Health Care Resource Utilization and Costs among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France

Objective To describe health care resource utilization and costs for patients with advanced soft tissue sarcoma (STS) in the United Kingdom (UK), Spain, Germany, and France. Methods Physicians abstracted data for adult patients with a diagnosis of advanced STS (other than Kaposi's sarcoma or gastrointestinal stromal tumor) who received ≥1 lines of systemic therapy. Health care resource utilization related to advanced STS treatment was recorded; associated costs were estimated by applying unit costs. Results A total of 130 physicians provided data for 807 patients (UK: 199; Spain: 203; Germany: 204; and France: 201). The site of care during active treatment varied based on differences in the health care systems of these four countries. Total mean per-patient health care cost in the UK was £19,457; in Spain, €26,814; in Germany, €20,468; and in France, €24,368. Advanced STS-related systemic treatment costs were driven primarily by drug acquisition and administration costs. Treatment-related costs increased during later lines of therapy for all countries except France, where they decreased after first-line therapy. Pain control and antiemetics were the most common supportive care medications. Conclusions This study provides real-world data on resource utilization and estimated costs in advanced STS and could inform policymakers about treatment burden.


Introduction
ere are more than 50 histological subtypes of soft tissue sarcoma (STS), a rare and heterogeneous group of malignant neoplasms [1]. STSs account for approximately 1% of all incident malignancies [2], with an estimated 23,574 incident cases in the European Union in 2013 [3]. An estimated 40% to 50% of patients with STS are initially diagnosed with or later develop metastatic disease [4], for which treatment options are limited. Chemotherapy (e.g., doxorubicin or ifosfamide, alone or in combination with each other or other agents) is most commonly used to treat patients with inoperable, advanced STS [5][6][7][8].
e intent of these treatments is primarily palliative, and the response rates are low (i.e., 10%-25% with monotherapy) [6]. Median overall survival among patients with metastatic STS varies depending on histologic subtype, grade, performance status, and other prognostic factors but generally is estimated to be 12 to 18 months [9].
Limited data have been published to date on health care resource use and costs associated with treatment of a broad sample of patients with advanced STS in European countries, despite the considerable disease burden of STS. e Sarcoma Treatment and Burden of Illness in North America and Europe (SABINE) study, a multicenter, multicountry, retrospective medical record review study of a highly restricted population of patients with metastatic STS who demonstrated a favorable response to chemotherapy after four cycles, found that advanced STS is associated with considerable economic burden, and significant resources are devoted to treating it across European countries [10]. e SABINE study [10] focused on lifetime health care resource use (only number of resource use days), estimated costs among STS patients, and presented the results by treatment line, chemotherapy use, and disease progression. Judson et al. [11] appear to be the first researchers in the public domain who provided detailed cost estimates for metastatic STS in the UK. Guest et al. [12] and Amdahl et al. [13] conducted cost-effectiveness analyses (of doxorubicin/ifosfamide versus trabectedin and of pazopanib, resp.). Both reported that use of trabectedin or pazopanib in later lines of therapies can be cost effective. e objective of this study was to fill gaps in the literature, including providing data on health care resource use (proportion with resource use events and number of visits) and estimating STS-related treatment costs (i.e., drug acquisition, drug administration, and treatment-related adverse events) for patients with advanced STS in real-world clinical settings in the United Kingdom (UK), Spain, Germany, and France. We also evaluated treatment patterns and outcomes in this population; these results are reported separately [14][15][16][17][18].

