Supplementary material
Statistical analysis for the non-LT survival model
Qualitative data were described using frequencies and percentages. Quantitative data were
described in terms of medians and interquartile ranges (IQR). There were no missing data for these
variables.
Overall survival was calculated from the baseline visit until death due to any cause or latest
follow-up. Length of follow-up and survival were expressed as medians (IQR). Overall survival
was calculated from the baseline visit until death due to any cause or latest follow-up.
We tested several multivariate survival models (Cox’s semi-parametric model, and the parametric
exponential, log-normal, Weibull, and log-logistic models), using the following: Child (Pugh class,
non-LT therapy, and the AFP Model ordinal variables (diameter, number of nodules, AFP values).
The log-logistic model was ultimately chosen because it showed the lowest Akaike Information
Criterion (AIC).[1]
Cross-validation was used to examine the reproducibility of the survival model: the data were
randomly divided into three equal subsets and the coefficients were recalculated after removing one
data subset at a time. The likelihood ratio chi-squared test was computed using the new coefficients
on the remaining data. The results obtained with the model are shown as beta estimates and their
standard errors, together with the corresponding p values.
Statistical significance was set at p < .05. The calculations were done with the JMP® 9.0.1 package
(1989–2010 SAS Institute Inc.) and the smcure package in R.app GUI 1.51 (S. Urbanek & H.-J.
Bibiko, ©R Foundation for Statistical Computing, 2012).
Markov model and lifetime cost utility analysis
To calculate life expectancy after LT (LT arm) we used the AFP Model.[2] In particular, as in the
Duvoux study,[2] we assumed a post-LT early mortality of 10% and a median risk of recurrence
within 5 years of 20%. The monthly risk of recurrence was calculated using the median risk of
recurrence and hazard ratios for AFP, diameter of largest nodule, and multinodular HCC, derived
from the Duvoux study.[2] Survival of HCC patients with post-transplant recurrences was assumed
to be 10 months.[3] The post-LT survival model proved to be well calibrated with the survival
curves in the Duvoux study.[2]
Since most HCC recurrences occur within the first 2 years, we assumed that the mortality rate
beyond 5 years after LT would be low, and set this at 2% a year.[4]
Base-case estimates for all utilities extracted from the literature are detailed in Supplementary Table
1. Ranges were assumed to be within 20% of the base-case values.
Costs were assessed from the health care provider’s perspective and converted into 2014 US dollars
using the US Consumer Price Index for Medical Care Costs.[5] (Supplementary Table 2)
In this study, we considered all real-life treatment costs for the study cohort (for both first-line
therapy and the treatment of recurrences). In the post-LT model, we assumed that the cost of
treating recurrences would be similar to that of patients with recurrences after non-LT treatments,
plus the high post-LT follow-up costs. The high costs of LT related to the median expected number of
post-LT complications and hospitalizations were included in the costs of post-LT follow-up (supplementary
Table 2).
The costs and utilities were discounted at an annual rate of 3%.[5] The cost-effectiveness analysis
was based on the EVEREST guidelines.[6]
The endpoints were: survival benefit measured in quality-adjusted life years (QALYs), costs (C) in
US$, incremental cost-effectiveness (ICER), willingness to pay (WTP), and net health benefit
(NHB). The NHB of LT was calculated using the formula employed by Stinnett et al.[7]: NHB =
survival benefit – ICER / WTP. The Italian per capita gross domestic product (GDP) ($32,946) was
adopted as a reference value, assuming an ICER of 1xGDP for an intervention to be defined as costeffective.[8,9]
A probabilistic sensitivity analysis, the Monte-Carlo simulation, was performed to
understand the impact of variable uncertainties on the results of the model, and to estimate the
confidence that can be placed in analyzing the results. A total of 10,000 HCC patients in each arm
were compared. The outcomes measured were life months (LMs), quality-adjusted life months
(QALMs), incremental costs, ICER, and NHB. Transitional probabilities were varied within their
relative 95% confidence intervals, while costs and utilities were varied within their plausible ranges,
assuming a uniform distribution.
The impact of the different variables on the NHB distribution of 10,000 outcomes obtained
from the Monte Carlo simulation was ascertained using the multivariate standard least square
regression method. Statistical significance was set at p < 0.05.
The calculations were done with the JMP package version 9.0 (2010 SAS Institute Inc.) and
TreeAge Pro version 2013 (1988-2013 TreeAge Software, Williamstown, MA).
