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Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients

Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced... Hindawi Sarcoma Volume 2019, Article ID 3234205, 11 pages https://doi.org/10.1155/2019/3234205 Research Article Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients 1 1 2 2 Michiel C. Verboom , Hans Gelderblom , J. Martijn Kerst, Neeltje Steeghs , 3 4 5 Anna K. L. Reyners, Stefan Sleijfer, Winette T. A. van der Graaf, and Wilbert B. van den Hout Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE Amsterdam, Netherlands Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 5201, 3008 AE Rotterdam, Netherlands Department of Medical Oncology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, Netherlands Department of Medical Decision Making, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands Correspondence should be addressed to Michiel C. Verboom; m.c.verboom@lumc.nl Received 23 January 2019; Accepted 9 May 2019; Published 2 June 2019 Academic Editor: Kanya Honoki Copyright © 2019 Michiel C. Verboom et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Trabectedin and ifosfamide are among the few cytostatic agents active in advanced soft tissue sarcomas (STSs). Trabectedin is most potent against so-called L-sarcomas (leiomyosarcoma and liposarcoma). (e survival gain and cost-effectiveness of these agents in a second-line setting were analysed in the setting of advanced STS after failure of anthracyclines. A prospective observational trial had previously been performed to assess the use of trabectedin in a Dutch real-world setting. Data on ifosfamide monotherapy were acquired from previous studies, and an indirect comparison of survival was made. A state-transition economic model was constructed, in which patients could be in mutually exclusive states of being preprogression, postprogression, or deceased. (e costs and quality-adjusted life years (QALYs) for both treatments were assessed from a Dutch health-care perspective. Separate analyses for the group of L-sarcomas and non-L-sarcomas were performed. Trabectedin treatment resulted in a median progression-free survival of 5.2months for L-sarcoma patients, 2.0months for non-L-sarcoma patients, and a median overall survival of 11.8 and 6.0months, respectively. For L-sarcoma patients, trabectedin offered an increase of 0.368 life years and 0.251 QALYs compared to ifosfamide and€20,082 in additional costs, for an incremental cost-effectiveness ratio (ICER) of€80,000 per QALY gained. In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of€4,698. (e difference in survival between drugs and the acquisition costs of trabectedin were the main influences in these models. Trabectedin was shown to have antitumour efficacy in advanced L-sarcoma. From a health economics perspective, the costs per QALY gained compared to ifosfamide monotherapy that may be acceptable, considering what is currently regarded as acceptable in the Netherlands. all adult malignancies. STSs in general are relatively in- 1. Introduction sensitive to chemotherapy compared to tumours of epithelial Soft tissue sarcomas (STSs) are a rare group of malignancies origin. Some drugs, such as doxorubicin, have been found arising from mesenchymal cells comprising one percent of active in a range of different sarcoma subtypes, whereas 2 Sarcoma others show only activity in specific subtypes, such as cri- Institutional Review Board approved informed consent form zotinib in the inflammatory myofibroblastic tumour [1]. [4]. At the time of the ET-D-010-10 observational trial, no Trabectedin is a drug active in several subtypes, with most notable effect in leiomyosarcoma and liposarcoma. It has a study had yet directly compared the efficacy of trabectedin to unique mechanism of action in binding to the minor groove BSC. Hence, the choice of treatment was with the patient and of DNA and also in influencing the tumour environment local physician, as long as the patient was deemed fit enough [2, 3]. to receive chemotherapy. It was intended to include 100 Trabectedin was approved for clinical use in Europe in patients, of whom 80 would have received trabectedin and 20 2007 for patients with advanced STS after failure to would have chosen BSC. In reality, however, a larger portion anthracyclines and ifosfamide or for patients unsuited to of patients wished to be treated with trabectedin (91%) than receive these agents. At this time, studies with a randomised predicted, and too few patients chose the BSC arm (total 9%: comparison with other treatment options were not available. 6% only BSC and 3% received additional or other systemic (erefore, before market authorization in the Netherlands antitumour therapies). Despite an extension of the trial duration, accrual of the BSC arm was insufficient to be able could be granted, a prospective observational trial was designed, which aimed to analyse the use of trabectedin in to perform a viable comparison of the collected data. STS in a real-world setting. To account for the lack of a trial-generated comparator (e original aim of this observational trial was to analyse group, it was decided to perform an indirect comparison of the use of trabectedin compared to best supportive care the data in the trabectedin arm with data obtained from (BSC) and derive an incremental cost-effectiveness ratio previous studies. As appropriate data on patients on BSC (ICER) for its use compared to BSC. All patients eligible for were not available, an agent active as second-line treatment trabectedin were also given the option of BSC, but only a few was sought. (ese data were obtained from two EORTC patients opted for BSC, which made it impossible to draw clinical trials with ifosfamide in patients with advanced STS, meaningful conclusions from this small number of patients. published by Nielsen et al. and van Oosterom et al., hereafter Instead, as an alternative, a comparison with ifosfamide in termed “the EORTC trials” [5, 6]. (ese two trials used the 1979 WHO criteria for response evaluation. According to retrospective data was sought, as this drug is a treatment option for patients with advanced STS after failure to the 2018 ESMO guideline on STS treatment, after doxoru- anthracyclines. Ifosfamide is an alkylating agent and bicin, patients may be treated with ifosfamide, if they did not available since the 1980s for the treatment of STSs. progress on it previously [1]. (erefore, a second-line setting (erefore, this study aims to compare both survival and was chosen for comparing the phase IV ET-D-010-10 data cost-effectiveness between trabectedin and ifosfamide in the on trabectedin with the EORTC data on ifosfamide. setting of second-line cytostatic treatment of STS in the (e efficacy of ifosfamide differs in STS subtypes to a Netherlands. certain extent, but has not been shown to differ as much between subtypes as trabectedin does. Trabectedin has a markedly better efficacy in leiomyosarcoma and liposarcoma 2. Methods subtypes, the so-called L-sarcomas. (is difference in effi- cacy between L-sarcomas and non-L-sarcomas has led to 2.1. Patient Selection. In order to facilitate the entry and reimbursement of trabectedin in the Dutch health-care clinical trials which specifically included patients with one of these two subtypes [2]. Due to the prominence of the system, a cost-effectiveness analysis was designed to eval- uate trabectedin and BSC usage patterns and outcomes in L-sarcomas in trabectedin clinical research, it was decided to split the study population into two subsets, consisting of advanced STS in a real-world setting, including data on quality of life and associated utilities. (is prospective ob- L-sarcomas and non-L-sarcomas. servational phase IV trial was to provide the Dutch health Out of all patients included in the phase IV trial, 54 authority (Zorginstituut Nederland) with sufficient data on patients received trabectedin as second-line treatment. (e the effectiveness and optimal use of trabectedin to ensure a remaining 39 patients received trabectedin as third or higher line of treatment and were excluded from the cost- proper evaluation for permanent registry in the Regulation Orphan Drugs. (is trial was named ET-D-010-10, with trial effectiveness analysis. (e drug was prescribed in the ac- cepted regimen of 1.5 mg/m registration number NCT01299506. (e RECIST 1.1 criteria once every 3 weeks during a were used for response evaluation. Quality-of-life data were 24-hour hospital admission. Due to dose reductions, the scored using patient-reported EQ-5D questionnaires. Pa- average administered trabectedin dose was 1.3mg/m . tients with all subtypes of STS were recruited in this trial if From the ifosfamide trials, a total of 50 patients were they were eligible for trabectedin, after the failure of identified to fit the criterion of second-line treatment. (e anthracyclines and/or ifosfamide, or in case, these patients ifosfamide dosage was 9g/m given in 3 consecutive days were unsuited to receive these drugs. (e patients in this every 3 weeks (19 patients) [6], or 12g/m as a 3-day observational trial were offered treatment with trabectedin continuous infusion every 4 weeks (31 patients) [5], to- or BSC, and the latter could consist of no systemic che- gether with intravenous Mesna to prevent hemorrhagic motherapy or other systemic antitumour therapies. Some of cystitis. For the cost-effectiveness analysis, the regimen of the included patients received trabectedin in a different line 9 g/m was modelled, as it is current practice in the of therapy than second line, and those patients were not used Netherlands. Based on the EORTC trials, a dose intensity of in the current analysis. All patients were adult and signed an 95% was implemented. Sarcoma 3 2.2. Survival Analysis. (e duration of progression-free 2.3.1. Survival. PFS