Cost-Effectiveness Analysis of Liver Resection Versus Transplantation for Early Hepatocellular Carcinoma Within the Milan Criteria Kheng Choon Lim,1,2* Vivian W. Wang,3* Fahad J. Siddiqui,1,4 Luming Shi,2,5 Edwin S.Y. Chan,1,2,4 Hong Choon Oh,3 Say Beng Tan,1,2 and Pierce K.H. Chow2,6,7 Both liver resection (LR) and cadaveric liver transplantation (CLT) are potentially curative treatments for patients with hepatocellular carcinoma (HCC) within the Milan criteria and with adequate liver function. Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of LR against CLT for patients with HCC within the Milan criteria using a decision analytic model. A Markov cohort model was developed to simulate a cohort of patients aged 55 years with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, undergoing LR or CLT, and followed up over their remaining life expectancy. Analysis was performed in different geographical cost settings: the USA, Switzerland and Singapore. Transition probabilities were obtained from systematic literature reviews, supplemented by databases from Singapore and the Organ Procurement and Transplantation Network (USA). Utility and cost data were obtained from open sources. LR produced 3.9 quality-adjusted life years (QALYs) while CLT had an additional 1.4 QALYs. The incremental cost-effectiveness ratio (ICER) of CLT versus LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland, and was above thresholds for cost-effectiveness in all three countries. Sensitivity analysis revealed that CLTrelated 5-year cumulative survival, one-time cost of CLT, and post-LR 5-year cumulative recurrence rates were the most sensitive parameters in all cost scenarios. ICERs were reduced below threshold when CLT-related 5-year cumulative survival exceeded 84.9% and 87.6% in Singapore and the USA, respectively. For Switzerland, the ICER remained above the cost-effectiveness threshold regardless of the variations. Conclusion: In patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, LR is more cost-effective than CLT across three different costing scenarios: the USA, Switzerland, Singapore. (HEPATOLOGY 2014;00:000-000)
H
epatocellular carcinoma (HCC) is a common cancer with a higher disease burden in East Asia due to the prevalence of chronic viral hepatitis in the region.1 For patients with HCC within
the Milan criteria and adequate liver function for resection (Child-Pugh A/B cirrhosis), both liver resection (LR) and liver transplantation (LT) are potentially curative treatments. There is, however, ongoing debate
Abbreviations: CLT, cadaveric liver transplantation; DEALE, declining exponential approximation of life expectancy; HCC, hepatocellular carcinoma; ICER, incremental cost-effectiveness ratio; LR, liver resection; LT, liver transplantation; OPTN, Organ Procurement Transplant Network Database; QALYs, qualityadjusted life years. From the 1Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; 2Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore; 3Centre for Health Services Research, SingHealth, Singapore; 4Singapore Clinical Research Institute, Singapore; 5Epidemiology and Disease Control Division, Ministry of Health, Singapore; 6Department of HPB and Transplantation Surgery, Singapore General Hospital, Singapore; 7Department of Surgical Oncology, National Cancer Centre, Singapore. Received September 20, 2013; accepted March 13, 2014. This study was supported by the Khoo Clinical Discovery Project Award of the Duke-NUS Graduate Medical School. This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. *These authors contributed equally to this work. 1
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about which treatment is more appropriate.2,3 While specialized centers demonstrate that LT for HCC within the Milan criteria can achieve 5-year survival rates of more than 80%,4-7 reports from large registries such as the Organ Procurement Transplant Network Database (OPTN) show 5-year survival rates of between 60-65%.8 Emerging data show improving trends in LR outcomes, possibly due to better patient selection, postoperative management, and multimodality treatment for recurrences.9 While recurrence rates in LT are often lower than LR, LT faces considerable resource challenges in many countries, such as the limited supply of cadaveric transplant organs, leading to cancer progression during long waiting times that limit intention-to-treat survival for LT.10 LT patients also require long-term immune suppression, with attendant risks and significant lifetime costs. Randomized trials comparing the two treatments are neither ethical nor practical. Due to the large financial outlay and recurrent costs needed to run a liver transplant program for a large number of HCC patients,11 the decision to adopt either therapy as a first-line option carries major implications with respect to costs, utility of scarce resources, and expectations of the population for quality healthcare. It is in this setting that a decision analytical model can help compare the two treatments from the perspective of the healthcare system. The aim of this study was to estimate the relative cost-effectiveness of LR versus LT for HCC patients within the Milan criteria and adequate liver function using a decision analytic model.
Materials and Methods A Markov cohort model12 was developed to simulate a cohort of patients aged 55 years with early HCC (defined by the Milan criteria) and adequate liver function (defined as Child-Pugh A/B cirrhosis), who have undergone either LR or cadaveric liver transplantation (CLT) and followed over a time horizon of their remaining life expectancy (Fig. 1). Among the two alternatives, the baseline comparator is LR. Early HCC was defined as HCC meeting the Milan criteria (solitary nodule not exceeding 5 cm; not more than
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three nodules, none exceeding 3 cm; no evidence of macrovascular invasion or distant metastasis).13 While living donor liver transplantation is increasing, especially in Asia,14 this study is focused on CLT as it remains the primary form of transplantation internationally.15 In the model, a 1-month cycle time was selected as the clinically most pertinent interval short enough to reflect the cost and quality of life impact from major surgical treatment episodes.16 During each cycle, a patient occupied one health state and moved to another according to transition probabilities (Fig. 1). Each health state had associated costs and utilities, and these were accumulated over the lifetime of the simulated population. Monthly transition probabilities were derived from cumulative probabilities using the declining exponential approximation of life expectancy (DEALE) method.17 Literature reviews were conducted to derive values for the transition probabilities, utilities, and costs. A full list of parameters used in the model is presented in Tables 1 to 3. Details on parameters used to derive transition probabilities between two states and references used to derive values for these parameters are found in Supporting Material 1. When possible, transition probabilities for LR were obtained from studies from Lim et al.,9 which is a systematic review of recent LR outcomes in early HCC patients. This is supplemented by additional analyses performed on the Singapore General Hospital (SGH) LR database comprising 241 patients (Supporting Material 2), and the OPTN database for LT comprising 4,381 patients (Supporting Material 3). In the absence of published data, several modeling assumptions listed below were made. Base Case Clinical Estimates in the LR Arm. We assumed that patients in the LR arm underwent surgery within a cycle time of 1 month and were in a state of compensated cirrhosis. Here, they were subjected to the risks of decompensation, tumor recurrence, and age-related mortality. As there was a paucity of prospective data on risk of progression to decompensated cirrhosis in this group of patients, we obtained data from studies involving non-HCC patients with cirrhosis. Further, we assumed that the
Address reprint requests to: Prof. Pierce Chow, Office of Clinical Sciences, Duke-NUS Graduate Medical School, The Academia, Level 6, 20 College Road, Singapore 169856. E-mail: [email protected]; fax: 165 6220 9323. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27135 Potential conflict of interest: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that they have no financial interests that may be relevant to the submitted work.
