DOI: https://doi.org/10.21203/rs.3.rs-2209279/v1
The results of the KHBO1401-MITSUBA trial suggested the effectiveness of triplet therapy using gemcitabine, cisplatin, and S-1; however, the cost-effectiveness of this treatment regimen remains unclear.
We conducted a cost-utility analysis comparing triplet therapy using gemcitabine, cisplatin, and S-1 and doublet therapy using gemcitabine and cisplatin for advanced biliary tract cancer from the perspective of a Japanese healthcare payer to investigate the economic sustainability of healthcare interventions.
Based on the results of the KHBO1401-MITSUBA clinical trial, a partitioned survival model set over a 10-year time horizon was developed. Cost and utility data were sourced from earlier studies. Health outcomes were measured as quality-adjusted life-years. Direct medical costs included drug costs and medical fees. The uncertainty and robustness of the model were evaluated using one-way and probabilistic sensitivity analyses. The willingness-to-pay threshold was set at 7.5 million Japanese yen.
Base case analysis revealed that the incremental cost-effectiveness ratio for triplet therapy was 5,257,388 Japanese yen (47,881 United States dollars) per quality-adjusted life-year. The one-way sensitivity analysis indicated that parameters influencing the overall survival curve for doublet and triplet therapy affected the incremental cost-effectiveness ratio. Probabilistic sensitivity analysis suggested that triplet therapy had a 72.5 % chance of being cost-effective at a willingness-to-pay threshold of 7.5 million yen per quality-adjusted life-year.
Triplet therapy using gemcitabine, cisplatin, and S-1 is cost-effective in the primary treatment of biliary tract cancer in the Japanese healthcare system.
Biliary tract cancers (BTCs) are classified as intrahepatic bile duct cancer, extrahepatic bile duct cancer (or perihepatic and distal bile duct cancer), gallbladder cancer, and ampullary cancer. Uncommon tumours of the biliary tract account for > 1% of all malignancies worldwide [1]. BTC is common in Asian populations and is ranked as the sixth leading cause of cancer-related deaths in Japan [2]. Localised tumours are surgically treated; however, 65% of patients have unresectable tumours [3]. Disease recurrence has been reported in some patients who underwent potentially curative surgery. The recurrence rate after surgical resection is not low, and disease recurrence presents as either localised tumours or distant metastasis [4]. Owing to the lack of early diagnosis, the number of patients eligible for curative surgery and adjuvant therapy is low [5]. BTCs have a poor prognosis 5-year overall survival of less than 10% for all patients, therefore the patients have an urgent unmet clinical need [6, 7].
Chemotherapy is the standard systemic treatment option for advanced BTC. Fluoropyrimidine, platinum, and gemcitabine are effective therapeutic options for advanced BTC. The ABC-02 trial demonstrated the efficacy of cisplatin and gemcitabine as first-line chemotherapeutic agents for individuals with locally advanced or metastatic cholangiocarcinoma or gallbladder cancer [8]. The phase II BT22 trial yielded results comparable to those of the ABC-02 trial [9]. Gemcitabine plus S-1 (tegafur, gimeracil, and oteracil potassium) (GS) was observed to be non-inferior to gemcitabine plus cisplatin (GC) in the JCOG1113 trial. GS exhibited minimal toxicity except for the gastrointestinal toxicity caused by S-1 [10]. The KHBO1401-MITSUBA trial, a recent randomised phase III trial, assessed the superiority of GEM + cisplatin (CDDP) + S-1 (GCS) over GC. The results of the trial revealed that the median OS in the GCS arm (13.5 months) was significantly higher than in the GC arm (12.6 months). The hazard ratio (HR) in the GCS arm was 0.79, and although the combination of the three drugs increased S-1-specific diarrhoea and mucositis, the toxicity was not too extreme [11]. Based on these results [12], GCS therapy was approved as a novel first-line chemotherapy for BTC. Although the available treatment options for BTC have improved survival outcomes, concerns over their economic impact persist. The cost-effectiveness of GCS therapy as first-line chemotherapy for BTC remains unclear.
We conducted an economic evaluation of chemotherapeutic interventions to ensure maximum utilisation of limited healthcare resources. The prevalence of BTC is higher in Thailand, Japan, China, and South Korea as compared with the Western countries, indicating considerable geographic differences in the occurrence of BTC [13]. Treatment costs for diseases significantly burden the health insurance systems of a country. Thus, based on the results of the KHBO1401-MITSUBA trial [11], we compared the cost-effectiveness of GCS therapy and GC therapy for BTC from the perspective of a Japanese healthcare payer.
