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Cost-effectiveness of proton radiotherapy versus photon radiotherapy for non-small cell lung cancer patients: Exploring the model-based approach

  • L. Aldenhoven
    Affiliations
    Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, the Netherlands
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  • B. Ramaekers
    Correspondence
    Corresponding author at: Department of Clinical Epidemiology & Health Technology Assessment, Maastricht UMC+, Oxfordlaan 10 , P. Debyelaan 25, Postbus 5800, 6202 AZ, Maastricht
    Affiliations
    Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, the Netherlands
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  • J. Degens
    Affiliations
    Department of Respiratory Medicine, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, Maastricht, the Netherlands
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  • C. Oberije
    Affiliations
    The D-Lab: Decision Support for Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands
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  • J. van Loon
    Affiliations
    Department of Radiation Oncology (MAASTRO clinic), GROW School for Developmental Biology and Oncology, Maastricht University Medical Center, Maastricht, the Netherlands
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  • A.C. Dingemans
    Affiliations
    Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
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  • D. De Ruysscher
    Affiliations
    Department of Radiation Oncology (MAASTRO clinic), GROW School for Developmental Biology and Oncology, Maastricht University Medical Center, Maastricht, the Netherlands
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  • M. Joore
    Affiliations
    Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center, Maastricht, the Netherlands
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Open AccessPublished:November 11, 2022DOI:https://doi.org/10.1016/j.radonc.2022.11.006

      Highlights

      • Patient selection for whom PT is expected to be beneficial is crucial.
      • Normal tissue complication probability models are important for patient selection.
      • Clinical experience can increase throughput, improving cost-effectiveness of PT.

      Abstract

      Introduction

      Proton radiotherapy (PT) is a promising but more expensive strategy than photon radiotherapy (XRT) for the treatment of non-small cell lung cancer (NSCLC). PT is probably not cost-effective for all patients. Therefore, patients can be selected using normal tissue complication probability (NTCP) models with predefined criteria. This study aimed to explore the cost-effectiveness of three treatment strategies for patients with stage III NSCLC: 1. photon radiotherapy for all patients (XRTAll); 2. PT for all patients (PTAll); 3. PT for selected patients (PTIndividualized).

      Methods

      A decision-analytical model was constructed to estimate and compare costs and QALYs of all strategies. Three radiation-related toxicities were included: dyspnea, dysphagia and cardiotoxicity. Costs and QALY’s were incorporated for grade 2 and ≥3 toxicities separately. Incremental Cost-Effectiven Ratios (ICERs) were calculated and compared to a threshold value of €80,000. Additionally, scenario, sensitivity and value of information analyses were performed.

      Results

      PTAll yielded most QALYs, but was also most expensive. XRTAll was the least effective and least expensive strategy, and the most cost-effective strategy. For thresholds higher than €163,467 per QALY gained, PTIndividualized was cost-effective. When assuming equal minutes per fraction (15 minutes) for PT and XRT, PTIndividualized was considered the most cost-effective strategy (ICER: €76,299).

      Conclusion

      Currently, PT is not cost-effective for all patients, nor for patient selected on the current NTCP models used in the Dutch indication protocol. However, with improved clinical experience, personnel and treatment costs of PT can decrease over time, which potentially leads to PTIndividualized, with optimal patient selection, will becoming a cost-effective strategy.

      Keywords

      Introduction

      Proton radiotherapy (PT) is a potentially beneficial (e.g. reduced toxicities) but significantly more expensive treatment strategy for patients with stage I-III non-small cell lung cancer (NSCLC) compared to photon-based radiotherapy (XRT).

      Verma V, Shah C, Rwigema J-CM, Solberg T, Zhu X, Simone II CB. Cost-comparativeness of proton versus photon therapy. Chinese Clin Oncol Vol 5, No 4 (August 2016) Chinese Clin Oncol (prot Ther Ed Minesh Mehta, Arpit Chhabra). 2016. http://cco.amegroups.com/article/view/11097.

      Vyfhuis MAL, Onyeuku N, Diwanji T, et al. Advances in proton therapy in lung cancer. Ther Adv Respir Dis. 2018;12:1753466618783878-1753466618783878. doi:10.1177/1753466618783878

      Furthermore, treatment capacity is limited.
      • Boersma L.J.
      • van Vulpen M.
      • Rasch C.R.N.
      • Jlal.
      Protonencentra: ze zijn er, wat nu?.
      Considering the limited treatment capacity, costs and the substantial number of patients with NSCLC, great attention should be paid to optimal patient selection, since not all patients will benefit from PT. Hence, using PT instead of XRT without optimal patient selection would lead to unnecessary high costs, inefficient and unfair healthcare provision.
      Currently, XRT with or without chemotherapy is the main treatment modality for the management of stage III NSCLC.
      • Calikusu Z.
      • Altinok P.
      Treatment of locally advanced, unresectable or medically inoperable stage III non-small-cell lung cancer; the past, present and future of chemoradiotherapy.
      Considering the proximity of the target volume to the lungs, esophagus and the heart, XRT causes dyspnea in 10% of the lung cancer patients and grade ≥3 dysphagia in approximately 5% of the patients. A larger group of patients experience grade 2 symptoms of dyspnea (18%) and dysphagia (22%).
      • van Baardwijk A.
      • Wanders S.
      • Boersma L.
      • et al.
      Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non–Small-Cell Lung Cancer.
      Cardiotoxicity is a less investigated toxicity but has since recently been recognized as a matter of concern, also for lung cancer patients.
      • Verma V.
      • Simone 2nd, C.B.
      • Werner-Wasik M.
      Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer.
      • Dess R.T.
      • Sun Y.
      • Matuszak M.M.
      • et al.
      Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non–Small-Cell Lung Cancer.
      • Charpidou A.G.
      • Gkiozos I.
      • Tsimpoukis S.
      • et al.
      Therapy-induced Toxicity of the Lungs: An Overview.
      Cardiac events occurs in 33% of the patients within five years after diagnosis.

      Degens J, De Ruysscher D, Houben R, et al. Cardiac events in stage III non-small lung cancer treated in daily practice: Is it time for cardiovascular screening and follow-up?

      An advantage of PT is its favorable in-depth dose distribution, reducing treatment toxicity by minimizing the exposure of radiation to surrounding normal tissues relative to the target dose.
      • Langendijk J.A.
      • Lambin P.
      • De Ruysscher D.
      • Widder J.
      • Bos M.
      • Verheij M.
      Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach.
      A reduction of toxicities could limit the impact on health related quality of life and could pose decreased costs of toxicity management, which could potentially reduce the overall costs for PT.
      • Smith W.P.
      • Richard P.J.
      • Zeng J.
      • Apisarnthanarax S.
      • Rengan R.
      • Phillips M.H.
      Decision analytic modeling for the economic analysis of proton radiotherapy for non-small cell lung cancer.
      However, despite the clinical benefits, effects are not likely to outweigh the costs for the total lung cancer population receiving radiotherapy. Optimal patient selection is therefore of importance to use PT in a cost-effective way.
      • Verma V.
      • Mishra M.V.
      • Mehta M.P.
      A systematic review of the cost and cost-effectiveness studies of proton radiotherapy.
      At present, patient selection is based on normal tissue complication probability (NTCP) models which estimate the risk reduction in toxicity of healthy tissue by using PT compared to XRT (ΔNTCP).
      • Boersma L.J.
      • van Vulpen M.
      • Rasch C.R.N.
      • Jlal.
      Protonencentra: ze zijn er, wat nu?.
      Using predefined ΔNTCP criteria as described, for example, in the Dutch indication protocol, patients can be selected for PT.