Study Design and Population.
is study was a retrospective review of medical records of patients with advanced STS (excluding those diagnosed with Kaposi's sarcoma or gastrointestinal stromal tumor) in the UK, Spain, Germany, and France. Oncologists who had personally treated at least 3 patients with advanced STS in the previous year abstracted anonymized data from their patients' medical records. To enhance geographic representativeness, physicians across all regions of each country were contacted to participate in the study. Patients were eligible if diagnosed with advanced, histologically confirmed STS (at presentation or after progression from limited disease), between 1 January 2005 and 18 months before the initiation of record abstraction. Eligible patients were aged 18 years or older at initial diagnosis of STS, had started at least one line of systemic therapy for advanced STS, and had records from diagnosis of advanced STS until the date of record abstraction or death that were accessible to the abstracting physician. Patients were excluded if they had received treatment with curative intent after diagnosis of advanced disease; had received treatment with doxorubicin or other anthracyclines or anthracenediones at any time before initiating first-line treatment for advanced STS; had evidence of concurrent malignancy, except adequately treated nonmelanoma skin cancer or in situ neoplasm; or had received first-line treatment within an interventional clinical trial. e relevant national competent authorities reviewed and approved the study in all four countries, as appropriate. In Germany and Spain, the ethics committee at the study site of the principal investigator in each country reviewed and approved the study, as required by national authorities.
is site-level approval applied to all participating sites within each country. Specifically, the study received ethical review board approval from Medizinische Fakultät Mannheim der Universität Heidelberg, Universitätsklinikum Mannheim (reference ID: 2015-824R-MA) in Germany and received ethical review board approval from Unidad Administrativa Ceic Instituto de Investigación Hospital 12 de Octubre (reference ID: 15/169 EPA-OD; LY3012207) in Spain. In addition, the study received national approval from the Commission Nationale de l'informatique et des Libertés (n/Ref: MMS/CWR/AAR1514906) and Le Comité consultatif sur le traitement de l'information en matière de recherche (CCTIRS) (Dossier no. 15.464bis) in France. In the UK, the National Health Service and National Research Authority considered this study a service evaluation and did not require a detailed ethics review. In addition, the study was determined to be exempt from full review by the RTI International Institutional Review Board.

Study
Measures. Patient and disease characteristics and treatments that were abstracted from the medical records included race/ethnicity (except in France, where collection of such information is prohibited), age, sex, STS histology, and the number of lines of therapy received. Individual histologic subtypes were grouped into broader categories based on the World Health Organization Classification of Tumours of Soft Tissue and Bone [1]. Histologic categories subsequently analyzed were leiomyosarcoma (smooth muscle tumours), fibroblastic/myofibroblastic sarcoma, liposarcoma (adipocytic tumor), vascular sarcoma, rhabdomyosarcoma (skeletal muscle tumor), synovial sarcoma, and others or not otherwise specified.
Advanced STS-related health care utilization measures were abstracted directly from the patient's medical record according to care setting (e.g., inpatient, physician office) and whether encounters were for chemotherapy administration. Visits were stratified by the treatment line in which they occurred or, as a separate category, the period from the end of last observed treatment line to the end of the patient record or death. e following data were collected: outpatient consult visits (collected in the UK), office visits 2 Sarcoma (collected in Spain, Germany, and France), outpatient hospital visits (collected in Spain, Germany, and France), palliative care visits, outpatient nurse visits (collected in the UK), accident and emergency or emergency department (ED) visits, inpatient hospitalizations (including hospitalizations after a line of therapy), and transfers to long-term or hospice care. Finally, patients' receipt of specific categories of supportive care was collected. A cost analysis among the four study countries was then conducted using a payer or health system perspective, as was done in the SABINE study [10]. Specifically, costs related to advanced STS were calculated by multiplying the amount of each type of resource used with a corresponding unit cost (Supplementary Tables 1-4). Systemic anticancer therapy costs were calculated in total and are also presented broken down into those for anticancer therapy drug costs, anticancer therapy administration costs, and treatment-related adverse event costs (except for France, for which drug costs were generally included within administration costs). Other direct health care costs were calculated as the sum of all costs associated with outpatient and ED visits, inpatient stays that were not adverse event-related, selected supportive care services, and inpatient long-term care and hospice care. Reported summary statistics for other direct health care costs were calculated in total and are also presented broken down into those for period of follow-up and weekly costs, with measures provided both with and without surgery/radiotherapy. Because cost data are not available in patient medical records, unit costs were obtained for the various products and services from published literature and other standard cost sources. Specifically, systemic anticancer therapy and supportive care costs were obtained for the UK from the British National Formulary [19] and MIMS [20]; for Spain from BOT PLUS [21], and for Germany from Lauer-Taxe [22]. For France, supportive care costs were obtained from Base des Médicaments et Informations Tarifaires [23]. Systemic anticancer drug administration costs were obtained for the UK from the National Health Service [24], for Spain from E-Salud [25], for Germany from Kassenärztliche Vereinigung Nordrhein [26] and Kassenärztliche Vereinigung Sachsen [27], and for France from data on file sources. Unit costs for all four countries were adjusted to 2015/2016 values using relevant inflation indices (in the UK, Curtis and Burns [28]; in Spain, INEbase [29]; in Germany, Statistisches Bundesamt [30]; and in France, INSEE database [31]).

