<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03775863</url>
  </required_header>
  <id_info>
    <org_study_id>17-065</org_study_id>
    <nct_id>NCT03775863</nct_id>
  </id_info>
  <brief_title>AFP Model and Liver Transplantation.</brief_title>
  <official_title>Evaluation of the AFP Model in Predicting Recurrence of Hepatocellular Carcinoma After Liver Transplantation in Patients Without Microvascular Invasion.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Austral University, Argentina</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Austral University, Argentina</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background &amp; Aim: Presence of microvascular invasion (mvi) in the explanted liver defines a&#xD;
      higher risk of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT).&#xD;
      The aim of this study is to evaluate pre LT selection models of HCC recurrence specifically&#xD;
      in patients without mvi in the explanted liver.&#xD;
&#xD;
      Methods: Three multicenter cohorts are going to be included: a Latin American, a French and&#xD;
      an Italian cohort of consecutive adult patients with HCC a first LT performed during two&#xD;
      different periods: 2005-2011 and 2012-2016. AFP model is going to be compared against Milan&#xD;
      and San Francisco criteria according to each models accuracy and prediction of HCC recurrence&#xD;
      among patients without microvascular invasion in the explanted liver considering these&#xD;
      candidates as &quot;Low-risk patients&quot;. Multivariate Cox regression analysis, with hazard ratios&#xD;
      (HR) and 95% confidence intervals (CI) for 5-year recurrence is going to be done with&#xD;
      Competing Risk Regression analysis and corresponding Subhazard Ratios (SHR).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is&#xD;
      a catastrophic event, with limited therapeutics and poor survival [1]. Prior to 1990s,&#xD;
      transplantation for HCC was a limited option with high recurrence and poor recipient&#xD;
      survival, largely because of a lack of accurate selection of transplant candidates and a late&#xD;
      diagnosis.&#xD;
&#xD;
      The Milan criteria have remained as the gold standard selection criteria, with&#xD;
      post-transplant 5-year recurrence less than 15% and 5-year survival over 70% [2]. These&#xD;
      criteria do not contemplate a relevant histological variable and a risk marker of recurrence,&#xD;
      microvascular invasion (mvi). Presence of mvi in the explanted liver has been identified as&#xD;
      an independent variable related to recurrence that categorizes patients with low and high&#xD;
      risk of HCC recurrence [3]. That is why other selection criteria, beyond Milan criteria, have&#xD;
      tried to find pre-transplant surrogate markers of mvi or other related risk factors for&#xD;
      recurrence [4-6].&#xD;
&#xD;
      Serum alpha-fetoprotein (AFP) is a marker of renewed interest as a selection criterion, which&#xD;
      has been identified as an independent risk variable associated with recurrence and as a&#xD;
      surrogate marker of mvi [4,5,7,8]. Evaluation of mvi before LT by a tumor biopsy has many&#xD;
      caveats; on the one hand, the risk of tumor seeding, bleeding and other complications and on&#xD;
      the other hand, the absence of it does not exclude of its presence in the explanted liver&#xD;
      analysis.&#xD;
&#xD;
      Consequently, while it is known that the presence of mvi defines a greater risk, its absence&#xD;
      generates uncertainty regarding the risk of recurrence in this population. The Up-to 7&#xD;
      criteria showed that the occurrence of mvi at any size and tumor number was paralleled by a&#xD;
      significant lower patient survival and higher recurrence [3]. However, the Metroticket&#xD;
      calculator excluded important pre transplant variables such as serum AFP and tumor treatment&#xD;
      or progression while on the waitlist [9]. A recently predicting model, the RETREAT score,&#xD;
      showed that when considering pre and post transplant variables, the AFP at different&#xD;
      cut-offs, presence of mvi and the sum of the largest tumor diameter and tumor number were&#xD;
      associated with HCC recurrence [7]. While it has been published earlier in Italian and French&#xD;
      cohorts that the prevalence of mvi is 24% [4,11], in another Latin American validation cohort&#xD;
      of the AFP model the prevalence of mvi was 22.2% [10].&#xD;
&#xD;
      Our objective therefore, is to evaluate the AFP model against Milan and San Francisco&#xD;
      criteria (UCSF) in the prediction of HCC recurrence and patient survival specifically in&#xD;