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Fig. 1. Markov Cohort Model. Lines with arrows indicate transition from one health state to another (or itself) per cycle.
history of LR for early HCC does not alter these two risks. The annual decompensation rate of 11.8% was based on Fleming et al.,18 which was the latest study with the largest sample size among the relevant studies.18-21 The remaining studies provided the range for the sensitivity analysis. The decompensated cirrhosis 5year cumulative survival of 35% was the median value derived from another series of studies.19,20,22-24 The 62% post-LR 5-year cumulative recurrence rate and the 30.1% annual mortality risk of recurrent HCC were the medians derived from studies included in Lim et al.25-31 and data from the SGH LR database (Supporting Material 2). The modeling of the recurrence state was necessary, as LR patients generally suffer from frequent recurrence, and an increasing variety of therapies are used to manage recurrences in actual clinical settings, impacting overall cost-effectiveness of the treatment.9 As there was no universally accepted protocol for treating tumor recurrences,32-34 it was assumed that patients underwent a variety of therapies but had a consolidated postrecurrence outcome. We assumed the cost of these treatments to be equivalent to three transarterial-chemoembolization (TACE) sessions. The 30-day postoperative mortality of 2.2% was the median derived from studies within Lim et al.’s review.25,26,31,35-39 Age-related mortality risks were based on United States life tables.40
Base Case Clinical Estimates in the CLT Arm. Similarly, we assumed that patients waiting for CLT started in a state of compensated cirrhosis and were at risk of decompensation, tumor progression (beyond the Milan criteria), and age-related mortality. Patients with early HCC were assumed to carry no additional short-term cancer mortality risks, and were subjected to the same annual decompensation rate of 11.8% for non-HCC patients. The risk of tumor progression to beyond Milan criteria was assumed to be constant and independent from the state of cirrhosis. Very few studies evaluated the dropout rate from the LT waitlist due to tumor progression. Only one study reported a 53% cumulative dropout probability at 24 months among 103 HCC patients,41 which was adopted as the base case estimate. In USA, the state of cirrhosis affects the LT waiting time through the Model for Endstage Liver Disease (MELD) score.42 However, we opted to apply a constant transplantation probability irrespective of their state of cirrhosis to simplify the model, as not all countries adopt this prioritization scheme. The median waiting-list time to CLT of 110 days was taken from our OPTN analysis (Supporting Material 3). Likewise, the CLT-related 30-day perioperative mortality of 3.2% and 5-year cumulative survival of 67.8% were derived. Once tumor progressed, CLT was contraindicated and patients were assumed to receive only up to
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Table 1. Base Case Value and Sensitivity Range Extracted From Literature for Transition Probabilities Parameter
Background (all-cause) mortality40 Cirrhosis annual decompensation rate (%)18-21 Derived monthly decompensation rate (%)* Decompensated cirrhosis-related 5-year cumulative survival (%)19,20,22-24 Derived monthly mortality risk (%)† LR-related 30-day perioperative mortality (%)25,26,31,35-39 Post-LR 5-year cumulative recurrence rate (%)25,27-31,# Derived monthly recurrence rate (%)‡ Annual mortality risk of recurrent HCC (%)26,28,§,# Derived monthly mortality risk (%)‡ Median waiting-list time to CLT (days)7,**,†† Derived monthly probability of obtaining CLT (%)¶ 24 month dropout risk due to tumor progression (%)41 Monthly dropout risk due to tumor progression (%)†† Derived monthly dropout risk (%)‡ Annual mortality risk of HCC outside Milan (%)44-47 Derived monthly mortality risk (%)‡ CLT-related 30-day perioperative mortality (%)35,**,†† CLT-related 5-year cumulative survival (%)3,5,7,8,25,35,**,†† Derived monthly mortality risk (%)†
Base Case Value (Median of Literature Range Unless Separately Referenced)
Literature Range Tested
Age-specific 11.818 0.98 35 1.73 2.2 62 1.60 30.1 2.94 110** 17.44 5341 3.10 44.2 4.75 3.2** 67.8** 0.65
3.9-12.5 0.32-1.04 14-50.8 1.12-3.22 0-5.3 42-78 0.90-2.49 23.6-38.7 2.22-4.00 36-234 8.62-44.33 2.3-5.6 2.3-5.6 33.8-51.0 3.38-5.77 0-9.88 60-90 0.18-0.85
*Annual decompensation rate was converted to monthly probability using the formula: 1-e (-rate x time), where time is 1/12. Using the assumption of a declining exponential approximation of life expectancy, the monthly probability was derived from 5-year cumulative survival by using the formula: 1-(prob)1/60, where prob is 5-year cumulative survival. ‡ Using the assumption of a declining exponential approximation to disease- or progression- free survival, post-LR 5-year cumulative recurrence rate, annual mortality risk and 24 month dropout risk from tumor progression were converted to the monthly probability using the formula: 1-(1-prob)1/time, where prob refers to the parameter and time refers to 60, 12, 24 respectively. § Annual mortality risk of recurrent HCC is first calculated from post recurrence 5-year cumulative survival or time to median survival by using 1-(prob)1/time, where prob refers to the 5-year cumulative survival or 50% for median survival, and time refers to 5 or 1.42 years. ¶ Monthly probability of getting CLT is calculated by using the formula 1-(1-prob)(365/12)/time, where prob is 50% and the time is median wait list time to CLT. # Also refers to Supporting Material 2. **Also refers to Supporting Material 3. †† Refer to Supporting Material 8 for detailed list of supporting references used. †
three sessions of TACE. We could not find any study reporting mortality risk specifically in patients who dropped out of the transplantation waiting list due to tumor progression. Hence, it was assumed to be similar to the mortality risk of unresectable HCC treated with TACE. Based on a recent review on TACE for unresectable HCC,43 four randomized controlled trials involving patients with Child-Pugh A/B cirrhosis were selected to derive the median annual mortality risk of HCC beyond Milan at 44%.44-47 We did not model post-CLT recurrence as a separate state as these recurrences usually have poor survival48 and there is paucity of suitable data. Patients in decompensated cirrhosis state were assumed to carry only the mortality risk from decompensated cirrhosis and not from cancer. Costs. Our analysis was performed from the perspective of the healthcare system, and hence only direct medical costs were accounted for. Rather than using hypothetical cost data, we chose to build cost scenarios using actual country-specific data reported from open sources. Medline was searched for primary cost studies in English and published between January
1, 2000 to December 31, 2012, with the following Medical subject heading (MESH) terms and their free text variants: “Carcinoma, Hepatocellular,” “Liver Transplantation,” “Hepatectomy,” “Liver Cirrhosis” in combination with “Costs and cost analysis.” Complete articles were short-listed from potentially relevant citations and retrieved. The reference lists of these articles were also examined. Articles that reported charges but not costs, overlapping datasets, and those without specific costs applicable to the health states in our model were excluded. Adopting this approach, the most relevant and complete data were available from Singapore, the USA, and Switzerland. In addition, the large OPTN liver transplantation registry was also from the USA. Incidentally, these countries represent different costing scenarios over three continents. All reported costs were converted to year 2012 U.S. dollars49 using the U.S. Consumer Price Index for Medical Care Costs.50 Costs obtained from the literature were used as our base case. If a range of data was available, the median cost was used as the base case value. Expert opinion on cost supplemented the information if no
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Table 2. Base Case Value and Sensitivity Range for Costs
Parameter
Costs in USA ($) One time cost of surgical treatments LR cost* CLT cost16,* TACE per session* Monthly follow-up cost Compensated cirrhosis16,* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* HCC recurrence Contraindication to CLT Costs in Switzerland ($) One time cost of surgical treatments LR cost* CLT cost57,* Unit cost of TACE per session57 Monthly follow-up cost Compensated cirrhosis* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* HCC recurrence Contraindication to CLT Costs in Singapore ($) One time cost of surgical treatments LR cost§ CLT cost§ TACE per session§ Monthly cost of follow-up Compensated cirrhosis63 Decompensated cirrhosis63 Post-CLT in Year 163 Post-CLT in Year 2 and onwards63 HCC recurrence‡ Contraindication to CLT‡
Base Case Value (Median or Range Tested Point Estimate From (50% to 200% of Literature) Base Case Value)
25,086 137,701 25,961
12,543–50,172 68,851–275,402 12,981–51,922
61 1,519 5,410† 958 1,770‡ 3,894‡
31-122 760-3,038 2,705-10,820 344-2,215 885-3,540 1,947-7,788
59,848 223,236 6,855
29,924-119,696 111,618-446,472 3,428-13,710
42 1,889 2,640 1,503 467‡ 1,028‡
21-84 945-3,778 1,320-5,280 752-3,006 234-934 514-2,056
12,698 158,730 5,952
6,349-25,396 79,365-317,460 2,976-11,904
79 1,029 1,159 713 406‡ 893‡
40-160 515-2,058 580-2,318 357-1,426 203-812 447-1,786
*Refer to Supporting Material 8 for detailed list of supporting references used. Baseline derived from sum of values obtained from the references. ‡ Cost of 3 TACE sessions divided by X months, where X is the estimated average survival of the patient calculated from annual mortality rate using the assumption of a declining exponential approximation to survival. § Based on expert opinion. Abbreviation: TACE, transarterial-chemoembolization. †
cost was available from the literature. Both utilities and costs were discounted by 3% yearly.51 The endpoint used to assess both health benefits and costs was the incremental cost-effectiveness ratio (ICER), which was the difference in costs divided by the corresponding difference in quality-adjusted life years (QALYs). For the USA, we adopted the commonly cited cost-effectiveness threshold of $50,000/ QALY.52 For Switzerland and Singapore, we adopted the value proposed by the WHO53 for highly costeffective interventions (less than GDP per-capita), as there was no established threshold, $51,507/QALY for Switzerland54 and $50,123/QALY for Singapore.55
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Sensitivity Analyses. One-way sensitivity analysis was performed for all transition probabilities, costs, and utilities. For transition probabilities and utilities, the sensitivity analysis was done by varying each parameter over the range of variations reported in the literature and evaluating the impact on the outcome. For costs, given the lack of range data for most parameters, a wider range of 50%-200% on the base case value was deemed sufficient for cost estimates to account for potential cost disparities in centers with different volumes of patients (Tables 123). The transition probabilities within the top five most sensitive parameters were then further analyzed using scenario analysis, which assumed the most pessimistic extremes of these parameters to evaluate their impact on model outcome. Probabilistic sensitivity analysis using the MonteCarlo simulation was also performed. Point estimates for key input parameters were replaced with distributions, from which random draws were made during 10,000 reiterations. The uncertainty in all binary probability parameters was assumed to have a beta distribution, cost parameters were assumed to have a lognormal distribution, and the parameter start age was assumed to have a normal distribution (Supporting Material 4). TreeAge Pro (TreeAge Software, Williamstown, MA) was used for modeling.
