Budget Impact Analysis for Proton Beam Therapy for pediatric population in Poland

Objective: Proton beam therapy (PBT) is increasingly used as an alternative radiotherapy for cancer. It is often used in cases where the position of the tumor in relation to critical structures, sensitive to radiation, significantly limits or prevents the use of classical radiotherapy. Use of the PBT minimizes long-term negative effects of radiotherapy, which is especially important in the treatment of children. The aim of the analysis was to assess the budget impact of using PBT from perspective of public payer in Poland. Methods: The analysis was carried out in a 3-year time horizon. Cost data reflect the estimated costs incurred by the public payer (NHF) in providing health benefits. The estimation of the financial consequences was based on the Polish current tariffs for the included health benefits. Sources of data, including patient population, were opinions of clinical experts, scientific evidence, NHF. Results: The analysis was carried out in the base, minimum and maximum scenario. In the base case 102 patients in 9 cancer indications were included. Total incremental costs were: €1.560 million, €1.769 million and €2.045 million in each year of analysis. There were no differences in the model parameters related to the costs of health services. Costs in the minimum scenario were approximately 30% lower and in the maximum scenario 10% higher than in the base case within 3 years. Conclusion: PBT generated additional cost for treatment of pediatric populations with 9 oncological indications for public payer in Poland. Our findings can be used by decision makers in Poland.


INTRODUCTION
Proton beam therapy (PBT) is a relatively new technique of radiation therapy that uses high-energy proton beams to irradiate neoplastic lesions. It is particularly beneficial in cases where the position of the tumor in relation to critical structures, sensitive to radiation, significantly limits or prevents the use of classical radiotherapy. [1] PBT reduces normal tissue toxicity due to better local control of the radiation dose over the target areas. Despite its high costs many studies show that PBT is cost effective in terms of treatment complications and indirect costs. [2] Currently, PBT is used in a very small number of cancers. Most countries use PBT in the pediatric population, where the incidence of radiation-related complications is relatively higher due to the longer life expectancy and the higher sensitivity of healthy tissues to radiation. In the adult population, PBT is used for large-scale cancers such as lung or breast cancer. However, the list of indications di ers from country to country. In European countries, coverage decisions are most o en taken at the national level. [3] By the end of 2019, approximately 222,425 people worldwide were being treated with PBT. Currently, hospital proton irradiation centers operate in 19 countries, including all G7 countries with publicly funded healthcare systems, except Canada. [4] By the end of 2021, 102 PBT centers were established around the world, including 29 centers in the EU. [5] According to estimates the importance of PBT will increase due to growing number of cancer cases and the necessity to increase the radiotherapy safety pro le. Currently tumors rank second on the list of the most frequent deaths in Poland and Europe. According to forecasts, by 2025 an increase in the incidence of cancer in Poland is expected from 310,000 up to 350,000. [2] e aim of the study was to evaluate a budget impact of PBT from the public payer perspective in Poland. [5] METHODS e budget impact analysis (BIA) concerns the nancial consequences of extending the use of PBT from the perspective of the Polish public payer (National Health Fund, NHF) in 9 oncological indications in pediatric population (table 1). e analysis was performed according to the recommendations for conducting BIA. [6,7,8] e nancial consequences of introducing the proposed changes were presented as an incremental cost expressed as the di erence in costs between the 'new' and 'existing' scenario. e 'existing' scenario presents the estimated costs of the NHF for services in the eld of intensity-modulated radiation therapy (IMRT) and stereotactic teleradiotherapy (RT) in the above-mentioned indications. Under this scenario PBT is not covered by the NHF. e 'new' scenario presents the estimated costs of treatment with PBT as the basic RT option. Since not all patients eligible for PBT will undergo it, some of them will receive other forms of RT, i.e. IMRT or stereotactic RT. It is caused by: personal preferences of patients or their parents/guardians regarding the optimal form of radiotherapy, or geographic limitations related to access to PBT (only one PBT center in Poland).
Due to the limitations of our model and possible variability of some key input parameters the sensitivity analysis was also performed with the minimum and maximum scenarios.
e analysis was carried out in a 3-year time horizon. Cost data re ect the estimated costs incurred by the public payer in providing health bene ts. e estimation of the nancial consequences was based on the Polish current tari s for the included health bene ts. No ethics committee review was required since this research did not include human subject data. Individual patient level information was not used, and the research relies purely on published or simulated data.

Data sources
Sources of data included into analysis were: opinions of clinical experts, scienti c evidence, NHF data on the valuation of accounting healthcare products.
Population e patient population for each indication was estimated based on available epidemiological data and opinions of clinical experts (questionnaire and personal communication). e target population in both scenarios is equal due to: the same eligibility criteria for particular types of radiotherapy, and no patients meeting eligibility criteria only if the indications for PBT were extended. e analysis of the impact on the payer's budget also assumes 10% annual increase in the target population compared to the previous year (base case). In the minimum and maximum scenario annual increase of population were 5 and 20% respectively. Estimations of the volume of the target population in the each year were presented in table 1.

Costs parameters
The BIA includes the costs related to the irradiation treatment itself, its planning and related hospitalization as well as treatment of adverse events. Table 2 presents detailed values concerning evaluation of health services related to radiotherapy in Poland by the NHF. In order to correctly estimate the consequences of introducing the proposed changes, the analysis was based on variables determined on the basis of the opinions of clinical experts and scientific evidence. Key assumptions were presented in table 3. One of the important assumption was that in case of % of patients who received PBT One of the key assumptions was the percentage of patients receiving PBT. In base case we assumed that 100% of children would receive PBT due to the speci city of the target population and the particular signi cant of clinical e cacy.