      patients without mvi in the explanted liver and evaluate if the AFP model can assure and&#xD;
      identify good candidates for LT that are beyond Milan and UCSF in this subgroup of patients.&#xD;
&#xD;
      Patients and Methods Study design, setting and participating centers This study is going to&#xD;
      include three multicenter cohorts of consecutive adult patients (&gt;17 years of age) who&#xD;
      underwent a first LT between January 1 2005 and December 31 2016 [4,10,11]. Participating&#xD;
      centers will appoint a study coordinator responsible for data collection. In cases of&#xD;
      conflicting or missing data, central revision and resubmission were requested. All the&#xD;
      requested variables are going to be included in a written CRF.&#xD;
&#xD;
      Eligibility criteria and study variables Criteria for inclusion required patients to be adult&#xD;
      cirrhotic or non-cirrhotic recipients with confirmed HCC in the explanted liver. Patients are&#xD;
      going to be excluded if: 1) other tumors than HCC are confirmed in the explanted liver, or 2)&#xD;
      there are missing relevant information; 3) extrahepatic or macrovascular tumor invasion were&#xD;
      observed during pre transplant evaluation or in the explanted liver 4) incidental HCC, 5) had&#xD;
      a previous liver transplant and 6) patients with microvascular invasion in the explanted&#xD;
      liver (this latter criteria is going to be assessed for the final inclusion criteria).&#xD;
&#xD;
      Recipient characteristics, pre-transplant tumor characteristics and serum α-fetoprotein (AFP)&#xD;
      levels are going to be recorded at listing and at last pre-LT evaluation. Subjects with HCC&#xD;
      diagnosis prior to transplant based on imaging criteria are going to be classified according&#xD;
      to Milan (MC) and University of California San Francisco (UCSF) [12] and the AFP model [4],&#xD;
      depending on size and number of lesions detected on pre-LT computerized tomography (CT) or&#xD;
      magnetic resonance images (MRI) and on serum pre-LT AFP levels ng/ml including the following&#xD;
      cut-offs values ≤100 ng/ml, 101-1000 ng/ml, and &gt;1000 ng/ml [4].&#xD;
&#xD;
      Tumor treatment before transplantation is going to be recorded (date and type of treatments&#xD;
      performed) including trans-arterial chemoembolization (TACE), radiofrequency ablation (RFA),&#xD;
      percutaneous ethanol injection (PEI) and liver resection (LR).&#xD;
&#xD;
      Explanted liver findings will include macroscopic and microscopic evaluation of each nodule,&#xD;
      number and diameter (cm) of each, presence of mvi, and degree of tumor differentiation&#xD;
      according to Edmonson-Steiner grading system. Nodules of largest diameter are going to be&#xD;
      identified as the major nodule. Necrotic nodules are going to be also measured including&#xD;
      necrotic and viable tumor diameter. Finally, Milan and Up-to seven criteria are going to also&#xD;
      be applied to the explanted liver specimen.&#xD;
&#xD;
      Study end-points Primary end-points analyzed are going to be 5-year patient survival and HCC&#xD;
      recurrence. Recurrence is going to be determined on the basis of imaging criteria plus serum&#xD;
      AFP or by biopsy. Time to recurrence (TTR) is going to be calculated considering it a robust&#xD;
      clinical outcome measure and calculated as the time in months elapsed between transplantation&#xD;
      and diagnosis of recurrence.&#xD;
&#xD;
      Secondary aims include the development of tumor progression while on the waitlist according&#xD;
      to RECIST 1.1 criteria.&#xD;
&#xD;
      Statistical Analysis Categorical data were compared using Fisher's exact test or Chi-Square&#xD;
      (Χ2) test (2-tailed). Continuous variables were compared with Student's T test or Wilcoxon&#xD;
      rank-sum test according to their distribution, respectively. First of all, in order to&#xD;
      evaluate if microvascular invasion in the explant is an independent risk variable for&#xD;
      recurrence, a multivariate Cox regression analysis, with hazard ratios (HR) and 95%&#xD;
      confidence intervals (95% CI) for identifying explanted liver risk variables for 5-year&#xD;
      recurrence is going to be carried out evaluating potential confounding variables. After&#xD;
      calculation of each adjusted HR separately in each overall cohort (French, Italian and&#xD;
      LATAM), cumulative incidence of recurrence by a competing risk regression analysis with death&#xD;
      is going to be compared among patients with or without mvi (&quot;high&quot; and &quot;low&quot; risk patients,&#xD;
