Liver Transplant Disorder Clinical Trial
Official title:
Evaluation of the AFP Model in Predicting Recurrence of Hepatocellular Carcinoma After Liver Transplantation in Patients Without Microvascular Invasion.
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.
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