PharmacoEconomics Open (2018) 2:125–139 https://doi.org/10.1007/s41669-017-0045-0 SYSTEMATIC REVIEW The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 1 1 1 1 • • • • Ashley Enstone Maire Greaney Manca Povsic Robin Wyn 2 2 John R. Penrod Yong Yuan Published online: 18 August 2017 The Author(s) 2017. This article is an open access publication Abstract such as hospitalisation, nurse visits, emergency room visits, Background Small cell lung cancer (SCLC), the most follow-up appointments and outpatient care. aggressive form of lung carcinoma, represents approxi- Conclusions SCLC and its treatment have a substantial mately 15% of all lung cancers; however, the economic impact on costs. The scarcity and heterogeneity of eco- and healthcare burden of SCLC is not well-deﬁned. nomic cost data negated meaningful cost comparison, Objective The aim of this study was to explore the impact highlighting the need for further research. Capturing the of SCLC on healthcare costs through a systematic literature economic burden of SCLC may help patients and clinicians review (SLR). make informed treatment choices and improve SCLC Methods Using the OVID search engine, the SLR was management. conducted in PubMed, MEDLINE In–Process, EMBASE, EconLIT and the National Health Service Economic Evaluation Database (NHS EED). Searches were limited to Key Points for Decision Makers studies published between January 2005 and 24 February 2016, and excluded preclinical studies. Additional internet- Chemotherapy and associated costs were identiﬁed based searches were conducted. In total, 229 abstracts were as major cost components in several publications; retrieved and systematically screened for eligibility, with costs related to screening methods and administering 17 publications retained. screening were also high. Results The majority of publications provided data on Treatment costs represented a signiﬁcant proportion limited and extensive disease of SCLC. The reported bur- of direct costs, speciﬁcally small cell lung cancer den was categorised as direct costs and indirect costs, with (SCLC) medication costs or surgical costs, which the majority of the publications (n = 16) reporting on direct costs and one reporting on both direct and indirect included high associated costs from hospitalisation, nurse visits, emergency room visits, follow-up costs. The only indirect costs reported for SCLC were lost appointments and outpatient care. productivity (premature mortality costs) and caregiver burden. Chemotherapy, diagnostic costs and treatment Only limited information on the indirect costs of costs were identiﬁed as signiﬁcant costs when managing SCLC is available in the published literature SCLC patients, including the associated treatment costs (namely, data on productivity loss due to premature death). & Ashley Enstone The varied nature of the studies captured indicates email@example.com that a more uniform and consistent approach is Yong Yuan needed when reporting on the costs of SCLC. firstname.lastname@example.org Adelphi Values, Adelphi Mill, Bollington, Cheshire, UK Bristol-Myers Squibb, Princeton, NJ, USA 126 A. Enstone et al. impacts. These included social costs (e.g. lost productivity, 1 Introduction caregiver burden, absenteeism, presenteeism, out-of-pocket Lung cancer is the second most prevalent cancer world- expenses, burden of premature mortality) and healthcare costs (e.g. direct medication costs, primary care costs and wide, with more than one quarter (27%) of all cancer deaths in 2015 attributed to lung cancer . It is a leading secondary care costs, such as hospital admissions). The secondary objectives were to understand how the cost cause of cancer mortality, responsible for 1.69 million deaths worldwide in 2015 . As the symptoms associated burden associated with SCLC varies across different patient subpopulations, where data allowed. The following with lung cancer are often non-speciﬁc, it is frequently diagnosed in the late stages; this is reﬂected in a 5-year subpopulations were examined when analysing the results: smokers and non-smokers; programmed death-ligand 1 survival rate estimated at \20% . (PD-L1) positive and PD-L1 negative; relapse/refractory SCLC accounts for approximately 15% of all lung cancers disease (second-/third-line therapy) and non-advanced and has its highest occurrence in smokers . While repre- (ﬁrst-line therapy) SCLC; limited- and extensive-stage senting a comparatively small proportion of lung cancers, SCLC is the most aggressive from of lung cancer, with faster disease; and brain metastases associated with SCLC. A further exploratory objective investigated in the SLR was growth and earlier metastasis than any other pulmonary cancer . It is characterised by a rapid doubling time and the potential to distinguish between ‘disease symptom burden’ and ‘treatment burden’. early onset of dissemination . Although SCLC is initially sensitive to existing forms of chemotherapy, progression A literature search was conducted to identify publica- tions relating to the costs of SCLC. The following com- occurs rapidly and a high incidence of recurrence has been puterised bibliographic databases were searched using the observed [4, 6]. Surgical resection is the mainstay of treat- OVID search engine for the economic burden SLR: ment for patients with non-small cell lung cancer (NSCLC), PUBMED (MEDLINE), MEDLINE In-Process, however nearly 70% of patients present with metastatic or EMBASE, EconLIT and National Health Service economic locally advanced disease . Compared with NSCLC, evaluation database (NHS EED). The search was limited to curative surgery is rarely an option in SCLC as most patients present with already widely metastatic or locally advanced studies published in the past 10 years (1 January 2005–24 February 2016) and excluded preclinical studies. To ensure disease at diagnosis. Untreated patients typically have a median lifespan of 2–4 months following diagnosis . all publications of interest were captured, both English and non-English language publications were included in the The limited rate of early diagnosis, rapid development of resistance