Road safety assessment and risks prioritization using an integrated SWARA and MARCOS approach under spherical fuzzy environment.

There are a lot of elements that make road safety assessment situations unpredictable and hard to understand. This could put people's lives in danger, hurt the mental health of a society, and cause permanent financial and human losses. Due to the ambiguity and uncertainty of the risk assessment process, a multi-criteria decision-making technique for dealing with complex systems that involves choosing one of many options is an important strategy of assessing road safety. In this study, an integrated stepwise weight assessment ratio analysis (SWARA) with measurement of alternatives and ranking according to compromise solution (MARCOS) approach under a spherical fuzzy (SF) set was considered. Then, the proposed methodology was applied to develop the approach of failure mode and effect analysis (FMEA) for rural roads in Cosenza, southern Italy. Also, the results of modified FMEA by SF-SWARA-MARCOS were compared with the results of conventional FMEA. The risk score results demonstrated that the source of risk (human) plays a significant role in crashes compared to other sources of risk. The two risks, including landslides and floods, had the lowest values among the factors affecting rural road safety in Calabria, respectively. The correlation between scenario outcomes and main ranking orders in weight values was also investigated. This study was done in line with the goals of sustainable development and the goal of sustainable mobility, which was to find risks and lower the number of accidents on the road. As a result, it is thus essential to reconsider laws and measures necessary to reduce human risks on the regional road network of Calabria to improve road safety.

Effect of direct-acting antivirals on future occurrence of hepatocellular carcinoma in compensated cirrhotic patients.

BACKGROUND: The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events. AIMS: To investigate whether hepatocellular carcinoma (HCC) occurrence could change due to the DAA-induced increase in life-expectancy. METHODS: A Markov model was built on clinical data of 494 cirrhotic patients and available literature to estimate probabilities of "death before HCC" and of "HCC occurrence" without and with DAA. RESULTS: In comparison to untreated patients, DAA therapy reduced the 20-year mortality before HCC by 21.9% in patients without varices and by 21.5% in those with varices, considering an SVR of 95% and no direct effect on hepatocarcinogenesis. Tumour occurrence increased by 5%-8.2% and the proportion of HCCs diagnosed in compensated stages increased to >98%. If we consider DAA as having "anti-tumoral" effects, the benefit becomes greater, achieving a 20-year survival of 81.5% in patients without varices, and 52.2% in patients with varices. Instead, if we consider DAA as having a "pro-tumoral" effect, then, the increased incidence of HCC nullifies the survival benefits. CONCLUSION: DAAs drastically reduce the mortality caused by the liver function worsening, increasing the proportion of HCCs diagnosed in compensated stages. Knowledge of the DAA effect on hepatocarcinogenesis remains pivotal.

Selection of patients with hepatocellular cancer: a difficult balancing between equity, utility, and benefit.

Although liver transplantation (LT) represents the gold-standard strategy for hepatocellular cancer (HCC), its use is circumscribed by several factors like donor shortage, perioperative complications, or competition with other candidates without HCC. Moreover, different alternative approaches like resection or loco-regional therapies may be attempted in selected cases. The best option for the treatment of an HCC patient is a complex decision, involving several ethical principles including: equity (horizontal equity and vertical equity or urgency), and utility. These principles influence the different phases of the patient selection process for LT: inscription in the waiting list (WL), deciding upon patient priority and drop-out before LT, allocating the liver donor to the best matched recipient. The best end-point for describing the principle of utility is the "transplant benefit" (TB). This concept expresses the survival gain obtained comparing LT with the best alternative therapies (i.e., difference between life years obtained with and without LT). The TB used with a mid-term time horizon (post-transplant 5-10 years), has the intrinsic potential to reach the dignity of an independent LT selection principle. Thus, the present review investigates the role of organ allocation using a TB model with the intent to introduce equity among patients transplanted having HCC or non-tumoral diseases.

Liver Resection for Breast Cancer Liver Metastases: A Cost-utility Analysis.