Statistical Analyses.
All analyses were descriptive and exploratory in nature and conducted using the SAS software package (version 9.4). No formal statistical tests comparing results across countries or lines of therapy were conducted. e results are presented in tabular displays of frequencies, proportions, means, and other descriptive statistics as appropriate.
Systemic anticancer therapy costs were estimated for each of the five most common first-line, second-line, and third-line regimens identified (with all other regimens in each line reported as a group in an "other" category). Other direct health care costs were estimated by line of treatment, through third line, as well as after discontinuation of firstand second-line treatment.
Health care resource use and costs were summarized only for patients for whom the number of visits/encounters for each particular resource category was available. For instance, a physician may have indicated that a patient was hospitalized, but the data needed to quantify the number of unique hospitalizations or inpatient visits were not recorded; such patients would be included in the count of the number (ever) hospitalized but would not be included in the calculation of the total number of hospitalizations. Annual health care utilization rates were calculated by dividing the number of visits by the observation time (duration of treatment line in years).

Physician Characteristics.
Overall, 130 physicians participated in the study (21 in the UK, 34 in Spain, 40 in Germany, and 35 in France). In the previous year, the participating physicians reported treating an average of 45 patients (standard deviation, 37) with advanced STS.

Patient Characteristics.
Overall, 807 patients were included in the study population: 199 in the UK, 203 in Spain, 204 in Germany, and 201 in France (Table 1). e population was 59% male in the overall sample (UK, 63%; Spain, 61%; Germany, 64%; France, 48%), and 93% of patients were white (UK, 90%; Spain, 99%; Germany, 90%; race/ethnicity not collected in France). Mean age at the time of advanced diagnosis was 57.1 years (range, 21-90 years). e median observed follow-up time (from diagnosis of advanced STS to death or the last medical encounter before the abstraction date) was 20.3 months (range, 0-133 months). e most common identified histologic categories were leiomyosarcoma (29%), liposarcoma (13%), and rhabdomyosarcoma (11%). All patients had received at least one line of therapy (as an eligibility criterion), and the mean total number of lines of therapy received was 1.6 (standard deviation, 0.8). Table 2 presents resource utilization during active treatment with systemic therapy for advanced STS in the UK, Spain, Germany, and France; Supplementary Tables 5-8 present resource utilization by line of therapy for each country.

Health Care Resource Utilization.
During active treatment, the patients received substantial amounts of care, although the predominant site of care varied somewhat based on the health care system. Care in the outpatient setting (i.e., outpatient visits to a hospital clinic) was common in all countries, with a mean of 15.0, 26.4, 22.4, and 38.7 outpatient visits per year (annual rate) among patients with at least one visit in France, the UK, Spain, and Germany, respectively. e majority of outpatient visits included chemotherapy administration, although more than 30% of the patients from France had chemotherapy administered in other venues (often office or inpatient visits) (Supplementary Table 12).

Sarcoma 3
Utilization of other sites of care varied by country. In Spain, 55% of patients had outpatient palliative care visits (versus 13%-24% in other countries), and outpatient nurse visits were utilized only in the UK. More patients from Spain had ED visits (86% versus 18%-24% in other countries), while France had both the highest proportion of patients having inpatient visits (46% versus 17%-37% in other countries) and the most annualized inpatient visits per patient with at least one such visit (12 versus 4-5).
End-of-life care rarely included long-term care in any of the study countries (<3%). Hospice care was relatively common in Germany (40%), rarer in Spain and the UK (27% and 19%, resp.), and not received by any patients in France. e most common supportive care medications (Table 3) were for pain control (UK, 54.8%; Spain, 65.0%; Germany, 60.8%; France, 50.3%) and antiemetics (UK, 44.2%; Spain, 59.6%; Germany, 50.0%; France, 69.7%). Opioid analgesics were the most common form of pain medication (among those who received pain medication: UK, 89.0%; Spain, 84.9%; Germany, 74.2%; France, 83.2%). Tables 4-7 present estimated health care costs related to first-, second-, and third-line treatment of advanced STS by country; detailed costs for the five most common regimens and the other combined regimens are presented in Supplementary Tables 13-16.