to existing treatment, and low 5-year survival search. The search utilised a combination of disease and cost burden subject headings and free-text searching in rates present a signiﬁcant unmet need in the disease area . Although SCLC is only a small subset of total lung order to ensure that the most relevant literature was iden- tiﬁed and reviewed (see Appendix A). cancers, it is still a considerable social, economic and All abstracts identiﬁed in the search were screened for humanistic burden, with close to 30,000 new cases being reported in the US annually [6, 8]. full-publication review by two independent reviewers (MP and RW). Any disagreement was resolved by a third senior The overarching objective of this systematic literature review (SLR) was to conduct a comprehensive search to synthesise the researcher (AE). Publications reporting costs associated with patients without speciﬁc reference to SCLC, or reporting direct and indirect costs associated with SCLC in Australia, Brazil, Canada, Europe, Japan, Russia and the US. The authors data on treatment efﬁcacy/interventional data in SCLC, which did not assess the economic burden, were excluded. deemed these populous regions to represent various levels of socioeconomic development, across ﬁve continents. Publications reporting data for patients \16 years of age, study populations of\30 patients, or publications consisting Key components and drivers of the economic burden of of letters, editorials or commentaries, as well as publications SCLC were examined across different SCLC patient sub- with no study length restrictions, were also excluded. populations. Economic burden was deﬁned as any direct Publications were included in the full-text review based and indirect costs of SCLC, including diagnosis and treatment costs, loss of work productivity, or costs to on the following inclusion criteria: publications presenting data speciﬁc to or including SCLC patient populations in the caregivers or family members. following geographical regions: Australia, Brazil, Canada, Europe, Japan, Russia or the US; publications reporting the 2 Methodology direct or indirect costs associated with the management of SCLC across these countries and regions; and publications The primary objective of this literature review was to presenting data speciﬁc to or including patients with SCLC. summarise the economic burden of SCLC and to deﬁne and All included publications were assessed for quality understand the key drivers and factors that underpin these against an adapted version of the DRUMMOND checklist The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 127 . Some publications identiﬁed through the primary No further publications were retained from the search of search were abstracts and posters, therefore a full quality internet-based sources (such as disease-speciﬁc and patient assessment was not possible. advocacy websites and conference proceedings from As recommended by the Cochrane Collaboration , ISPOR, ASCO, ECC, ESMO and the WCLC), as the 12 when studies provided sufﬁcient methodological informa- conference abstracts identiﬁed did not provide data speciﬁc tion, cost data were converted to a common currency and to SCLC and costs [29–40]. year (2016 US$) using a cost converter tool provided by The number of publications identiﬁed and the type of the Campbell and Cochrane Economics Methods Group publications included in the SLR are presented in Fig. 2. and the Evidence for Policy and Practice Information and Three literature reviews were included in this review as Co-ordinating Centre (see Appendix B). they undertook economic evaluations of SCLC costs; An additional internet-based search was conducted to however, the primary publications reported in these identify any further relevant literature. This internet-based reviews did not report SCLC-speciﬁc costs and were search was conducted using a combination of keywords therefore not included in the review [15, 19, 21]. and included both non-peer-reviewed publically available The publications were grouped based on the costs information and peer-reviewed publications that may not reported in direct and indirect costs. yet be indexed in databases such as PUBMED or Embase, The majority of publications reported on direct costs because of their recent publication date, or because they (n = 16) and only one publication reported on both direct were published in journals that are not indexed within and indirect costs (n = 1). Further details of publications these databases. Conference proceedings from the annual included within the SLR are presented in Table 1. European, US, Asia–Paciﬁc and Latin American con- gresses of the International Society for Pharmacoeco- 3.1 Quality Assessment nomics and Outcomes Research (ISPOR), the American Society of Clinical Oncology (ASCO) annual meeting, the To assess the quality of all included publications, an annual European Cancer Congress (ECC), European adapted DRUMMOND checklist for economic evaluation Society for Medical Oncology (ESMO) and the annual quality assessment was used . The assessment included World Conference on Lung Cancer (WCLC) were three aspects (study design, data collection, and analysis reviewed. and interpretation of results) and a total of 36 criteria. Each publication was independently assessed for quality by two researchers and given a score of 0 = not reported, 1 = not 3 Results clear, or 2 = reported (or NA if not applicable). Scores were then summed and a percentage given for each pub- A total of 229 publications were identiﬁed: 217 in the lication from the number of questions that were applicable OVID search and 12 in the additional internet-based to that publication. search. As the search retrieved only a small number of For example, a publication may have information publications, indicating a paucity of primary studies on the reported for ﬁve items (equating to 10 points), not reported cost burden of SCLC, it was decided that the review should for three items (=0 points), not clear for three items (=3 also capture secondary evidence such as economic mod- points) and not applicable for two items, totalling 13 