OBJECTIVE: To estimate the cost-effectiveness of liver resection followed by adjuvant systemic therapy relative to systemic therapy alone for patients with breast cancer liver metastasis. BACKGROUND: Data on cost-effectiveness of liver resection for advanced breast cancer with liver metastasis are lacking. METHODS: A decision-analytic Markov model was constructed to evaluate the cost-effectiveness of liver resection followed by postoperative conventional systemic therapy (strategy A) versus conventional therapy alone (strategy B) versus newer targeted therapy alone (strategy C). The implications of using different chemotherapeutic regimens based on estrogen receptor and human epidermal growth factor receptor 2 status was also assessed. Outcomes included quality-adjusted life months (QALMs), incremental cost-effectiveness ratio, and net health benefit (NHB). RESULTS: NHB of strategy A was 10.9 QALMs compared with strategy B when letrozole was used as systemic therapy, whereas it was only 0.3 QALMs when docetaxel + trastuzumab was used as a systemic therapy. The addition of newer biological agents (strategy C) significantly decreased the cost-effectiveness of strategy B (conventional systemic therapy alone). The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C; similarly, strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy. CONCLUSIONS: Liver resection in patients with breast cancer liver metastasis proved to be cost-effective when compared with systemic therapy alone, particularly in estrogen receptor-positive tumors or when newer agents were used.

Utility-based criteria for selecting patients with hepatocellular carcinoma for liver transplantation: A multicenter cohort study using the alpha-fetoprotein model as a survival predictor.

The lifetime utility of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is still controversial. The aim of this study was to ascertain when LT is cost-effective for HCC patients, with a view to proposing new transplant selection criteria. The study involved a real cohort of potentially transplantable Italian HCC patients (n = 2419 selected from the Italian Liver Cancer group database) who received nontransplant therapies. A non-LT survival analysis was conducted, the direct costs of therapies were calculated, and a Markov model was used to compute the cost utility of LT over non-LT therapies in Italian and US cost scenarios. Post-LT survival was calculated using the alpha-fetoprotein (AFP) model on the basis of AFP values and radiological size and number of nodules. The primary endpoint was the net health benefit (NHB), defined as LT survival benefit in quality-adjusted life years minus incremental costs (US $)/willingness to pay. The calculated median cost of non-LT therapies per patient was US $53,042 in Italy and US $62,827 in the United States. On Monte Carlo simulation, the NHB of LT was always positive for AFP model values ≤ 3 and always negative for values > 7 in both countries. A multivariate model showed that nontumor variables (patient's age, Child-Turcotte-Pugh [CTP] class, and alternative therapies) had the potential to shift the AFP model threshold of LT cost-ineffectiveness from 3 to 7. LT proved always cost-effective for HCC patients with AFP model values ≤ 3, whereas the cost-ineffectiveness threshold ranged between 3 and 7 using nontumor variables.

Liver Resection for Advanced Intrahepatic Cholangiocarcinoma: A Cost-Utility Analysis.

BACKGROUND: Data on cost-effectiveness and efficacy of hepatic resection (HR) for advanced intrahepatic cholangiocarcinoma (ICC) are lacking. We sought to estimate the cost-effectiveness of upfront HR resulting in an R1 resection (strategy A) relative to initial systemic chemotherapy (sCT) followed by possible curative HR (strategy B) for patients with advanced ICC. METHODS: A Markov model was developed using data from a systematic literature review. Three base cases were considered: (1) ICC >6 cm (2) ICC with vascular invasion (3) multi-focal ICC. A Monte Carlo simulation assessed outcomes including quality-adjusted life months (QALMs) and incremental cost-effectiveness ratio (ICER). RESULTS: The net health benefit (NHB) of strategy A versus strategy B was 1.4 QALMs for ICC >6 cm and 1.3 QALMs for ICC and vascular invasion; in contrast, there was a negative NHB for HR versus sCT for multi-focal ICC (-0.3 QALMs). In single nodule ICC >6 cm, the ICER of HR versus sCT was $22,482/quality-adjusted life years (QALY) and the ICER of HR versus sCT was $20,953/QALY for ICC with vascular invasion. In multi-focal ICC, the ICER of HR compared with sCT was $83,604/QALY. Patients with a higher American Society of Anesthesiologists score (coefficient 0.94), male sex (coefficient 0.43), low quality of life after sCT (coefficient -2.57) and T3 tumors (coefficient 0.53) had a better NHB for HR relative to sCT followed by potential surgery. CONCLUSIONS: For patients with large ICC or ICC and vascular invasion, HR was more cost-effective than sCT. In contrast, HR was not associated with a positive NHB relative to sCT for patients with multi-focal ICC, and therefore these patients should be treated with sCT rather than HR.

Age and equity in liver transplantation: An organ allocation model.