      Zorginstituut Nederland. Landelijk Indicatieprotocol Protonentherapie - Longcarcinoom.; 2019. https://nvro.nl/images/documenten/rapporten/LIPP_longen_final_01122019.pdf.

      This “model-based” approach for patient selection as described by the Dutch Healthcare Institute uses fixed thresholds per grade of toxicity and can be incorporated in a decision-analytical model to explore the cost-effectiveness of PT for selected patients, compared to XRT.
      • Boersma L.J.
      • van Vulpen M.
      • Rasch C.R.N.
      • Jlal.
      Protonencentra: ze zijn er, wat nu?.
      The cost-effectiveness of PT versus XRT for patients with early stage NSCLC has been explored in 2010 using a decision-analytical model.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • De R.D.
      • et al.
      The cost-effectiveness of particle therapy in non-small cell lung cancer: Exploring decision uncertainty and areas for future research.
      However, no studies have been performed yet on cost-effectiveness of PT versus XRT for patients with stage III NSCLC using the “model-based” approach to select patients. Patients with Stage III NSCLC are currently being considered as potentially eligible patients for PT based on planning studies. Hence, a decision-analytical state-transition model was developed to investigate whether the additional effects of PT for all patients or PT for selected patients are worth the extra costs for patients with NSCLC stage III, compared to XRT. With this decision-analytical modeling technique, evidence of various sources for probabilities, costs and utilities can be synthesized in order to inform decisions and to reflect the posed decision uncertainty.
      • Briggs A.
      • Sculpher M.
      • Claxton K.
      Decision Modelling for Health Economic Evaluation.
      Therefore, the aim of the study was to explore the cost-effectiveness of the model-based approach for selecting patients with NSCLC for PT and XRT. Although Dutch indication protocols are used, PT capacity is limited globally, patient selection remains fundamental. Therefore, this study is likely to be relevant to other countries and can serve as a methodological approach to overcome unnecessary high costs, inefficient and unfair healthcare provision.
      Methods State-transition model approach and structure
      A probabilistic decision-analytical state-transition model was used to assess the cost-effectiveness of three treatment strategies for patients with NSCLC stage III: 1. XRT for all patients (XRTAll); 2. PT for all patients (PTAll); 3. PT for selected patients (PTIndividualized). In the third treatment strategy, eligibility of patients was based on the model-based approach. Currently, models for dyspnea16, pneumonitis17, dysphagia18 and mortality related to heart dose19 have been published. For this exploratory analysis, three out of the four models (pneumonitis, dysphagia and mortality related to heart dose) from the Dutch indication protocol were used.

      Zorginstituut Nederland. Landelijk Indicatieprotocol Protonentherapie - Longcarcinoom.; 2019. https://nvro.nl/images/documenten/rapporten/LIPP_longen_final_01122019.pdf.

      Accordingly, patients were eligible for PT according to ΔNTCP criteria and ineligible patients received XRT. Patient are eligible for PT with a clinical relevant ΔNTCP of ≥10% for grade 2 toxicities, ≥5% for grade 3 and ≥2% for grade 4-5 toxicities. In case of multiple complications, the sum of ΔNTCP should be minimal 15%, 7.5% and 3%, respectively.

      Zorginstituut Nederland. Landelijk Indicatieprotocol Protonentherapie - Longcarcinoom.; 2019. https://nvro.nl/images/documenten/rapporten/LIPP_longen_final_01122019.pdf.

      While the Dutch indication criteria are determined by the models to predict pneumonitis, dysphagia and mortality related to heart dose, in this exploratory analysis the model to predict pneumonitis was replaced by the model predicting dyspnea. The latter model incorporated baseline dyspnea, which is considered as an important for the face validity of the model.
      The state-transition model was constructed using cohort simulation and adopted a cycle length of three months. According to the Dutch health economic guidelines, a life-time time horizon, a societal perspective and a discount rate of 4.0% for costs and 1.5% for effects was applied.
      • IJzerman MJ, de Boer A, Brouwer WBF, van Busschbach JJ, Al. E.
      Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidszorg.
      The model was divided in two timeframes. Within six months, health states were based on whether patients experienced acute toxicities (dyspnea or dysphagia) with or without disease progression. From six-months onwards, patients could be free of toxicities, but could also develop cardiotoxicity, dyspnea or cardiotoxicity concurrently with dyspnea, all with or without disease progression (figure 1.) Disease progression was defined as loco-regional or distant dissemination of cancer cells. “Death” was the absorbing health state in the model, either due to cancer or due to other causes.Fig C1.Fig C2.Fig C1.Fig C2.
      Figure thumbnail gr1
      Figure 1Schematic representation of the Markov Model structure. The model is divided is an acute (<6 months) and late (≥ 6 months) time frame. Additionally, the model consists a progression free and progressed disease part. Grading of toxicities was not used in the schematic model structure in order to prevent unnecessary complexity. PF = Progression free; PD = Progressed disease.
      Figure thumbnail gr2
      Fig. C1Cumulative incidence curve Cardiac Events
      Figure thumbnail gr3
      Fig. C2Parametric model curve Cardiac Events
      Toxicity was graded according to the Common Terminology Criteria of Adverse Events (CTCAE) 3.0.

      Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0. August 9. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf#search=%22ctcae%22. Published 2006. Accessed May 1, 2018.

      Grade 2 was set as cut-off point. Costs and resource use for toxicities were incorporated for grade 2 and grade ≥3 separately to provide more granularity to reflect toxicity costs and resource use. The occurrence ratio of grade 2 and grade ≥3 toxicities, based transition probabilities, was used to calculate a weighted cost average. Microsoft Office Excel 2016 was used to implement the state-transition model.
      Model assumptions Regarding the model, several assumptions were made:
      • 1.
        Within the first six months after treatment, patients could only experience one toxicity at a time.
      • 2.
        The probability of late onset dyspnea and dysphagia after six months was not taken into account. NTCP models only accurately predict dyspnea onset until six months. Acute dysphagia is most common in the first 2-3 weeks after treatment initiation.
        • Baker S.
        • Fairchild A.
        Radiation-induced esophagitis in lung cancer.
        Based on expert opinion, occurrence of dysphagia after six months is rare.
      • 3.
        For patients with dyspnea and/or cardiotoxicity at six months, it was assumed that these toxicities were irreversible.
      • 4.
        After experiencing disease progression, either in acute or late time frame, patients entered a progressed disease state reflecting the same toxicities as before disease progression.

