation of each nodule number and diameter cm of each presence of mvi and degree of tumor differentiation according to Edmonson-Steiner grading system Nodules of largest diameter are going to be identified as the major nodule Necrotic nodules are going to be also measured including necrotic and viable tumor diameter Finally Milan and Up-to seven criteria are going to also be applied to the explanted liver specimen
Study end-points Primary end-points analyzed are going to be 5-year patient survival and HCC recurrence Recurrence is going to be determined on the basis of imaging criteria plus serum AFP or by biopsy Time to recurrence TTR is going to be calculated considering it a robust clinical outcome measure and calculated as the time in months elapsed between transplantation and diagnosis of recurrence
Secondary aims include the development of tumor progression while on the waitlist according to RECIST 11 criteria
Statistical Analysis Categorical data were compared using Fishers exact test or Chi-Square Χ2 test 2-tailed Continuous variables were compared with Students T test or Wilcoxon rank-sum test according to their distribution respectively First of all in order to evaluate if microvascular invasion in the explant is an independent risk variable for recurrence a multivariate Cox regression analysis with hazard ratios HR and 95 confidence intervals 95 CI for identifying explanted liver risk variables for 5-year recurrence is going to be carried out evaluating potential confounding variables After calculation of each adjusted HR separately in each overall cohort French Italian and LATAM cumulative incidence of recurrence by a competing risk regression analysis with death is going to be compared among patients with or without mvi high and low risk patients respectively
Second after evaluating the effect of mvi as a selection criteria of low and high risk patients the following analysis is going to be done after excluding patients with mvi in each cohort in order to evaluate the performance of the AFP model in these low-risk patients
A multivariate Cox regression analysis HR 95 CI is going to be done in order to identify the effect of each pre-LT model on prediction of HCC 5-year recurrence adjusted with potential confounding variables Variables with a P value 005 after the univariate analysis are going to be included in the multivariate model generated by stepwise forward elimination evaluating P values Wald test and considering adjusted HR with confounding variables 20 of change in crude HR For each multivariate model 1 variable per 10 events were included Adjustment of each final model is going to be evaluated with proportional hazards through graphic and statistical evaluation Schoenfeld residual test Calibration is going to be assessed by comparison of observed and predicted curves and evaluation of the goodness of fit of the model by Harrells c-statistic index
Finally a competing risk analysis with death and recurrence is going to be done with calculation of subharzard ratios SHR and 95 CI Kaplan Meier survival curves were compared using the log-rank test Mantel-Cox Collected data were analyzed with STATA 100
Agenda
1 Collection and analysis of data until 1-January-2018
2 Full statistical analysis and overall results until 1-January to February-2019
3 Submission of overall results to all co-authors included in the 3 cohorts March 2019
4 Manuscript figures and tables done March 2019
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