A moral liver allocation policy must be fair. We considered a 2-step, 2-principle allocation system called "age mapping." Its first principle, equal opportunity, ensures that candidates of all ages have an equal chance of getting an organ. Its second principle, prudential lifespan equity, allocates younger donor grafts to younger candidates and older donors to older candidates in order to increase the likelihood that all recipients achieve a "full lifespan." Data from 2476 candidates and 1371 consecutive adult liver transplantations (from 1999 to 2012) were used to determine whether age mapping can reduce the gap in years of life lost (YLL) between younger and older recipients. A parametric Weibull prognostic model was developed to estimate total life expectancy after transplantation using survival of the general population matched by sex and age as a reference. Life expectancy from birth was calculated by adding age at transplant and total life expectancy after transplantation. In multivariate analysis, recipient age, hepatitis C virus status, Model for End-Stage Liver Disease score at transplant of >30, and donor age were significantly related to prognosis after surgery (P < 0.05). The mean (and standard deviation) number of years of life from birth, calculated from the current allocation model, for various age groups were: recipients 18-47 years (n = 340) = 65.2 (3.3); 48-55 years (n = 387) = 72.7 (2.1); 56-61 years (n = 372) = 74.7 (1.7) and for recipients >61 years (n = 272) = 77.4 (1.4). The total number of YLL equaled 523 years. Redistributing liver grafts, using an age mapping algorithm, reduces the lifespan gap between younger and older candidates by 33% (from 12.3% to 8.3%) and achieves a 14% overall reduction of YLL (73 years) compared to baseline liver distribution. In conclusion, deliberately incorporating age into an allocation algorithm promotes fairness and increases efficiency.

Hepatic Resection for Disappearing Liver Metastasis: a Cost-Utility Analysis.

BACKGROUND: We sought to estimate the cost-effectiveness of hepatic resection (HR) (strategy A) relative to surveillance plus 6 months of additional systemic chemotherapy (sCT) (strategy B) for patients with colorectal disappearing liver metastases (DLM). METHODS: A Markov model was developed using data from a systematic literature review. Three base cases were evaluated: (1) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT, had normalized carcinoembryonic antigen (CEA), and was diagnosed with DLM through a computed tomography (CT) scan; (2) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT, had normalized CEA, and was diagnosed with DLM through a magnetic resonance imaging (MRI) scan; and (3) a 60-year-old patient with three lesions in the right hemi-liver who underwent 6 months of sCT plus hepatic artery infusion (HAI), had normalized CEA, and was diagnosed with DLM through a MRI scan. The outcomes evaluated were quality-adjusted life months (QALMs), incremental cost-effectiveness ratio (ICER), and net health benefit (NHB). RESULTS: The NHB of strategy A versus strategy B was positive in base case 1 (7.7 QALMs, ICER $34.449/quality-adjusted life year (QALY)) and base case 2 (1.6 QALMs, ICER $43,948/QALY). In contrast it was negative (-0.2 QALMs, ICER $72,474/QALY) for base case 3. Monte Carlo simulation showed that strategy B is acceptable only in old patients (>60 years) with normalized CEA and MRI-based diagnosis. In younger patients, strategy B may reach cost-effectiveness only after sCT plus HAI. CONCLUSION: Surveillance of DLM after sCT was more beneficial and cost-effective among patients >60 years with multiple factors predictive of true complete pathological response, such as normalization of CEA, HAI therapy, BMI ≤30 kg/m(2), and diagnosis of DLM made through MRI.

Net health benefit of hepatic resection versus intraarterial therapies for neuroendocrine liver metastases: A Markov decision model.

BACKGROUND: Management of patients with neuroendocrine liver metastasis (NELM) remains controversial. We sought to compare the net health benefit (NHB) of hepatic resection (HR) versus intraarterial therapy (IAT) among patients with NELM. METHODS: A decision analytic Markov model was created to estimate and compare the cost effectiveness associated with different management strategies (HR vs IAT) for a simulated cohort of patients with NELM. The primary (base case) analysis was calculated based on a 57-year-old male patient with metachronous, symptomatic NELM that involved <25% of the liver in the absence of extrahepatic disease. The endpoints were quality-adjusted life-months (QALMs), quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), and NHB. RESULTS: In the base case analysis, HR was strongly favored over IAT providing NHB of 20.0 QALMs and an ICER of $8,427 per QALY. In the Monte Carlo simulation, the greatest NHB for HR was among patients with functioning/symptomatic NELM, regardless of liver tumor burden. In the symptomatic group, IAT was favored only in a minority of old patients (>60 years) with extrahepatic disease and synchronous NELM. In contrast, in patients with nonfunctioning/asymptomatic NELM, hepatic tumor burden was the most important variable and HR was always cost ineffective in large tumors, independent of patient age and extrahepatic disease characteristics. CONCLUSION: A Markov decision model demonstrated that HR was the preferred strategy among patients with symptomatic NELM, regardless of hepatic disease burden. In contrast, IAT should be preferred for patients with large volume nonfunctioning/asymptomatic NELM.