Health Care Costs.
Estimated advanced STS-related systemic treatment costs (i.e., drug acquisition, administration, and treatmentrelated costs) were greater than other estimated direct health care costs in each country, largely driven by drug acquisition and administration costs. Drug acquisition costs increased across lines of therapy in the UK (ranging from £5,998 in the first line to £20,586 in the third line), Spain (€2,029 to €25,446, resp.), and Germany (€4,399 to €23,540, resp.), potentially driven by the more common use of branded agents such as pazopanib (Votrient) and trabectedin (Yondelis) in later lines of therapy than in the first line (see Supplementary Tables 13-15). However, in France, estimated drug acquisition and administration costs were greatest in the first line of therapy (€8,708) and decreased across subsequent lines of therapy, to €6,563 in the third line. e high cost of first-line therapy in France could be driven primarily by greater utilization (number of administrations) of doxorubicin-ifosfamide relative to other countries (Supplementary Table 16) and greater costs for single-agent pazopanib in the first line relative to other lines of therapy (data not presented). Estimated total systemic treatment costs across all lines of therapy (drug acquisition, administration, and treatment-related adverse event costs combined) were £16,363 in the UK, €19,264 in Spain, €16,662 in Germany, and €17,433 in France (Tables 4-7).
Advanced STS-related costs unrelated to anticancer therapy were captured for outpatient visits, accident and

Discussion
is study was a retrospective analysis of medical records of patients with advanced STS who received systemic treatment in the UK, Spain, Germany, and France. e objective of the study was to present a descriptive review of the estimated costs of treatment in these countries. It should be noted that owing to differences across countries in the organization of medical care and other potentially confounding factors, the study was not designed to compare results among the countries, although substantial variations were noted where apparent. In particular, some notable variations in health care resource utilization across the four countries were observed, including more inpatient visits reported in France and greater numbers of outpatient and ED visits reported in Spain compared with the other countries. Variations in the organization of medical care across the study countries may be an explanation for these differences, such as chemotherapy being administered primarily in hospital settings in France [32].
Before this study, there had been little published data on resource use and costs associated with STS. Nonetheless, the findings of previous studies, particularly the SABINE study [10], provide context for this study. Both studies reported that systemic treatment was the greatest cost driver, representing 65% to 80% of total costs in our study (versus about 52% for treatment plus concomitant medications in SABINE), and that costs generally rose in later lines of therapy [10]. However, estimated absolute costs were much higher in the SABINE study. Our study reported mean total cost per patient to be £19  [10]. ese differences probably relate to the requirement in the SABINE study that patients had a favorable response to at least one line of chemotherapy, which likely influenced both the number of lines of therapy and the length of therapy; 65% of patients received at least three lines of therapy in SABINE, compared with only 11% in our study. For Germany, the SABINE study included only patients alive at the time of chart abstraction.
Judson et al. [11] conducted a retrospective study in the UK and reported direct medical costs of STS to be £12,019 per patient. e population in that study was somewhat similar to our sample in that, on average, patients received 1.6 lines of therapy, compared with 1.4 among UK patients in our study. However, Judson and colleagues' study was conducted before the approval of newer treatments for advanced STS such as pazopanib and trabectedin, which limits comparability of the studies. Although previous costeffectiveness studies (e.g., Guest et al. [12] and Amdahl et al. [13]) have reported on costs in advanced STS, their results are not directly comparable with ours, owing to differences in the study design and sources used for cost estimation. Guest et al. [12] relied on expert interviews to derive estimates of resource utilization, and Amdahl et al. [13] used resource utilization as reported in a clinical trial.
Given the limited data available on the costs of advanced STS, published data on costs of two other cancers with similar survival might provide additional context for our results. Using a study design and methodology similar to the current study, Kurosky et al. [33] conducted an observational review of medical records in patients with non-small-cell lung cancer (NSCLC) in France, Germany, Previous research has identified considerable symptom burden in STS, with pain being among the most prevalent symptoms [35]. Kuo et al. [36] conducted a study of an STS population in a UK sarcoma unit and found that more than half of assessed patients reported pain. Gough et al. [37] conducted a medical record abstraction in the UK and deduced that patients with metastatic STS have a significant symptom burden, with pain being a substantial problem. Our results indicate that more than half of the patients in each country utilized some form of pain medication, with more than 74% of those in each country reported opioid use  e results of this study are subject to several limitations inherent to many retrospective medical record review studies. Although we attempted to achieve balance in SD � standard deviation. Note: systemic treatment administration costs include the costs of administration and the costs of outpatient visits or hospitalizations that were for chemotherapy administration. Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia) and costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. For systemic treatment costs by line of therapy, costs are reported among those patients who received each line of therapy. Costs for all patients are reported by line of therapy, but costs for those using specific treatment regimens are not provided for third-and fourth-line patients due to small sample sizes. a Costs are in 2015/2016 British pounds and were inflated when necessary using the Hospital and Community Health Services price inflation index [27]. b Systemic treatment administration costs include the costs of administration, as well as the costs of outpatient visits or hospitalizations that were for chemotherapy administration. c Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia), as well as costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. d Costs are reported among those patients who received each line of therapy. e Other direct health care costs include costs unrelated to anticancer therapy (i.e., other direct health care costs exclude costs associated with anticancer drug acquisition and administration and treatment-related adverse events). ese other direct health care costs include costs associated with outpatient visits, accident and emergency visits, inpatient hospitalizations, inpatient long-term care and hospice care, and supportive care.
8 Sarcoma geographic distribution within and across countries, the participating physicians and patient sample may not be completely representative of the population in the countries studied. e extent to which physicians self-selected for participation in this study is unknown and could influence results. Because of the patient inclusion and exclusion criteria SD � standard deviation. Note: systemic treatment administration costs include the costs of administration and the costs of outpatient visits or hospitalizations that were for chemotherapy administration. Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia) and costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. For systemic treatment costs by line of therapy, costs are reported among those patients who received each line of therapy. Costs for all patients are reported by line of therapy, but costs for those using specific treatment regimens are not provided for third-and fourth-line patients due to small sample sizes. a Costs are in 2016 euros and were inflated when necessary using the indice de precios de consumo, medicina [28]. b One patient with dactinomycin use was excluded from this analysis. c Systemic treatment administration costs include the costs of administration, as well as the costs of outpatient visits or hospitalizations that were for chemotherapy administration. d Costs are reported among those patients who received each line of therapy. e Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia), as well as costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. f Other direct health care costs include costs unrelated to anticancer therapy (i.e., other direct health care costs exclude costs associated with anticancer drug acquisition and administration and treatment-related adverse events). ese other direct health care costs include costs associated with outpatient visits, accident and emergency visits, inpatient hospitalizations, inpatient long-term care and hospice care, and supportive care.