This study did not include the use of human participants or animals.
Patients with unresectable or recurrent biliary tract cancer with histologically confirmed adenocarcinoma or adenosquamous carcinoma were included in the KHBO1401-MITSUBA trial [11]. Patients who were at least 20 years old, had never received chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2 and had functioning major organs were eligible for the study.
Patients in the GCS group received 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin infusions on day 1. S-1 was orally administered twice a day for seven consecutive days, and this treatment regimen was repeated every two weeks. Based on the body surface area (BSA), the following doses of S-1 were administered: BSA < 1.25 m2, 80 mg/day; 1.25 m2 ≤ BSA < 1.5 m2, 100 mg/day; and BSA ≥ 1.5 m2, 120 mg/day. Patients in the GC group received 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin infusions on days 1 and 8 and every three weeks. All patients were treated until disease progression, the occurrence of intolerable adverse effects and toxicity or the trial was terminated if any patient withdrew consent.
Using data from the KHBO1401-MITSUBA trial [11], a decision-analytic model comparing the costs and benefits of GCS and GC therapies for advanced BTC was developed. From the perspective of a Japanese healthcare payer, we assessed only the direct medical costs. Each cycle of the model was set for four weeks. The following three health states: 1) progression-free survival (PFS) with responsive/stable disease, 2) post-progression survival (PPS), and 3) death, were built into a partitioned survival model. In the early stages of the model, based on the survival curve analysis, patients were in the PFS state, and patients in each cycle remained in the PFS state or moved to the PPS state. Based on the survival curve analysis, each cycle begins in the PFS state; subsequently, the model moves each cycle to the PPS state and finally to the death state.
As the disease progressed, patients moved into the PPS state for subsequent therapy and optimum supportive care. The analysis was conducted over a time horizon of 10 years as it provided sufficient time for the percentage of deaths to exceed 99.99%. According to the guidelines of the Center for Outcomes Research and Economic Evaluation for Health [14], the cost and quality-adjusted life year (QALY) estimations were discounted at a rate of 2% annually. The incremental cost-effectiveness ratio (ICER) of GCS therapy was calculated by dividing the incremental cost by the incremental effectiveness. According to the Japanese drug pricing system for anticancer drugs, we set the willingness-to-pay (WTP) threshold at 7.5 million Japanese yen (JPY). TreeAge Pro 2022 R2.0 from TreeAge Software, LLC (Williamstown, MA, USA) was used to set up the model and examine the data.
This study assessed direct medical costs, such as drug costs, follow-up testing costs, costs for management of treatment-related significant adverse events, and terminal care costs, from the perspective of Japanese healthcare payers (Table 1). Costs for optimum supportive care were excluded in this study since this data was not accurately recorded for BTC patients and was considered to be comparable for patients across different groups. The cost in JPY was converted to cost in United States dollars (USD) using the average 2021 exchange rate of 109.8 JPY per USD [15]. The Japanese Society of Nephrology states that the average height and weight are 170 cm and 63 kg [16]. Therefore, patients in the simulated population were assumed to have a BSA of 1.73 m2. Drug prices were sourced from the Japanese social insurance reimbursement schedule and drug tariff [17, 18]. The hospital treatment cost was estimated based on the diagnosis procedure combination/per-diem payment system [19, 20]. The treatment cost for febrile neutropenia was sourced from an earlier study [21]. End-of-life care costs were estimated based on the Cost of End-of-Life Care Survey conducted in Japan [22]. Cost for grade 3 and higher treatment-related adverse events that occurred at a rate of 5% was included in the study estimates. This cost was determined by multiplying the adverse event incidence by the unit treatment cost. S-1 monotherapy is the most popular treatment option post-GCS or GC therapies. Thus, the cost of therapy included S-1 monotherapy and terminal care costs [10, 11, 23]. The cost and loss of utility values for treatment-related adverse events of grade ≥ 3 that occurred at a rate of ≥ 5% in the data source were estimated [24].