Results Base Case Analysis. The model projected 1-year, 3-year, and 5-year overall survival of 94%, 74%, 53% for LR arm, and 89%, 69%, and 57% for CLT arm (Supporting Fig. S5). LR treatment provided an average gain of 5.5 years life expectancy, while CLT offered 1.8 years more. With quality of life adjustments, LR treatment resulted in 3.9 QALYs while CLT had an additional 1.4 QALYs. ICERs of CLT compared to LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland (Table 4). The ICERs were above the country-specific thresholds for costTable 3. Base Case Value and Sensitivity Range Extracted From Literature for Utilities
Parameter
Compensated cirrhosis* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* Contraindication to CLT* HCC recurrence*
Base Case Value (Median of Literature Range)
Literature Range Tested
0.76 0.66 0.69 0.73 0.63 0.63
0.65-0.90 0.37-0.86 0.64-0.71 0.62-0.84 0.26-0.86 0.26-0.86
*Refer to Supporting Material 8 for detailed list of supporting references used.
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Table 4. Incremental Cost-Effectiveness Ratios Comparing Liver Resection Versus Cadaveric Liver Transplantation in the Three Countries at the Base Case USA Various Costs
QALYs (years) Incremental QALY gained (years) Lifetime cost (US$) Incremental cost (US$) ICER (US$) Cost-effectiveness threshold (US$) Is CLT cost-effective?
Switzerland
Singapore
LR
CLT
LR
CLT
LR
CLT
3.9 — 81,870 — —
5.3 1.4 244,876 163,005 115,743
3.9 — 100,256 — —
5.3 1.4 320,379 220,122 156,300
3.9 — 39,097 — —
5.3 1.4 196,578 157,481 111,821
50,000 No
effectiveness in all three countries, suggesting that CLT was consistently not a cost-effective option compared to LR in all three cost scenarios. Sensitivity Analysis. Figure 2 demonstrates the tornado diagrams of the various input parameters for the USA, Switzerland, and Singapore. CLT-related 5-year cumulative survival was the most sensitive parameter in all three scenarios. The next most sensitive parameters were one-time treatment cost for CLT, utility, and monthly cost for post-CLT in year 2 and onwards, and post-LR 5-year cumulative recurrence rate. For the USA, if the CLT-related 5-year cumulative survival was improved to 87.6% or above, the corresponding ICER would reduce below the threshold and be more costeffective compared to LR. Likewise, a similar outcome was achieved in Singapore if CLT-related 5-year cumulative survival was 84.9% or above. All other parameters were not sufficiently sensitive to bring ICER below the cost-effectiveness threshold. For Switzerland, ICER was always above the cost-effectiveness threshold regardless of the variation in any single parameter. Scenario Analysis. The transition probabilities within the top five most sensitive parameters were CLTrelated 5-year cumulative survival and post-LR 5-year cumulative recurrence rate. These were included in the scenario analysis. Annual mortality risk post-LR recurrence, which represented the outcomes of different modalities used to treat post-LR recurrences such as TACE or radiofrequency ablation (RFA), were also included in the scenario analysis. This was because of uncertainties from the lack of consensus for treating post-LR recurrences and varied combinations employed by different centers tailored to local needs. Assuming the most pessimistic post-LR recurrence rate and annual mortality risk post-LR recurrence, and CLT-related 5year cumulative survival of 80%, ICER would be $52,967 in the USA, $71,661 in Switzerland and $48,622 in Singapore (Fig. 3A). In the same scenario, one-time cost of CLT would need to be kept below $125,000, $134,000, $166,000 for CLT to be cost-
51,507 No
50,123 No
effective in the USA, Switzerland, and Singapore, respectively (Fig. 3B-D). The corresponding one-time CLT cost would have to be less than $73,000 in the USA, $93,000 in Switzerland, and $107,000 in Singapore, if the 5-year survival rate for CLT was subsequently reduced to 70%. In the pessimistic scenario of LR, if the one-time CLT cost was kept at the base case estimate, the CLT-related 5-year cumulative survival would need to be above 83% and 79% for CLT to be cost-effective in the USA and Singapore, respectively. CLT was not cost-effective even at 90% CLT-related 5year cumulative survival in Switzerland. Probabilistic Sensitivity Analysis (PSA) and Willingness-to-Pay Analysis. For the three countries, CLT could gain more QALYs but ICER would exceed country-specific cost-effectiveness thresholds. For the USA, median ICER was $110,712/QALY ($72,400 to $315,114/QALY for 95% of the trials). The median was $151,599 ($99,020 to $437,213/QALY) and $108,889 ($69,139 to $303,741/QALY) for Switzerland and Singapore, respectively. Overall, CLT was shown to be less cost-effective as compared to LR consistently across all three countries (Supporting Fig. S6). The willingness-to-pay analysis (Supporting Fig. S7) indicated the proportion of trials that attained costeffectiveness of a given strategy for willingness-to-pay thresholds up to 3 times GDP per capita of a specific country. For the USA, all trials showed that LR is the optimal strategy at a willingness-to-pay threshold of $50,000/ QALY. If decision makers were willing to pay $111,079/ QALY or higher, CLT would likely be favored as supported by more than 50% of trials. Likewise, for Switzerland and Singapore, the willingness-to-pay thresholds have to be at least $152,658/QALY and $109,471/QALY, respectively, for CLT to be more favorable than LR.