Cost-effectiveness of pretransplant sofosbuvir for preventing recurrent hepatitis C virus infection after liver transplantation.

There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost-effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post-LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004-2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12-24 weeks of SOF+ ribavirin for pre-LT anti-HCV treatment versus on-demand post-LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14,421€ per patient). HCV etiology had a strong impact on post-LT survival (hazard ratio = 1.59, 95% CI = 1.22-2.09, P = 0.0007). After Monte Carlo simulation, pre-LT SOF therapy showed a median survival benefit of 1.5 quality-adjusted life years and an Incremental cost-effectiveness ratio (ICER) of 30,663€/QALY, proving cost-effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipient's age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real-life data from northern Italy for adjusting the costs of pre-LT direct-acting antiviral therapies to the actual sustained virological response reached after LT.

Management of hepatitis C infection before and after liver transplantation.

Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.

The relative net health benefit of liver resection, ablation, and transplantation for early hepatocellular carcinoma.

BACKGROUND: There are no conclusive cost-effectiveness studies measuring the efficacy of salvage LT after liver resection (LR) and radiofrequency ablation (RFA) in patients with early hepatocellular carcinoma (HCC) and compensated cirrhosis. The aim of the present study is to compare liver transplantation (LT) versus locoregional therapy plus salvage LT (to treat tumor recurrence) in patients with early HCC and compensated cirrhosis. METHODS: Reference case: 55-year old male with HCC within Milan criteria and Child-Pugh A cirrhosis. The analysis was performed in two geographical cost settings: USA and Italy. Survival benefit measured in quality-adjusted life years (QALYs), costs (C) in US$, incremental cost-effectiveness, willingness to pay, and net health benefit (NHB). RESULTS: In the base-case analysis, NHB of LT vs. LR and RFA was -1.7 and -1.3 years for single tumor ≤3 cm, -1.2 and -0.7 for single nodules measuring 3.1-5 cm and -0.7 and -0.7 for multi-nodular tumor ≤3 cm in Italy. In USA, NHB of LT versus LR and RFA were -1.2 and -0.8 years for single tumor ≤3 cm, -0.9 and -0.5 for single nodules measuring 3.1-5 cm, and -0.5 and -0.4 for multi-nodular tumor ≤ 3 cm. On the Monte Carlo simulation, only young patients with multi-nodular HCC and short waiting list time had a positive NHB. Salvage LT proved to be an ineffective cost strategy after RFA or LR. CONCLUSION: In patients with HCC within Milan criteria and Child-Pugh A cirrhosis, LR and RFA were more cost-effective than LT. Salvage LT was not cost-effective.

Survival Benefit of Liver Transplantation Versus Resection for Hepatocellular Carcinoma: Impact of MELD Score.

BACKGROUND: We sought to measure the impact of model for end stage liver disease (MELD) score, tumor staging, and microvascular invasion (MVI) on the relative survival benefit of liver transplantation (LT) versus liver resection (LR) for hepatocellular carcinoma (HCC). METHODS: The study population comprised 1,106 HCC patients with cirrhosis undergoing LR from one Eastern (n = 424) and two Western (n = 682) surgical units. Exclusion criteria were very large (>10 cm) tumors, macrovascular invasion, and metastases. We identified three tumor stages: stage I (within Milan, n = 806), stage II (beyond Milan within Up-to-7, n = 123), and stage III (beyond Milan and Up-to-7, n = 177). Patient survival after LR was compared to that predicted after LT by the Metroticket calculator in relationship with staging, MVI, and MELD score using Monte Carlo simulation. RESULTS: Two hundred eighty-three patients (26 %) with a MELD score of ≥10 had an acceptable 5-year survival after LR of 47 %, while that of patients with a low MELD score was 67 % (p < 0.0001). Mean 5-year LT benefit was -4.50 months (95 % confidence interval [CI] -4.73 to -4.27) for patients with a MELD score of <10, and 0.81 months (95 % CI 0.58 to 1.04) for those with a MELD score of ≥10. MELD score and MVI were the strongest predictors of transplant survival benefit. LT reached a survival benefit, versus LR only in HCC patients with a MELD score of ≥10 and without MVI (3.08 months, 95 % CI 2.78 to 3.39), whatever the tumor stage. CONCLUSIONS: LT proved to be harmful in patients with resectable HCC with a low MELD score (<10) or with aggressive tumors (with MVI). As a result of a shortage of donors, only selected resectable tumors with a MELD score of ≥10 should be considered for transplantation.