elling studies, if these presented evidence on the costs of points. In this case, the total number of applicable items the disease. Primary references within existing systematic (items that score 0, 1, or 2) is 11, and hence the total reviews were also examined to identify further relevant number of possible points is 22; therefore, the publication’s data, even if these primary sources were not captured ﬁnal quality score is 59% [(13722) 9 100]. directly by this search. The assessed publications received a high-quality score, Following abstract screening and full-text review, a total ranging from 73.1 to 91.7% (see Table 2). Four publications of 12 full-text publications from the OVID search [12–25] could not be assessed in this way as they were abstracts or were taken forward for inclusion in the SLR (Fig. 1). posters only and therefore could not be scored [22, 26–28]. OVID searching identiﬁed four conference abstracts and However, due to the paucity of data retrieved from the primary one poster that were relevant in the context of this review, search, these publications were included in the ﬁnal SLR. however full-text publications could not be sourced [26–28]. These publications will be referred to as ‘grey 3.2 Direct Costs literature’ throughout this manuscript. As there was a paucity of publications identiﬁed on the cost burden of The direct costs of SCLC were reported in 17 studies. The SCLC, these grey literature sources were included in the research focus varied across publications and different cost ﬁnal SLR, resulting in a total of 17 inclusions [12–28]. items were reported, as described in Table 1. 128 A. Enstone et al. Fig. 1 PRISMA ﬂow chart of the included and excluded publications. PRISMA Preferred reporting items for systematic reviews and meta-analyses Direct cost components were chosen arbitrarily by the bone scans and screening administration [12, 16, 18, 20, 21, authors on the basis of their respective objective, and could 28]. Treatment costs represented a signiﬁcant proportion of not be compared. This was indicative of the paucity of data direct costs, speciﬁcally SCLC medication costs or surgical found on SCLC costs and the varied nature of how they were costs, which included high associated treatment costs, such reported. Several direct cost components were identiﬁed as as hospitalisation, nurse visits, emergency room visits, fol- potential cost drivers for the economic burden of SCLC. low-up appointments, and inpatient and outpatient care Chemotherapy and associated costs were identiﬁed as major [12, 16, 17, 20, 23, 25, 27]. cost components in ﬁve publications [12–14, 16, 26]. Diag- Several publications investigated cost components of nostic costs were high in SCLC, including costs of computed lung cancer [12, 13, 16, 27]. In Turkey, the mean total cost tomography, positron emission tomography (PET), chest per lung cancer patient was reported by Cakir and Kar- x-ray, magnetic resonance imaging (MRI), cytohistology, likaya as $14,306 (USD, cost year not speciﬁed), and the The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 129 between SCLC ($6015) and NSCLC patients ($6993) . A review investigated PET-based staging for SCLC in Australia, reporting its cost to be AU$1189.10 per patient, compared with conventional staging costs of AU$1194.29 (2010 Australian Medicare Beneﬁts Schedule costings, adjusted to 2016 US$) . The costs of SCLC and NSCLC management were investigated in Australia, where the costs of managing NSCLC and SCLC were found to be comparable . 3.2.1 Direct Costs of Limited- and Extensive-Stage Small Cell Lung Cancer (SCLC) Several publications reported on direct costs of extensive- stage SCLC speciﬁcally [12, 15–19, 21, 22, 25, 27]. Kang et al. investigated the costs of SCLC management and found that the median cost of lung cancer in Australia was highest for limited-stage SCLC ($19,046 vs. $12,688 for Fig. 2 PRISMA graph of the included publications, grouped by type extensive-stage) [AU$, review of patient records of publication. PRISMA Preferred reporting items for systematic reviews and meta-analyses 2005–2008, applying 2005 Australian Medicare Beneﬁts Schedule costings, adjusted to 2016 US$]. Patients with median total cost per patient was reported by Turk et al. as extensive-stage SCLC had the highest proportion of their €910 (€, cost year not speciﬁed) [12, 27]. High costs were management costs spent on hospitalisation (see Table 5) reported in treatment and inpatient services in Turkey, as . well as direct medical costs (Table 3). Costs in the US Turk et al. examined the diagnosis costs of SCLC were $896.73 per chemotherapy visit or $10,760.85 per patients hospitalised in Turkey (€, cost year not speciﬁed) course of treatment (Table 4). In Australia, the median and reported the total cost of diagnosis per patient as €937 cost per month of survival for all lung cancer (SCLC and in limited-stage SCLC and €502 in extensive-stage SCLC NSCLC) patients was AU$1854 (AU$, review of patient . Furthermore, Patrice et al. found that the addition of records 2005–2008, applying 2005 Australian Medicare thoracic radiation therapy to prophylactic cranial irradia- Beneﬁts Schedule costings, adjusted to 2016 US$) . tion (PCI) in extensive-stage SCLC patients in the US Hospitalisation and chemotherapy were the highest direct resulted in a $4066 cost increase (US$, cost year not costs reported (see Table 5). speciﬁed) . Chemotherapy costs were also a major component of Karve et al. reported on healthcare costs per patient for lung cancer costs [12, 27]. Intravenous chemotherapy extensive-stage SCLC and metastatic NSCLC in the US administration and other visit-related drugs and services (US$, cost year not speciﬁed). In both the SCLC and accounted for nearly half of the total cost per intravenous NSCLC cohorts, hospitalisation was the predominant cost visit day in one study . A substantial economic burden driver, accounting for approximately half of all costs (see on patients with extensive-stage SCLC and NSCLC was Table 6). SCLC disease-related costs were a larger per- observed in the US (see Table 6). The primary drivers centage of