SENSITIVITY ANALYSIS
One-way sensitivity analysis was performed for all model inputs. Sensitivity analysis was presented as a minimum and maximum scenario.

Results of the base case
The budget impact results from the perspective of the Polish public payer in three years horizon were presented in table 4. We assumed that the entire pediatric population will be treated with the PBT in the base case. In the base case the total expenditures on treatment of all of the analyzed indications with the PBT were estimated to be €5.374m. over 3 years. What's important most costly component is irradiation therapy (cost of PBT is about 2.6 times higher than IMRT -this include only cost of irradiation without cost of planning or hospitalization). Parameters related to the necessity of repeated radiotherapy Patients that undergo repeated PBT (%) 5 10 10 Patients that undergo repeated IMRT/ stereotactic RT (%) 5 10 10

Results of the sensitivity analysis
Due to the limitations of our model and assumptions, a sensitivity analysis was performed in two scenarios: minimum and maximum.. There was no difference in the model parameters related to the costs of the health benefits. Result of the sensitivity analysis were presented in the table 5 as an incremental cost between scenarios.
Results of the analysis suggest that the total cost in the minimum scenario is about 30% lower than total cost in base case. Comparing base case with maximum scenario we observed approximately 10% higher total cost over 3 years.

DISCUSSION
This study is the first economic analysis in Poland to show the real impact of the PBT for the treatment of pediatric patients with specific cancers. The base-case model of the current analysis revealed that the PBT would generate the additional cost each year for public payer in Polish settings. Furthermore annual additional costs for NHF (€1.5 million up to €2.0 million) were related to only 90-118 pediatric patients with nine cancer indications eligible to the treatment with the PBT. e main cost component was associated with the expenditure for indication VII and VIII -respectively: pediatric cancers where the optimal photon radiotherapy plan does not safely protect critical organs (various types of cancer) and Hodgkin and non-Hodgkin lymphoma that requires mediastinal irradiation.
According to the available data the average costs for treatment per patient (together for the adult and pediatric populations) for PBT were estimated around: €148,452 (Canada) €117,527 (United Kingdom) and €132,548-€185,567 (Australia).
[10] e average costs are much higher than estimated cost in Poland. e above di erences could be related to the treatment of other population (indications, numbers of patients) but also with other values of direct costs a ecting the value of the total cost.
Additionally PBT is still growing technology around the world but with increasing role in the treatment of some cancer indications especially in pediatric populations. PBT provides the opportunity to deliver a therapeutic dose of radiation directly to the tumor with simultaneous protection of normal tissue, including critical structures such as: heart, brain. us it is recommended in certain cancer indications. Our BIA has both limitations and strengths. One of the limitations was the lack of data. Our model was strongly associated with clinical experts assumptions and lack of high quality clinical data. The BIA did not take into account possible differences in therapy (including: irradiation time, number of cycles, radiation dose received) between the individual indications included in the analysis. Another limitation of our analysis was associated with a small sample size in some indications. Above limitations can affect the uncertainty of cost estimates. Due to adopted short horizon of the analysis (3 years), we did not take into account adverse events that appeared at least 3 years after radiotherapy. The above approach was also adopted due to the limited clinical data from relatively low-quality studies with usually short follow-up periods. The cost of treating adverse events lower than grade 3 was also not taken into account. It should also be noted that the analysis does not take into account the maximum capacity of the Polish PBT center.
In the longer term, it is possible to estimate not only the costs of influencing the payer's budget resulting from the therapy itself, but also the costs related to depreciation. Additionally we can estimate costs from the patient's perspective e.g. travel costs, child's and guardian's accommodation; and from a social perspective e.g. indirect costs defined as costs of lost productivity of patients and their informal carers. The above described approach would make it possible to comprehensively estimate the total costs associated with introduction of PBT in pediatric population in Poland.
High cost of BIA for PBT in Poland could suggest that this technology is not cost saving for public payer but other analyses have revealed that the 5-year budget impact for four-room PBT center in Canada was about €92 million (cost per patient €35,790). Increasing the number the PBT rooms by one generated a lower budget impact of €11.3 million within the 5-year time horizon. If we assume building PBT centers would substitute for new photon therapy centers, then the 5-year budget impact could be further reduced to approximately €9.7 million (one room) or €70 million (four rooms). [4] Nevertheless above could suggested that PBT is potentially cost saving not only for a patient based on the clinical data but also for a payers based on the reduction of total cost in case of building PBT centers with a wide range of health services. Additionally, the PBT cost per patient is closely related to: number of patients treated, included cost (direct, indirect), tariffs.

CONCLUSIONS
PBT generated additional costs for treatment of pediatric populations with 9 oncological indications for public payer in Poland in 3-year time horizon. Our findings can be used by decision makers in Poland. High incremental costs of PBT are associated mostly with the small potential number of patient eligible for therapy with PBT.

HIGHLIGHTS
1. First comprehensive BIA of the PBT in the Polish setting. 2. Total expenditures on treatment with the PBT were estimated to be €5.374 million within 3 years. 3. Irradiation therapy occurred the most important cost driver.

AUTHORS' CONTRIBUTIONS:
Paweł Moćko, PhD and Radosław Rudź, PhD -study design and provide all calculations; all authors -assisted in writing and editing of manuscript, data check-up, critical revision and final approval.