A method for establishing allocation equity among patients with and without hepatocellular carcinoma on a common liver transplant waiting list.

BACKGROUND & AIMS: The current organ allocation system for liver transplantation (LT) creates an imbalance between patients with and without hepatocellular carcinoma (HCC). We describe a model designed to re-establish allocation equity among patient groups using transplant benefit as the common endpoint. METHODS: We enrolled consecutive adult patients entering the waiting list (WL group, n=2697) and undergoing LT (LT group, n=1702) during the period 2004-2009 in the North Italy Transplant program area. Independent multivariable regressions (WL and LT models) were created for patients without HCC and for those with stage T2 HCC. Monte Carlo simulation was used to create distributions of transplant benefit, and covariates such as Model for End-stage Liver Disease (MELD) and alpha-fetoprotein (AFP) were combined in regression equations. These equations were then calibrated to create an "MELD equivalent" which matches HCC patients to non-HCC patients having the same numerical MELD score. RESULTS: Median 5 year transplant benefit was 15.12 months (8.75-25.35) for the non-HCC patients, and 28.18 months (15.11-36.38) for the T2-HCC patients (p<0.001). Independent predictors of transplant benefit were MELD score (estimate=0.89, p<0.001) among non-HCC patients, and MELD (estimate=1.14, p<0.001) and logAFP (estimate=-0.46, p<0.001) among HCC patients. The equation "HCC-MELD"=1.27∗MELD - 0.51∗logAFP+4.59 calculates a numerical score for HCC patients, whereby their transplant benefit is equal to that of non-HCC patients with the same numerical value for MELD. CONCLUSIONS: We describe a method for calibrating HCC and non-HCC patients according to survival benefit, and propose that this method has the potential, if externally validated, to restore equity to the organ allocation system.

Model for end-stage liver disease-sodium and survival benefit in liver transplantation.

There are currently no studies calculating the survival benefit of liver transplantation (LT) according to model for end-stage liver disease-sodium (MELD-Na) and based on the competing risk (CR) method. We enrolled consecutive adult patients with chronic end-stage liver disease entering the waiting list (WL) for primary LT (WL group = 337) and undergoing LT (LT group = 220) in the period 2006-2009. Two independent multivariable regressions (WL and LT models) were created to measure the prognostic power of MELD-Na with respect to MELD. For the WL model, both Cox and CR multivariable analyses were performed. Estimates were finally included in a Markov model to calculate 3-year survival benefit. WL Cox model: MELD-Na (P < 0.0001) and MELD (P < 0.0001) significantly predicted survival. WL CR model: MELD-Na (P = 0.0045) and MELD (P = 0.0109) significantly predicted survival. LT Cox model: MELD-Na (P = 0.7608) and MELD score (P = 0.9413) had not correlation with survival. Benefit model: MELD and MELD-Na had an overlapping significant impact on 3-year survival benefit; CR method determined a significant decrease in 3-year life expectancy (LE) estimations. MELD-Na and MELD scores similarly predicted 3-year LT survival benefit, but the gain in LE is significantly lower when a CR method is adopted.

Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study.