Discussion Our results indicated that although CLT offered improved life expectancy, it was not cost-effective
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Fig. 2. Tornado diagrams of one-way sensitivity analyses for three countries. Blue color indicates low-range input values, while red color indicates high-range. Cost-effectiveness threshold is indicated by the broken blue line. Ranges are shown in Table 1. TACE: transarterial-chemoembolization. (A) USA: The ICER will be below the cost-effectiveness threshold when the CLT-related 5-year cumulative survival increases to 87.6% or above. (B) Switzerland: As long as parameters were varied within the ranges, the ICER was always above the cost-effectiveness threshold. (C) Singapore: The ICER will be below the cost-effectiveness threshold when the CLT-related 5-year cumulative survival increases to 84.9% or above.
compared to LR across all three countries at the base case. One-way sensitivity analysis also revealed LR to be more cost-effective unless CLT-related 5-year cumulative survival was greater than 87.6% for the USA or 84.9% for Singapore. LR was always more costeffective regardless of the variation in any single parameter for Switzerland. When CLT-related 5-year cumulative survival was less than 83% in the USA or
79% in Singapore, LR was always more cost-effective even with the most pessimistic post-LR 5-year cumulative recurrence rate and annual mortality risk of recurrent HCC. Although it has been demonstrated that patients with HCC undergoing CLT could achieve 5year survival rate greater than 80% in specialized centers,4-7 emerging data from OPTN and the European Liver Transplant Registry reported 5-year survival of
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Fig. 2. (Continued)
65% and 66%, respectively.8,56 This study revealed that at CLT-related 5-year cumulative survival of 70%, the one-time cost of CLT needed to be kept below $73,000 for CLT to be more cost-effective than LR in the USA.
As it is widely accepted that the etiology and natural history of HCC varies with the geographic locations, our sensitivity analysis tested the entire range of outcomes that is available from the published literature,
Fig. 3. Scenario analyses: the most pessimistic scenario for liver resection. (A) Impact of CLT-related 5-year cumulative survival on ICER. (B) USA: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER. (C) Switzerland: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER. (D) Singapore: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER.
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and included studies from Europe, the USA, and Asia. Our model and results can thus be applied to any country, provided clinical outcomes (and costs) in that country fall within the range we have tested. To our knowledge, our model is the first to use a distinct health state to account for the impact of nonCLT treatments used in managing post-LR recurrence. Previous modeling studies had confined such treatments only to palliation,57 which may not be reflective of clinical practice today, as many centers employ various modalities to manage recurrences.28,58,59 Many of these treatments such as RFA and TACE could possibly achieve good outcomes of more than 50% on 5-year overall survival in selected patients.27,60 Emerging treatment such as selective internal radiation therapy using yittrium-90 has also shown promise.61,62 These efforts would likely continue to improve postrecurrence outcomes for LR patients and make it an increasingly effective option. The outcomes from these and newer modalities can be easily incorporated into our model by updating the relevant transition probabilities. A key limitation of this study was the paucity of published data on LR and CLT outcomes that are specific for HCC with Child-Pugh A/B cirrhosis. While many studies had been conducted for this group of patients undergoing LR, the overwhelming majority were retrospective studies. Many of the studies on CLT did not specifically report outcomes for patients with Child-Pugh A/B cirrhosis, as CLT was mainly indicated for patients with poor liver function at most centers. However, as more specific data become available more precise estimations of model parameters by regions or countries can be made, and our decision analytic model will progressively improve and strengthen. Another limitation involved the estimation of utility values for different health states. There was little data on direct patient-elicited utilities for different stages of liver diseases such as early HCC, advanced HCC, and post-LR with or without recurrence. In the absence of large longitudinal studies, utility estimates for chronic cirrhosis conditions were subjected to the high heterogeneity of using different estimation methods and different patient samples in available studies. There was little data available on country-specific cost estimates for each health state in the model.63 The evidence synthesis was further challenged by two major factors: 1) different methodologies were used to assess costs within and across countries; 2) studies were completed in different time-periods with majority reporting costs of historical cohorts over a decade ago. Thus, it was difficult to make any intercountry comparison or direct generalization on the cost estimates. The uncer-
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tainties associated with these limitations, however, have been accounted for by testing wide ranges of input parameters in sensitivity analyses to come to a robust conclusion. In conclusion, patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, liver resection is more cost-effective than CLT, across three different costing scenarios: the USA, Switzerland, and Singapore. Acknowledgment: The authors thank Duke-NUS/ SingHealth Academic Medicine Research Institute for support and the writing assistance of Taara Madhavan (Associate, Clinical Sciences, Duke-NUS Graduate Medical School). The authors also thank the Organ Procurement Transplant Network Database (OPTN) for providing the data dated 30 June 2010. Author contributions: Study concept and design: All authors; Acquisition of data: Lim, Wang, Siddiqui; Analysis and interpretation: All authors; Draft of article: Lim, Wang; Critical evaluation of the article for important intellectual content: All authors; Final approval of the version to be published: All authors; Guarantor: Lim, Wang. Data Sharing: Consent was not obtained but the presented data are anonymized and risk of identification is low.
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hepatocellular carcinoma using organ procurement transplant network data. Liver Transpl 2009;15:859-868. Lim KC, Chow PK, Allen JC, Siddiqui FJ, Chan ES, Tan SB. Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria. Br J Surg 2012;99: 1622-1629. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. HEPATOLOGY 1999;30:1434-1440. van der Hilst CS, Ijtsma AJ, Slooff MJ, Tenvergert EM. Cost of liver transplantation: a systematic review and meta-analysis comparing the United States with other OECD countries. Med Care Res Rev 2009; 66:3-22. Naimark D, Krahn M, Naglie G, Redelmeier D, Detsky A. Primer on medical decision analysis: Part 5. Working with Markov processes. Med Decis Making 1997;17:152-159. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693699. Hwang S, Lee SG, Belghiti J. Liver transplantation for HCC: its role: Eastern and Western perspectives. J Hepatobiliary Pancreat Sci 2010; 17:443-448. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917. Northup PG, Abecassis MM, Englesbe MJ, Emond JC, Lee VD, Stukenborg GJ, et al. Addition of adult-to-adult living donation to liver transplant programs improves survival but at an increased cost. Liver Transpl 2009;15:148-162. Beck J, Kassirer J, Pauker S. A convenient approximation of life expectancy (the “DEALE”). I. Validation of the method. Am J Med 1982;73: 883-888. Fleming KM, Aithal GP, Card TR, West J. The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study. Aliment Pharmacol Ther 2010;32:1343-1350. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;112: 463-472. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. HEPATOLOGY 1995;21:77-82. Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. HEPATOLOGY 1999;29:1311-1316. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217-231. de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992;103: 1630-1635. Planas R, Balleste B, Alvarez MA, Rivera M, Montoliu S, Galeras JA, et al. Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients. J Hepatol 2004;40:823-830. Baccarani U, Isola M, Adani GL, Benzoni E, Avellini C, Lorenzin D, et al. Superiority of transplantation versus resection for the treatment of small hepatocellular carcinoma. Transpl Int 2008;21:247-254. Bigourdan JM, Jaeck D, Meyer N, Meyer C, Oussoultzoglou E, Bachellier P, et al. Small hepatocellular carcinoma in Child A cirrhotic patients: hepatic resection versus transplantation. Liver Transpl 2003;9: 513-520. Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010;252:903-912.