      Transition probabilities

      NTCP models for dyspnea16, dysphagia18 and two-year mortality related to heart dose (used to adjust OS until two years)

      Defraene G, Dankers F, Price G, et al. Tumour volume and cardiac dose as risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer. :9.

      were used to derive treatment dependent transition probabilities (table 1) of grade 2 and grade ≥3 toxicities using dosimetric parameters and patient characteristics (appendix A). Dosimetric parameters were extracted from results of a multicentric in silico clinical trial (ROCOCO)
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • et al.
      Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer.
      , which compared XRT and PT for patients with stage I-III NSCLC (72% stage III patients). Patient characteristics (age, gender, smoking, WHO performance status, chemotherapy24, GTV25 and baseline dyspnea26) were extracted from literature. However, these studies only reported mean values. Therefore, patient values were randomly sampled from a Gaussian distribution (patient characteristics) or Gamma distribution (dosimetric parameters and Gross Tumor Volume (GTV)).
      Treatment independent transition probabilities were estimated for cardiac events (cardiotoxicity) as this is expected to have a substantial impact on costs and consequences. These probabilities were derived from time to event data from a study by Degens et al.
      • Langendijk J.A.
      • Lambin P.
      • De Ruysscher D.
      • Widder J.
      • Bos M.
      • Verheij M.
      Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach.
      This study investigated the incidence of cardiac events in patients with stage III NSCLC within five years after conformal radiotherapy treatment completion.

      Degens J, De Ruysscher D, Houben R, et al. Cardiac events in stage III non-small lung cancer treated in daily practice: Is it time for cardiovascular screening and follow-up?

      The probability of cardiotoxicity was based on three most common categories: arrhythmia (43.9%), heart failure (HF) (including valve defects) (33.9%) and ischemic heart disease (IHD) (22.2%).

      Degens J, De Ruysscher D, Houben R, et al. Cardiac events in stage III non-small lung cancer treated in daily practice: Is it time for cardiovascular screening and follow-up?

      From the time to event dataset, a Kaplan-Meier curve of these merged categories was generated in R Statistical Software (version 3.5.1) to calculate time dependent transition probabilities (appendix C). The randomized Phase III NVALT-11/DLCRG-02 study was used to extract overall survival (OS) and progression free survival (PFS) rates with a median follow-up time of 51.3 months (95% CI: 47.5 - 60.2 months).
      • De Ruysscher D.
      • Dingemans A.-M.-C.
      • Praag J.
      • et al.
      Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non–Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.
      Additionally, Table 1 presents transition probabilities derived from NTCP models. Detailed information about NTCP models and cardiotoxicity can be found in appendix B and C, respectively.Table 2.Table 3.Table 3.Table 3.Table 2.Table 3.
      Table 1Treatment dependent probabilities estimated based on NTCP models
      ParameterEstimated ValueSEDistributionSource
      Photon-based radiotherapy for all patients (once only probability implemented in the first cycle)
      Probability of dyspnea grade 214.0 %12.1Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dyspnea grade ≥317.3 %18.0Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dysphagia grade 230.3 %25.8Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of dysphagia grade ≥310.8 %13.9Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of mortality related to heart dose (two-year)16.6 %0.04Normal*

      Defraene G, Dankers F, Price G, et al. Tumour volume and cardiac dose as risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer. :9.

      Proton radiotherapy for all patients (once only probability implemented in the first cycle)
      Probability of dyspnea grade 212.9 %10.4Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dyspnea grade ≥313.5 %14.8Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dysphagia grade 228.4 %24.8Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of dysphagia grade ≥310.3 %13.1Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of mortality related to heart dose (two-year)13.7 %0.03Normal*

      Defraene G, Dankers F, Price G, et al. Tumour volume and cardiac dose as risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer. :9.

      Proton radiotherapy for selected patients (once only probability implemented in the first cycle)
      Probability of dyspnea grade 213.2 %12.6Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dyspnea grade ≥314.3 %14.2Normal*

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      Probability of dysphagia grade 228.9 %26.4Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of dysphagia grade ≥310.5 %12.7Normal*
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      Probability of mortality related to heart dose (two-year)14.6 %0.03Normal*

      Defraene G, Dankers F, Price G, et al. Tumour volume and cardiac dose as risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer. :9.

      Survival rates (per three-month cycle)
      Progression free survival for all strategies83.5 %0.03Gamma**
      • De Ruysscher D.
      • Dingemans A.-M.-C.
      • Praag J.
      • et al.
      Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non–Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.
      Overall survival XRT90.9 %0.02Gamma**
      • De Ruysscher D.
      • Dingemans A.-M.-C.
      • Praag J.
      • et al.
      Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non–Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study.
      Overall survival PT For all patients (adjusted mortality related to heart dose)92.5 %0.02Gamma**-
      Overall survival PT For selected patients (adjusted mortality related to heart dose)92.3 %0.01Gamma**-
      SE = Standard error
      * Distribution based on used NTCP models
      ** Distribution based on OS and PFS months
      Detailed information about NTCP models and cardiotoxicity can be found in appendix B and C.
      Table 2Input parameters: Health state utilities (reference value) and disutilities
      ParameterEstimated ValueSEDistributionSource
      Health state utility
      Progression Free - No Toxicity0.8000.029Beta
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Progressed Disease - No Toxicity0.7940.038Beta
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Disutility
      Dyspnea-0.050.012Normal
      • Doyle S.
      • Lloyd A.
      • Walker M.
      Health state utility scores in advanced non-small cell lung cancer.
      DysphagiaAssumed the same as dyspnea
      CardiotoxicityMyocardial infarction-0.060.011Normal
      • Davies E.W.
      • Matza L.S.
      • Worth G.
      • et al.
      Health state utilities associated with major clinical events in the context of secondary hyperparathyroidism and chronic kidney disease requiring dialysis.
      Heart Failure-0.140.022Normal
      • Davies E.W.
      • Matza L.S.
      • Worth G.
      • et al.
      Health state utilities associated with major clinical events in the context of secondary hyperparathyroidism and chronic kidney disease requiring dialysis.
      Arrhythmia-0.020.004Normal

      Wehler E, Storm M, Kowal S, Al E. A Health State Utility Model Estimating the Impact of Ivosidenib on Quality of Life in Patients with Relapsed/Refractory Acute Myeloid Leukemia. In: Congress of the European Hematology Association. Stockholm, Sweden; 2018. http://investor.agios.com/static-files/25de7161-9a10-4d8c-8a03-8bd5e7d0a5d3.

      Age 75+(Age at baseline: 66)-0.010.002Normal

      Szende A, Janssen B, Cabases J. EQ-5D Populations Norms - National Surveys. In: Self-Reported Population Health: An International Perspective Based on EQ-5D. Dordrecht (NL): Springer; 2014. https://www.ncbi.nlm.nih.gov/books/NBK500354/.

      Table 3Treatment costs for proton radiotherapy and radiotherapy
      ParameterPTXRTSource
      Building
      Depreciation period (Years)5050

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      34
      Interest rate4.2%4.2%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Building€15,500,000€10,798,444PT:

      Hendrikx A. Eerste patiënt met protonen bestraald. De Limburger. February 7, 2019.

      XRT:
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Medical equipment
      Depreciation period (Years)1010

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Interest rate4.2%4.2%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Medical equipment€25,000,000€5,881,506PT:

      Hendrikx A. Eerste patiënt met protonen bestraald. De Limburger. February 7, 2019.

      XRT:
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Personnel
      Total annual personnel costs€392,091€392,091MC,

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Nederlandse Federatie van Universitair Medische Centra (NFU). Cao Universitair Medische Centra 2018-2020.; 2019. https://www.nfu.nl/img/pdf/19.2084_Uitgave_2019_-_Cao_umc_NL_2018-2020_v8.pdf.