total (all-cause) costs compared with NSCLC of costs were hospitalisation, ofﬁce visits, and hospital (62.6% vs. 56.4%) . outpatient visits, and chemotherapy use was signiﬁcantly Seven other publications reported on extensive- and more prevalent in SCLC compared with NSCLC . limited-stage SCLC, however the costs reported were not In Italy, the economic impact of patients enrolling in separated by extensive and limited SCLC sponsored clinical trials on national healthcare spending [12, 15, 18, 19, 21, 22, 25]. was examined . The costs of chemotherapy agents were reported to be high and the enrolment of 44 patients in 3.2.2 Direct Costs of Prophylactic Therapies sponsored clinical trials produced a saving of 30% of the pharmaceutical expenses for antineoplastic agents, how- Prophylactic therapy costs were reported frequently, with ever no speciﬁc cost data were reported . two modelling and one observational publication reporting In Japan, median hospital length of stay was longer for on the direct costs of multiple prophylactic therapies, or SCLC (20 days) than NSCLC (18 days) patients, and total presenting mean costs of prophylactic therapy [22–24]. charges (US$, cost year not speciﬁed) differed signiﬁcantly Timmer-Bonte et al. investigated the economic burden of 130 A. Enstone et al. Table 1 Characteristics of publications included in the SLR Authors Year Type of study Country Objective NSCLC Stage of Subgroup of SCLC interest reported reported Direct costs Cakir et al. 2007 Prospective Turkey To evaluate the individual and societal burden of lung cancer in Turkey Reported Mixed Not reported  observational study Decroisette 2011 Prospective France To document the epidemiology, management, and bone metastatic disease Not Extensive Not reported et al.  observational treatment costs of patients with lung cancer with bone metastatic disease reported study Duh et al. 2008 Retrospective US To assess costs associated with intravenous (IV) chemotherapy in patients with Not Not reported Not reported  observational SCLC from the perspective of large employer-payers reported study Grossi et al. 2013 Retrospective Italy To evaluate the economic effect of clinical trials of new lung cancer treatments Reported Not reported Not reported  observational on the total pharmaceutical expenditure on these treatments study Hartwell 2010 Literature review UK To assess the clinical and cost-effectiveness of topotecan within its licensed Not Mixed Second-line et al.  indications for patients with relapsed SCLC. This review discusses the possible reported treatment implications of appraising this technology from the perspective of the United Kingdom (UK) healthcare system Kang et al. 2012 Retrospective Australia To describe the current pattern of resource use and direct medical costs Reported Mixed Not reported  observational associated with managing lung cancer in South Western Sydney, Australia study Karve et al. 2012 Retrospective US To provide a summary of trends in treatment patterns and direct healthcare costs Reported Not reported Not reported  observational among elderly Medicare patients diagnosed with and receiving cancer-directed study treatment for distant stage SCLC and NSCLC Kuwabara 2009 Retrospective Japan To investigate the differences in practice between SCLC and NSCLC patients Reported Mixed Not reported et al.  observational and examine how lung cancer-related severity, such as pathological diagnosis study or cancer staging, impacts on costs Louie et al. 2015 Model US To evaluate the clinical beneﬁts and cost-effectiveness of prophylactic cranial Not Limited Brain  irradiation (PCI) with hippocampal avoidance (HA) for limited stage SCLC reported metastases patients Loveman 2010 Literature review UK To assess the clinical effectiveness and cost-effectiveness of topotecan as a Not Mixed Brain et al.  second-line treatment for SCLC. This health technology assessment document reported metastases discusses the possible implications of appraising this technology from the perspective of the UK healthcare system Patrice et al. 2015 Model US To evaluated the cost-effectiveness of adding thoracic radiation therapy to Not Extensive Second-line  chemotherapy and PCI in extensive stage SCLC patients reported treatment Pertile et al. 2015 Prospective Italy To estimate the cost-effectiveness of the PREDICA (population-based cohort Reported Not reported Smokers; ﬁrst-  observational study of chest X-ray screening in smokers) screening line treatment study The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 131 Table 1 continued Authors Year Type of study Country Objective NSCLC Stage of Subgroup of SCLC interest reported reported Ruben and 2012 Literature review Australia To establish the efﬁcacy of a positron emission tomography (PET)-based staging Not Mixed First-line Ball  of SCLC compared to conventional methods, the potential impact on patient reported treatment management and outcomes, and cost implications for the Australian health system Tan Sean 2009 Retrospective France To evaluate the economic implications of using pegﬁlgrastim versus granulocyte Not Not reported Not reported et al.  observational colony-stimulating factor (G-CSF) to prevent febrile aplasia induced by reported study chemotherapy for SCLC Timmer- 2008 Model Netherlands To use a Markov model to investigate the economic consequences of secondary Reported Not reported First-line Bonte et al. prophylactic use of different prophylactic strategies (antibiotics, antibiotics treatment  plus G-CSF, and a combined sequential approach) in a population at risk of febrile neutropenia Turk et al. 2015 Retrospective Turkey To establish the direct costs of diagnosing lung cancer in hospitalised patients in Reported Mixed Not reported  observational Turkey study Weycker 2011 Model Not reported To use a model to investigate the consequences of a single screening of Reported Not reported Smokers; ﬁrst- et al.  (abstract screening-naı¨ve older adult smokers for lung cancer using an autoantibody test line treatment only) (AABT) versus computer tomography (CT) screening Indirect costs Cakir and 2007 Prospective Turkey To evaluate the individual and societal burden of lung cancer in Turkey Reported Mixed Not reported Karlikaya observational  study SLR Systematic literature review, CT computed tomography, G-CSF granulocyte colony-stimulating factor, SCLC small cell lung cancer, NSCLC non-small cell lung cancer, PCI prophylactic cranial irradiation, HA hippocampal avoidance, AABT autoantibody test, PET positron emission tomography, IV intravenous This is a longitudinal cohort study, years of data collected in the body of the report Mixed SCLC is deﬁned as limited- and extensive-stage SCLC reported in the same publication 132 A. Enstone et al. Table 2 Quality assessment of the included publications using the The cost of PCI with hippocampal avoidance was adapted DRUMMOND checklist  reported as $13,377.61 versus $6388.28 for PCI in limited- stage SCLC patients in the US (Medicare’s 2014 reim- Publication Total Number of Total score applicable quality bursement rate adjusted to 2016 US$) . questions percentage 3.2.3 Direct Costs of Bone Metastatic Disease Cakir and Karlikaya 21 13 80.8  As part of the secondary objectives of this SLR, the costs of Decroisette et al.  19 13 73.1 bone metastasis were investigated. A French prospective, Duh et al.  22 13 84.6 observational study reported on bone metastasis in SCLC Grossi et al.  20 12 83.3 . The total cost of bone metastatic disease for both Hartwell et al.  22 12 91.7 SCLC and NSCLC was €1,715,213 (cost year not speci- Kang et al.  21 13 80.8 ﬁed) for the entire cohort of patients (n = 554) . The Karve et al.  22 13 84.6 mean management cost during the ﬁrst year after onset was Kuwabara et al.  20 13 76.9 €3999, of which 49.5% was linked to the management of Loveman et al.  23 13 88.5 patients with skeletal-related events. Metastatic bone dis- Ruben and Ball  21 13 80.8 ease presented a signiﬁcant driver of oncology costs, with Timmer-Bonte et al. 19 13 73.1 skeletal-related events being the most burdensome cost of  bone metastatic disease management . Pertile et al.  21 13 80.8 Tan Sean et al.  20 13 76.9 3.2.4 Cost of SCLC by Subpopulations The economic burden of disease in different SCLC sub- secondary prophylactic use of different prophylactic groups was also explored in this review. Due to the diverse strategies in extensive-stage SCLC patients at risk of feb- study designs of publications presenting smoking and non- rile neutropenia in The Netherlands and found that the most smoking populations, comparisons could not be made on expensive strategy was antibiotics plus granulocyte colony- any variation in cost between these subpopulations. stimulating factor (G-CSF), with a mean cost of $13,338 The costs of SCLC staging were investigated in two per patient (converted from 2002 € to 2016 US$; original publications, with Kang et al. presenting cost differences cost year derived from a further publication on the same between each stage of SCLC in Australia , while Karve study, cited within the captured publication)  (Table 7). et al. reported on the most used ﬁrst-, second- and third-line The relatively high price of administering G-CSF was the treatments in extensive SCLC in US . Kang et al. determining cost factor . reported that the median total cost increased along with In France, the economic implications of using pegﬁl- progressing stage for NSCLC and SCLC, with the median grastim to prevent febrile neutropenia induced by total cost for limited SCLC reported as AU$20,826, and chemotherapy in SCLC were explored . The difference AU$13,874 for extensive-stage SCLC (AU$, review of in the costs of preventing and managing febrile neutropenia patient records 2005–2008, applying 2005 Australian between the two strategies was €1743 for the pegﬁlgrastim Medicare Beneﬁts Schedule costings, adjusted to 2016 strategy and €1466 for the G-CSF strategy (€, cost years US$). The median cost per patient was highest for limited- not consistently reported). Pegﬁlgrastim was more costly stage SCLC (see Table 5), while the median cost per month than ﬁrst-generation G-CSF; however, concern about the of survival for all lung cancer (SCLC and NSCLC) patients excess cost may be reduced by the perceived convenience was AU$1854 . Hospitalisation and chemotherapy of the pegﬁlgrastim strategy . Table 3 The cost of lung Type of cost N Total Mean ± SD Upper and lower limits cancer in Turkey (US$, cost year not speciﬁed)  Direct medical costs 103 $564,490 $5480 ± 4088 $316–24,574 Additional medical costs 10 $7755 $775 ± 1097 $3–3316 Direct non-medical costs 103 $34,415 $334 ± 1324 $5–13,500 Total direct costs 103 $606,660 $5890 ± 4186 $436–24,779 Total cost of lung cancer 103 $1,473,530 $14,306 ± 17,705 $771–104,079 SD Standard deviation Five patients died during the study, therefore only 103 were included in the cost analyses The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 133 Table 4 Estimated costs per IV chemotherapy visit and course of treatment in SCLC (n = 802) in the US (US$, 2007 costs adjusted to 2016 US$)  Category Cost per visit (mean ± SD) Cost per course (mean ± SD) % of total IV chemotherapy drugs $450.01 ± 786 $5400.15 ± 9442 50.2 IV chemotherapy administration procedures $105.56 ± 136 $1266.71 ± 1646 11.8 Other visit-related drugs and services $341.16 ± 802 $4094.01 ± 9635 38.0 Total cost $896.73 ± 1352 $10,760.85 ± 16,242 100.0 IV Intravenous, SD standard deviation, SCLC small cell lung cancer A course of IV chemotherapy is assumed to include 12 visits (3 visits per cycle 9 4 cycles) Drugs included cisplatin, etoposide, irinotecan, carboplatin, topotecan, and CAV (cyclophosphamide/adriamycin/vincristine) Other visit-related drugs and services included chemotherapy assessments, erythropoietic agents, evaluation and management, laboratory services, other IV drugs, other IV administration procedures, other medical services, radiology, saline, serotonin antagonists, supplies/durable medical equipment, and surgical procedures Table 5 Total and mean treatment costs by stage and modality (AU$, review of patient records 2005–2008, applying 2005 Australian Medicare Beneﬁts Schedule costings, adjusted to 2016 US$)  N Surgery (%) Radiotherapy (%) Chemotherapy (%) Hospitalisation (%) Total cost Mean cost SCLC Limited-stage 8 $0 (0) $47,991 (39) $29,482 (24) 44,787 (37) $122,260 $19,046 Extensive-stage 21 $1416 (1) $15,940 (8) $43,147 (22) $138,510 (69) $199,013 $12,688 Total (NSCLC and SCLC cohort) 210 $73,577 $420,708 $599,904 $1,162,494 SCLC Small cell lung cancer, NSCLC non-small cell lung cancer were the greatest components of cost, representing 44 and Two publications reported on patients with brain 22% of total costs, respectively. Overall, the total costs of metastases but did not present separate costs for patients managing SCLC and NSCLC were comparable . with these metastases, therefore no conclusions could be Karve et al. also reported on high hospitalisation costs in drawn [19, 22]. The lack of information on the costs of both the extensive-stage SCLC and metastatic NSCLC brain metastases in SCLC highlights this as a crucial area cohorts, accounting for approximately half of all costs . where more research is needed. Chemotherapy use was signiﬁcantly more prevalent in extensive-stage SCLC compared with metastatic NSCLC, 3.2.5 Symptom Burden versus Treatment Burden while surgery and radiation therapy were more prevalent in metastatic NSCLC. Utilisation of haematopoietic growth Despite the systematic nature of this review, no publica- factors and some supportive care therapies were signiﬁcantly tions were found that distinguished between symptom and higher in extensive-stage SCLC patients, however the treatment burden directly, therefore no conclusions could authors did not explore the reasons for this . be drawn. Table 6 Mean total healthcare a All-cause Lung-cancer-related costs per patient in the US (US$, cost year not speciﬁed) SCLC NSCLC p-Value SCLC NSCLC p-Value  Hospitalisations $32,456 $32,027 0.403 $12,498 $9778 \0.001 Ofﬁce visits $22,340 $18,027 \0.001 $19,168 $15,822 \0.001 Hospital outpatient visits $7253 $7040 0.270 $6044 $5767 0.116 Hospice $3099 $3693 \0.001 $2933 $3419 \0.001 Other ancillary care $2624 $2502 0.086 $1656 $1495 0.001 Skilled nursing facility $2453 $2607 0.111 $1790 $1775 0.846 ER visits $324 $312 0.022 $78 $76 0.389 Total costs $70,548 $67,175 \0.001 $44,167 $37,932 \0.001 SCLC Small cell lung cancer, NSCLC non-small cell lung cancer, ER emergency room Lung cancer- and non-lung cancer-related healthcare costs 134 A. Enstone et al. Table 7 Cost per patient per a Patient group Bootstrap secondary prophylactic strategy in baseline model (US$, Mean per patient 95% CI converted from 2002 € to 2016 Antibiotics $6660 $5387–8052 US$)  Antibiotics plus G-CSF $13,328 $11,269–15,504 Primary antibiotics, secondary G-CSF $8843 $7209–10,745 CI Conﬁdence interval, G-CSF granulocyte colony-stimulating factor In bootstrap analysis, the original cost data sample was parameterised normally by bootstrapping the original sample 3.3 Indirect Costs signiﬁcantly to the understanding of the true magnitude of costs associated with SCLC. The varied nature of the Indirect SCLC costs, such as lost productivity (e.g. studies captured indicates the need for a uniform and absenteeism), care costs (indirect costs associated with consistent approach when reporting on costs of SCLC, as caring and house work), out-of-pocket expenses, income well as a clear need for more research in this ﬁeld. foregone due to illness-related early retirement, and pre- It must be noted that the authors of the identiﬁed pub- senteeism were investigated in this SLR. The indirect costs lications based the reported costs (e.g. costs associated with of SCLC were captured in a single publication by Cakir diagnosis, surgery, treatment, hospitalisation) on different and Karlikaya and included lost productivity due to pre- sources, such as published literature, databases, operative mature death (total $866,870; US$, cost data not speciﬁed; unit reviews and individual hospital data. They also used 59% of total lung cancer costs) . This study found that different currencies, and the cost components (e.g. inpa- the indirect costs experienced by patients in Turkey varied tient costs, outpatient costs, administration) contributing to widely, ranging from $500 to $99,000 . Indirect costs reported total costs varied widely and were chosen arbi- were high in relation to the total costs presented, however trarily by the authors of the identiﬁed publications, in these costs were not compared with indirect costs of other accordance with the research questions the research was cancers . Work productivity was the only indirect cost trying to address. To this end, the data included in this component reported for SCLC patients, highlighting the review are very heterogeneous in type and magnitude, need for more studies in this area. making direct comparison and conclusions challenging. In comparison to a systematic review previously con- ducted on NSCLC, there were very limited data on the 4 Discussion and Conclusions indirect costs of SCLC . The only indirect costs of SCLC captured were lost productivity due to premature The publications included within this SLR varied widely in death . The most commonly reported indirect cost in methodology, patient characteristics (e.g. age, proportion NSCLC was lost productivity, along with caregiver burden, of male patients, cancer stage), analytical methods, type of although only ﬁve papers reported on indirect costs in that reported costs (costs associated with, for example, diag- review . As information on indirect costs of SCLC was nosis, surgery, treatment), and cost components (e.g. scarce in the peer-reviewed literature, grey literature inpatient costs, outpatient costs, administration). Publica- sources were identiﬁed to augment the ﬁndings of the SLR. tions also varied by region of interest, including studies Increased caregiver work and activity impairment in lung conducted in Europe [12, 14, 15, 19, 20, 23–25, 27], North cancer were reported in conference proceedings , and a America [13, 17, 22, 26], Oceania [16, 21], and Asia . high economic burden of lung cancer illness was also The majority of identiﬁed publications were observa- reported ; however, none of these additional ﬁndings tional