and OS data of trabectedin and ifos- survival (PFS) was taken as the time from the first dose famide treatments were directly taken from the ET-D-010- of either study drug until disease progression. (e latter 10 and EORTC trials, respectively. Table 1 details the could be based on radiology findings or in case of tra- number of patients from each study, as well as baseline bectedin on clinical evaluation and cessation of treatment characteristics. To estimate average survival times, para- due to it. Duration of overall survival (OS) was counted from metric survival analyses were used, in which all patients were the day of the first study drug dose until death by any cause. pooled, regardless of treatment. (is facilitated extrapolating To perform an indirect nonparametric analysis of survival, survival beyond study follow-up and correcting for the the Kaplan–Meier method and the logrank test were used. (nonsignificant) difference in the ECOG performance score (e ECOG performance score was considered to be prog- between the prospective trabectedin and retrospective nostic for survival, more so than sex or age in patients who ifosfamide patients. Lognormal distributions were used, require second-line chemotherapy for STS. An ECOG based on the Akaike information criterion (data not shown, performance score of 0 was classified as low and a score of 1 considered alternative distributions were loglogistic, expo- or 2 as high. A Cox regression analysis was used for mul- nential, gamma, Gompertz, and Weibull distributions). tivariate tests, in which ECOG performance score and the Table 2 shows the estimated μ and σ for each treatment in drug received were included into the analysis. Survival each group of sarcomas for PFS and OS, as well as the probabilities at 3 and at 6months per treatment and group of associated average survival duration in months and years. sarcomas were calculated based on observed progression- free survival, and the number of treatment cycles was noted. 2.3.2. Utilities. Utility values represent the valuation of health, on a scale anchored at 1 for perfect health and 0 for health as poor as deceased. (e ET-D-010-10 trial could only 2.3. Cost-Effectiveness Analysis. A state-transition model provide preprogression utility data, which was scored using was constructed to estimate healthcare costs and quality- the EQ-5D and on average was 0.764. (erefore, EQ-5D adjusted life years (QALY), separately for the L-sarcoma and utility estimates for patients receiving second-line chemo- the non-L-sarcoma patients. In this model, patients were in a therapy from the SABINE trial were used. In the SABINE mutually exclusive state of either preprogression survival, trial, the health-related quality of life was assessed in patients postprogression survival (being overall survival (OS) minus with metastatic sarcoma from North America and Europe, preprogression survival), or deceased. (e pre- and post- including patients from the Netherlands [8]. Converting the progression average discounted life expectancies (DLEs) UK tariff to the Dutch tariff resulted in the pre- and were calculated for each treatment. Lifetime costs and postprogression utility score of 0.754 and 0.614, respectively. QALYs for treatment T, being either trabectedin or ifos- As the preprogression utility in the SABINE trial was very famide, were calculated as follows: similar to the utility found in the ET-D-010-10 trial, the costs � C + C × DLE usage of the SABINE utilities was considered appropriate. T T preprogression T,preprogression Utilities were assumed equal for L-sarcoma and non-L- + C × DLE , postprogression T,postprogression sarcoma patients and equal for both trabectedin and ifos- (1) famide treatment groups, except for the disutility caused by QALY �−U + U × DLE T T preprogression T,preprogression adverse events. + U × DLE , postprogression T,postprogression where C is the cost for treatment, such as drug acquisition 2.3.3. Health-Care Costs. Costs for trabectedin and ifosfa- and administration, and also those due to adverse events and mide cycles included drug acquisition costs and drug ad- U is the QALY loss due to adverse events. (e C ministration costs, as shown in Table 3. Drug administration T preprogression and C denote the annual treatment-unrelated costs included the costs for hospitalization and blood tests postprogression costs before and after progression. Similarly, U and imaging. (e majority of costs for trabectedin cycles preprogression and U denote the utilities before and after consisted of trabectedin acquisition costs, €4,238 out of postprogression progression. Each of these model parameters is described in €5,877 per cycle. For ifosfamide cycles, on the other hand, more detail below. Subsequently, the incremental cost- the 5-day hospitalization formed the largest part of the costs, effectiveness ratio (ICER) was calculated as follows: €2,470 out of €4,474 per cycle. A one-time treatment cost was added to include the cost for insertion of a central costs −costs trabectedin ifosfamide ICER � . (2) venous catheter (CVC), which was mandatory for all pa- QALY −QALY trabectedin ifosfamide tients receiving trabectedin and amounted to €1,015. Consistent with the Dutch guidelines [7], life years (LYs), Nontreatment-related monthly healthcare costs were esti- QALYs, and costs were discounted at 0%, 1.5%, and 4%, mated for patients by extracting these data from the ET-D- respectively. A lifetime horizon was used, and costs are 010-10 study. (ese costs were estimated separately from the reported in Euros at price level 2018. Other model com- pre- and postprogression period and assumed equal for ponents are described below. Additional lines of antitumour L-sarcoma and non-L-sarcoma patients and equal for the therapies had not been recorded in the EORTC or ET-D- trabectedin and ifosfamide treatment groups. During pre- 010-10 trial, and these were not assumed in the cost- progression survival, monthly costs were €284, and during effectiveness analysis. postprogression survival, this rose to €461, as shown in 4 Sarcoma Table 1: Baseline characteristics of study population. L-Sarcoma number (%) Non-L-sarcoma number (%) Baseline characteristics of study population Trabectedin Ifosfamide Trabectedin Ifosfamide Age at first dose Mean (SD) 55 (12) 54 (10) 57 (14) 45.3 (14) Female 16 (42.1) 9 (47.4) 9 (56.3) 19 (61.3) Sex Male 22 (57.9) 10 (52.6) 7 (43.8) 12 (38.7) 0 18 (47.4) 10 (52.6) 9 (56.3) 8 (25.8) ECOG PS 1+2 20 (52.6) 9 (47.4) 7 (43.8) 23 (74.2) ET-D-010-10 38 (100.0) — 16 (100.0) — Study size Nielsen et al. — 14 (73.7) — 17 (54.8) Oosterom et al. — 5 (26.3) — 14 (45.2) Trabectedin 38 (100.0) — 16 (100.0) — Drug received Ifosfamide — 19 (100.0) — 31 (100.0) Local disease 10 (26.3) 1 (5.3) 2 (12.5) 9 (29.0) Disease status Metastatic disease 28 (73.7) 18 (94.7) 14 (87.5) 22 (71.0) Leiomyosarcoma 19 (50.0) 13 (68.4) — — Liposarcoma 19 (50.0) 6 (31.6) — — UPS — 6 (37.5) 4 (19.4) Synovial sarcoma — 5 (31.3) 7 (22.6) Tumour histology Neurogenic sarcoma — — 4 (12.9) Hemangiosarcoma — — 3 (9.7) Rhabdomyosarcoma — — 3 (9.7) Others — 5 (31.3) 8 (25.8) SD: standard deviation; ECOG-PS: ECOG performance score; UPS: undifferentiated pleomorphic sarcoma. Table 2: Progression-free survival rate age at 3 and at 6months, the mean and median number of treatment cycles received, the parametric description of survival with the lognormal distribution, and average survival times. (e estimated average survival time with the lognormal distribution is calculated by exp (μ+ σ /2). L-Sarcoma Non-L-sarcoma Progression-free survival Trabectedin Ifosfamide Trabectedin Ifosfamide At 3months 59.5 47.4 37.5 51.6 PFS probability (%) At 6months 41.7 15.8 18.8 22.6 Mean 6.1 3.8 3.8 3.4 N treatment cycles Median 6 4 3 3 Parametric analysis of survival μ 1.50 1.08 1.00 1.20 PFS σ 1.05 1.05 1.04 1.04 In months 7.75 5.07 4.64 5.71 Average PFS In years 0.65 0.42 0.39 0.48 μ 2.42 2.15 1.77 2.21 OS σ 1.00 1.00 0.94 0.94 In months 18.58 14.17 9.09 14.18 Average OS In years 1.55 1.18 0.76 1.18 PFS: progression-free survival; OS: overall survival. ifosfamide, whereas ifosfamide gave more neutropenia, with Table 4. Costs were taken from Dutch publicly available sources. Prices were corrected for inflation to obtain 2018 its associated febrile neutropenia. (e total QALY loss due to levels. adverse events was 0.00153 for trabectedin and 0.00352 for ifosfamide, with costs of €1,119 and €1,841, respectively. 