      Other charges
      Maintenance5%5%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Housing and depreciation6%6%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Overhead38%38%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Operation
      Working days per week55
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Working hours per day1414
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Days of operation per year251251
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Treatment room utilization98%100%
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Treatment room availability98%98%
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Time per fraction in minutes (Range)35 (30-40)15 (10-20)EO,
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Fractions per year5,78313,769-
      Costs per fraction€1,062€256-
      EO = Expert Opinion, MC = MAASTRO Clinic (G. Bosman, personal communication, May 29, 2019)

      Health related quality of life

      Utility scores were used to reflect the impact of toxicity, disease progression and mortality on quality of life. “No toxicity” utilities for both progression free and progressed disease were derived from a study of Ramaekers et al28, in which utilities were based on the Dutch EuroQoL-5D-3L.
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Disutilities were assigned to patients with toxicity. Since cardiotoxicity was based on three major categories, a weighted disutility, consisting of a disutility for arrhythmia (43.9%), HF (33.9%) and myocardial infraction (22.2%), was used to calculate a utility for patients with cardiotoxicity. An accurate disutility for dysphagia could not be found, therefore the disutility for dyspnea was also assigned to patients with dysphagia. No distinction could be made between grade 2 and grade ≥3 (dis)utilities due to lack of data. Therefore, the same disutility was used for both grade 2 and ≥3. Additionally, an age related disutility, based on gender, was assigned to patients aged 75 or over. (Dis)utilities are reported in table 2.

      Treatment costs for proton radiotherapy and photon-based radiotherapy

      For treatment costs of PT and XRT a separate cost-analysis was performed (table 3 and appendix D). The study of Peeters et al33 was used as starting point to extract purchase prices and operational information. Depreciation values, annuity factors, personnel costs, overhead percentages and maintenance costs were based on the Dutch costing manual34, expert opinion and news articles.

      Hendrikx A. Eerste patiënt met protonen bestraald. De Limburger. February 7, 2019.

      Costs were divided in three main categories: Building (incl. structure costs, depreciation and interest charges), medical equipment (incl. depreciation and interest charges) and personnel costs of radiation technologists, physicians and physicists (incl. allowances). Based on these categories, total annual costs were defined. Total annual costs included maintenance, overhead and housing costs which were based on annual depreciation costs and interest charges of both building and medical equipment. Next, total costs per fraction for PT and XRT was calculated based on information of the operation of a facility.

      Health state and event resource use and costs

      We included related and unrelated healthcare costs, patient and family costs and inter-sectoral costs. Costs of toxicities were calculated for grade 2 and grade ≥3 separately, except for cardiotoxicity. Since it is difficult to distinguish the origin of dyspnea, which could be either from cardiac or lung diseases, guidelines for treating (radiation-induced) dyspnea are lacking. Therefore, costs of Chronic Obstructive Pulmonary Disease (COPD) were assumed to reflect healthcare utilization for dyspnea. The healthcare costs were derived from a study which included costs of primary, hospital and paramedical care (homecare and rehabilitation), as well as medication.
      • Goossens L.M.A.
      • Rutten-van Mölken M.P.M.H.
      • Boland M.R.S.
      • et al.
      ABC Index: quantifying experienced burden of COPD in a discrete choice experiment and predicting costs.
      Costs of moderate and severe COPD were assumed to reflect costs of grade 2 and grade ≥3 dyspnea, respectively. For dysphagia, hospitalization, medication use and portion of liquid nutrition were derived from literature.
      • Ramaekers B.L.T.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • Lambin P.
      • Joore M.A.
      • Langendijk J.A.
      Protons in Head-and-Neck Cancer: Bridging the Gap of Evidence.
      Other resource use was based on expert opinion. According to CTCAE 3.0, hospitalization regarding dysphagia is indicated for grade ≥3. Hence, it was assumed that hospitalization was not applicable to grade 2 dysphagia and therefore not included in the cost calculation.

      Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0. August 9. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf#search=%22ctcae%22. Published 2006. Accessed May 1, 2018.

      For implementation in the model, costs for grade 2 and grade ≥3 were merged for dyspnea and dysphagia according to the proportion of probabilities. Dysphagia was only included once, as it only occurs during the first cycle.
      For healthcare costs of cardiotoxicity, the Practical Application tool to Include Disease Costs (PAID), version 1.1.
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      was used. Based on ICD-9 codes, coronary heart diseases reflected the costs of IHD and other heart diseases and HF reflected the costs of arrhythmia and HF (including valve defects).
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      A weighted average of cardiotoxicity costs was based on the categories as previously described. Costs of cardiotoxicity were age- and gender specific, which implies different costs per patient in each cycle. Follow-up costs were distributed among different cycles in the first five years. The PAID tool was also used to estimate unrelated healthcare costs.
      Travel distance for PT was defined using the geographical midpoint of the Netherlands. A weighted average for distance was calculated based on the annual capacity of three PT centers (appendix E). Distance for XRT was extracted from a report in which frequencies in distance categories were reported.
      • van der Meer F.M.
      • Latta J.
      • Dik J.W.
      • Ziekenvervoer -,
      In case of private vehicle traveling, it was assumed that the patient would be accompanied by an informal caregiver. Unit costs were based on the Dutch costing manual.

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Productivity losses were included and were calculated using the Friction cost approach (consistent with the Dutch pharmacoeconomic guideline). Information of age-specific full-time and part-time labor participation was based on data from CBS Statline.

      Centraal Bureau voor Statistiek. Arbeidsdeelname; Ouderen. Statline. https://statline.cbs.nl/Statweb/publication/?DM=SLNL&PA=82914NED&D1=0-2,11-18,21-23&D2=0&D3=12-. Published 2019. Accessed May 6, 2019.

      The distribution was used to calculate a weighted average of costs for productivity losses (appendix F). These costs were implemented once for each patient at baseline, assuming that all patients will pose costs of productivity losses after diagnosis.
      All costs were converted to 2019 price levels and reported in Euros (Table 4).Table 5.Table A1.Table B1.Table B2.Table B3.Table B4.Table B5.Table C1.Table C2.Table D1.Table E1.Table F1.Table A1.Table B1.Table B2.Table B3.Table B4.Table B5.Table C1.Table C2.Table D1.Table E1.Table F1.Table A1.Table B1.Table B2.Table B3.Table B4.Table B5.Table C1.Table C2.Table D1.Table E1.Table F1.Table 5.Table A1.Table B1.Table B2.Table B3.Table B4.Table B5.Table C1.Table C2.Table D1.Table E1.Table F1.
      Table 4Costs and resource use (Price level: 2019)
      ParameterEstimated ValueSEDistributionSource
      Costs
      Treatment Costs a
      Photon RadiotherapyNumber of fractions b300.2Gamma
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Minutes per fraction155GammaEO
      Costs per fraction b€256-Beta (PERT)CA
      Proton RadiotherapyNumber of fractions b300.2Gamma
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Costs per fraction b€1,062-Beta (PERT)CA
      Minutes per fraction355GammaEO
      Related Health Care Costs
      Dyspnea grade 2Total costs incl. home care and rehab. c€974-Fixed
      • Goossens L.M.A.
      • Rutten-van Mölken M.P.M.H.
      • Boland M.R.S.
      • et al.
      ABC Index: quantifying experienced burden of COPD in a discrete choice experiment and predicting costs.
      Dyspnea grade ≥3Total costs incl. home care and rehab. c€2,859-Fixed
      • Goossens L.M.A.
      • Rutten-van Mölken M.P.M.H.
      • Boland M.R.S.
      • et al.
      ABC Index: quantifying experienced burden of COPD in a discrete choice experiment and predicting costs.
      Dysphagia grade 2Months of medication for dysphagia b10.2GammaEO
      Costs of medication per month b€46-FixedMP,

      Zorginstituut Nederland. Medicijnkosten.