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(including previous treatments rendering a patient ineligible for the study), the sample is subject to selection bias, and the study findings may not be fully generalizable to the entire population of adult patients with advanced STS who undergo systemic treatment in the study countries. Moreover, due to administrative censoring, it is possible that the number of  SD � standard deviation. Note: systemic treatment administration costs include the costs of administration and the costs of outpatient visits or hospitalizations that were for chemotherapy administration. Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia) and costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. For systemic treatment costs by line of therapy, costs are reported among those patients who received each line of therapy. Costs for all patients are reported by line of therapy, but costs for those using specific treatment regimens are not provided for third-and fourth-line patients due to small sample sizes. a Costs are in 2015/2016 euros and were inflated when necessary using the relevant inflation index [30]. b None of the systemic anticancer drugs reported required extra-DRG. erefore, most drug costs in France are included within the administration costs and are not accounted for separately. e exception is pazopanib, for which a separate drug cost was applied. Systemic drug and administration costs include the cost of drug (pazopanib), costs of administration, as well as the costs of outpatient visits or hospitalizations that were for chemotherapy administration. c Treatment-related adverse event costs include costs associated with growth factors (which were assumed to have been used to prevent and/or treat neutropenia or anemia), as well as costs associated with hospitalizations to manage toxicities/side effects related to treatments or procedures. d Costs are reported among those patients who received each line of therapy. e Other direct health care costs include costs unrelated to anticancer therapy (i.e., other direct health care costs exclude costs associated with anticancer drug acquisition and administration and treatment-related adverse events). ese other direct health care costs include costs associated with outpatient visits, accident and emergency visits, inpatient hospitalizations, inpatient long-term care and hospice care, and supportive care. therefore an analysis of time trends in treatment was not possible.

Conclusions
is was one of the first large-scale, real-world studies of health care utilization and estimated associated costs in a multinational population of patients with advanced STS who received systemic treatment. Treatment costs were substantial in this population, primarily relating to systemic therapy but were less than costs for other cancers such as non-small-cell lung cancer and colorectal cancer, where patients have similar expected survival. Pain is a very common issue in patients with STS, often treated by opiate analgesics.
is study, together with findings from other economic analyses, may help inform future economic and health technology assessments for novel treatments for advanced STS.

Data Availability
e data used to support the findings of this study are not publicly available but are available for collaborative research from Eli Lilly and Company, on reasonable request.

Disclosure
Daniel S. Mytelka was affiliated with Eli Lilly and Company when this research was conducted. Maria Lorenzo was affiliated with Eli Lilly and Company Limited when this research was conducted.

Conflicts of Interest
Sean D. Candrilli, James A. Kaye, Elizabeth M. La, and Saurabh P. Nagar are salaried employees of RTI Health Solutions. Yulia D'yachkova is a salaried employee of Eli Lilly and Company.