2.3.4. Adverse Events. Adverse events were scored in the EORTC and wider ET-D-010-10 trials, and the incidence 2.3.5. Sensitivity Analyses. To assess the sensitivity of the and duration of adverse events were taken directly from model for variations of key parameters, univariate sensitivity these trials, as shown in Table 5. Adverse events were as- analyses were performed and presented in a tornado dia- sumed equal for L-sarcoma and non-L-sarcoma patients. gram. (e difference in PFS and OS between trabectedin and Disutility and costs of data per adverse event were taken ifosfamide was varied over the 95% confidence interval (95% from the literature and converted to Dutch tariffs and 2018 CI) in the parametric survival analysis. (e other tested price levels. In this indirect comparison, trabectedin resulted variables were increased or decreased by 20%, which in- in more frequent elevation of liver enzymes compared to cluded costs of trabectedin, costs of ifosfamide, costs of Sarcoma 5 Table 3: Treatment-related costs of trabectedin and ifosfamide, for the average number of treatment cycles (see Table 2). Treatment-related costs Trabectedin Ifosfamide Unit Price Source Use Costs Use Costs Trabectedin 1mg vial €1,956 [9] 2.17 €4,238 — — Trabectedin 0.25mg vial €506 [9] 1.85 €938 — — Ifosfamide 2mg vial €121 [9] — — 8.87 €1,070 Dexamethasone 20mg vial €9 [9] 1 €9 — — Granisetron 1mg vial €4 [9] 2 €8 4 €16 Dexamethasone 8mg vial €3 [9] 1 €3 4 €11 Mesna 0.4mg vial €9 [9] — — 1 €718 Hospitalization per day €494 [7] 1 €494 5 €2,470 Full laboratory test €43 [10] 1 €43 1 €43 Haematological test €18 [10] 0.25 €5 0.25 €5 CT scan €157 [11] 0.25 €71 0.25 €71 MRI scan €264 [11] 0.25 €13 0.25 €13 Blood transfusion €224 [7] 0.25 €56 0.25 €56 Drug costs per cycle Drug acquisition costs €5,175 €1,070 Drug administration costs €702 €3,403 Drug costs, total per cycle €5,877 €4,474 One-time treatment costs CVC insertion €1,015 [11] 1 €1,015 0.30 €305 Total treatment costs (i) L-Sarcoma €36,895 €17,081 (ii) Non-L-sarcoma €23,595 €15,601 Mesna: 2-mercaptoethanesulfonate sodium. Table 4: Nontreatment-related costs per month during preprogression survival and postprogression survival. Nontreatment-related costs per month Preprogression survival Postprogression survival Unit Price Source Average use Cost Average use Cost Hospitalization per day €494 [7] 0.21 €106 0.48 €236 Full laboratory test €43 [10] 1.02 €44 1.24 €54 Haematological test €18 [10] 0.16 €3 0.13 €2 CT scan €157 [11] 0.31 €49 0.37 €58 MRI scan €265 [11] 0.01 €2 0.00 €0 Blood transfusion €224 [7] 0.09 €20 0.00 €0 General practitioner visit €34 [7] 0.01 €0 0.03 €1 Medical oncologist visit €102 [7] 0.58 €59 1.08 €110 Nurse €34 [7] 0.01 €0 0.02 €1 Psychologist €82 [7] 0.01 €1 0.00 €0 Total costs per period €284 €461 hospitalization per day, utility preprogression, utility post- as shown in Table 6. (e difference in PFS in this indirect progression, and body surface area. comparison showed a trend favouring trabectedin, but did not reach statistical significance with a p value of 0.074. In the multivariate regression, the drug received continued to 3. Results show a trend with a hazard ratio (HR) of 0.60 (95% CI, 0.33–1.07) and p value of 0.086. (e median OS for 3.1. Patient Characteristics. A total of 54 patients received L-sarcoma patients on trabectedin was 11.8months, and on trabectedin after doxorubicin in the phase IV trial from ifosfamide 8.2months, also a nonsignificant difference (p December 2010 to April 2014, and a total 50 patients were value, 0.184). For OS, high ECOG performance score at included from the EORTC trials published by Nielsen et al. baseline showed an association with reduced survival in both and van Oosterom et al. (e subsets of L-sarcoma and non- univariate and multivariate tests, with a HR of 1.91 (95% CI, L-sarcoma consisted of 57 and 47 patients, respectively, as 1.06–3.45) and p value 0.032, in the multivariate analysis. shown in Table 1. For non-L-sarcoma patients receiving trabectedin, the PFS was 2.0months, and for patients who received ifosfa- 3.2. Survival Analysis. L-Sarcoma patients had a median PFS mide, PFS was 3.3months, p value 0.819. High ECOG of 5.2months on trabectedin, and 2.6months on ifosfamide, performance score was associated with a worse PFS in both 6 Sarcoma Table 5: Adverse events, frequency, duration, disutility, and costs during trabectedin and ifosfamide treatment. Frequency of patients Average duration (days) QALY loss Total costs (%) Adverse events Disutility value Source Cost per event Source Trabectedin Ifosfamide Trabectedin Ifosfamide Trabectedin Ifosfamide Trabectedin Ifosfamide Fatigue and asthenia 2.1 2.2 5.0 5.0 0.216 [12] 0.00006 0.00007 €153 [13] €3 €3 Nausea 1.0 7.0 10.0 10.0 0.295 [12] 0.00008 0.00056 €1,464 [13] €15 €120 Vomiting 2.1 5.3 7.5 7.5 0.295 [12] 0.00013 0.00032 €1,464 [13] €31 €78 Anaemia 5.3 9.6 5.0 5.0 0.098 [14] 0.00007 0.00013 €1,864 [15] €99 €179 Neutropenia 14.9 39.0 7.5 5.0 0.124 [16] 0.00038 0.00066 €1,329 [15] €198 €518 Febrile neutropenia 4.3 19.7 12.5 13.0 0.124 [16] 0.00018 0.00087 €2,919 [15] €6 €575 (rombocytopenia 13.0 6.1 8.5 1.0 0.089 [17] 0.00027 0.00001 €3,503 [15] €445 €214 Elevation of liver enzymes 44.7 0.0 3.0 0.0 0.089 # 0.00033 — €153 [13] €68 — Alopecia 0.0 8.3 0.0 36.0 0.094 [16] — 0.00077 €512 [18] — €42 Neurotoxicity 0.0 5.7 1.0 1.0 0.195 [12] — 0.00003 €1,650 [13] — €94 Acute renal failure 0.0 1.8 0.0 16.0 0.124 [19] — 0.00010 €1,593 [20] — €29 Catheter-related infection 2.1 0.1 3.0 0.0 0.161 [17] 0.00003 — €5,920 [21] €124 €6 Total QALY loss 0.00153 0.00352 Total costs €1,119 €1,841 ∗ † # Translated to Dutch utilities; translated to 2018 costs in euro’s; assumed similar to thrombocytopenia. Sarcoma 7 Table 6: Nonparametric analysis of survival for L-sarcoma and non-L-sarcoma patients, univariate Kaplan–Meier analysis with median survival in months and logrank test, and multivariate Cox regression. (e univariate hazard ratio for age per year increase was 0.99 for all tests. L-Sarcoma Non-L-sarcoma Nonparametric survival Univariate Kaplan–Meier Median PFS 95% CI p value Median PFS 95% CI p value Progression-free survival Age 0.96–1.02 0.395 0.97–1.01 0.460 Sex (i) Female 3.19 0.00–6.62 0.621 2.89 1.76–4.03 0.931 (ii) Male 4.57 2.43–6.71 2.30 0.81–3.80 ECOG PS (i) 0 3.68 1.08–6.28 0.602 3.22 0.00–6.45 0.022 (ii) 1+2 3.29 0.00–7.90 1.91 0.46–3.35 Drug received (i) Trabectedin 5.19 3.31–7.07 0.074 2.04 1.52–2.55 0.819 (ii) Ifosfamide 2.63 0.43–4.83 3.25 2.33–4.18 Disease status (i) Local 3.29 0.00–7.01 0.740 3.25 0.00–6.80 0.875 (ii) Metastatic 3.94 1.40–6.48 2.43 1.27–4.30 Multivariate Cox regression HR 95% CI p value HR 95% CI p value (i) Drug received 0.60 0.33–1.07 0.086 1.35 0.67–2.74 0.403 (ii) ECOG PS 1.11 0.63–1.95 0.715 2.43 1.16–5.07 0.018 Univariate Kaplan–Meier Median OS 95% CI p value Median OS 95% CI p value Overall survival Age 0.96–1.02 0.498 0.97–1.01 0.273 Sex (i) Female 8.35 2.66–14.0 0.071 9.17 5.63–12.7 0.796 (ii) Male 14.85 10.2–19.5 5.55 3.68–7.42 ECOG PS (i) 0 13.41 7.57–19.2 0.033 13.77 7.72–19.8 0.008 (ii) 1+2 8.35 3.92–12.8 5.23 3.64–6.81 Drug received (i) Trabectedin 11.80 7.78–15.8 0.184 5.98 0.70–11.3 0.903 (ii) Ifosfamide 8.22 0.00–21.2 8.94 5.97–11.9 Disease status (i) Local 7.43 2.82–12.0 0.666 11.80 6.30–17.3 0.594 (ii) Metastatic 13.41 7.85–19.0 6.97 2.81–11.1 Multivariate Cox regression HR 95% CI p value HR 95% CI p value (i) Drug received 0.66 0.37–1.18 0.162 1.73 0.85–3.50 0.128 (ii) ECOG PS 1.91 1.06–3.45 0.032 2.99 1.44–6.20 0.003 PFS: progression-free survival; OS: overall survival; 95% CI: 95% confidence interval; ECOG PS: ECOG performance score; HR: hazard ratio. univariate test and multivariate test, with a HR of 2.43 (95% nonparametric survival analyses. For L-sarcoma patients, CI, 1.16–5.07) and p value 0.018 in the latter test. Median OS trabectedin produced longer PFS and OS than ifosfamide in this group was 6.0months for trabectedin and 8.9months did. For non-L-sarcoma patients, ifosfamide treatment for ifosfamide treatment (p value, 0.903). High ECOG produced longer PFS and OS than trabectedin. performance score was associated with shorter duration of For patients with L-sarcoma, the total discounted costs OS, and in the multivariate test, a HR of 2.99 (95% CI, were €44,879 for trabectedin and €24,797 for ifosfamide. 1.44–6.20), p value 0.003. Costs for trabectedin acquisition were higher than for Patients with an L-sarcoma had a PFS probability at ifosfamide (€31,597 vs. €4,113, respectively), but drug ad- 3months of 59.5%, and at 6months of 41.7% when receiving ministration costs were lower for trabectedin than ifosfa- trabectedin, as shown in Table 2. In this group, a mean of 6.1 mide (€5,298 vs.€13,380, respectively). (e latter difference and median of 6 treatment cycles were given. Patients who was due to longer hospitalization needed for ifosfamide had a non-L-sarcoma or who received ifosfamide had cycles. (e nontreatment related monthly costs were higher shorter survival and received fewer cycles of chemotherapy. for trabectedin owing to longer survival compared to ifos- famide (€6,866 vs.€5,464, respectively). (e costs for adverse events were lower for trabectedin than for ifosfamide (€1,119 3.3. Cost-Effectiveness Analysis. (e results from the cost- vs. €1,841, respectively). (ese treatments resulted in 1.524 effectiveness model are shown in Table 7. Results from the and 1.169 LY gained, respectively, which gives an ICER of parametric survival analysis were consistent with the €56,000 per LY gained. QALYs were 1,025 for trabectedin 8 Sarcoma Table 7: Estimated average costs and effectiveness, comparing trabectedin and ifosfamide in advanced L-sarcoma and non-L-sarcoma. L-Sarcoma Non-L-sarcoma Cost-effectiveness model Trabectedin Ifosfamide Difference Trabectedin Ifosfamide Difference Costs (all discounted) €44,879 €24,797 €20,082 €27,497 €22,799 €4,698 (i) Drug acquisition €31,597 €4,113 €27,484 €19,407 €3,660 €15,747 (ii) Drug administration €5,298 €13,380 −€8,082 €3,646 €11,941 − €8,295 (iii) Nonrelated costs €6,866 €5,464 €1,402 €3,325 €5,357 − €2,032 (iv) Adverse events costs €1,119 €1,841 −€722 €1,119 €1,841 − €722 Effectiveness (i) QALYs, discounted 1.025 0.773 0.251 0.516 0.781 −0.265 (ii) Preprogression LYs, undiscounted 0.646 0.423 0.223 0.386 0.476 −0.090 (iii) Postprogression LYs, undiscounted 0.902 0.758 0.144 0.371 0.694 −0.323 Cost-effectiveness ratios (i) Costs per LY gained €56,000 Ifosfamide dominant (ii) Costs per QALY gained €80,000 Ifosfamide dominant QALYs: quality-adjusted life years; LY: life years. and 0.773 for ifosfamide, leading to an ICER of€80,000 per ifosfamide dominated trabectedin as ifosfamide costs were QALY gained. lower but survival and QALYs gained higher compared to For patients with a non-L-sarcoma, ifosfamide domi- trabectedin treatment. Survival differences and trabectedin nated trabectedin since costs were higher for trabectedin acquisition costs had the strongest impact on the ICERs than ifosfamide (€27,497 vs. €22,799, respectively), while found. Future changes in trabectedin pricing would alter effectiveness for trabectedin was worse in terms of LYs the ICER. However, given the status of trabectedin as (0.754 vs. 1.170, respectively) and in terms of QALYs (0.516 “orphan