      Days of liquid nutrition b285.6GammaEO
      Portion of liquid nutrition per day b3.70.74Gamma
      • Ramaekers B.L.T.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • Lambin P.
      • Joore M.A.
      • Langendijk J.A.
      Protons in Head-and-Neck Cancer: Bridging the Gap of Evidence.
      Costs of liquid nutrition per portion b€3.60-FixedMP
      Dysphagia grade≥3Months of medication for dysphagia b10.2GammaEO,
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • De R.D.
      • et al.
      The cost-effectiveness of particle therapy in non-small cell lung cancer: Exploring decision uncertainty and areas for future research.
      Costs of medication per month b€46-Fixed

      Zorginstituut Nederland. Medicijnkosten.

      Hospitalization days b60.9Gamma
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Costs of hospital stay per day b€505-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Tube feeding days b142.8GammaEO
      Costs of tube feeding per day b€12-FixedMP
      Costs of placing and removing tube b€335-Fixed
      • Ramaekers B.L.
      • Joore M.A.
      • Béranger L.
      • Al E.
      Cost-effectiveness of Modified, Fractionation Radiotherapy versus Conventional Radiotherapy for Unresected Non-Small-Cell Lung Cancer Patients.
      Hours of Home care per day b0.50.1GammaEO
      Home care days b142.8GammaEO
      Costs of Home care per hour (nurse) b€77-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      CardiotoxicityIschemic Heart disease (Age range: 66-99) cRange:€62 - €293--
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      Heart failure and arrhythmia (Age range: 66 - 99) cRange:€53 - €710--
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      Follow-up visitsFollow-up visits first year b40.8Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      CT-scan first year b10.2Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      Follow-up visits second year b20.4Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      CT-scan second year b10.2Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      Follow-up visits per year after the second year until 5 years b10.2Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      CT-scan per year after the second year until 5 years b10.2Gamma

      Federatie Medisch Specialisten. Richtlijnen niet kleincellig longcarcinoom. https://richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom/nacontrole_en_nazorg.html. Published 2015. Accessed April 20, 2019.

      Costs per follow-up visit b€97-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Costs per CT-scan b€154-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Patient and Family Costs
      Traveling costsParking costs per day b€3.18-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Number of km (return) PT b14845.5Gamma-
      Number of km (return) XRT b469.2Gamma

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Taxi use (%)58.7%0.25Beta
      Private vehicle use (%)41.3%0.25Beta
      Costs Taxi (constant + costs per km) b€3.13 + €2.82-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Informal careHours of informal care PT51Gamma-
      Hours of informal care XRT20.4Gamma-
      Costs per hour of informal care€15-Fixed

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Unrelated healthcare costs
      Unrelated disease costsCosts of diseases in life-years gained (Age range: 66 - 99) cRange: €1,235 - €17,778--
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      Costs of progressionCosts of last year of living (Age range 66 - 99) cRange: €3,517 - €8,815--
      • van Baal P.H.M.
      • Wong A.
      • Slobbe L.C.J.
      • Polder J.J.
      • Brouwer W.B.F.
      • de Wit G.A.
      Standardizing the Inclusion of Indirect Medical Costs in Economic Evaluations.
      Inter-sectoral cost
      Productivity lossesFriction period (weeks)12.12.4

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Working population (%)17.5%3.5

      Centraal Bureau voor Statistiek. Arbeidsdeelname; Ouderen. Statline. https://statline.cbs.nl/Statweb/publication/?DM=SLNL&PA=82914NED&D1=0-2,11-18,21-23&D2=0&D3=12-. Published 2019. Accessed May 6, 2019.

      Full-time (%)28%5.6

      Centraal Bureau voor Statistiek. Arbeidsdeelname; Ouderen. Statline. https://statline.cbs.nl/Statweb/publication/?DM=SLNL&PA=82914NED&D1=0-2,11-18,21-23&D2=0&D3=12-. Published 2019. Accessed May 6, 2019.

      Part-time (%)72%14.4

      Centraal Bureau voor Statistiek. Arbeidsdeelname; Ouderen. Statline. https://statline.cbs.nl/Statweb/publication/?DM=SLNL&PA=82914NED&D1=0-2,11-18,21-23&D2=0&D3=12-. Published 2019. Accessed May 6, 2019.

      Table 5Results of probabilistic sensitivity analyses (Sorted by costs)
      Compared with XRT For all patientsCompared with next best
      AnalysisStrategyCostsQALYNMBΔCostsΔQALYICERICER
      Base CaseXRTAll€45,9121,769€95,627----
      PTIndividualized€70,8661,922€82,885€24,9540,153€163,467€163,467
      PTAll€79,6951,951€76,400€33,7830,182€185,673€301,396
      Healthcare perspectiveXRTAll€41,2311,769€100,289----
      PTIndividualized€61,7261,922€92,034€20,4950,153€134,256€134,256
      PTAll€68,9041,951€87,176€27,6730,182€152,094€245,053
      Excluding productivity losses PTXRTAll€41,9121,769€95,608----
      PTIndividualized€69,6621,922€84,098€23,7500,153€155,582€155,582
      PTAll€78,0231,951€78,057€32,1110,181€176,485€285,415
      Equal minutes per fractionXRTAll€45,4101,753€97,794----
      PTIndividualized€57,4161,910€95,376€12,0070,157€76,299€76,299
      PTAll€61,1891,940€94,023€15,7800,188€84,106€124,719
      QALY = Quality Adjusted Life Years
      NBM = Net Monetary Benefit
      ICER = Incremental Cost Effectiveness Ratio
      Table A1Patient characteristics
      XRTPTPSource
      Mean age (years)66 (SD 10)
      • Oberije C.
      • De Ruysscher D.
      • Houben R.
      • et al.
      A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.
      Gender
      • Oberije C.
      • De Ruysscher D.
      • Houben R.
      • et al.
      A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.
      Male69.2%
      Female30.8%
      Smoking (yes)36.9%
      • Oberije C.
      • De Ruysscher D.
      • Houben R.
      • et al.
      A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.
      Chemotherapy88.0%
      • Oberije C.
      • De Ruysscher D.
      • Houben R.
      • et al.
      A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.
      Concurrent36.9%
      WHO-PS (≥2)11.6%
      • Oberije C.
      • De Ruysscher D.
      • Houben R.
      • et al.
      A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.
      Baseline dyspnea grade 128.7%
      • De Ruysscher D.
      • Dehing C.
      • Yu S.
      • et al.
      Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer.
      Baseline dyspnea grade ≥211.0%
      • De Ruysscher D.
      • Dehing C.
      • Yu S.
      • et al.
      Dyspnea evolution after high-dose radiotherapy in patients with non-small cell lung cancer.
      Mean GTV (cm3)112.6 (SD 64.3)
      • Agrawal S.
      • Kumar S.
      • Maurya A.K.
      Potential for adaptive dose escalation in radiotherapy for patients with locally advanced non-small-cell lung cancer in a low mid income setting.
      OTT (days)40 (SD 8.0)
      MHDMean (Gy)14.3 (SD 10.3)7.6 (SD 7.2)<0.001
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • et al.
      Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer.
      MLDMean (Gy)16.4 (SD 5.5)13.5 (SD 6.2)<0.001
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • et al.
      Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer.
      MEDMean (Gy)26.0 (SD 12.1)24.4 (SD 13.7)<0.001
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • et al.
      Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer.
      MAXEDMean (Gy)64.7 (SD 15.8)63.6 (SD 17.8)<0.001
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • et al.
      Results of a Multicentric In Silico Clinical Trial (ROCOCO): Comparing Radiotherapy with Photons and Protons for Non-small Cell Lung Cancer.
      Abbreviations: WHO-PS = World Health Organizations Performance Status; GTV = Gross Tumor Volume; OTT = Overall Treatment Time; MHD = Mean Heart Dose; MLD = Mean Lung Dose; MED = Mean Esophagus Dose; MAXED = Maximum Esophagus Dose; Gy = Gray.
      Table B124 months’ mortality NTCP models →GTV-smoker-MHD model