| Parameter | Unit cost, JPY (USD) | Range(%) | Distribution | Reference | |
|---|---|---|---|---|---|
| Outpatient chemotherapy (monthly) | |||||
| CT scan diagnostic fee (once in 3 months) | 3,330 | (30.3) | 70–130 | Gamma | 17 |
| Contrast medium (once in 3 months) | 1,670 | (15.2) | 70–130 | Gamma | 17 |
| Peripheral blood tests (> 10) | 1,060 | (9.63) | 70–130 | Gamma | 17 |
| Plasma protein immunological test | 160 | (1.46) | 70–130 | Gamma | 17 |
| Blood drawing fee | 740 | (6.74) | 70–130 | Gamma | 17 |
| Peripheral blood tests diagnostic fee | 1,250 | (11.4) | 70–130 | Gamma | 17 |
| Biochemical tests fee | 1,440 | (13.1) | 70–130 | Gamma | 17 |
| Immunological test fee | 1,440 | (13.1) | 70–130 | Gamma | 17 |
| Tumour maker tests fee | 4,000 | (36.4) | 70–130 | Gamma | 17 |
| Prescription fee | 420 | (3.83) | 70–130 | Gamma | 17 |
| Dispensing fee | 110 | (1.00) | 70–130 | Gamma | 17 |
| Dispensing Technology Basic fee | 140 | (1.28) | 70–130 | Gamma | 17 |
| Urinary examination | 260 | (2.37) | 70–130 | Gamma | 17 |
| Outpatient chemotherapy fee (Once per administration) | 7,000 | (63.8) | 70–130 | Gamma | 17 |
| Drug cost | |||||
| Paronosetron | 10,209 | (93.0) | 70–130 | Gamma | 18 |
| Aprepitant set | 7,466 | (68.0) | 70–130 | Gamma | 18 |
| Dexamethason 1.65 mg IV | 95 | (0.865) | 70–130 | Gamma | 18 |
| Dexamethason 4 mg PO | 29 | (0.261) | 70–130 | Gamma | 18 |
| Saline solution 100 mL | 132 | (1.20) | 70–130 | Gamma | 18 |
| Acetic acid Ringer's solution 500 mL | 189 | (1.72) | 70–130 | Gamma | 18 |
| TS-1 25 mg tablet | 404 | (3.68) | 70–130 | Gamma | 18 |
| TS-1 25 mg tablet | 492 | (4.48) | 70–130 | Gamma | 18 |
| TS-1 20 mg tablet | 404 | (3.68) | 70–130 | Gamma | 18 |
| Gemcitabine 1000 mg | 5,891 | (53.7) | 70–130 | Gamma | 18 |
| Gemcitabine 200 mg | 1,295 | (11.8) | 70–130 | Gamma | 18 |
| Cisplatine 50 mg | 3,351 | (30.5) | 70–130 | Gamma | 18 |
| Second-line S1 | 492 | (4.48) | 70–130 | Gamma | 18 |
| Adverse effect treatment cost | |||||
| Biliary tract infection | 147,320 | (1,342) | 70–130 | Gamma | 20 |
| Febrile neutropenia | 317,208 | (2,889) | 70–130 | Gamma | 21 |
| End-of-life care cost | 1,919,414 | (17,481) | 95% CI | Uniform | 22 |
| Exchange rate in 2021, 1 USD = 109.8 JPY. JPY, Japanese yen; USD, United States dollar. | |||||
WebPlotDigitizer software (version 4.6, https://automeris.io/WebPlotDigitizer/) was used to analyse the Kaplan–Meier curve of the KHBO1401-MITSUBA trial and then reconstruct the individual patient data using the method proposed by Guyot et al. [25]. Akaike information criterion, Bayesian information criterion, and visual evaluation were used to determine the optimum distribution. For both therapies, the OS curves were extrapolated using log-logistic distributions, and the PFS curves were extrapolated using log-normal distributions (Fig. 1). Distribution parameters are presented in Table 2. The primary health outcomes were assessed based on QALYs, which are often referred to as utility (the utility of health status ranges from 0 [death] to 1 [perfect health]). Owing to the rarity of BTC, no independent health state utility values have been reported. We collected health state utility estimates from an earlier study [26]. The utility was set at 0.550 for PFS, 0.541 for PPS, and 0 for mortality (Table 2). Since the clinical study from which the data was sourced did not include subgroup analysis, the entire population was evaluated.