drug” due to the low incidence of malignancies vs. 0.781, respectively). trabectedin is currently registered for, its price is not ex- pected to change in the foreseeable future. When this cost-effectiveness analysis was designed, a 3.4. Sensitivity Analyses. (e sensitivity analysis of L-sar- comparator group was sought that could provide for a coma showed the ICER to be most affected by the difference sensible comparison to second-line trabectedin. Ifosfamide in survival between trabectedin and ifosfamide, as shown in was chosen as this drug was widely tested in STS, and data Figure 1. (is effect was most prominent in OS. (e 95% CI for second-line treatment were available at the EORTC. Due of the difference in OS for trabectedin and ifosfamide was to the adverse events and the long hospital admission per −3.6 to 18.4months, and this meant an overlap of OS du- treatment cycle, this drug has been used less extensively over ration. (is resulted in ICER ranging from €28,000 per last decade, and alternatives are available. In terms of ex- QALY gained in favour of trabectedin to ifosfamide being pected antitumour effect, ifosfamide was still considered to dominant for OS. (e ICER across the 95% CI of PFS also represent a realistic comparator group. Additionally, po- varied substantially, but QALYs remained in favour of tential alternative data sets would not match the patient trabectedin, with the ICER ranging from€59,000 to€98,000 population of the trabectedin-treated patients. per QALY gained. Another clear influence on ICER varia- (is cost-effectiveness study was not a randomised tion was the cost of trabectedin, with the ICER ranging from comparison, contrary to the designs of the original ifosfa- €55,000 to €105,000. mide studies. To reduce bias, survival was counted from the As the base-case analysis showed ifosfamide to dominate moment of first drug infusion, not the moment of trial trabectedin in patients with non-L-sarcoma, a sensitivity inclusion as in the original trials. (is was done to evade a analysis for non-L-sarcoma was not performed. potential bias, wherein the duration of survival of either ifosfamide or trabectedin would have been longer due to effects other than drug effects. (erefore, the difference in 4. Discussion survival now reported is accurately reflecting survival fol- lowing treatment. (e EORTC STBSG has used progression- Trabectedin was shown to be an active drug in the second- line treatment of L-sarcomas (either leiomyosarcoma or free rates (PFRs) as an indicator whether a drug is active as a second-line agent in STS [22]. Agents considered active have liposarcoma). In this nonrandomised comparison, the median survival of patients with L-sarcomas was an estimated PFR at 3months of 39% and at 6months of 2.5months longer if they received trabectedin instead of 14%. For L-sarcoma, trabectedin showed, by this standard, ifosfamide, not meeting the criterion for statistical sig- to be an active drug in this population with a PFR of 59% and nificance (p � 0.074). In non-L-sarcoma, ifosfamide 42%, respectively. For non-L-sarcoma, trabectedin was less resulted in longer survival, but the difference was not potent with a PFR at 3months just below the threshold at significant. (e cost-effectiveness analysis of trabectedin 37% and PFR at 6months at 19%. (e PFRs for ifosfamide were above the EORTC STBSG number in both L-sarcoma compared to ifosfamide showed an ICER of €80,000 per QALY gained in case of L-sarcoma. For non-L-sarcoma, and non-L-sarcoma. Sarcoma 9 Base case €80.000 Overall survival (95% CI) €28.000 Costs for trabectedin (±20%) €55.000 €105.000 Body surface area (±20%) €61.000 €105.000 Progression-free survival (95% CI) €59.000 €98.000 Utility preprogression (±20%) €71.000 €92.000 Utility postprogression (±20%) €75.000 €86.000 Costs for hospitalization (±20%) €75.000 €85.000 Costs for ifosfamide (±20%) €77.000 €83.000 Costs for preprogression (±20%) €79.000 €81.000 Costs for postprogression (±20%) €79.000 €80.000 Costs for adverse events (±20%) €79.000 €80.000 €0 €40.000 €80.000 €120.000 –20%/low end of 95% CI +20%/high end of 95% CI Figure 1: Tornado diagram representing the univariate sensitivity analysis for L-sarcoma, numbers abbreviated to thousands. All variables other than survival were increased (light-shaded bars) or decreased (dark-shaded bars) by 20%. For progression-free survival and overall survival, the 95% confidence interval (95% CI) of the survival difference between trabectedin and ifosfamide was used (low end: light-shaded bars; high end: dark-shaded bars). Note that the bar for the low end of the difference in OS does not stop and no number is given, as ifosfamide dominated trabectedin at that point, with a negative ICER. OS: overall survival; PFS: progression-free survival. Several studies have previously investigated the cost- four phase II studies of patients receiving trabectedin for effectiveness of trabectedin in STS compared to other treat- advanced STS was used in a 2015 study comparing the cost- ments. In a 2011 study by Soini et al., trabectedin was effectiveness of trabectedin and the tyrosine kinase inhibitor pazopanib [25]. (e HR calculated was 1.11 in favour of compared to ifosfamide [23]. Trabectedin data were taken from a 2009 randomised trial comparing trabectedin treat- pazopanib (with 95% CI of 0.94–1.31). Pazopanib treatment costs were half the cost of trabectedin cycles. As pazopanib is ment regimen and ifosfamide data from the same studies by van Oosterom and Nielsen used in the current study [5, 6]. All oral medication which is taken without the need for hospital patients on trabectedin had an L-sarcoma, whereas sarcoma admissions, the majority of patients will prefer pazopanib for subtypes were not clear for patients with ifosfamide. (e study that fact alone, regardless of costs. A study comparing found an ICER per LY gained of€ 31,590 and€ 42,633–47,735 pazopanib to placebo in advanced STS patients resulted in an per QALY gained when prescribing trabectedin. (ese ICERs ICER of €77,120 per QALY gained when taking pazopanib are lower than in the current study, suggesting better tra- treatment, illustrating the high costs of therapies aimed at bectedin cost-effectiveness. (e most evident cause for this treating advanced STS [13]. difference is the higher survival benefit due to ifosfamide in Compared to the 2016 randomised phase III trial by Demetri et al. comparing trabectedin vs. dacarbazine in the current study compared to Soini et al. (1.17 LY vs. 0.60 LY, respectively), whereas there were higher costs of ifosfamide pretreated metastatic L-sarcoma patients, patients on tra- treatment in Soini et al. (€13,053–14,286 vs. €7,568, re- bectedin in the current study in a real-life setting had a spectively). (e difference in survival gained due to ifosfa- higher median PFS (4.2 vs. 5.2months, respectively), mide, even though these are taken from the same studies, whereas OS was slightly lower (12.4months vs. 11.8months, suggests a difference in patient selection between the cost- respectively) [26]. A possible explanation for the PFS dif- effectiveness studies. ference is the blinded radiologic evaluation of imaging to A 2013 indirect comparison into the cost-effectiveness of assess PFS in the randomised trial. (e efficacy of tra- doxorubicin-ifosfamide combination vs. trabectedin also bectedin vs. dacarbazine showed better PFS for trabectedin but equal OS [26]. Unfortunately, this trial did not include showed more QALYs gained at lower health-care costs for doxorubicin-ifosfamide [24]. A pooled patient cohort from QALY assessments. 10 Sarcoma A study by Le Cesne ABJYC et al. presented at the 2018 in an estimated ICER of€80,000. (is ICER is at the top end ASCO meeting randomised pretreated advanced STS pa- of what is generally considered acceptable in the Netherlands tients between trabectedin and BSC, giving the comparison [30]. As there is a clinically unmet need for antitumour originally attempted for this cost-effectiveness analysis [27]. agents in the group of rare malignancies, this threshold may In that trial, trabectedin showed better PFS than BSC for not be the most relevant factor in the decision to continue to L-sarcomas (5.3 vs. 1.4months, respectively), but not for prescribe trabectedin to these patients. For non-L-sarcoma, non-L-sarcomas (1.8 vs. 1.5months, respectively). OS did ifosfamide treatment dominated trabectedin. not differ, and this was deemed due to per-protocol crossover to trabectedin after progressive disease on BSC. Data Availability (is trial demonstrates the efficacy of trabectedin for (e raw data used to support the findings of this study are L-sarcomas compared to BSC. (e efficacy of trabectedin available from the corresponding author upon request. within the group of L-sarcomas also varies, and it offers the largest benefit in patients with myxoid liposarcoma [28]. (e Conflicts of Interest actual size of the antitumour effect in myxoid liposarcoma is blunted in clinical trials as other liposarcoma subtypes, in (e authors declare that there are no conflicts of interest which trabectedin is less active, and are included in the same regarding the publication of this paper. trials. (e number of patients in this cost-effectiveness analysis was too small to detect any differences between Acknowledgments leiomyosarcomas vs. liposarcomas or myxoid liposarcomas vs. other liposarcoma subtypes. (is study was funded by a grant from ZonMw (152001018). (is cost-effectiveness analysis has several limitations, especially since it was not possible to perform the study References originally set out to do. 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Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients

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Hindawi Publishing Corporation