      Defraene G, Dankers F, Price G, et al. Tumour volume and cardiac dose as risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer. :9.

      CoefficientSEOR95% CI
      Intercept β0-0.0900.0180.914Normal
      Gross Tumor Volume (GTV) (+1 cc)0.0050.0031.0050.999 - 1.011Normal
      Current smoker (yes/no)0.4560.4322.4901.067 - 5.809Normal
      Mean Heart Dose (MHD) (+1 Gy)0.0330.0251.0330.985 - 1.084Normal
      Table B2NTCP model Dyspnea = 2

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      CoefficientSEOR95% CI
      Intercept β0-3.1860.9480.0410.006 - 0.266Normal
      Mean Lung Dose (MLD) (+1Gy)0.0430.0481.0440.950 - 1.147Normal
      Chemotherapy (vs none)-0.8070.4830.4460.173 - 1.150Normal
      Baseline dyspnea grade 1 vs 01.6350.7915.1291.087 - 24.191Normal
      Baseline dyspnea grade ≥2 vs 03.3820.80229.4306.110 - 141.741Normal
      Table B3NTCP model Dyspnea ≥ 3 Endpoint

      Defraene G, Schuit E, De Ruysscher D. Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

      CoefficientSEOR95% CI
      Intercept β0-4.0811.0200.0170.002 - 0.125Normal
      Mean Lung Dose (MLD) (+1Gy)0.1500.0611.1621.031 - 1.309Normal
      Chemotherapy (vs none)-0.9370.5720.3920.128 - 1.202Normal
      Baseline dyspnea grade 1 vs 00.2990.6921.3490.348 - 5.233Normal
      Baseline dyspnea grade ≥2 vs 02.5160.66612.3803.350 - 45.696Normal
      Table B4NTCP model Dysphagia grade ≥2
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      CoefficientSEOR95% CIDistribution
      Intercept β0-0.1950.9360.8230.128 - 5.156Normal
      Age-0.0300.0100.9700.950 - 0.990Normal
      Female (vs male)0.5010.1981.6501.120 - 2.430Normal
      WHO-PS ≥2 (vs 0-1)0.5680.2281.7601.130 - 2.750Normal
      Concurrent chemotherapy (vs no/sequential)0.9280.2222.5301.640 - 3.910Normal
      Mean esophagus dose (MED)0.0610.0141.0601.040 - 1.090Normal
      Maximum esophagus dose (MAXED)0.0300.0101.0301.010 - 1.050Normal
      Overall treatment time (OTT)-0.0590.0110.9400.920 - 0.960Normal
      Table B5NTCP model Dysphagia grade ≥3
      • Dehing-Oberije C.
      • De Ruysscher D.
      • Petit S.
      Development, external validation and clinical usefulness of a practical prediction model for radiation-induced dysphagia in lung cancer patients.
      CoefficientSEOR95% CIDistribution
      Intercept β0-2.3510.9190.0950.015 - 0.577Normal
      Age-0.0300.0100.9700.950 - 0.990Normal
      Female (vs male)0.5010.1981.6501.120 - 2.430Normal
      WHO-PS ≥2 (vs 0-1)0.5680.2281.7601.130 - 2.750Normal
      Concurrent chemotherapy (vs no/sequential)0.9280.2222.5301.640 - 3.910Normal
      Mean esophagus dose (MED)0.0610.0141.0601.040 - 1.090Normal
      Maximum esophagus dose (MAXED)0.0300.0101.0301.010 - 1.050Normal
      Overall treatment time (OTT)-0.0590.0110.9400.920 - 0.960Normal
      Abbreviations: Se = standard error, OR = Odds ratio, CI = confidence interval, NTCP = normal tissue complication probability
      Table C1Distribution of Cardiac events

      Degens J, De Ruysscher D, Houben R, et al. Cardiac events in stage III non-small lung cancer treated in daily practice: Is it time for cardiovascular screening and follow-up?

      PercentageSEDistribution
      Arrhythmia43.9%11.5Beta
      Atrial + Ventricular
      Ischemic heart disease22.2%3.3Beta
      Myocardial infarction + Coronary artery disease + Angina pectoris (cardiac cause)
      Heart Failure33.9%5.1Beta
      Acute + Chronic heart failure + Valve defects
      Table C2Lognormal Time to event model for cardiotoxicity
      Estimated valueSE95% CIDistribution
      MeanLog2.030.1731.69 – 2.37Normal
      SDLog0.7850.0670.65 – 0.91Normal
      Table D1Cost-analysis PT vs XRT
      DescriptionXRTPTSource
      Equipment
      Depreciation period (years)10

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Interest rate4.2%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Annuity factor8.0

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Purchase price€5,881,506€25,000,000XRT:
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      PT:

      Hendrikx A. Eerste patiënt met protonen bestraald. De Limburger. February 7, 2019.

      Annual depreciation and interest costs€732,374€3,113,038
      Building
      Depreciation period (years)50

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Interest rate4.2%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Annuity factor20.8

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Purchase price€10,798,444€15,500,000XRT:
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      PT:

      Hendrikx A. Eerste patiënt met protonen bestraald. De Limburger. February 7, 2019.

      Annual depreciation and interest costs€520,004€746,409
      Personnel
      Irregularity rate radiation technologists and physicist per month (between 20.00-22.00h)7%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Irregularity rate physician per month10%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Allowances rate radiation technologist/physicist per month37%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Allowances radiation physician per month€523

      Nederlandse Federatie van Universitair Medische Centra (NFU). Cao Universitair Medische Centra 2018-2020.; 2019. https://www.nfu.nl/img/pdf/19.2084_Uitgave_2019_-_Cao_umc_NL_2018-2020_v8.pdf.