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28. Poon RT, Fan ST, Lo CM, Liu CL,Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373-382. 29. Takahashi S, Kudo M, Chung H, Inoue T, Nagashima M, Kitai S, et al. Outcomes of nontransplant potentially curative therapy for earlystage hepatocellular carcinoma in Child-Pugh stage A cirrhosis is comparable with liver transplantation. Dig Dis 2007;25:303-309. 30. Tanaka H, Kubo S, Tsukamoto T, Shuto T, Takemura S, Yamamoto T, et al. Recurrence rate and transplantability after liver resection in patients with hepatocellular carcinoma who initially met transplantation criteria. Transplant Proc 2005;37:1254-1256. 31. Taura K, Ikai I, Hatano E, Yasuchika K, Nakajima A, Tada M, et al. Influence of coexisting cirrhosis on outcomes after partial hepatic resection for hepatocellular carcinoma fulfilling the Milan criteria: an analysis of 293 patients. Surgery 2007;142:685-694. 32. Bruix J, Sherman M. Management of hepatocellular carcinoma. HEPATOLOGY 2005;42:1208-1236. 33. Llovet J, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10:S115-S120. 34. Omata M, Lesmana L, Tateishi R, Chen P-J, Lin S-M, Yoshida H, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. 2010:439-474. 35. Bellavance E, Lumpkins K, Mentha G, Marques H, Capussotti L, Pulitano C, et al. Surgical management of early-stage hepatocellular carcinoma: resection or transplantation? J Gastrointest Surg 2008;12:1699-1708. 36. Cha C, Ruo L, Fong Y, Jarnagin W, Shia J, Blumgart L,et al. Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003;238:315-321; discussion 321-313. 37. Itamoto T, Nakahara H, Tashiro H, Ohdan H, Hino H, Ochi M, et al. Indications of partial hepatectomy for transplantable hepatocellular carcinoma with compensated cirrhosis. Am J Surg 2005;189:167-172. 38. Sakaguchi T, Suzuki S, Morita Y, Oishi K, Suzuki A, Fukumoto K, et al. Impact of the preoperative des-gamma-carboxy prothrombin level on prognosis after hepatectomy for hepatocellular carcinoma meeting the Milan criteria. Surg Today 2010;40:638-645. 39. Ueno S, Sakoda M, Kubo F, Hiwatashi K, Tateno T, Baba Y, et al. Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria. J Hepatobiliary Pancreat Surg 2009;16:359-366. 40. CDC. United States Life Tables. Atlanta, GA: Centers for Disease Control and Prevention; 2008. 41. Vitale A, Boccagni P, Brolese A, Neri D, Srsen N, Zanus G, et al. Progression of hepatocellular carcinoma before liver transplantation: dropout or liver transplantation? Transplant Proc 2009;41:1264-1267. 42. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96. 43. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011:CD004787. 44. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. N Engl J Med 1995;332: 1256-1261. 45. Doffoel M, Bonnetain F, Bouche O, Vetter D, Abergel A, Fratte S, et al. Multicentre randomised phase III trial comparing tamoxifen alone or with transarterial lipiodol chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Federation Francophone de Cancerologie Digestive 9402). Eur J Cancer 2008;44:528-538. 46. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734-1739. 47. Pelletier G, Ducreux M, Gay F, Luboinski M, Hagege H, Dao T, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol 1998;29:129-134.
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48. Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gondolesi GE, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl 2004;10:534-540. 49. The World Bank. Official exchange rate (LCU per US$, period average). Available from: http://data.worldbank.org/indicator/PA.NUS. FCRF/countries?page51&display5default: http://data.worldbank.org/ indicator/PA.NUS.FCRF/countries?page51&display5default. 50. United States Department of Labor. Consumer Price Index, Bureau of Labor Statistics. Washington, DC: United States Department of Labor; 2012. 51. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL. Methods for the economic evaluation of health care programmes, 3rd ed. Oxford, UK: Oxford University Press, 2005. 52. Grosse SD. Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold. Expert Rev Pharmacoecon Outcomes Res 2008;8:165-178. 53. World Health Organization. Cost-effectiveness threshold. chooosing interventions that are cost effective (WHO-CHOICE). Geneva, Switzerland: WHO. 54. OECD. Stat extracts. Gross Domestic Product (GDP): GDP per head, US $, current prices, current PPPs. Paris: OECD; 2013. 55. .Department of Statistics — Singapore. Time series on per capita GDP at current market prices. 56. Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675-688. 57. Sarasin F, Giostra E, Mentha G, Hadengue A. Partial hepatectomy or orthotopic liver transplantation for the treatment of resectable hepato-
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cellular carcinoma? A cost-effectiveness perspective. HEPATOLOGY 1998; 28:436-442. Park Y, Kim B, Wang H, Kim M. Hepatic resection for hepatocellular carcinoma meeting Milan criteria in Child-Turcotte-Pugh class a patients with cirrhosis. Transplant Proc 2009;41:1691-1697. Cillo U, Vitale A, Brolese A, Zanus G, Neri D, Valmasoni M, et al. Partial hepatectomy as first-line treatment for patients with hepatocellular carcinoma. J Surg Oncol 2007;95:213-220. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi K, Kojiro M, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. HEPATOLOGY 2000;32:1224-1229. Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011;140:497-507 e492. Sangro B, Salem R, Kennedy A, Coldwell D, Wasan H. Radioembolization for hepatocellular carcinoma: a review of the evidence and treatment recommendations. Am J Clin Oncol 2011;34:422-431. Li SC, Ong SC, Lim SG, Yeoh KG, Kwong KS, Lee V, et al. A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore. J Clin Gastroenterol 2004;38:S136-143.
Supporting Information Additional Supporting Information may be found in the online version of this article.
H
epatocellular carcinoma (HCC) is a common cancer with a higher disease burden in East Asia due to the prevalence of chronic viral hepatitis in the region.1 For patients with HCC within
the Milan criteria and adequate liver function for resection (Child-Pugh A/B cirrhosis), both liver resection (LR) and liver transplantation (LT) are potentially curative treatments. There is, however, ongoing debate
Abbreviations: CLT, cadaveric liver transplantation; DEALE, declining exponential approximation of life expectancy; HCC, hepatocellular carcinoma; ICER, incremental cost-effectiveness ratio; LR, liver resection; LT, liver transplantation; OPTN, Organ Procurement Transplant Network Database; QALYs, qualityadjusted life years. From the 1Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; 2Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore; 3Centre for Health Services Research, SingHealth, Singapore; 4Singapore Clinical Research Institute, Singapore; 5Epidemiology and Disease Control Division, Ministry of Health, Singapore; 6Department of HPB and Transplantation Surgery, Singapore General Hospital, Singapore; 7Department of Surgical Oncology, National Cancer Centre, Singapore. Received September 20, 2013; accepted March 13, 2014. This study was supported by the Khoo Clinical Discovery Project Award of the Duke-NUS Graduate Medical School. This work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. *These authors contributed equally to this work. 1
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about which treatment is more appropriate.2,3 While specialized centers demonstrate that LT for HCC within the Milan criteria can achieve 5-year survival rates of more than 80%,4-7 reports from large registries such as the Organ Procurement Transplant Network Database (OPTN) show 5-year survival rates of between 60-65%.8 Emerging data show improving trends in LR outcomes, possibly due to better patient selection, postoperative management, and multimodality treatment for recurrences.9 While recurrence rates in LT are often lower than LR, LT faces considerable resource challenges in many countries, such as the limited supply of cadaveric transplant organs, leading to cancer progression during long waiting times that limit intention-to-treat survival for LT.10 LT patients also require long-term immune suppression, with attendant risks and significant lifetime costs. Randomized trials comparing the two treatments are neither ethical nor practical. Due to the large financial outlay and recurrent costs needed to run a liver transplant program for a large number of HCC patients,11 the decision to adopt either therapy as a first-line option carries major implications with respect to costs, utility of scarce resources, and expectations of the population for quality healthcare. It is in this setting that a decision analytical model can help compare the two treatments from the perspective of the healthcare system. The aim of this study was to estimate the relative cost-effectiveness of LR versus LT for HCC patients within the Milan criteria and adequate liver function using a decision analytic model.