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Copyright © 2019 Michiel C. Verboom et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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DOI
10.1155/2019/3234205
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Abstract

Hindawi Sarcoma Volume 2019, Article ID 3234205, 11 pages https://doi.org/10.1155/2019/3234205 Research Article Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients 1 1 2 2 Michiel C. Verboom , Hans Gelderblom , J. Martijn Kerst, Neeltje Steeghs , 3 4 5 Anna K. L. Reyners, Stefan Sleijfer, Winette T. A. van der Graaf, and Wilbert B. van den Hout Department of Medical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, P.O. Box 90203, 1006 BE Amsterdam, Netherlands Department of Medical Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, Netherlands Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 5201, 3008 AE Rotterdam, Netherlands Department of Medical Oncology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, Netherlands Department of Medical Decision Making, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, Netherlands Correspondence should be addressed to Michiel C. Verboom; m.c.verboom@lumc.nl Received 23 January 2019; Accepted 9 May 2019; Published 2 June 2019 Academic Editor: Kanya Honoki Copyright © 2019 Michiel C. Verboom et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Trabectedin and ifosfamide are among the few cytostatic agents active in advanced soft tissue sarcomas (STSs). Trabectedin is most potent against so-called L-sarcomas (leiomyosarcoma and liposarcoma). (e survival gain and cost-effectiveness of these agents in a second-line setting were analysed in the setting of advanced STS after failure of anthracyclines. A prospective observational trial had previously been performed to assess the use of trabectedin in a Dutch real-world setting. Data on ifosfamide monotherapy were acquired from previous studies, and an indirect comparison of survival was made. A state-transition economic model was constructed, in which patients could be in mutually exclusive states of being preprogression, postprogression, or deceased. (e costs and quality-adjusted life years (QALYs) for both treatments were assessed from a Dutch health-care perspective. Separate analyses for the group of L-sarcomas and non-L-sarcomas were performed. Trabectedin treatment resulted in a median progression-free survival of 5.2months for L-sarcoma patients, 2.0months for non-L-sarcoma patients, and a median overall survival of 11.8 and 6.0months, respectively. For L-sarcoma patients, trabectedin offered an increase of 0.368 life years and 0.251 QALYs compared to ifosfamide and€20,082 in additional costs, for an incremental cost-effectiveness ratio (ICER) of€80,000 per QALY gained. In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of€4,698. (e difference in survival between drugs and the acquisition costs of trabectedin were the main influences in these models. Trabectedin was shown to have antitumour efficacy in advanced L-sarcoma. From a health economics perspective, the costs per QALY gained compared to ifosfamide monotherapy that may be acceptable, considering what is currently regarded as acceptable in the Netherlands. all adult malignancies. STSs in general are relatively in- 1. Introduction sensitive to chemotherapy compared to tumours of epithelial Soft tissue sarcomas (STSs) are a rare group of malignancies origin. Some drugs, such as doxorubicin, have been found arising from mesenchymal cells comprising one percent of active in a range of different sarcoma subtypes, whereas 2 Sarcoma others show only activity in specific subtypes, such as cri- Institutional Review Board approved informed consent form zotinib in the inflammatory myofibroblastic tumour [1]. [4]. At the time of the ET-D-010-10 observational trial, no Trabectedin is a drug active in several subtypes, with most notable effect in leiomyosarcoma and liposarcoma. It has a study had yet directly compared the efficacy of trabectedin to unique mechanism of action in binding to the minor groove BSC. Hence, the choice of treatment was with the patient and of DNA and also in influencing the tumour environment local physician, as long as the patient was deemed fit enough [2, 3]. to receive chemotherapy. It was intended to include 100 Trabectedin was approved for clinical use in Europe in patients, of whom 80 would have received trabectedin and 20 2007 for patients with advanced STS after failure to would have chosen BSC. In reality, however, a larger portion anthracyclines and ifosfamide or for patients unsuited to of patients wished to be treated with trabectedin (91%) than receive these agents. At this time, studies with a randomised predicted, and too few patients chose the BSC arm (total 9%: comparison with other treatment options were not available. 6% only BSC and 3% received additional or other systemic (erefore, before market authorization in the Netherlands antitumour therapies). Despite an extension of the trial duration, accrual of the BSC arm was insufficient to be able could be granted, a prospective observational trial was designed, which aimed to analyse the use of trabectedin in to perform a viable comparison of the collected data. STS in a real-world setting. To account for the lack of a trial-generated comparator (e original aim of this observational trial was to analyse group, it was decided to perform an indirect comparison of the use of trabectedin compared to best supportive care the data in the trabectedin arm with data obtained from (BSC) and derive an incremental cost-effectiveness ratio previous studies. As appropriate data on patients on BSC (ICER) for its use compared to BSC. All patients eligible for were not available, an agent active as second-line treatment trabectedin were also given the option of BSC, but only a few was sought. (ese data were obtained from two EORTC patients opted for BSC, which made it impossible to draw clinical trials with ifosfamide in patients with advanced STS, meaningful conclusions from this small number of patients. published by Nielsen et al. and van Oosterom et al., hereafter Instead, as an alternative, a comparison with ifosfamide in termed “the EORTC trials” [5, 6]. (ese two trials used the 1979 WHO criteria for response evaluation. According to retrospective data was sought, as this drug is a treatment option for patients with advanced STS after failure to the 2018 ESMO guideline on STS treatment, after doxoru- anthracyclines. Ifosfamide is an alkylating agent and bicin, patients may be treated with ifosfamide, if they did not available since the 1980s for the treatment of STSs. progress on it previously [1]. (erefore, a second-line setting (erefore, this study aims to compare both survival and was chosen for comparing the phase IV ET-D-010-10 data cost-effectiveness between trabectedin and ifosfamide in the on trabectedin with the EORTC data on ifosfamide. setting of second-line cytostatic treatment of STS in the (e efficacy of ifosfamide differs in STS subtypes to a Netherlands. certain extent, but has not been shown to differ as much between subtypes as trabectedin does. Trabectedin has a markedly better efficacy in leiomyosarcoma and liposarcoma 2. Methods subtypes, the so-called L-sarcomas. (is difference in effi- cacy between L-sarcomas and non-L-sarcomas has led to 2.1. Patient Selection. In order to facilitate the entry and reimbursement of trabectedin in the Dutch health-care clinical trials which specifically included patients with one of these two subtypes [2]. Due to the prominence of the system, a cost-effectiveness analysis was designed to eval- uate trabectedin and BSC usage patterns and outcomes in L-sarcomas in trabectedin clinical research, it was decided to split the study population into two subsets, consisting of advanced STS in a real-world setting, including data on quality of life and associated utilities. (is prospective ob- L-sarcomas and non-L-sarcomas. servational phase IV trial was to provide the Dutch health Out of all patients included in the phase IV trial, 54 authority (Zorginstituut Nederland) with sufficient data on patients received trabectedin as second-line treatment. (e the effectiveness and optimal use of trabectedin to ensure a remaining 39 patients received trabectedin as third or higher line of treatment and were excluded from the cost- proper evaluation for permanent registry in the Regulation Orphan Drugs. (is trial was named ET-D-010-10, with trial effectiveness analysis. (e drug was prescribed in the ac- cepted regimen of 1.5 mg/m registration number NCT01299506. (e RECIST 1.1 criteria once every 3 weeks during a were used for response evaluation. Quality-of-life data were 24-hour hospital admission. Due to dose reductions, the scored using patient-reported EQ-5D questionnaires. Pa- average administered trabectedin dose was 1.3mg/m . tients with all subtypes of STS were recruited in this trial if From the ifosfamide trials, a total of 50 patients were they were eligible for trabectedin, after the failure of identified to fit the criterion of second-line treatment. (e anthracyclines and/or ifosfamide, or in case, these patients ifosfamide dosage was 9g/m given in 3 consecutive days were unsuited to receive these drugs. (e patients in this every 3 weeks (19 patients) [6], or 12g/m as a 3-day observational trial were offered treatment with trabectedin continuous infusion every 4 weeks (31 patients) [5], to- or BSC, and the latter could consist of no systemic che- gether with intravenous Mesna to prevent hemorrhagic motherapy or other systemic antitumour therapies. Some of cystitis. For the cost-effectiveness analysis, the regimen of the included patients received trabectedin in a different line 9 g/m was modelled, as it is current practice in the of therapy than second line, and those patients were not used Netherlands. Based on