Background
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cancer-related cause of death, and carries a substantial healthcare spending burden worldwide [
1]. Despite recent improvements in surveillance programs, a considerable proportion of patients have vascular invasion or extrahepatic metastasis (advanced stage) at time of diagnosis [
2,
3]. Sorafenib, an oral multi-kinase inhibitor, is the standard systemic therapy in the treatment of advanced HCC, based on two multicenter randomized controlled trials (RCTs), which demonstrate improved overall survival of full-dose sorafenib compared with best supportive care (BSC) [
4,
5]. In routine clinical practice, sorafenib is recommended to be administered as 800 mg daily, based on the RCT data. However, a substantial portion of patients receiving sorafenib require dose adjustment due to the relatively high rate of adverse effects during the treatment period in the real clinical setting. Moreover, the high cost of full-dose sorafenib is a heavy financial burden for patients with advanced HCC. Recent studies have suggested that a dose-adjusted sorafenib regimen might achieve a better efficacy-safety balance [
6‐
8]. Nevertheless, dose-adjusted sorafenib has not been recommended by the current guidelines due to lack of enough robust data.
Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage HCC [
9]. However, intrahepatic tumor control with TACE might be reasonable and beneficial for advanced HCC considering the fact that more than two-thirds of patients with advanced HCC die of liver failure or intrahepatic tumor progression [
10‐
12]. Some studies have already reported the potential benefits of TACE for patients in this stage [
12‐
21], even after sorafenib was universally established as the first-line treatment. Although several comparative studies tried to compare efficacy between TACE and sorafenib in advanced HCC [
14,
15,
22,
23], results were controversial and no RCT has been performed to address this question. It remains unknown how TACE compares with sorafenib for treatment of advanced HCC. Particularly, dose-adjusted regimen is not available when sorafenib is first administered, so full-dose sorafenib will be compared with TACE. Moreover, there may be a significant difference in costs among these three treatments, which may significantly impact the treatment selection due to practical considerations.
Until now, no cost-effectiveness (CE) analysis has been performed on this issue. The Markov model would be a proper solution for this issue. By dividing a disease into distinct states and assigning transitions probabilities for movement between those states, then attaching estimates of costs and health outcomes to the states and running the model over many cycles, the model is able to estimate the long-term costs and outcomes associated with that disease and the related healthcare interventions [
24]. The advantage of Markov model by taking into accounts both costs and outcomes over a period of time makes it particularly suited to evaluate the cost-effectiveness of strategies in the treatment of chronic disease. For example, Markov model is widely adopted in the evaluation of disease screening or treatments around the world [
25‐
27]. Therefore, we aimed to construct a Markov model to evaluate and compare the CE of full-dose, dose-adjusted regimens of sorafenib and TACE for advanced HCC, in order to provide useful information for patients and healthcare providers in the current era of limited health resources.
Discussion
Our study shows that dose-adjusted sorafenib is cost-effective compared to full-dose sorafenib or TACE for advanced HCC in both China and the USA based on the base case analysis, sensitivity analysis and WTP analysis. To the best of our knowledge, this is the first study to compare the CE of sorafenib with TACE. Previous CE studies have confined the comparison of sorafenib to BSC [
48,
50,
55,
58]. However, since BSC is simply a form of palliative treatment without offering improvement in health outcomes, comparing an active treatment like TACE to sorafenib is a better strategy when investigating the current most appropriate therapy for advanced HCC. Moreover, it is also the first study to compare sorafenib in different doses (full-dose and dose-adjusted) with TACE in the treatment of advanced HCC.
Regarding the CE of full-dose sorafenib itself, a QALY of 0.435 gained at a cost of $16,703 in China in our study was similar to that in the previous Chinese study (QALY, 0.45; cost, $19,149) [
48], but was not consistent with that in the Italian study (QALY, 0.16; cost, $14,841;) [
55]. The poorer efficacy of full-dose sorafenib for Italian patients represented by the much shorter QALY could explain the inconsistency. Meanwhile, for the dose-adjusted sorafenib group, its CE in China in our study were better than that in the Italian study [
55], which might be explained by the higher expenditures (Italy: $16,625 vs. China: 10,488) but lower QALY in Italy (Italy: 0.440 vs. China: 0.482).