      respectively).&#xD;
&#xD;
      Second, after evaluating the effect of mvi as a selection criteria of &quot;low&quot; and &quot;high&quot; risk&#xD;
      patients, the following analysis is going to be done after excluding patients with mvi in&#xD;
      each cohort in order to evaluate the performance of the AFP model in these &quot;low-risk&quot;&#xD;
      patients.&#xD;
&#xD;
      A multivariate Cox regression analysis (HR, 95% CI) is going to be done in order to identify&#xD;
      the effect of each pre-LT model on prediction of HCC 5-year recurrence adjusted with&#xD;
      potential confounding variables. Variables with a P value &lt;0.05 after the univariate analysis&#xD;
      are going to be included in the multivariate model, generated by stepwise forward elimination&#xD;
      evaluating P values (Wald test) and considering adjusted HR with confounding variables (&gt;20%&#xD;
      of change in crude HR). For each multivariate model, 1 variable per 10 events were included.&#xD;
      Adjustment of each final model is going to be evaluated with proportional hazards through&#xD;
      graphic and statistical evaluation (Schoenfeld residual test). Calibration is going to be&#xD;
      assessed by comparison of observed and predicted curves and evaluation of the goodness of fit&#xD;
      of the model by Harrell's c-statistic index.&#xD;
&#xD;
      Finally, a competing risk analysis with death and recurrence is going to be done with&#xD;
      calculation of subharzard ratios (SHR) and 95% CI. Kaplan Meier survival curves were compared&#xD;
      using the log-rank test (Mantel-Cox). Collected data were analyzed with STATA 10.0.&#xD;
&#xD;
      Agenda.&#xD;
&#xD;
        1. Collection and analysis of data: until 1-January-2018.&#xD;
&#xD;
        2. Full statistical analysis and overall results: until 1-January to February-2019.&#xD;
&#xD;
        3. Submission of overall results to all co-authors included in the 3 cohorts: March 2019.&#xD;
&#xD;
        4. Manuscript, figures and tables done: March 2019.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 11, 2017</start_date>
  <completion_date type="Actual">December 12, 2018</completion_date>
  <primary_completion_date type="Actual">December 12, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of recurrent hepatocellular carcinoma after liver transplantation.</measure>
    <time_frame>2003-2012</time_frame>
    <description>Competing risk regression, SHR (95% CI)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Survival in patients with hepatocellular carcinoma after liver transplantation.</measure>
    <time_frame>2003-2012</time_frame>
    <description>Cox regression multivariable adjusted models, HR (95% CI)</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">1200</enrollment>
  <condition>Liver Carcinoma</condition>
  <condition>Liver Transplant Disorder</condition>
  <arm_group>
    <arm_group_label>Latin American multicenter Cohort</arm_group_label>
    <description>Transplanted patients with HCC in LATAM from 2005-2011</description>
  </arm_group>
  <arm_group>
    <arm_group_label>French mutlicenter Cohort</arm_group_label>
    <description>Transplanted patients with HCC in France from 2003-2005</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Italian multicenter Cohort</arm_group_label>
    <description>Transplanted patients with HCC in Italy from 2005-2011</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Liver transplantation</intervention_name>
    <description>Liver transplantation for patients with hepatocellular carcinoma</description>
    <arm_group_label>French mutlicenter Cohort</arm_group_label>
    <arm_group_label>Italian multicenter Cohort</arm_group_label>
    <arm_group_label>Latin American multicenter Cohort</arm_group_label>
    <other_name>Locorregional therapy for HCC before liver transplantation.</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Study design, setting and participating centers This study is going to include three&#xD;
        multicenter cohorts of consecutive adult patients (&gt;17 years of age) who underwent a first&#xD;
        LT between January 1 2005 and December 31 2016. Participating centers will appoint a study&#xD;
        coordinator responsible for data collection. In cases of conflicting or missing data,&#xD;
        central revision and resubmission were requested. All the requested variables are going to&#xD;
        be included in a written CRF.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        . Criteria for inclusion required patients to be adult cirrhotic or non-cirrhotic&#xD;