the EORTC trials, a dose intensity of in the current analysis. All patients were adult and signed an 95% was implemented. Sarcoma 3 2.2. Survival Analysis. (e duration of progression-free 2.3.1. Survival. PFS and OS data of trabectedin and ifos- survival (PFS) was taken as the time from the first dose famide treatments were directly taken from the ET-D-010- of either study drug until disease progression. (e latter 10 and EORTC trials, respectively. Table 1 details the could be based on radiology findings or in case of tra- number of patients from each study, as well as baseline bectedin on clinical evaluation and cessation of treatment characteristics. To estimate average survival times, para- due to it. Duration of overall survival (OS) was counted from metric survival analyses were used, in which all patients were the day of the first study drug dose until death by any cause. pooled, regardless of treatment. (is facilitated extrapolating To perform an indirect nonparametric analysis of survival, survival beyond study follow-up and correcting for the the Kaplan–Meier method and the logrank test were used. (nonsignificant) difference in the ECOG performance score (e ECOG performance score was considered to be prog- between the prospective trabectedin and retrospective nostic for survival, more so than sex or age in patients who ifosfamide patients. Lognormal distributions were used, require second-line chemotherapy for STS. An ECOG based on the Akaike information criterion (data not shown, performance score of 0 was classified as low and a score of 1 considered alternative distributions were loglogistic, expo- or 2 as high. A Cox regression analysis was used for mul- nential, gamma, Gompertz, and Weibull distributions). tivariate tests, in which ECOG performance score and the Table 2 shows the estimated μ and σ for each treatment in drug received were included into the analysis. Survival each group of sarcomas for PFS and OS, as well as the probabilities at 3 and at 6months per treatment and group of associated average survival duration in months and years. sarcomas were calculated based on observed progression- free survival, and the number of treatment cycles was noted. 2.3.2. Utilities. Utility values represent the valuation of health, on a scale anchored at 1 for perfect health and 0 for health as poor as deceased. (e ET-D-010-10 trial could only 2.3. Cost-Effectiveness Analysis. A state-transition model provide preprogression utility data, which was scored using was constructed to estimate healthcare costs and quality- the EQ-5D and on average was 0.764. (erefore, EQ-5D adjusted life years (QALY), separately for the L-sarcoma and utility estimates for patients receiving second-line chemo- the non-L-sarcoma patients. In this model, patients were in a therapy from the SABINE trial were used. In the SABINE mutually exclusive state of either preprogression survival, trial, the health-related quality of life was assessed in patients postprogression survival (being overall survival (OS) minus with metastatic sarcoma from North America and Europe, preprogression survival), or deceased. (e pre- and post- including patients from the Netherlands [8]. Converting the progression average discounted life expectancies (DLEs) UK tariff to the Dutch tariff resulted in the pre- and were calculated for each treatment. Lifetime costs and postprogression utility score of 0.754 and 0.614, respectively. QALYs for treatment T, being either trabectedin or ifos- As the preprogression utility in the SABINE trial was very famide, were calculated as follows: similar to the utility found in the ET-D-010-10 trial, the costs � C + C × DLE usage of the SABINE utilities was considered appropriate. T T preprogression T,preprogression Utilities were assumed equal for L-sarcoma and non-L- + C × DLE , postprogression T,postprogression sarcoma patients and equal for both trabectedin and ifos- (1) famide treatment groups, except for the disutility caused by QALY �−U + U × DLE T T preprogression T,preprogression adverse events. + U × DLE , postprogression T,postprogression where C is the cost for treatment, such as drug acquisition 2.3.3. Health-Care Costs. Costs for trabectedin and ifosfa- and administration, and also those due to adverse events and mide cycles included drug acquisition costs and drug ad- U is the QALY loss due to adverse events. (e C ministration costs, as shown in Table 3. Drug administration T preprogression and C denote the annual treatment-unrelated costs included the costs for hospitalization and blood tests postprogression costs before and after progression. Similarly, U and imaging. (e majority of costs for trabectedin cycles preprogression and U denote the utilities before and after consisted of trabectedin acquisition costs, €4,238 out of postprogression progression. Each of these model parameters is described in €5,877 per cycle. For ifosfamide cycles, on the other hand, more detail below. Subsequently, the incremental cost- the 5-day hospitalization formed the largest part of the costs, effectiveness ratio (ICER) was calculated as follows: €2,470 out of €4,474 per cycle. A one-time treatment cost was added to include the cost for insertion of a central costs −costs trabectedin ifosfamide ICER � . (2) venous catheter (CVC), which was mandatory for all pa- QALY −QALY trabectedin ifosfamide tients receiving trabectedin and amounted to €1,015. Consistent with the Dutch guidelines [7], life years (LYs), Nontreatment-related monthly healthcare costs were esti- QALYs, and costs were discounted at 0%, 1.5%, and 4%, mated for patients by extracting these data from the ET-D- respectively. A lifetime horizon was used, and costs are 010-10 study. (ese costs were estimated separately from the reported in Euros at price level 2018. Other model com- pre- and postprogression period and assumed equal for ponents are described below. Additional lines of antitumour L-sarcoma and non-L-sarcoma patients and equal for the therapies had not been recorded in the EORTC or ET-D- trabectedin and ifosfamide treatment groups. During pre- 010-10 trial, and these were not assumed in the cost- progression survival, monthly costs were €284, and during effectiveness analysis. postprogression survival, this rose to €461, as shown in 4 Sarcoma Table 1: Baseline characteristics of study population. L-Sarcoma number (%) Non-L-sarcoma number (%) Baseline characteristics of study population Trabectedin Ifosfamide Trabectedin Ifosfamide Age at first dose Mean (SD) 55 (12) 54 (10) 57 (14) 45.3 (14) Female 16 (42.1) 9 (47.4) 9 (56.3) 19 (61.3) Sex Male 22 (57.9) 10 (52.6) 7 (43.8) 12 (38.7) 0 18 (47.4) 10 (52.6) 9 (56.3) 8 (25.8) ECOG PS 1+2 20 (52.6) 9 (47.4) 7 (43.8) 23 (74.2) ET-D-010-10 38 (100.0) — 16 (100.0) — Study size Nielsen et al. — 14 (73.7) — 17 (54.8) Oosterom et al. — 5 (26.3) — 14 (45.2) Trabectedin 38 (100.0) — 16 (100.0) — Drug received Ifosfamide — 19 (100.0) — 31 (100.0) Local disease 10 (26.3) 1 (5.3) 2 (12.5) 9 (29.0) Disease status Metastatic disease 28 (73.7) 18 (94.7) 14 (87.5) 22 (71.0) Leiomyosarcoma 19 (50.0) 13 (68.4) — — Liposarcoma 19 (50.0) 6 (31.6) — — UPS — 6 (37.5) 4 (19.4) Synovial sarcoma — 5 (31.3) 7 (22.6) Tumour histology Neurogenic sarcoma — — 4 (12.9) Hemangiosarcoma — — 3 (9.7) Rhabdomyosarcoma — — 3 (9.7) Others — 5 (31.3) 8 (25.8) SD: standard deviation; ECOG-PS: ECOG performance score; UPS: undifferentiated pleomorphic sarcoma. Table 2: Progression-free survival rate age at 3 and at 6months, the mean and median number of treatment cycles received, the parametric description of survival with the lognormal distribution, and average survival times. (e estimated average survival time with the lognormal distribution is calculated by exp (μ+ σ /2). L-Sarcoma Non-L-sarcoma Progression-free survival Trabectedin Ifosfamide Trabectedin Ifosfamide At 3months 59.5 47.4 37.5 51.6 PFS probability (%) At 6months 41.7 15.8 18.8 22.6 Mean 6.1 3.8 3.8 3.4 N treatment cycles Median 6 4 3 3 Parametric analysis of survival μ 1.50 1.08 1.00 1.20 PFS σ 1.05 1.05 1.04 1.04 In months 7.75 5.07 4.64 5.71 Average PFS In years 0.65 0.42 0.39 0.48 μ 2.42 2.15 1.77 2.21 OS σ 1.00 1.00 0.94 0.94 In months 18.58 14.17 9.09 14.18 Average OS In years 1.55 1.18 0.76 1.18 PFS: progression-free survival; OS: overall survival. ifosfamide, whereas ifosfamide gave more neutropenia, with Table 4. Costs were taken from Dutch publicly available sources. Prices were corrected for inflation to obtain 2018 its associated febrile neutropenia. (e total QALY loss due to levels. adverse events was 0.00153 for trabectedin and 0.00352 for ifosfamide, with costs of €1,119 and €1,841, respectively. 