Materials and Methods A Markov cohort model12 was developed to simulate a cohort of patients aged 55 years with early HCC (defined by the Milan criteria) and adequate liver function (defined as Child-Pugh A/B cirrhosis), who have undergone either LR or cadaveric liver transplantation (CLT) and followed over a time horizon of their remaining life expectancy (Fig. 1). Among the two alternatives, the baseline comparator is LR. Early HCC was defined as HCC meeting the Milan criteria (solitary nodule not exceeding 5 cm; not more than
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three nodules, none exceeding 3 cm; no evidence of macrovascular invasion or distant metastasis).13 While living donor liver transplantation is increasing, especially in Asia,14 this study is focused on CLT as it remains the primary form of transplantation internationally.15 In the model, a 1-month cycle time was selected as the clinically most pertinent interval short enough to reflect the cost and quality of life impact from major surgical treatment episodes.16 During each cycle, a patient occupied one health state and moved to another according to transition probabilities (Fig. 1). Each health state had associated costs and utilities, and these were accumulated over the lifetime of the simulated population. Monthly transition probabilities were derived from cumulative probabilities using the declining exponential approximation of life expectancy (DEALE) method.17 Literature reviews were conducted to derive values for the transition probabilities, utilities, and costs. A full list of parameters used in the model is presented in Tables 1 to 3. Details on parameters used to derive transition probabilities between two states and references used to derive values for these parameters are found in Supporting Material 1. When possible, transition probabilities for LR were obtained from studies from Lim et al.,9 which is a systematic review of recent LR outcomes in early HCC patients. This is supplemented by additional analyses performed on the Singapore General Hospital (SGH) LR database comprising 241 patients (Supporting Material 2), and the OPTN database for LT comprising 4,381 patients (Supporting Material 3). In the absence of published data, several modeling assumptions listed below were made. Base Case Clinical Estimates in the LR Arm. We assumed that patients in the LR arm underwent surgery within a cycle time of 1 month and were in a state of compensated cirrhosis. Here, they were subjected to the risks of decompensation, tumor recurrence, and age-related mortality. As there was a paucity of prospective data on risk of progression to decompensated cirrhosis in this group of patients, we obtained data from studies involving non-HCC patients with cirrhosis. Further, we assumed that the
Address reprint requests to: Prof. Pierce Chow, Office of Clinical Sciences, Duke-NUS Graduate Medical School, The Academia, Level 6, 20 College Road, Singapore 169856. E-mail: [email protected]; fax: 165 6220 9323. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27135 Potential conflict of interest: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that they have no financial interests that may be relevant to the submitted work.
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Fig. 1. Markov Cohort Model. Lines with arrows indicate transition from one health state to another (or itself) per cycle.
history of LR for early HCC does not alter these two risks. The annual decompensation rate of 11.8% was based on Fleming et al.,18 which was the latest study with the largest sample size among the relevant studies.18-21 The remaining studies provided the range for the sensitivity analysis. The decompensated cirrhosis 5year cumulative survival of 35% was the median value derived from another series of studies.19,20,22-24 The 62% post-LR 5-year cumulative recurrence rate and the 30.1% annual mortality risk of recurrent HCC were the medians derived from studies included in Lim et al.25-31 and data from the SGH LR database (Supporting Material 2). The modeling of the recurrence state was necessary, as LR patients generally suffer from frequent recurrence, and an increasing variety of therapies are used to manage recurrences in actual clinical settings, impacting overall cost-effectiveness of the treatment.9 As there was no universally accepted protocol for treating tumor recurrences,32-34 it was assumed that patients underwent a variety of therapies but had a consolidated postrecurrence outcome. We assumed the cost of these treatments to be equivalent to three transarterial-chemoembolization (TACE) sessions. The 30-day postoperative mortality of 2.2% was the median derived from studies within Lim et al.’s review.25,26,31,35-39 Age-related mortality risks were based on United States life tables.40
Base Case Clinical Estimates in the CLT Arm. Similarly, we assumed that patients waiting for CLT started in a state of compensated cirrhosis and were at risk of decompensation, tumor progression (beyond the Milan criteria), and age-related mortality. Patients with early HCC were assumed to carry no additional short-term cancer mortality risks, and were subjected to the same annual decompensation rate of 11.8% for non-HCC patients. The risk of tumor progression to beyond Milan criteria was assumed to be constant and independent from the state of cirrhosis. Very few studies evaluated the dropout rate from the LT waitlist due to tumor progression. Only one study reported a 53% cumulative dropout probability at 24 months among 103 HCC patients,41 which was adopted as the base case estimate. In USA, the state of cirrhosis affects the LT waiting time through the Model for Endstage Liver Disease (MELD) score.42 However, we opted to apply a constant transplantation probability irrespective of their state of cirrhosis to simplify the model, as not all countries adopt this prioritization scheme. The median waiting-list time to CLT of 110 days was taken from our OPTN analysis (Supporting Material 3). Likewise, the CLT-related 30-day perioperative mortality of 3.2% and 5-year cumulative survival of 67.8% were derived. Once tumor progressed, CLT was contraindicated and patients were assumed to receive only up to
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Table 1. Base Case Value and Sensitivity Range Extracted From Literature for Transition Probabilities Parameter
Background (all-cause) mortality40 Cirrhosis annual decompensation rate (%)18-21 Derived monthly decompensation rate (%)* Decompensated cirrhosis-related 5-year cumulative survival (%)19,20,22-24 Derived monthly mortality risk (%)† LR-related 30-day perioperative mortality (%)25,26,31,35-39 Post-LR 5-year cumulative recurrence rate (%)25,27-31,# Derived monthly recurrence rate (%)‡ Annual mortality risk of recurrent HCC (%)26,28,§,# Derived monthly mortality risk (%)‡ Median waiting-list time to CLT (days)7,**,†† Derived monthly probability of obtaining CLT (%)¶ 24 month dropout risk due to tumor progression (%)41 Monthly dropout risk due to tumor progression (%)†† Derived monthly dropout risk (%)‡ Annual mortality risk of HCC outside Milan (%)44-47 Derived monthly mortality risk (%)‡ CLT-related 30-day perioperative mortality (%)35,**,†† CLT-related 5-year cumulative survival (%)3,5,7,8,25,35,**,†† Derived monthly mortality risk (%)†
Base Case Value (Median of Literature Range Unless Separately Referenced)
Literature Range Tested
Age-specific 11.818 0.98 35 1.73 2.2 62 1.60 30.1 2.94 110** 17.44 5341 3.10 44.2 4.75 3.2** 67.8** 0.65
3.9-12.5 0.32-1.04 14-50.8 1.12-3.22 0-5.3 42-78 0.90-2.49 23.6-38.7 2.22-4.00 36-234 8.62-44.33 2.3-5.6 2.3-5.6 33.8-51.0 3.38-5.77 0-9.88 60-90 0.18-0.85