BACKGROUND: Allocation of deceased-donor livers to patients with chronic liver failure is improved by prioritising patients by 5-year liver transplantation survival benefit. The Barcelona Clinic Liver Cancer (BCLC) staging has been proposed as the standard means to assess for prognosis of patients with hepatocellular carcinoma. We aimed to create a prediction model linking the BCLC stage of patients with hepatocellular carcinoma to their 5-year liver transplant benefit. METHODS: A large cohort of consecutive patients with hepatocellular carcinoma (n=1328) from the ITA.LI.CA database (n=2951) were judged as potentially eligible for liver transplantation according to the following criteria: absence of macroscopic vascular invasion or metastases, age 70 years or younger, and absence of relevant extra-hepatic comorbidities. To assess the correlation between BCLC staging and non-liver transplantation survival, we did Cox univariate and multivariate analyses including the following covariates: BCLC stage, year of diagnosis, age, sex, cause of cirrhosis, model for end-stage liver disease score, α-fetoprotein concentrations, and treatment. Liver-transplantation survival benefit for patients was calculated, using Monte Carlo simulation analysis, as the patient's 5-year life expectancy with liver transplantation (estimated by the Metroticket model) minus the 5-year life expectancy without liver transplantation according to BCLC stage. FINDINGS: 83 (6%) of 1328 patients had BCLC 0 stage disease, 614 (46%) had BCLC A, 500 (38%) had BCLC B-C, and 131 (10%) had BCLC D. In the Cox non-liver transplantation survival multivariate model, hazard ratios associated with increasing BCLC stages were 1.530 (95% CI 1.107-2.116) for BCLC A versus BCLC 0, 1.572 (1.350-1.830) for BCLC B-C versus BCLC A, and 1.470 (1.164-1.856) for BCLC D versus BCLC B-C. Results of the Monte Carlo simulation analysis confirmed the significant effect of BCLC classification on transplant benefit; in the adjusted model, a median 5-year transplant benefit of 11.19 months (IQR 10.73-11.67) for BCLC 0, 13.49 months (11.51-15.57) for BCLC A, 17.36 months (15.06-19.28) for BCLC B-C, and 28.46 months (26.38-30.34) for BCLC D. INTERPRETATION: Liver transplantation could result in survival benefit for patients with hepatocellular carcinoma and advanced liver cirrhosis (BCLC stage D) and in those with intermediate tumours (BCLC stages B-C), regardless of the nodule number-size criteria (ie, Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent. FUNDING: None.

The survival benefit of liver transplantation in hepatocellular carcinoma patients.

BACKGROUND: There are no studies evaluating the survival benefit of liver transplantation over alternative therapies for patients with hepatocellular carcinoma. METHODS: The short- to mid-term survival benefit (study group=135 aggressively treated patients with hepatocellular carcinoma, 52% beyond Milan criteria at pathology) was calculated by comparing the mortality rates of liver transplantation vs alternative therapies patients. A Markov prediction model was then created to estimate the long-term survival benefit of liver transplantation (gain in life expectancy) over alternative therapies. The long-term survival rates in the liver transplantation group were calculated using the Metroticket website calculator (http://89.96.76.14/metroticket/calculator/). RESULTS: The short- to mid-term analysis indicated that liver transplantation afforded no significant survival benefit in the group of patients with hepatoma as a whole (hazard ratio=1.229, 95% confidence interval 0.544-2.773, p=.6200). The benefit was concentrated in patients with a poor initial response to alternative therapies (hazard ratio=3.137, 95% confidence interval 1.428-6.891, p=.0044). In the long-term analysis, the gain in life expectancy of liver transplantation vs alternative therapies was 6.115 years (base-case analysis) and the main determinants of gain in life expectancy were the 5-year survival prospects after alternative therapies and the patient's age. CONCLUSIONS: The survival benefit of liver transplantation for patients with hepatocellular carcinoma is strongly related to the patient's age and the effectiveness of available alternative therapies.

Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost-benefit analysis while awaiting data on sorafenib safety.

UNLABELLED: The role of bridging therapies for patients with hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT) remains controversial. There is strong evidence to support the effectiveness of sorafenib in extending the time to progression of HCC. Using a Markov model, we compared two strategies: one using sorafenib as neoadjuvant therapy before LT (Strategy A), and the other using no bridging therapy in the first 6 months (Strategy B). Reference case: T2 HCC patient with compensated cirrhosis. The benefit of sorafenib in delaying time to HCC progression was expressed as the hazard ratio (HR) and taken from recently published randomized trials. The endpoints considered were: survival benefit measured in quality-adjusted life days (QALDs), transplant probability, costs (C) in euro, willingness to pay (WTP), and net health benefit (NHB), where NHB = survival benefit - C/WTP. The calculated WTP of sorafenib in Italy was 346 euro per QALD. Probabilistic sensitivity analysis showed a median survival benefit of 94 QALDs (10% percentile = 38, 90% percentile = 210). In the base-case scenario (HR = 0.47, monthly dropout probability = 5%, median time to LT = 3 months), the gain in LT probability due to sorafenib was 5% and it increased proportionally with increasing median times to LT and decreasing HR. In the cost-benefit analysis, the incremental NHB of Strategy A versus Strategy B was 37 QALDs; it increased as sorafenib HR decreased and when median times to LT were shorter than 6 months, whereas for longer times it gradually dropped, particularly when Strategy B included effective locoregional treatments. CONCLUSION: Sorafenib neoadjuvant therapy is cost-effective by comparison with no therapy for T2-HCC patients waiting for LT, particularly for median times to LT under 6 months.