Supplementary table 1. Base case value and sensitivity range for the study group and extracted
from the literature for transition probabilities and quality of life utilities
Variables
Base-case
Range tested or
Source
analysis
standard error
Age-based
18-70
[10]
0.2
0.3
0.05
0.08
Table 3
Table 3
0.3
0.3
0.3
0.06
0.10
0.06
Table 3
Table 3
Table 3
0.1
0.2
0.4
0.07
0.05
0.05
Table 3
Table 3
Table 3
0.4
0.5
0.05
0.10
Table 3
Table 3
Resection (% for patient)*
32%
25%-40%
SG
Percutaneous ablation (% for patient)*
88%
80%-100%
SG
Trans arterial chemo-embolization (% for patient)*
104%
95%-115%
SG
Sorafenib (% for patient)*
39%
30%-50%
SG
Pre-transplant quality-of-life utility*
0.7
0.6 - 0.8
[9]
Incurable HCC quality-of-life utility*
0.4
0.3-0.5
[9]
Post-LT early mortality
10%
5%-15%
[2]
Median recurrence risk within 5 years
20%
10%-30%
[2]
Diameter of largest lesion (cm) – Hazard ratio for risk of recurrence
≤3
3-6
>6
1
1.3
3.8
0.8-2.0
2.2-6.6
[2]
[2]
AFP (ng/ml) – Hazard ratio for risk of recurrence
≤ 100
100-1000
> 1000
1
1.9
2.6
1.2-3.2
1.6-4.3
[2]
[2]
Number of nodules – Hazard ratio for risk of recurrence
1-3
>3
1
2.
1.2-3.5
[2]
Post-transplant quality-of–life utility
0.7
0.6-0.8
[9]
PRE-TRANSPLANT VARIABLES
Background (all-cause) mortality
Diameter of largest lesion (cm) – Beta estimate for risk of death
3-6 vs. ≤ 3
> 6 vs. 3-6
AFP (ng/ml) - Beta estimate for risk of death
100-1000 vs. ≤ 100
> 1000 vs. 100-1000
Multinodular - Beta estimate for risk of death
Alternative therapy - Beta estimate for risk of death
Ablation vs. hepatic resection
TACE vs ablation
BSC vs. TACE
CTP class - Beta estimate for risk of death
B vs. A
C vs. B
POST-TRANSPLANT VARIABLES
0.4
0.3-0.5
[9]
Recurrent HCC quality-of-life utility
AFP, alpha-fetoprotein; TACE, trans-arterial chemoembolization; BSC, best supportive care; CTP, Child Turcotte Pugh; SG, study
group; HCC, hepatocellular carcinoma; LT, liver transplantation
* These percentages represent the (number of total procedures / number of patients) * 100.
Supplementary table 2. Base case value and sensitivity range for the study group in terms of costs
VARIABLES FOR COST ANALYSIS
Base-case
Range tested
Source
analysis
ITALY
Follow-up of HCC patients without LT ($/month)
100
80-120
N/A
Transplantation ($)
80,000
60,000-100,000
N/A
Hepatic resection ($)
8,600
7,000-10,000
N/A
Percutaneous ablation ($)
3,600
3,000-5,000
N/A
Trans-arterial chemo-embolization ($)
3,500
3,000-5,000
N/A
Sorafenib ($)
15,750
10,000-20,000
N/A
Total costs of non-LT therapies for patients without LT*
15,700
10,000-20,000
N/A
Follow-up of HCC patients after transplantation ($/month)
394
300-500
N/A
HCC after dropout ($/month)
4,467
3,000-6,000
N/A
Per capita GDP ($)
35,926
N/A
10
Follow-up of HCC patients without LT ($/month)
292
83-417
11
Transplantation ($)
137,701
68,851-275,406
5
Hepatic resection ($)
25,086
12,543-50,172
5
Percutaneous ablation ($)
5,000
2,500-10,000
11
Trans-arterial chemo-embolization ($)
25,961
12,981-51,922
5
Sorafenib ($)
60,000
30,000-100,000
12
Total costs of non-LT therapies for patients without LT*
62,827
50,000-70,000
N/A
Follow-up of HCC patients after transplantation ($/month)
958
344-2,215
5
HCC after dropout ($/month)
4,500
3,000-6,000
5
Per capita GDP ($)
53,042
NA
10
Time horizon (years)
Life time
N/A
N/A
USA
HCC, hepatocellular carcinoma; LT, liver transplantation
* Total costs were obtained by multiplying single treatment cost by percentages of treatments in Supplementary Table 1
Supplementary figure. The event pathway: decision tree and states of health
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