*Annual decompensation rate was converted to monthly probability using the formula: 1-e (-rate x time), where time is 1/12. Using the assumption of a declining exponential approximation of life expectancy, the monthly probability was derived from 5-year cumulative survival by using the formula: 1-(prob)1/60, where prob is 5-year cumulative survival. ‡ Using the assumption of a declining exponential approximation to disease- or progression- free survival, post-LR 5-year cumulative recurrence rate, annual mortality risk and 24 month dropout risk from tumor progression were converted to the monthly probability using the formula: 1-(1-prob)1/time, where prob refers to the parameter and time refers to 60, 12, 24 respectively. § Annual mortality risk of recurrent HCC is first calculated from post recurrence 5-year cumulative survival or time to median survival by using 1-(prob)1/time, where prob refers to the 5-year cumulative survival or 50% for median survival, and time refers to 5 or 1.42 years. ¶ Monthly probability of getting CLT is calculated by using the formula 1-(1-prob)(365/12)/time, where prob is 50% and the time is median wait list time to CLT. # Also refers to Supporting Material 2. **Also refers to Supporting Material 3. †† Refer to Supporting Material 8 for detailed list of supporting references used. †
three sessions of TACE. We could not find any study reporting mortality risk specifically in patients who dropped out of the transplantation waiting list due to tumor progression. Hence, it was assumed to be similar to the mortality risk of unresectable HCC treated with TACE. Based on a recent review on TACE for unresectable HCC,43 four randomized controlled trials involving patients with Child-Pugh A/B cirrhosis were selected to derive the median annual mortality risk of HCC beyond Milan at 44%.44-47 We did not model post-CLT recurrence as a separate state as these recurrences usually have poor survival48 and there is paucity of suitable data. Patients in decompensated cirrhosis state were assumed to carry only the mortality risk from decompensated cirrhosis and not from cancer. Costs. Our analysis was performed from the perspective of the healthcare system, and hence only direct medical costs were accounted for. Rather than using hypothetical cost data, we chose to build cost scenarios using actual country-specific data reported from open sources. Medline was searched for primary cost studies in English and published between January
1, 2000 to December 31, 2012, with the following Medical subject heading (MESH) terms and their free text variants: “Carcinoma, Hepatocellular,” “Liver Transplantation,” “Hepatectomy,” “Liver Cirrhosis” in combination with “Costs and cost analysis.” Complete articles were short-listed from potentially relevant citations and retrieved. The reference lists of these articles were also examined. Articles that reported charges but not costs, overlapping datasets, and those without specific costs applicable to the health states in our model were excluded. Adopting this approach, the most relevant and complete data were available from Singapore, the USA, and Switzerland. In addition, the large OPTN liver transplantation registry was also from the USA. Incidentally, these countries represent different costing scenarios over three continents. All reported costs were converted to year 2012 U.S. dollars49 using the U.S. Consumer Price Index for Medical Care Costs.50 Costs obtained from the literature were used as our base case. If a range of data was available, the median cost was used as the base case value. Expert opinion on cost supplemented the information if no
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Table 2. Base Case Value and Sensitivity Range for Costs
Parameter
Costs in USA ($) One time cost of surgical treatments LR cost* CLT cost16,* TACE per session* Monthly follow-up cost Compensated cirrhosis16,* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* HCC recurrence Contraindication to CLT Costs in Switzerland ($) One time cost of surgical treatments LR cost* CLT cost57,* Unit cost of TACE per session57 Monthly follow-up cost Compensated cirrhosis* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* HCC recurrence Contraindication to CLT Costs in Singapore ($) One time cost of surgical treatments LR cost§ CLT cost§ TACE per session§ Monthly cost of follow-up Compensated cirrhosis63 Decompensated cirrhosis63 Post-CLT in Year 163 Post-CLT in Year 2 and onwards63 HCC recurrence‡ Contraindication to CLT‡
Base Case Value (Median or Range Tested Point Estimate From (50% to 200% of Literature) Base Case Value)
25,086 137,701 25,961
12,543–50,172 68,851–275,402 12,981–51,922
61 1,519 5,410† 958 1,770‡ 3,894‡
31-122 760-3,038 2,705-10,820 344-2,215 885-3,540 1,947-7,788
59,848 223,236 6,855
29,924-119,696 111,618-446,472 3,428-13,710
42 1,889 2,640 1,503 467‡ 1,028‡
21-84 945-3,778 1,320-5,280 752-3,006 234-934 514-2,056
12,698 158,730 5,952
6,349-25,396 79,365-317,460 2,976-11,904
79 1,029 1,159 713 406‡ 893‡
40-160 515-2,058 580-2,318 357-1,426 203-812 447-1,786
*Refer to Supporting Material 8 for detailed list of supporting references used. Baseline derived from sum of values obtained from the references. ‡ Cost of 3 TACE sessions divided by X months, where X is the estimated average survival of the patient calculated from annual mortality rate using the assumption of a declining exponential approximation to survival. § Based on expert opinion. Abbreviation: TACE, transarterial-chemoembolization. †
cost was available from the literature. Both utilities and costs were discounted by 3% yearly.51 The endpoint used to assess both health benefits and costs was the incremental cost-effectiveness ratio (ICER), which was the difference in costs divided by the corresponding difference in quality-adjusted life years (QALYs). For the USA, we adopted the commonly cited cost-effectiveness threshold of $50,000/ QALY.52 For Switzerland and Singapore, we adopted the value proposed by the WHO53 for highly costeffective interventions (less than GDP per-capita), as there was no established threshold, $51,507/QALY for Switzerland54 and $50,123/QALY for Singapore.55
5
Sensitivity Analyses. One-way sensitivity analysis was performed for all transition probabilities, costs, and utilities. For transition probabilities and utilities, the sensitivity analysis was done by varying each parameter over the range of variations reported in the literature and evaluating the impact on the outcome. For costs, given the lack of range data for most parameters, a wider range of 50%-200% on the base case value was deemed sufficient for cost estimates to account for potential cost disparities in centers with different volumes of patients (Tables 123). The transition probabilities within the top five most sensitive parameters were then further analyzed using scenario analysis, which assumed the most pessimistic extremes of these parameters to evaluate their impact on model outcome. Probabilistic sensitivity analysis using the MonteCarlo simulation was also performed. Point estimates for key input parameters were replaced with distributions, from which random draws were made during 10,000 reiterations. The uncertainty in all binary probability parameters was assumed to have a beta distribution, cost parameters were assumed to have a lognormal distribution, and the parameter start age was assumed to have a normal distribution (Supporting Material 4). TreeAge Pro (TreeAge Software, Williamstown, MA) was used for modeling.
Results Base Case Analysis. The model projected 1-year, 3-year, and 5-year overall survival of 94%, 74%, 53% for LR arm, and 89%, 69%, and 57% for CLT arm (Supporting Fig. S5). LR treatment provided an average gain of 5.5 years life expectancy, while CLT offered 1.8 years more. With quality of life adjustments, LR treatment resulted in 3.9 QALYs while CLT had an additional 1.4 QALYs. ICERs of CLT compared to LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland (Table 4). The ICERs were above the country-specific thresholds for costTable 3. Base Case Value and Sensitivity Range Extracted From Literature for Utilities
Parameter
Compensated cirrhosis* Decompensated cirrhosis* Post-CLT in Year 1* Post-CLT in Year 2 and onwards* Contraindication to CLT* HCC recurrence*
Base Case Value (Median of Literature Range)
Literature Range Tested
0.76 0.66 0.69 0.73 0.63 0.63
0.65-0.90 0.37-0.86 0.64-0.71 0.62-0.84 0.26-0.86 0.26-0.86
*Refer to Supporting Material 8 for detailed list of supporting references used.
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Table 4. Incremental Cost-Effectiveness Ratios Comparing Liver Resection Versus Cadaveric Liver Transplantation in the Three Countries at the Base Case USA Various Costs
QALYs (years) Incremental QALY gained (years) Lifetime cost (US$) Incremental cost (US$) ICER (US$) Cost-effectiveness threshold (US$) Is CLT cost-effective?