      Monthly salary radiation technologist (excl.)€3,242

      Nederlandse Federatie van Universitair Medische Centra (NFU). Cao Universitair Medische Centra 2018-2020.; 2019. https://www.nfu.nl/img/pdf/19.2084_Uitgave_2019_-_Cao_umc_NL_2018-2020_v8.pdf.

      Monthly salary physicist (excl.)€6,361

      Nederlandse Federatie van Universitair Medische Centra (NFU). Cao Universitair Medische Centra 2018-2020.; 2019. https://www.nfu.nl/img/pdf/19.2084_Uitgave_2019_-_Cao_umc_NL_2018-2020_v8.pdf.

      Monthly salary physician (excl.)€9,941

      Nederlandse Federatie van Universitair Medische Centra (NFU). Cao Universitair Medische Centra 2018-2020.; 2019. https://www.nfu.nl/img/pdf/19.2084_Uitgave_2019_-_Cao_umc_NL_2018-2020_v8.pdf.

      FTE radiation technologist4MC
      FTE physicist0.5MC
      FTE physician0.6MC
      Annual costs
      Overhead38%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Depreciation rate6%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Maintenance rate5%

      Hakkaart-van Roijen L, Van der Linden N, Bouwmans C, Kanters T, Tan S. Costing Manual: Methodology of Costing Research and Reference Prices for Economic Evaluations in Healthcare [in Dutch: Kostenhandleiding: Methodologie van Kostenonderzoek En Referentieprijzen Voor Economische Evaluaties in de Gezondheidszorg].; 2015.

      Total annual costs€3,535,598€6,142,667
      Operational information
      Working days per week5
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Hours per day14
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Downtime days per year10
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Utilizations100%98%
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Availability98%98%
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      Time per fraction (minutes)15 ± 535 ± 5MC
      Fractions per years13,7695,783
      Total costs per fraction€256€1,062
      MC = MAASTRO Clinic (G. Bosman, personal communication, May 29, 2019)
      Table E1Average travel distance PT centers
      Proton Radiotherapy
      Distance from Amersfoort to:KmAnnual capacity per PT center%
      Holland-PTC (Delft)9060037,5%
      ZON-PTC (Maastricht)19640025,0%
      Groningen-PTC17360037,5%
      Total annual capacity1600100%
      Weighted average distance147.6 ± 45.5 KmReturn
      Table F1Productivity losses
      Hours per weekSENr. of people%Costs friction period
      Working population32,00017.5
      Fulltime37.52.59,00028.1€16,309
      Less than 12 hours per week8411,00034.4€3,479
      12 – 20 hours per week1644,00012.5€6,959
      20 – 35 hours per week27.57.58,00025.0€11,960
      Friction period12.12.4
      Costs per hour€36.88
      Weighted average€1,731 Per treatment

      Base case analysis

      Expected life years (LYs), progression free life years (PFLYs), quality adjusted life-years (QALY), costs and net monetary benefit (NMB) were calculated for all strategies. Additionally, incremental cost-effectiveness ratios (ICERs) were calculated. A threshold value of €80,000 per QALY, established by the Dutch Healthcare Institute was used44. The analysis was performed in Microsoft Office Excel 2016.

      Sensitivity analysis

      Distributions were assigned to each individual input parameter in order to perform a probabilistic sensitivity analysis (PSA) with Monte Carlo simulation (2,000 simulations).

      Edlin R, McCabe C, Hulme C, Al E. Cost Effectiveness Modelling for Health Technology Assessment - A Pratical Course. Adis - Springer International Publishing Switzerland; 2015. doi:10.1007/978-3-319-15744-3

      The ICER was calculated based on the outputs of the PSA. To illustrate uncertainty surrounding the ICER, a cost-effectiveness plane was created. A cost-effectiveness acceptability curve (CEAC) was created to present the probability of strategies being cost-effective at different ceiling ratios. Additionally, deterministic one-way sensitivity analyses were performed.

      Scenario analysis

      Scenario analyses were performed to examine the cost-effectiveness from a healthcare perspective and possible future or alternative scenarios. Since PT is still in start-up phase in the Netherlands and fraction duration is expected to decrease over time, an analysis assuming that minutes per fraction of PT and XRT are equal was performed (15 minutes). Additionally, a threshold analysis was conducted in order to identify the maximum fraction duration for PTIndividualized still being cost-effective at the threshold value. In a second scenario analysis, productivity losses were excluded for PT since toxicity probabilities were lower compared to XRT and less toxicity might reduce productivity losses.

      Value of information analysis

      The expected value of perfect information (EVPI) represents the risk associated with the decision, i.e. the probability of making a wrong adoption decision (from the CEAC described above) multiplied by the consequences of a wrong adoption decision. In other words, the EVPI provides a maximum value to the amount of resources that should be spend on research to decrease the decision uncertainty.
      • Briggs A.
      • Sculpher M.
      • Claxton K.
      Decision Modelling for Health Economic Evaluation.
      By multiplying the per patient EVPI by the effective population, which reflects the number of patients that are affected by the decision, the population EVPI was calculated. The effective population for the next 10 years of 83,029 patients was based on the incidence of patients with NSCLC in 2019 in the Netherlands. Additionally, the value of partial perfect information (EVPPI) was calculated to determine which parameter(s) contributed the most to decision uncertainty (i.e. the EVPI for specific (groups) of parameters). Sheffield Accelerated Value of Information (SAVI) version 2.1.2 was used to retrieve the EVPPI.
      • Briggs A.
      • Sculpher M.
      • Claxton K.
      Decision Modelling for Health Economic Evaluation.
      • M S, Oakley J, Brennan A.
      Estimating multi-parameter partial Expected Value of Perfect Information from a probabilistic sensitivity analysis sample: a non-parametric regression approach.

      Results

      Total expected life-time cost per patient from a societal perspective were estimated to be €79,695 for PTAll, €68,904 for PTIndividualized and €41,231 for XRTAll. PTAll yielded most QALYs (1.951) and LYs (2.558). XRTAll was the least effective (1.769 QALYs), the least expensive strategy, and the most cost-effective strategy. For thresholds higher than €163,467 per QALY gained, PTIndividualized was cost-effective. PTAll will be cost-effective above a willingness to pay of €301,396 per QALY gained. XRTAll had the highest probability of being cost-effective (97%) at a threshold of €80,000 per QALY gained. CEACs and CE planes are presented in appendix G.
      The scenario analysis using a healthcare perspective resulted in similar outcomes with XRTAll as the most cost-effective treatment strategy until a value of €134,256 per QALY gained followed by PTIndividualized as next best up to €245,053 per QALY gained. Excluding productivity losses had a minor impact on cost and cost-effectiveness results. However, when considering equal minutes per fraction as future perspective, XRTAll was cost-effective until a value of €76,299 per QALY gained followed by PTIndividualized until a value of €124,719 per QALY gained. Above the latter value, PTAll became cost-effective. The probabilities of PTAll, XRTAll and PTIndividualized being cost-effective at the threshold value were 16%, 47%, and 38% respectively. When increasing the PT fraction duration by one minute, the ICER exceeded the threshold value (€81,665). Result are reported in table 5. The deterministic one-way sensitivity analyses showed that the cardiac event categories and “no toxicity” utilities were the most influential parameters. The tornado diagram can be found in appendix G.
      Regarding base case scenario, the estimated EVPI per patient was €84 at a threshold value of €80,000, the population EVPI for the effective population was €7 million. Further research focusing on NTCP models for mortality based on heart dose and OS (NTCP+OS: €388,629; OS: €244,312) would be most worthwhile. The population EVPI for different threshold values is shown in appendix G figure G.5.
      Assuming equal minutes for PT and XRT, the estimated EVPI per patient was €2,347, the population EVPI for the effective population was €195 million. The maximum expected value of further research that will jointly inform the set of parameters of NTCP models, patient and family cost (related to PT), utilities and related healthcare cost was €20 million, €3.7 million, €996,325 and €342,253, respectively.