2.3.4. Adverse Events. Adverse events were scored in the EORTC and wider ET-D-010-10 trials, and the incidence 2.3.5. Sensitivity Analyses. To assess the sensitivity of the and duration of adverse events were taken directly from model for variations of key parameters, univariate sensitivity these trials, as shown in Table 5. Adverse events were as- analyses were performed and presented in a tornado dia- sumed equal for L-sarcoma and non-L-sarcoma patients. gram. (e difference in PFS and OS between trabectedin and Disutility and costs of data per adverse event were taken ifosfamide was varied over the 95% confidence interval (95% from the literature and converted to Dutch tariffs and 2018 CI) in the parametric survival analysis. (e other tested price levels. In this indirect comparison, trabectedin resulted variables were increased or decreased by 20%, which in- in more frequent elevation of liver enzymes compared to cluded costs of trabectedin, costs of ifosfamide, costs of Sarcoma 5 Table 3: Treatment-related costs of trabectedin and ifosfamide, for the average number of treatment cycles (see Table 2). Treatment-related costs Trabectedin Ifosfamide Unit Price Source Use Costs Use Costs Trabectedin 1mg vial €1,956 [9] 2.17 €4,238 — — Trabectedin 0.25mg vial €506 [9] 1.85 €938 — — Ifosfamide 2mg vial €121 [9] — — 8.87 €1,070 Dexamethasone 20mg vial €9 [9] 1 €9 — — Granisetron 1mg vial €4 [9] 2 €8 4 €16 Dexamethasone 8mg vial €3 [9] 1 €3 4 €11 Mesna 0.4mg vial €9 [9] — — 1 €718 Hospitalization per day €494 [7] 1 €494 5 €2,470 Full laboratory test €43 [10] 1 €43 1 €43 Haematological test €18 [10] 0.25 €5 0.25 €5 CT scan €157 [11] 0.25 €71 0.25 €71 MRI scan €264 [11] 0.25 €13 0.25 €13 Blood transfusion €224 [7] 0.25 €56 0.25 €56 Drug costs per cycle Drug acquisition costs €5,175 €1,070 Drug administration costs €702 €3,403 Drug costs, total per cycle €5,877 €4,474 One-time treatment costs CVC insertion €1,015 [11] 1 €1,015 0.30 €305 Total treatment costs (i) L-Sarcoma €36,895 €17,081 (ii) Non-L-sarcoma €23,595 €15,601 Mesna: 2-mercaptoethanesulfonate sodium. Table 4: Nontreatment-related costs per month during preprogression survival and postprogression survival. Nontreatment-related costs per month Preprogression survival Postprogression survival Unit Price Source Average use Cost Average use Cost Hospitalization per day €494 [7] 0.21 €106 0.48 €236 Full laboratory test €43 [10] 1.02 €44 1.24 €54 Haematological test €18 [10] 0.16 €3 0.13 €2 CT scan €157 [11] 0.31 €49 0.37 €58 MRI scan €265 [11] 0.01 €2 0.00 €0 Blood transfusion €224 [7] 0.09 €20 0.00 €0 General practitioner visit €34 [7] 0.01 €0 0.03 €1 Medical oncologist visit €102 [7] 0.58 €59 1.08 €110 Nurse €34 [7] 0.01 €0 0.02 €1 Psychologist €82 [7] 0.01 €1 0.00 €0 Total costs per period €284 €461 hospitalization per day, utility preprogression, utility post- as shown in Table 6. (e difference in PFS in this indirect progression, and body surface area. comparison showed a trend favouring trabectedin, but did not reach statistical significance with a p value of 0.074. In the multivariate regression, the drug received continued to 3. Results show a trend with a hazard ratio (HR) of 0.60 (95% CI, 0.33–1.07) and p value of 0.086. (e median OS for 3.1. Patient Characteristics. A total of 54 patients received L-sarcoma patients on trabectedin was 11.8months, and on trabectedin after doxorubicin in the phase IV trial from ifosfamide 8.2months, also a nonsignificant difference (p December 2010 to April 2014, and a total 50 patients were value, 0.184). For OS, high ECOG performance score at included from the EORTC trials published by Nielsen et al. baseline showed an association with reduced survival in both and van Oosterom et al. (e subsets of L-sarcoma and non- univariate and multivariate tests, with a HR of 1.91 (95% CI, L-sarcoma consisted of 57 and 47 patients, respectively, as 1.06–3.45) and p value 0.032, in the multivariate analysis. shown in Table 1. For non-L-sarcoma patients receiving trabectedin, the PFS was 2.0months, and for patients who received ifosfa- 3.2. Survival Analysis. L-Sarcoma patients had a median PFS mide, PFS was 3.3months, p value 0.819. High ECOG of 5.2months on trabectedin, and 2.6months on ifosfamide, performance score was associated with a worse PFS in both 6 Sarcoma Table 5: Adverse events, frequency, duration, disutility, and costs during trabectedin and ifosfamide treatment. Frequency of patients Average duration (days) QALY loss Total costs (%) Adverse events Disutility value Source Cost per event Source Trabectedin Ifosfamide Trabectedin Ifosfamide Trabectedin Ifosfamide Trabectedin Ifosfamide Fatigue and asthenia 2.1 2.2 5.0 5.0 0.216 [12] 0.00006 0.00007 €153 [13] €3 €3 Nausea 1.0 7.0 10.0 10.0 0.295 [12] 0.00008 0.00056 €1,464 [13] €15 €120 Vomiting 2.1 5.3 7.5 7.5 0.295 [12] 0.00013 0.00032 €1,464 [13] €31 €78 Anaemia 5.3 9.6 5.0 5.0 0.098 [14] 0.00007 0.00013 €1,864 [15] €99 €179 Neutropenia 14.9 39.0 7.5 5.0 0.124 [16] 0.00038 0.00066 €1,329 [15] €198 €518 Febrile neutropenia 4.3 19.7 12.5 13.0 0.124 [16] 0.00018 0.00087 €2,919 [15] €6 €575 (rombocytopenia 13.0 6.1 8.5 1.0 0.089 [17] 0.00027 0.00001 €3,503 [15] €445 €214 Elevation of liver enzymes 44.7 0.0 3.0 0.0 0.089 # 0.00033 — €153 [13] €68 — Alopecia 0.0 8.3 0.0 36.0 0.094 [16] — 0.00077 €512 [18] — €42 Neurotoxicity 0.0 5.7 1.0 1.0 0.195 [12] — 0.00003 €1,650 [13] — €94 Acute renal failure 0.0 1.8 0.0 16.0 0.124 [19] — 0.00010 €1,593 [20] — €29 Catheter-related infection 2.1 0.1 3.0 0.0 0.161 [17] 0.00003 — €5,920 [21] €124 €6 Total QALY loss 0.00153 0.00352 Total costs €1,119 €1,841 ∗ † # Translated to Dutch utilities; translated to 2018 costs in euro’s; assumed similar to thrombocytopenia. Sarcoma 7 Table 6: Nonparametric analysis of survival for L-sarcoma and non-L-sarcoma patients, univariate Kaplan–Meier analysis with median survival in months and logrank test, and multivariate Cox regression. (e univariate hazard ratio for age per year increase was 0.99 for all tests. L-Sarcoma Non-L-sarcoma Nonparametric survival Univariate Kaplan–Meier Median PFS 95% CI p value Median PFS 95% CI p value Progression-free survival Age 0.96–1.02 0.395 0.97–1.01 0.460 Sex (i) Female 3.19 0.00–6.62 0.621 2.89 1.76–4.03 0.931 (ii) Male 4.57 2.43–6.71 2.30 0.81–3.80 ECOG PS (i) 0 3.68 1.08–6.28 0.602 3.22 0.00–6.45 0.022 (ii) 1+2 3.29 0.00–7.90 1.91 0.46–3.35 Drug received (i) Trabectedin 5.19 3.31–7.07 0.074 2.04 1.52–2.55 0.819 (ii) Ifosfamide 2.63 0.43–4.83 3.25 2.33–4.18 Disease status (i) Local 3.29 0.00–7.01 0.740 3.25 0.00–6.80 0.875 (ii) Metastatic 3.94 1.40–6.48 2.43 1.27–4.30 Multivariate Cox regression HR 95% CI p value HR 95% CI p value (i) Drug received 0.60 0.33–1.07 0.086 1.35 0.67–2.74 0.403 (ii) ECOG PS 1.11 0.63–1.95 0.715 2.43 1.16–5.07 0.018 Univariate Kaplan–Meier Median OS 95% CI p value Median OS 95% CI p value Overall survival Age 0.96–1.02 0.498 0.97–1.01 0.273 Sex (i) Female 8.35 2.66–14.0 0.071 9.17 5.63–12.7 0.796 (ii) Male 14.85 10.2–19.5 5.55 3.68–7.42 ECOG PS (i) 0 13.41 7.57–19.2 0.033 13.77 7.72–19.8 0.008 (ii) 1+2 8.35 3.92–12.8 5.23 3.64–6.81 Drug received (i) Trabectedin 11.80 7.78–15.8 0.184 5.98 0.70–11.3 0.903 (ii) Ifosfamide 8.22 0.00–21.2 8.94 5.97–11.9 Disease status (i) Local 7.43 2.82–12.0 0.666 11.80 6.30–17.3 0.594 (ii) Metastatic 13.41 7.85–19.0 6.97 2.81–11.1 Multivariate Cox regression HR 95% CI p value HR 95% CI p value (i) Drug received 0.66 0.37–1.18 0.162 1.73 0.85–3.50 0.128 (ii) ECOG PS 1.91 1.06–3.45 0.032 2.99 1.44–6.20 0.003 PFS: progression-free survival; OS: overall survival; 95% CI: 95% confidence interval; ECOG PS: ECOG performance score; HR: hazard ratio. univariate test and multivariate test, with a HR of 2.43 (95% nonparametric survival analyses. For L-sarcoma patients, CI, 1.16–5.07) and p value 0.018 in the latter test. Median OS trabectedin produced longer PFS and OS than ifosfamide in this group was 6.0months for trabectedin and 8.9months did. For non-L-sarcoma patients, ifosfamide treatment for ifosfamide treatment (p value, 0.903). High ECOG produced longer PFS and OS than trabectedin. performance score was associated with shorter duration of For patients with L-sarcoma, the total discounted costs OS, and in the multivariate test, a HR of 2.99 (95% CI, were €44,879 for trabectedin and €24,797 for ifosfamide. 1.44–6.20), p value 0.003. Costs for trabectedin acquisition were higher than for Patients with an L-sarcoma had a PFS probability at ifosfamide (€31,597 vs. €4,113, respectively), but drug ad- 3months of 59.5%, and at 6months of 41.7% when receiving ministration costs were lower for trabectedin than ifosfa- trabectedin, as shown in Table 2. In this group, a mean of 6.1 mide (€5,298 vs.€13,380, respectively). (e latter difference and median of 6 treatment cycles were given. Patients who was due to longer hospitalization needed for ifosfamide had a non-L-sarcoma or who received ifosfamide had cycles. (e nontreatment related monthly costs were higher shorter survival and received fewer cycles of chemotherapy. for trabectedin owing to longer survival compared to ifos- famide (€6,866 vs.€5,464, respectively). (e costs for adverse events were lower for trabectedin than for ifosfamide (€1,119 3.3. Cost-Effectiveness Analysis. (e results from the cost- vs. €1,841, respectively). (ese treatments resulted in 1.524 effectiveness model are shown in Table 7. Results from the and 1.169 LY gained, respectively, which gives an ICER of parametric survival analysis were consistent with the €56,000 per LY gained. QALYs were 1,025 for trabectedin 8 Sarcoma Table 7: Estimated average costs and effectiveness, comparing trabectedin and ifosfamide in advanced L-sarcoma and non-L-sarcoma. L-Sarcoma Non-L-sarcoma Cost-effectiveness model Trabectedin Ifosfamide Difference Trabectedin Ifosfamide Difference Costs (all discounted) €44,879 €24,797 €20,082 €27,497 €22,799 €4,698 (i) Drug acquisition €31,597 €4,113 €27,484 €19,407 €3,660 €15,747 (ii) Drug administration €5,298 €13,380 −€8,082 €3,646 €11,941 − €8,295 (iii) Nonrelated costs €6,866 €5,464 €1,402 €3,325 €5,357 − €2,032 (iv) Adverse events costs €1,119 €1,841 −€722 €1,119 €1,841 − €722 Effectiveness (i) QALYs, discounted 1.025 0.773 0.251 0.516 0.781 −0.265 (ii) Preprogression LYs, undiscounted 0.646 0.423 0.223 0.386 0.476 −0.090 (iii) Postprogression LYs, undiscounted 0.902 0.758 0.144 0.371 0.694 −0.323 Cost-effectiveness ratios (i) Costs per LY gained €56,000 Ifosfamide dominant (ii) Costs per QALY gained €80,000 Ifosfamide dominant QALYs: quality-adjusted life years; LY: life years. and 0.773 for ifosfamide, leading to an ICER of€80,000 per ifosfamide dominated trabectedin as ifosfamide costs were QALY gained. lower but survival and QALYs gained higher compared to For patients with a non-L-sarcoma, ifosfamide domi- trabectedin treatment. Survival differences and trabectedin nated trabectedin since costs were higher for trabectedin acquisition costs had the strongest impact on the ICERs than ifosfamide (€27,497 vs. €22,799, respectively), while found. Future changes in trabectedin