Switzerland
Singapore
LR
CLT
LR
CLT
LR
CLT
3.9 — 81,870 — —
5.3 1.4 244,876 163,005 115,743
3.9 — 100,256 — —
5.3 1.4 320,379 220,122 156,300
3.9 — 39,097 — —
5.3 1.4 196,578 157,481 111,821
50,000 No
effectiveness in all three countries, suggesting that CLT was consistently not a cost-effective option compared to LR in all three cost scenarios. Sensitivity Analysis. Figure 2 demonstrates the tornado diagrams of the various input parameters for the USA, Switzerland, and Singapore. CLT-related 5-year cumulative survival was the most sensitive parameter in all three scenarios. The next most sensitive parameters were one-time treatment cost for CLT, utility, and monthly cost for post-CLT in year 2 and onwards, and post-LR 5-year cumulative recurrence rate. For the USA, if the CLT-related 5-year cumulative survival was improved to 87.6% or above, the corresponding ICER would reduce below the threshold and be more costeffective compared to LR. Likewise, a similar outcome was achieved in Singapore if CLT-related 5-year cumulative survival was 84.9% or above. All other parameters were not sufficiently sensitive to bring ICER below the cost-effectiveness threshold. For Switzerland, ICER was always above the cost-effectiveness threshold regardless of the variation in any single parameter. Scenario Analysis. The transition probabilities within the top five most sensitive parameters were CLTrelated 5-year cumulative survival and post-LR 5-year cumulative recurrence rate. These were included in the scenario analysis. Annual mortality risk post-LR recurrence, which represented the outcomes of different modalities used to treat post-LR recurrences such as TACE or radiofrequency ablation (RFA), were also included in the scenario analysis. This was because of uncertainties from the lack of consensus for treating post-LR recurrences and varied combinations employed by different centers tailored to local needs. Assuming the most pessimistic post-LR recurrence rate and annual mortality risk post-LR recurrence, and CLT-related 5year cumulative survival of 80%, ICER would be $52,967 in the USA, $71,661 in Switzerland and $48,622 in Singapore (Fig. 3A). In the same scenario, one-time cost of CLT would need to be kept below $125,000, $134,000, $166,000 for CLT to be cost-
51,507 No
50,123 No
effective in the USA, Switzerland, and Singapore, respectively (Fig. 3B-D). The corresponding one-time CLT cost would have to be less than $73,000 in the USA, $93,000 in Switzerland, and $107,000 in Singapore, if the 5-year survival rate for CLT was subsequently reduced to 70%. In the pessimistic scenario of LR, if the one-time CLT cost was kept at the base case estimate, the CLT-related 5-year cumulative survival would need to be above 83% and 79% for CLT to be cost-effective in the USA and Singapore, respectively. CLT was not cost-effective even at 90% CLT-related 5year cumulative survival in Switzerland. Probabilistic Sensitivity Analysis (PSA) and Willingness-to-Pay Analysis. For the three countries, CLT could gain more QALYs but ICER would exceed country-specific cost-effectiveness thresholds. For the USA, median ICER was $110,712/QALY ($72,400 to $315,114/QALY for 95% of the trials). The median was $151,599 ($99,020 to $437,213/QALY) and $108,889 ($69,139 to $303,741/QALY) for Switzerland and Singapore, respectively. Overall, CLT was shown to be less cost-effective as compared to LR consistently across all three countries (Supporting Fig. S6). The willingness-to-pay analysis (Supporting Fig. S7) indicated the proportion of trials that attained costeffectiveness of a given strategy for willingness-to-pay thresholds up to 3 times GDP per capita of a specific country. For the USA, all trials showed that LR is the optimal strategy at a willingness-to-pay threshold of $50,000/ QALY. If decision makers were willing to pay $111,079/ QALY or higher, CLT would likely be favored as supported by more than 50% of trials. Likewise, for Switzerland and Singapore, the willingness-to-pay thresholds have to be at least $152,658/QALY and $109,471/QALY, respectively, for CLT to be more favorable than LR.
Discussion Our results indicated that although CLT offered improved life expectancy, it was not cost-effective
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Fig. 2. Tornado diagrams of one-way sensitivity analyses for three countries. Blue color indicates low-range input values, while red color indicates high-range. Cost-effectiveness threshold is indicated by the broken blue line. Ranges are shown in Table 1. TACE: transarterial-chemoembolization. (A) USA: The ICER will be below the cost-effectiveness threshold when the CLT-related 5-year cumulative survival increases to 87.6% or above. (B) Switzerland: As long as parameters were varied within the ranges, the ICER was always above the cost-effectiveness threshold. (C) Singapore: The ICER will be below the cost-effectiveness threshold when the CLT-related 5-year cumulative survival increases to 84.9% or above.
compared to LR across all three countries at the base case. One-way sensitivity analysis also revealed LR to be more cost-effective unless CLT-related 5-year cumulative survival was greater than 87.6% for the USA or 84.9% for Singapore. LR was always more costeffective regardless of the variation in any single parameter for Switzerland. When CLT-related 5-year cumulative survival was less than 83% in the USA or
79% in Singapore, LR was always more cost-effective even with the most pessimistic post-LR 5-year cumulative recurrence rate and annual mortality risk of recurrent HCC. Although it has been demonstrated that patients with HCC undergoing CLT could achieve 5year survival rate greater than 80% in specialized centers,4-7 emerging data from OPTN and the European Liver Transplant Registry reported 5-year survival of
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Fig. 2. (Continued)
65% and 66%, respectively.8,56 This study revealed that at CLT-related 5-year cumulative survival of 70%, the one-time cost of CLT needed to be kept below $73,000 for CLT to be more cost-effective than LR in the USA.
As it is widely accepted that the etiology and natural history of HCC varies with the geographic locations, our sensitivity analysis tested the entire range of outcomes that is available from the published literature,
Fig. 3. Scenario analyses: the most pessimistic scenario for liver resection. (A) Impact of CLT-related 5-year cumulative survival on ICER. (B) USA: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER. (C) Switzerland: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER. (D) Singapore: Combined impact of CLT-related 5-year cumulative survival and one-time treatment cost for CLT on ICER.
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and included studies from Europe, the USA, and Asia. Our model and results can thus be applied to any country, provided clinical outcomes (and costs) in that country fall within the range we have tested. To our knowledge, our model is the first to use a distinct health state to account for the impact of nonCLT treatments used in managing post-LR recurrence. Previous modeling studies had confined such treatments only to palliation,57 which may not be reflective of clinical practice today, as many centers employ various modalities to manage recurrences.28,58,59 Many of these treatments such as RFA and TACE could possibly achieve good outcomes of more than 50% on 5-year overall survival in selected patients.27,60 Emerging treatment such as selective internal radiation therapy using yittrium-90 has also shown promise.61,62 These efforts would likely continue to improve postrecurrence outcomes for LR patients and make it an increasingly effective option. The outcomes from these and newer modalities can be easily incorporated into our model by updating the relevant transition probabilities. A key limitation of this study was the paucity of published data on LR and CLT outcomes that are specific for HCC with Child-Pugh A/B cirrhosis. While many studies had been conducted for this group of patients undergoing LR, the overwhelming majority were retrospective studies. Many of the studies on CLT did not specifically report outcomes for patients with Child-Pugh A/B cirrhosis, as CLT was mainly indicated for patients with poor liver function at most centers. However, as more specific data become available more precise estimations of model parameters by regions or countries can be made, and our decision analytic model will progressively improve and strengthen. Another limitation involved the estimation of utility values for different health states. There was little data on direct patient-elicited utilities for different stages of liver diseases such as early HCC, advanced HCC, and post-LR with or without recurrence. In the absence of large longitudinal studies, utility estimates for chronic cirrhosis conditions were subjected to the high heterogeneity of using different estimation methods and different patient samples in available studies. There was little data available on country-specific cost estimates for each health state in the model.63 The evidence synthesis was further challenged by two major factors: 1) different methodologies were used to assess costs within and across countries; 2) studies were completed in different time-periods with majority reporting costs of historical cohorts over a decade ago. Thus, it was difficult to make any intercountry comparison or direct generalization on the cost estimates. The uncer-
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tainties associated with these limitations, however, have been accounted for by testing wide ranges of input parameters in sensitivity analyses to come to a robust conclusion. In conclusion, patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, liver resection is more cost-effective than CLT, across three different costing scenarios: the USA, Switzerland, and Singapore. Acknowledgment: The authors thank Duke-NUS/ SingHealth Academic Medicine Research Institute for support and the writing assistance of Taara Madhavan (Associate, Clinical Sciences, Duke-NUS Graduate Medical School). The authors also thank the Organ Procurement Transplant Network Database (OPTN) for providing the data dated 30 June 2010. Author contributions: Study concept and design: All authors; Acquisition of data: Lim, Wang, Siddiqui; Analysis and interpretation: All authors; Draft of article: Lim, Wang; Critical evaluation of the article for important intellectual content: All authors; Final approval of the version to be published: All authors; Guarantor: Lim, Wang. Data Sharing: Consent was not obtained but the presented data are anonymized and risk of identification is low.
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Supporting Information Additional Supporting Information may be found in the online version of this article.