        recipients with confirmed HCC in the explanted liver.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  other tumors than HCC are confirmed in the explanted liver,&#xD;
&#xD;
          -  there are missing relevant information;&#xD;
&#xD;
          -  extrahepatic or macrovascular tumor invasion were observed during pre transplant&#xD;
             evaluation or in the explanted liver&#xD;
&#xD;
          -  incidental HCC,&#xD;
&#xD;
          -  had a previous liver transplant&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Federico Piñero, MD, MSCE</last_name>
    <role>Principal Investigator</role>
    <affiliation>Austral University, Argentina</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Christophe Duvoux, MD</last_name>
    <role>Study Director</role>
    <affiliation>Henri Mondor Hospital, University of Paris-Est, Creteil, France.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Universidad Austral</name>
      <address>
        <city>Pilar</city>
        <state>Buenos Aires</state>
        <zip>1629</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henri Mondor Hospital, University of Paris-Est.</name>
      <address>
        <city>Creteil</city>
        <state>Paris</state>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>France</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 12, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>December 14, 2018</last_update_submitted>
  <last_update_submitted_qc>December 14, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Austral University, Argentina</investigator_affiliation>
    <investigator_full_name>Maria Julia Cremona</investigator_full_name>
    <investigator_title>UIC staff</investigator_title>
  </responsible_party>
  <keyword>Hepatocellular carcinoma</keyword>
  <keyword>models</keyword>
  <keyword>allocation</keyword>
  <keyword>selection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Extracts</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03775863
org study id: 17-065
nct id: NCT03775863
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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).
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 [4,5,7,8]. 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% [4,11], in another Latin American validation cohort
      of the AFP model the prevalence of mvi was 22.2% [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 [4,10,11]. 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 ng/ml including the following
      cut-offs values ≤100 ng/ml, 101-1000 ng/ml, and >1000 ng/ml [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 1.1 criteria.

      Statistical Analysis Categorical data were compared using Fisher's exact test or Chi-Square
      (Χ2) test (2-tailed). Continuous variables were compared with Student's 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 <0.05 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 Harrell's 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 10.0.

      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.
observational model: Cohort
time perspective: Prospective
measure: Incidence of recurrent hepatocellular carcinoma after liver transplantation.
time frame: 2003-2012
description: Competing risk regression, SHR (95% CI)
measure: Survival in patients with hepatocellular carcinoma after liver transplantation.
time frame: 2003-2012
description: Cox regression multivariable adjusted models, HR (95% CI)
arm group label: Latin American multicenter Cohort
description: Transplanted patients with HCC in LATAM from 2005-2011
arm group label: French mutlicenter Cohort
description: Transplanted patients with HCC in France from 2003-2005
arm group label: Italian multicenter Cohort
description: Transplanted patients with HCC in Italy from 2005-2011
intervention type: Procedure
intervention name: Liver transplantation
description: Liver transplantation for patients with hepatocellular carcinoma
arm group label: French mutlicenter Cohort
arm group label: Italian multicenter Cohort
arm group label: Latin American multicenter Cohort
other name: Locorregional therapy for HCC before liver transplantation.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
last name: Federico Piñero, MD, MSCE
role: Principal Investigator
affiliation: Austral University, Argentina
last name: Christophe Duvoux, MD
role: Study Director
affiliation: Henri Mondor Hospital, University of Paris-Est, Creteil, France.
facility: 
facility: 
country: Argentina
country: France
responsible party type: Principal Investigator
investigator affiliation: Austral University, Argentina
investigator full name: Maria Julia Cremona
investigator title: UIC staff
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Liver Extracts
sharing ipd: Undecided