      Discussion

      This study aimed to examine the cost-effectiveness of three treatment strategies for patients with stage III NSCLC: 1. XRTAll; 2. PTAll; 3.PTIndividualized. In the base-case analysis, PTAll was not cost-effective neither from a societal perspective, nor from a healthcare perspective when assuming a threshold value of €80,000. There was a substantial cost difference between PT and XRT which can be explained by primary treatment cost that are 4.1 times higher for PT compared to XRT. These results are uncertain and conditional on different assumptions. PTIndividualized will potentially be cost-effective compared to XRTAll when the fraction duration or the number fractions of PT decreases and would become more cost-effective if patient selection is further optimized. Therefore, selection of patients for whom PT is expected to be beneficial is crucial at this point to improve the cost-effectiveness of PT.
      To the authors knowledge, the present study is the first study in the Netherlands evaluating the cost-effectiveness of PT versus XRT for patients with stage III NSCLC from a societal perspective based on NTCP models. The previous model, developed in 2010 by Grutters et al.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • De R.D.
      • et al.
      The cost-effectiveness of particle therapy in non-small cell lung cancer: Exploring decision uncertainty and areas for future research.
      only included patients with early stage NSCLC and the model was restricted to two grade ≥3 toxicities (pneumonitis and esophagitis). The study showed that PT was cost-effective relative to conventional radiotherapy from a healthcare perspective. Differences between the previous and the current model can be explained by the newly performed cost-analysis which updated and expanded the previous analysis of Peeters et al.
      • Peeters A.
      • Grutters J.P.C.
      • Pijls-Johannesma M.
      • et al.
      How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.
      with additional information. With the current clinical experience, PT proved to be more expensive as essentially calculated in 2010. Additionally, the use of NTCP models allows individual toxicity probability calculation based on planning data and enables to distinguish between grade 2 and grade ≥3 toxicity which improves the accuracy of predicting potential benefit and moreover cost difference.
      Due to limited clinical experience treating patients with NSCLC in the Netherlands, there are some limitations. First, data necessary for treatment cost calculation is mainly not publicly available and hence difficult to get access to. Though, based on expert opinion and the best available evidence we attempted to estimate the treatment costs. However, the estimation of treatment costs might vary dramatically between PT centers and hence might limit the generalizability of our findings. Also, assumptions related to the depreciation period of radiotherapy equipment (based on the physical life of a piece of equipment and its useful clinical life), affects costs. Nevertheless, the main conclusions that PT is not cost-effective for all patients and with improving clinical experience, fraction duration or the number of fractions can decrease over time, potentially improving the cost-effectiveness of PT, is likely widely applicable. Similarly, the current analyses could be considered conservative for PT from multiple perspectives. The cost effectiveness might be improved through developments that would, among others, decrease the time per fraction, decrease the number of fractions, advancement of PT techniques and interaction of PT with immunotherapy. Second, we assumed no excess mortality due to heart dose after a time point of two years. This assumption can be influential when assessing the long-term effect of PT on mortality and the impact on cost-effectiveness. If there would be a benefit after two year receiving PT, PT would most likely become more cost-effective. Time restriction for dyspnea and dysphagia models is less important since late-onset of both toxicities is rare. For cardiotoxicity, a time-dependent probability could be calculated for a life-time time horizon. However, no distinction could be made between PT and XRT, since no NTCP model is available yet to calculate dose-related probabilities, which is a third limitation of the study. Using PT significantly lowers the MHD relative to XRT which would presumably result in a lower cardiotoxicity probability. Fourth, cardiotoxicity is the only toxicity for which no distinction could be made between grade 2 and ≥3 costs, since it has a broad spectrum of diseases which are often interrelated. Hence, it is difficult to separate costs per grade. Fifth, not having access to individual dose distributions and thus relying on the published aggregate data from the ROCOCO study has limitations. This includes sampling different dose parameters independently. Moreover, it was unclear whether organ motion was incorporated (i.e. whether static dose was used or not). Finally, utilities could not be defined per grade as (dis)utilities are often not reported per grade.
      The current model based approach adopted in the Netherlands10 has resulted in indication protocols that recommend PT in case a certain difference in NTCP between PT and XRT (ΔNTCP) is expected to be achieved. This ΔNTCP threshold differs according to grade of toxicity but not for type of toxicity. The current analyses showed that selecting patients based on anticipated benefit is expected to improve cost-effectiveness (compared to providing PT, unselected, to all patients). However, patient selection might be optimized further to increase cost-effectiveness. Optimal patient selection could potentially be achieved through applying different ΔNTCP thresholds according to toxicity type based on the impact on (cost-)effectives and could be explored using the model described in this paper. Without optimal patient selection, costs will be unnecessarily high and might impede healthcare provision to people who can potentially benefit of PT. Patient selection might change at a threshold of €80,000 per QALY when fraction duration of PT decreases towards XRT fraction duration (decreasing treatment costs of PT). Moreover, costs for PT are based on both the number of fractions and fractions duration. Hence, the cost effectiveness of PT can be improved by a reduced number of fractions (potentially in combination with a reduced duration per fraction). For example, PT can be considered cost effective when administered in 18 fractions with a 25 minute duration (assuming reducing the number of fractions will only affect costs), similarly for 15 fractions of 30 minutes and 25 fractions of 18 minutes.
      Based on the value of information analysis, it would be most valuable to perform further research on unrelated healthcare costs and NTCP models for mortality related to heart dose. Both are related, since unrelated healthcare costs are based on mortality. When fraction duration of PT decreases, the ICER will possibly become closer to the threshold value of €80,000. More or different parameters will then become more valuable to focus further research on. Additionally, in further research it would be worthwhile to include costs of multiple PT centers to get a comprehensive overview of PT cost in general. Furthermore, it would be of great value to incorporate NTCP models for cardiotoxicity when becoming available to obtain dose-related probabilities.
      This study illustrates a methodological approach to assess the cost-effectiveness of PT vs XRT and supporting optimization of patients selection for PT. In conclusion, based on this explorative analysis of the model-based approach, PTAll is not cost-effective in the current situation compared to XRTAll and PTIndividualized. With optimal patient selection, PTIndividualized can potentially become a cost-effective treatment when minutes per fraction decrease, the number of fractions decrease or an optimalization by the interaction of both.
      Funding
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
      Appendix
      Appendix A: Patient characteristics
      Cumulative incidence Cardiac Events

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