| Parameter | Base case | Range | Distribution | Reference |
|---|---|---|---|---|
| Curve parameter | ||||
| Meanlog of GC overall survival | 2.46 | 95% CI | Multi normal | 11 |
| Sdlog of GC overall survival | 0.86 | 95% CI | Multi normal | 11 |
| Meanlog of GC progression-free survival | 1.72 | 95% CI | Multi normal | 11 |
| Sdlog of GC progression-free survival | 0.84 | 95% CI | Multi normal | 11 |
| Scale of GCS overall survival | 14.6 | 95% CI | Multi normal | 11 |
| Shape of GCS overall survival | 1.84 | 95% CI | Multi normal | 11 |
| Scale of GCS progression-free survival | 7.34 | 95% CI | Multi normal | 11 |
| Shape of GCS progression-free survival | 1.92 | 95% CI | Multi normal | 11 |
| Utility value | ||||
| Progression-free survival | 0.550 | 70–130% | Beta | 26 |
| Post-progression survival | 0.541 | 70–130% | Beta | 26 |
| Disutility value | ||||
| Anaemia | -0.085 | 70–130% | Beta | 24 |
| Febrile neutropenia | -0.470 | 70–130% | Beta | 24 |
| Neutropenia | -0.06 | 70–130% | Beta | 24 |
| Biliary tract infection | -0.195 | 70–130% | Beta | 24 |
| Fatigue | -0.08 | 70–130% | Beta | 24 |
| Thrombopenia | -0.085 | 70–130% | Beta | 24 |
| Relative dose intensity | ||||
| Cisplatin in GC therapy | 0.78 | 70–130% | Beta | 11 |
| Gemcitabine in GC therapy | 0.75 | 70–130% | Beta | 11 |
| Cisplatin in GCS therapy | 0.86 | 70–130% | Beta | 11 |
| Gemcitabine in GCS therapy | 0.83 | 70–130% | Beta | 11 |
| Adverse effect rate | ||||
| Anaemia in GC | 0.15 | 70–130% | Beta | 11 |
| Anaemia in GCS | 0.08 | 70–130% | Beta | 11 |
| Biliary tract infection in GC | 0.16 | 70–130% | Beta | 11 |
| Biliary tract infection in GCS | 0.17 | 70–130% | Beta | 11 |
| Fatigue in GC | 0.07 | 70–130% | Beta | 11 |
| Fatigue in GCS | 0.05 | 70–130% | Beta | 11 |
| Febrile neutropenia in GC | 0.04 | 70–130% | Beta | 11 |
| Febrile neutropenia in GCS | 0.05 | 70–130% | Beta | 11 |
| Neutropenia in GC | 0.48 | 70–130% | Beta | 11 |
| Neutropenia in GCS | 0.39 | 70–130% | Beta | 11 |
| Thrombopenia in GC | 0.21 | 70–130% | Beta | 11 |
| Thrombopenia in GCS | 0.09 | 70–130% | Beta | 11 |
| Subsequent therapy rate after first-line | ||||
| GC therapy | 0.84 | 70–130% | Beta | 11 |
| GCS therapy | 0.64 | 70–130% | Beta | 11 |
| Discount rate | 0.02 | 0–0.05 | 14 | |
| GC, gemcitabine, cisplatin; GCS, gemcitabine, cisplatin, and S-1. | ||||
Patient-based literature was collected based on the availability of efficacy data and therapy and adverse event treatment costs. Patient-based estimates were made to cater to the universal Japanese health insurance system; however, uncertainties persist. Model variability and uncertainty were evaluated using one-way and probabilistic sensitivity analyses. A one-way sensitivity analysis was conducted to investigate the effect of a confidence interval or 20% change in each parameter used in the model. Probabilistic sensitivity analysis was conducted based on 10,000 Monte Carlo simulations using plausible distributions for each variable and varying them simultaneously. Tables 1 and 2 list the ranges and distributions of the parameters assessed in the sensitivity analysis.
Table 3 indicates that the QALYs for GCS and GC therapies were 0.643 and 0.797, respectively. The total GC and GCS therapy costs were 2,958,171 JPY (26,941 USD) and 3,767,169 JPY (34,309 USD), respectively. The ICER for GCS therapy was calculated to be 5,257,388 JPY/QALY (USD 47,881/QALY).
| Strategy | Cost | Incremental Cost | QALYs | Incremental QALYs | ICER, JPY/QALY ( USD/QALY) |
|---|---|---|---|---|---|
| GCS | 3,767,169 | 808,999 | 0.797 | 0.154 | 5,257,388 |
| GC | 2,958,171 | 0.643 | (47,881) | ||
| Exchange rate in 2021, 1 USD = 109.8 JPY. JPY, Japanese yen; USD, United States dollar; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year. | |||||
The tornado plot depicts the results of a univariate sensitivity analysis to identify the top ten parameters from the model that affected ICER (Fig. 2). The GCS OS scale parameter significantly influenced ICER, leading to variations in the ICER value from 3,140,291 JPY/QALY to 18,313,337 JPY/QALY. The GC OS mean log parameter led to a increase in ICER beyond the WTP threshold, whereas other parameters did facilitate such an increase.