pricing would alter effectiveness for trabectedin was worse in terms of LYs the ICER. However, given the status of trabectedin as (0.754 vs. 1.170, respectively) and in terms of QALYs (0.516 “orphan drug” due to the low incidence of malignancies vs. 0.781, respectively). trabectedin is currently registered for, its price is not ex- pected to change in the foreseeable future. When this cost-effectiveness analysis was designed, a 3.4. Sensitivity Analyses. (e sensitivity analysis of L-sar- comparator group was sought that could provide for a coma showed the ICER to be most affected by the difference sensible comparison to second-line trabectedin. Ifosfamide in survival between trabectedin and ifosfamide, as shown in was chosen as this drug was widely tested in STS, and data Figure 1. (is effect was most prominent in OS. (e 95% CI for second-line treatment were available at the EORTC. Due of the difference in OS for trabectedin and ifosfamide was to the adverse events and the long hospital admission per −3.6 to 18.4months, and this meant an overlap of OS du- treatment cycle, this drug has been used less extensively over ration. (is resulted in ICER ranging from €28,000 per last decade, and alternatives are available. In terms of ex- QALY gained in favour of trabectedin to ifosfamide being pected antitumour effect, ifosfamide was still considered to dominant for OS. (e ICER across the 95% CI of PFS also represent a realistic comparator group. Additionally, po- varied substantially, but QALYs remained in favour of tential alternative data sets would not match the patient trabectedin, with the ICER ranging from€59,000 to€98,000 population of the trabectedin-treated patients. per QALY gained. Another clear influence on ICER varia- (is cost-effectiveness study was not a randomised tion was the cost of trabectedin, with the ICER ranging from comparison, contrary to the designs of the original ifosfa- €55,000 to €105,000. mide studies. To reduce bias, survival was counted from the As the base-case analysis showed ifosfamide to dominate moment of first drug infusion, not the moment of trial trabectedin in patients with non-L-sarcoma, a sensitivity inclusion as in the original trials. (is was done to evade a analysis for non-L-sarcoma was not performed. potential bias, wherein the duration of survival of either ifosfamide or trabectedin would have been longer due to effects other than drug effects. (erefore, the difference in 4. Discussion survival now reported is accurately reflecting survival fol- lowing treatment. (e EORTC STBSG has used progression- Trabectedin was shown to be an active drug in the second- line treatment of L-sarcomas (either leiomyosarcoma or free rates (PFRs) as an indicator whether a drug is active as a second-line agent in STS [22]. Agents considered active have liposarcoma). In this nonrandomised comparison, the median survival of patients with L-sarcomas was an estimated PFR at 3months of 39% and at 6months of 2.5months longer if they received trabectedin instead of 14%. For L-sarcoma, trabectedin showed, by this standard, ifosfamide, not meeting the criterion for statistical sig- to be an active drug in this population with a PFR of 59% and nificance (p � 0.074). In non-L-sarcoma, ifosfamide 42%, respectively. For non-L-sarcoma, trabectedin was less resulted in longer survival, but the difference was not potent with a PFR at 3months just below the threshold at significant. (e cost-effectiveness analysis of trabectedin 37% and PFR at 6months at 19%. (e PFRs for ifosfamide were above the EORTC STBSG number in both L-sarcoma compared to ifosfamide showed an ICER of €80,000 per QALY gained in case of L-sarcoma. For non-L-sarcoma, and non-L-sarcoma. Sarcoma 9 Base case €80.000 Overall survival (95% CI) €28.000 Costs for trabectedin (±20%) €55.000 €105.000 Body surface area (±20%) €61.000 €105.000 Progression-free survival (95% CI) €59.000 €98.000 Utility preprogression (±20%) €71.000 €92.000 Utility postprogression (±20%) €75.000 €86.000 Costs for hospitalization (±20%) €75.000 €85.000 Costs for ifosfamide (±20%) €77.000 €83.000 Costs for preprogression (±20%) €79.000 €81.000 Costs for postprogression (±20%) €79.000 €80.000 Costs for adverse events (±20%) €79.000 €80.000 €0 €40.000 €80.000 €120.000 –20%/low end of 95% CI +20%/high end of 95% CI Figure 1: Tornado diagram representing the univariate sensitivity analysis for L-sarcoma, numbers abbreviated to thousands. All variables other than survival were increased (light-shaded bars) or decreased (dark-shaded bars) by 20%. For progression-free survival and overall survival, the 95% confidence interval (95% CI) of the survival difference between trabectedin and ifosfamide was used (low end: light-shaded bars; high end: dark-shaded bars). Note that the bar for the low end of the difference in OS does not stop and no number is given, as ifosfamide dominated trabectedin at that point, with a negative ICER. OS: overall survival; PFS: progression-free survival. Several studies have previously investigated the cost- four phase II studies of patients receiving trabectedin for effectiveness of trabectedin in STS compared to other treat- advanced STS was used in a 2015 study comparing the cost- ments. In a 2011 study by Soini et al., trabectedin was effectiveness of trabectedin and the tyrosine kinase inhibitor pazopanib [25]. (e HR calculated was 1.11 in favour of compared to ifosfamide [23]. Trabectedin data were taken from a 2009 randomised trial comparing trabectedin treat- pazopanib (with 95% CI of 0.94–1.31). Pazopanib treatment costs were half the cost of trabectedin cycles. As pazopanib is ment regimen and ifosfamide data from the same studies by van Oosterom and Nielsen used in the current study [5, 6]. All oral medication which is taken without the need for hospital patients on trabectedin had an L-sarcoma, whereas sarcoma admissions, the majority of patients will prefer pazopanib for subtypes were not clear for patients with ifosfamide. (e study that fact alone, regardless of costs. A study comparing found an ICER per LY gained of€ 31,590 and€ 42,633–47,735 pazopanib to placebo in advanced STS patients resulted in an per QALY gained when prescribing trabectedin. (ese ICERs ICER of €77,120 per QALY gained when taking pazopanib are lower than in the current study, suggesting better tra- treatment, illustrating the high costs of therapies aimed at bectedin cost-effectiveness. (e most evident cause for this treating advanced STS [13]. difference is the higher survival benefit due to ifosfamide in Compared to the 2016 randomised phase III trial by Demetri et al. comparing trabectedin vs. dacarbazine in the current study compared to Soini et al. (1.17 LY vs. 0.60 LY, respectively), whereas there were higher costs of ifosfamide pretreated metastatic L-sarcoma patients, patients on tra- treatment in Soini et al. (€13,053–14,286 vs. €7,568, re- bectedin in the current study in a real-life setting had a spectively). (e difference in survival gained due to ifosfa- higher median PFS (4.2 vs. 5.2months, respectively), mide, even though these are taken from the same studies, whereas OS was slightly lower (12.4months vs. 11.8months, suggests a difference in patient selection between the cost- respectively) [26]. A possible explanation for the PFS dif- effectiveness studies. ference is the blinded radiologic evaluation of imaging to A 2013 indirect comparison into the cost-effectiveness of assess PFS in the randomised trial. (e efficacy of tra- doxorubicin-ifosfamide combination vs. trabectedin also bectedin vs. dacarbazine showed better PFS for trabectedin but equal OS [26]. Unfortunately, this trial did not include showed more QALYs gained at lower health-care costs for doxorubicin-ifosfamide [24]. A pooled patient cohort from QALY assessments. 10 Sarcoma A study by Le Cesne ABJYC et al. presented at the 2018 in an estimated ICER of€80,000. (is ICER is at the top end ASCO meeting randomised pretreated advanced STS pa- of what is generally considered acceptable in the Netherlands tients between trabectedin and BSC, giving the comparison [30]. As there is a clinically unmet need for antitumour originally attempted for this cost-effectiveness analysis [27]. agents in the group of rare malignancies, this threshold may In that trial, trabectedin showed better PFS than BSC for not be the most relevant factor in the decision to continue to L-sarcomas (5.3 vs. 1.4months, respectively), but not for prescribe trabectedin to these patients. For non-L-sarcoma, non-L-sarcomas (1.8 vs. 1.5months, respectively). OS did ifosfamide treatment dominated trabectedin. not differ, and this was deemed due to per-protocol crossover to trabectedin after progressive disease on BSC. Data Availability (is trial demonstrates the efficacy of trabectedin for (e raw data used to support the findings of this study are L-sarcomas compared to BSC. (e efficacy of trabectedin available from the corresponding author upon request. within the group of L-sarcomas also varies, and it offers the largest benefit in patients with myxoid liposarcoma [28]. (e Conflicts of Interest actual size of the antitumour effect in myxoid liposarcoma is blunted in clinical trials as other liposarcoma subtypes, in (e authors declare that there are no conflicts of interest which trabectedin is less active, and are included in the same regarding the publication of this paper. trials. (e number of patients in this cost-effectiveness analysis was too small to detect any differences between Acknowledgments leiomyosarcomas vs. liposarcomas or myxoid liposarcomas vs. other liposarcoma subtypes. (is study was funded by a grant from ZonMw (152001018). (is cost-effectiveness analysis has several limitations, especially since it was not possible to perform the study References originally set out to do. 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