In terms of the relative CE between therapies, the Italian study and the Chinese study both suggested that full-dose sorafenib was not a cost-effective treatment compared to BSC [
48,
55]. However, the Italian study considered sorafenib as cost-effective under the dose-adjusted condition. Similarly in our study, dose-adjusted sorafenib was cost-effective whereas full-dose sorafenib and TACE were not. It might be due to the similar or higher survival benefit provided by dose-adjusted sorafenib at a lower cost. Sorafenib therapy within its licensed dose is effective but costly, thus, it is of great importance to find a way to improve its CE. Half-dose sorafenib with the comparable or even better efficacy and substantial expenditure reduction is clearly a good option. However, the issue of optimal sorafenib dose remained to be further investigated in the future studies.
Concerning the role of TACE in advanced HCC, our study revealed that TACE produced slightly shorter life expectancy and QALY to sorafenib. Although TACE could eradicate viable tumors to some extent, the promotion of proliferation and metastasis of remaining tumors by over-expressed angiogenic and inflammatory factors after TACE restricted the prolongation of the overall survival. Moreover, when taking the cost into consideration, TACE was not the cost-effective treatment under the current WTP set in the USA as shown in the acceptability curve because one session of this procedure ($25,961) costs more than 5.5 times of the monthly cost of full-dose sorafenib ($4592). Interestingly, in China, TACE was cost-effective compared to full-dose sorafenib if the WTP was set below $10,473. The underlying reason behind the difference between China and the USA might be the different medical charging system between these two countries representing by the relative cost of TACE and sorafenib. Unlike the high expense of TACE in the USA [
49], the price of TACE including the costs of procedure, hospitalization, specialist visits and various examinations during hospital stay ($3170) in China is even lower than the monthly cost of dose-adjusted sorafenib ($4060). However, under the accepted threshold of WTP in both countries, full-dose usage of sorafenib is still the cost-effective strategy compared with TACE for most patients. Only for some poor patients with the willingness to pay less $10,473 in China, TACE could be the cost-effective treatment.
Data constraints inevitably lead to several limitations within our model. First, there were limited studies that specifically reported TACE and sorafenib outcomes for compensated cirrhotic patients with or without progression. Such a limitation was unfortunately unavoidable in our type of analysis. This limitation obliged us to use the best available data in the literature review. The resulting uncertainties were not significant, which was confirmed by the unchanged results in the probabilistic sensitivity analysis. Second, the utility estimates for compensated cirrhosis with or without progression were extracted from NICE for the treatment of advanced renal carcinoma with sorafenib or BSC as the two previous relevant articles did. This adoption may not be the most rational because utilities might vary between populations with two different diseases. The third limitation concerns the paucity of data on cost estimates for each health state in different countries. It is well known that costs may vary with different regions and treatment plans. Thus, it restricted us to make comparisons among more countries. Despite these, we have performed the analyses on two different cost scenarios including the USA and China, representing the Western and Eastern countries to some extent, and have detected some differences between these two countries. Moreover, we have considered the uncertainties of costs in sensitivity analyses by inputting a wide range of cost values (50%–200% of base-case value). In a sense, our model could be applied in those countries with efficacy and cost data falling within the ranges we have set. Fourth, we assumed that the effectiveness estimations such as LYG and QALY were the same between China and the USA, however, there might be differences in these efficacy results between these two countries. Thus, more specific data for individual countries are required to obtain more accurate results for different countries respectively. Fifth, most of the included studies were retrospective and the analyses based on these retrospective data would inevitably result in selection bias. Sixth, the lack of information on vascular invasion, extrahepatic spread and/or symtoms in TACE versus sorafenib patients was present in our study, which required more detailed characteristics of patients to compare these two treatments in future studies.
Conclusions
In conclusion, dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. When confining the comparisons between them, full-dose sorafenib was cost-effective compared with TACE for advanced HCC patients, under the accepted thresholds of WTP. Our findings will require further high–quality studies to validate.