Figure 3 displays the cost-effectiveness plane with a sloping willingness-to-pay threshold line. The probability that GCS therapy would be cost-effective was 72.5%.
Based on the results of the KHBO1401-MITSUBA trial, GCS therapy has become the standard primary chemotherapy for advanced BTC. Our study is the first to examine the cost-effectiveness of GCS therapy for advanced BTC, and the results from this study validated the cost-effectiveness of GCS therapy. According to the one-way sensitivity analysis, changes in utility and cost did not increase the ICER value beyond the WTP threshold. All parameters affecting the OS and PFS curves influenced the ICER. Two of these parameters led to an increase in the ICER beyond the WTP threshold (variation in the OS scale parameter for GCS and variation in the OS mean log parameter for GC). In contrast, other parameters caused variations in the ICER within the WTP threshold. Probabilistic sensitivity analysis, which included analysis of these curve variations, revealed a robust and cost-effective trend for GCS therapy. Therefore, we believe that GCS therapy is efficacious for BTC patients and ensures efficient use of health insurance resources.
Despite its rarity, advanced BTC is characterised by a high rate of recurrence and metastasis. The information on the cost-effectiveness of the available first-line treatment options for advanced BTC is currently limited. In China, chemotherapy using capecitabine plus oxaliplatin (XELOX) is more cost-effective than chemotherapy using gemcitabine and oxaliplatin [27]. As the GCS and XELOX regimens were established independently, no clinical trials have been conducted to compare the efficiency of these regimens, further underscoring the need to investigate these differences. The cost-effectiveness of GC therapy was investigated in two earlier studies. Roth et al. reported the cost-effectiveness of gemcitabine and cisplatin combination therapy (ICER of 59,480 USD/QALY) in comparison to cisplatin monotherapy [28]. Tsukiyama et al. reported that the ICER of gemcitabine and cisplatin combination therapy in Japan was 14 million JPY/QALY compared with that using gemcitabine monotherapy [29]. Our study investigated the cost-effectiveness of GCS therapy. Collectively, the GCS regimen was a cost-effective first-line chemotherapeutic option for advanced BTC in the Japanese healthcare system.
Our study has several limitations. First, the utility estimates were based on data from a clinical trial that studied the efficacy of gemcitabine/pazopanib therapy in Greek patients and were not based on data from Japanese BTC patients, which may have influenced the results. One-way sensitivity analysis revealed that the ICER did increase beyond the WTP threshold, indicating the minimal influence of the ICER. Future advances in QOL research can be used to upgrade the model developed in this study. Second, several assumptions were made to minimise the impact of parameter uncertainty in the model, including the assumption that S-1 is the treatment of choice for a significant percentage of patients post-disease progression, which may not be accurate for all patients. Currently, the recommended treatment options for advanced BTC after first-line chemotherapy are not standardised. In addition to S1 monotherapy, regimens combining gemcitabine, CDDP, and S-1 may be recommended for post-disease progression. Although the impact of the drug choice post-disease progression was considered in this study, one-way sensitivity analysis results indicated that the impact of the cost of follow-up treatment post-disease progression was insignificant. Third, palliative care costs were not included in this study because they would be equivalent in both groups. The impact of palliative care costs is likely to be insignificant, similar to the impact of the cost of follow-up treatment post-disease progression described earlier. Nevertheless, the model can be updated to include palliative care costs based on the availability of palliative care estimates for advanced BTC. Fourth, although the long-term OS of patients with advanced BTC was modelled based on parametric distribution, its uncertainty is an unavoidable limitation of this study. Although the uncertainty of curve extrapolation was considered in the probabilistic sensitivity analysis, it did not influence the results, indicating that the model was robust. Updates to the present model based on the inclusion of long-term patient survival data would provide more accurate estimates.
Triplet therapy using GCS is a cost-effective and efficacious first-line chemotherapeutic option for patients with advanced BTC in the Japanese healthcare system.
This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no: 22K17325).
The authors have no competing interests that are relevant to the content of this article to declare.
MK designed the study and prepared the initial draft of the manuscript. RM contributed to the analysis and interpretation of data and assisted in preparing the manuscript. Both authors contributed to data collection and critical review of the manuscript. Both authors approved the final version of the manuscript and agreed to be held accountable for all aspects of the study and ensure that questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved.
The datasets generated and analysed during the current study are the corresponding author upon reasonable request.
This study did not include the use of human participants or animals.