studies (n = 10), followed by modelling studies investigated SCLC directly, providing only limited infor- (n = 4) and SLRs (n = 3). Most publications (9/17) mation for this literature review. reported data for both SCLC and NSCLC patients, while Direct costs, including drug costs and cost of hospital only eight studies reported on SCLC patients only admissions, were the most commonly reported costs for [13, 15, 19, 21–23, 25, 26]. Generally, SCLC patients were both NSCLC and SCLC (n = 17). Many publications the minority of lung cancer patients, while NSCLC patients included in this SLR reported on general lung cancer costs were the majority, results that are aligned with the general that included SCLC (9/17), but the proportion of SCLC population of lung cancer patients . To the authors’ patients was not always reported, creating uncertainty knowledge, this is the ﬁrst SLR of the economic burden of about the relevance of the data. Due to the heterogeneity SCLC and the results summarised here will contribute and limited availability of the economic burden of SCLC The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 135 data, the results from this systematic review and grey lit- reports are assessed for quality. In light of this, each pub- erature search have been presented as a narrative synthesis, lication was assessed for quality against an adapted version without any direct comparisons made. of the DRUMMOND checklist, which has been developed A secondary objective of the SLR was to identify for the purpose of assessing the quality of economic whether any differences exist between patient subpopula- evaluations . This checklist was used as it was perceived tions. The following patient subpopulations were reported as being the only published quality control guidance in the publications included within this review: smokers applicable to the objectives of this review; however, it was and non-smokers [20, 28], SCLC-stage costs [16, 17] and not directly relevant to all publications reviewed. In this brain metastases [19, 22], and SCLC versus NSCLC capacity, the DRUMMOND checklist was of limited [16–18, 27]. However, due to the heterogeneity of costs application to some publications reviewed (some publica- reported, no conclusive evidence for how costs vary tions were abstracts or posters and presented limited between these subpopulations could be provided. The SLR information, i.e. no full justiﬁcation of the methods etc., found no published data on the PD-L1 subgroup in SCLC. and some checklist questions were speciﬁc to modelling While PD-L1 expression strongly correlates with beneﬁt studies and were therefore not applicable to all types of for patients with NSCLC, there is a lower prevalence of publications). PD-L1 expression in SCLC, which is likely the reason for Several non-peer-reviewed publications were included the paucity of data found in this SLR [44–46]. A larger in this review as grey literature with the aim of augmenting population analysis is required to establish whether PD-L1 the ﬁndings of this SLR, particularly with regard to the expression correlates with beneﬁts in SCLC . economic burden, which could have limited validity [17, 22, 26–28]. In addition to this, the inclusion of sec- 4.1 Limitations ondary sources, such as economic models and literature reviews, within this review may reduce its validity . Certain limitations were noted during the course of this SLR. The broad research question of the SLR resulted in 4.2 Summary of Results the identiﬁcation of publications reporting a disparity of cost aspects related to SCLC disease diagnosis and man- In conclusion, the publications included within this review agement. Differences in study design, study objective and assessed the economic burden and/or indirect and direct methodology increased heterogeneity in data reporting, costs of SCLC in Australia, Brazil, Canada, Europe, Japan, and, as a result, no quantitative analysis, such as a meta- Russia and the US. Generally, there was a paucity of analysis, could be performed. publications identiﬁed in this review reporting on eco- Additionally, only a minority of the studies provided nomic burden and indirect costs, indicating a severe lack of sufﬁcient information to allow their cost results to be research in this area. SCLC accounts for approximately converted to a ﬁxed price-year, as is recommended by the 15% of all lung cancers, however few publications report Cochrane Collaboration . The majority of studies on its economic burden compared with NSCLC [4, 43]. providing relevant cost data were not eligible for conver- When reported, economic burden and indirect costs were sion: six studies stated when resource use had been cap- high in relation to the total costs presented . Despite the tured, but failed to provide the year of costing information direct costs being reported in numerous publications [12, 17, 18, 23, 25, 27], and one provided neither of these identiﬁed within this review, the costs reported were . This limitation identiﬁed within the captured studies diverse, ranging from costs of diagnosis to costs for therefore extends to this review, increasing the difﬁculty of speciﬁc treatments and cost comparison analyses . In comparing between studies. addition, the way in which costs were evaluated/analysed The time horizon of the literature search was 10 years and reported varied, making direct comparisons difﬁcult to and publications reporting on cost analyses performed in conduct. Although diverse, all direct cost publications 2005 or after were included. However, it is important to reported high direct costs in the context of the total costs note that some of these publications include patient or associated with SCLC. disease management data collated prior to 2005. Whether This review found that only a limited number of pub- data presented in this report can be extrapolated to the lications provided sufﬁcient context for costs to be con- wider SCLC patient population in Australia, Brazil, verted, and reinforces the ﬁnding that the available cost Canada, Europe, Japan, Russia and the US would require data in SCLC are diverse, both in magnitude and the further research. treatments or resources for which they are available. Fur- A key step of the systematic review process is to ensure ther research into the cost of SCLC is recommended, along all publications included within the ﬁnal analysis and with improved reporting to allow comparability. 136 A. Enstone et al. Compliance with Ethical Standards or both; drafting and/or critical revision of the manuscript for important intellectual content; and approval of the ﬁnal submitted Data Availability Statement Not applicable. All data used in this SLR version of the manuscript. are derived from published studies and are thus already available. Open Access This article is distributed under the terms of the Funding Financial support for this research was provided by Bristol- Creative Commons Attribution-NonCommercial 4.0 International Myers Squibb (BMS). License (http://creativecommons.org/licenses/by-nc/4.0/), which per- mits any noncommercial use, distribution, and reproduction in any Conﬂict of Interest Penrod J. and Yuan Y. are employees of BMS. medium, provided you give appropriate credit to the original Enstone A., Greaney M., Povsic M., Wyn R.are employees of Adelphi author(s) and the source, provide a link to the Creative Commons Values, who received a consulting fee from BMS to undertake this license, and indicate if changes were made. work. The authors have no other conﬂicts of interest. Preliminary results of this SLR have been presented as a poster at the ISPOR 19th Annual European Congress, Vienna, Austria, 29 October–2 Novem- ber 2016. Enstone A., Greaney M., Povsic M., Wyn R., Penrod J.R. Appendix A and Yuan Y. acknowledge that they contributed to all of the following aspects of the work: conception and planning of the work that led to See Table 8. the manuscript or acquisition, analysis and interpretation of the data, Table 8 Total number of ‘hits’ for each stage of the economic burden of the SCLC search Search terms Results SCLC or small cell lung carcinoma/or carcinoma, small cell/or small cell lung cancer/or small-cell lung cancer/or small cell 36,387 carcinoma/or small-cell carcinoma/or small cell undifferentiated carcinoma/or small-cell undifferentiated carcinoma/or oat cell carcinoma/or oat-cell carcinoma/or combined cell carcinoma/ AND Healthcare cost/or economic burden/or economic impact/or social cost/or caregiver/or sick leave/or health expenditures/or hospital 1,704,397 economics/or healthcare ﬁnancing/or pharmaceutical fees/or medical fees/or hospital charges/or job performance/or work disability/or medical leave/or sickness beneﬁt/or absenteeism/or productivity/or medical leave/or employer health costs/or sick leave/or employment/or informal care/or caregiver/or carer/or work impairment/or premature mortality/or life years lost/or *morbidity/or economic aspect or ﬁnancial aspect or cost of care or opportunity cost* or drug cost* or medical cost* or service cost* or supply cost* or administrative cost* or physician cost* or nurse cost* or infusion cost* or administration cost* or cost* or *hospitali$ation/ Total 458 Limited to human/humans 422 Limited to year 2005–current 236 Total (duplicates removed) 217 SCLC Small cell lung cancer The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature 137 Appendix B See Table 9. Table 9 Cost data conversion for the included publications Study name (location) Cost presented/reason for no cost conversion Cost Cost year and Corresponding reported currency 2016 US$ value Cakir and Karlikaya Cost year not reported in the publication, therefore no cost (Turkey)  conversion could be done Decroisette et al. Cost data not reported in the publication, therefore no cost conversion (France)  could be done Duh et al. (US)  Cost per chemotherapy visit 1183 2007 US$ 1347.24 Cost per course of treatment 14,196 16,166.93 Grossi et al. (Italy) Cost data not reported in this review, therefore no cost conversion  was done Hartwell et al. (UK) Cost data not reported in this review, therefore no cost conversion  was done Kang et al. (Australia) Median cost per patient of limited-stage disease 20,826 2005 AU$ 19046.12  Median cost per patient of extensive-stage disease 13,874 12688.27 Karve et al. (US)  Cost year not reported in publication, therefore no cost conversion could be done Kuwabara et al. Cost year not reported in publication, therefore no cost conversion (Japan)  could be done Louie et al. (US)  Prophylactic cranial irradiation with hippocampal avoidance 13,116.34 2014 US$ 13,377.61 Prophylactic cranial irradiation 6263.51 6388.28 Loveman et al. (UK) Cost data not reported in this review, therefore no cost conversion  was done Patrice et al. (US)  Cost data not reported in publication, therefore no cost conversion could be done Pertile et al. (Italy) Cost data not reported in this review, therefore no cost conversion  was done Ruben and Ball PET-based staging 1603 2010 AU$ 1189.10 (Australia)  Conventional staging 1610 1194.29 Tan Sean et al. Cost year for the data included in this review not reported in (France)  publication, therefore no cost conversion could be done Timmer-Bonte et al. Antibiotics in prophylaxis of febrile neutropenia 4496 2002 € 6659.75 (Netherlands)  G-CSF in prophylaxis of febrile neutropenia 8998 13,328.39 Primary antibiotics, secondary G-CSF in prophylaxis of febrile 5970 8843.13 neutropenia Turk et al. (Turkey) Cost year not reported in publication, therefore no cost conversion  could be done Weycker et al. (not Cost data not reported in this review therefore, no cost conversion reported)  was done PET Positron emission tomography, G-CSF granulocyte colony-stimulating factor https://seer.cancer.gov/statfacts/html/lungb.html. Accessed 11 Apr 2017. References 4. Gorman G. New and emerging strategies for the treatment of small cell lung cancer. J Pharm Sci Emerg Drugs. 2012;1(1):1–2. 1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J 5. Abidin A, Garassino M, Califano R, Harle A, Blackhall F. Tar- Clin. 2015;65(1):5–29. geted therapies in small cell lung cancer: a review. Ther Adv Med 2. World Health Organization. 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