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a1111111111 a1111111111 a1111111111 Background Recent advances in targeted therapies have raised expectations that the clinical application of biomarkers would improve patient's health outcomes and potentially save costs. How- OPENACCESS ever, the cost-effectiveness of biomarkers remains unclear irrespective of the cost-effective- ness of corresponding therapies. It is thus important to determine whether biomarkers for Citation: Seo MK, Cairns J (2018) Do cancer biomarkers make targeted therapies cost-effective? targeted therapies provide good value for money. This study systematically reviews eco- A systematic review in metastatic colorectal nomic evaluations of biomarkers for targeted therapies in metastatic colorectal cancer cancer. PLoS ONE 13(9): e0204496. https://doi. (mCRC) and assesses the cost-effectiveness of predictive biomarkers in mCRC. org/10.1371/journal.pone.0204496 Editor: Aamir Ahmad, University of South Alabama Mitchell Cancer Institute, UNITED STATES Methods Received: February 15, 2018 A literature search was performed using Medline, Embase, EconLit, NHSEED. Papers pub- Accepted: September 10, 2018 lished from 2000 until June 2018 were searched. All economic evaluations assessing bio- marker-guided therapies with companion diagnostics in mCRC were searched. To make Published: September 26, 2018 studies more comparable, cost-effectiveness results were synthesized as per biomarker Copyright:© 2018 Seo, Cairns. This is an open tests and corresponding therapies. Methodological quality was assessed using the Quality access article distributed under the terms of the Creative Commons Attribution License, which of Health Economic Studies (QHES) instrument. permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Results Data Availability Statement: All relevant data are Forty-six studies were included in this review. Of these, 17 studies evaluated the intrinsic within the paper and its Supporting Information value of cancer biomarkers, whereas the remaining studies focused on assessing the cost- files. effectiveness of corresponding drugs. Most studies indicated favourable cost-effectiveness Funding: MKS received a PhD studentship from of biomarkers for targeted therapies in mCRC. Some studies reported that biomarkers were Centre for Cancer Biomarkers (CCBIO), Centre of cost-effective, while their corresponding therapies were not cost-effective. A considerable Excellence at the Faculty of Medicine and Dentistry, University of Bergen. number of economic evaluations were conducted in pre-defined genetic populations and thus, often failed to fully capture the biomarker's clinical and economic values. The average Competing interests: The authors have declared that no competing interests exist. QHES score was 73.6. PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 1 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Conclusion Cancer biomarkers for targeted therapies in mCRC were mostly found to be cost-effective; otherwise, they at least improved the cost-effectiveness of targeted therapies by saving some costs. However, this did not necessarily make their corresponding therapies cost- effective. While companion biomarkers reduced therapy costs, the savings were not suffi- cient to make the corresponding agents cost-effective. Evaluation of biomarkers was often restricted to the cost of tests and did not consider their clinical values or biomarker prevalence. Introduction Colorectal cancer (CRC) is the third most common cancer and the third leading cause of can- cer deaths worldwide [1]. In Europe, it is the most common cause of cancer death after lung cancer. In 2012, 241,600 men and 205,200 women were diagnosed with CRC [2], and 113,200 men and 101,500 women died from CRC [2]. In the USA, 136,830 cases newly diagnosed with CRC and 50,310 deaths with CRC were projected in 2014 [3]. Despite recent developments in targeted therapies, gene sequencing and molecular diag- nostics, promising optimized and personalized treatment regimens tailored for individual patients, CRC remains one of the less treatable cancers. Most cases of CRC are sporadic and develop slowly over several years, progressing through a series of clinical and histopathological stages from single crypt lesions through benign adenomas to malignant carcinomas, as a result of an accumulation of mutations in tumor suppressor genes and oncogenes or a genetic insta- bility [4, 5]. The 5-year survival rate for early-stage CRC is about 90% but it falls to 10% for late-stage CRC metastasized to distant sites [6] and cancer mortality is mainly due to metasta- sis [7, 8]. There are multiple treatments available for patients with metastatic colorectal cancer (mCRC), including targeted therapies guided by biomarkers [9±11]. Recent advances in tar- geted therapies have raised expectations that clinical application of biomarkers might improve health benefits while avoiding unnecessary toxicity and adverse events. It can potentially reduce health care system costs by containing unnecessary costs without hurting patient health outcomes [12]. These therapies comprise epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and tyrosine kinase (TK) inhibitors. VEGF-targeted therapies include bevacizumab, aflibercept, and ramucirumab. EGFR inhibitors are cetuximab and panitumu- mab. Regorafenib is a TK inhibitor. Of these, only anti-EGFR therapies have a predictive bio- marker clearly established for guiding treatment options as an integral part of the clinical pathways [13, 14]. Current guidelines in Europe and the USA recommend that all mCRC patients receive Kirsten rat sarcoma (KRAS) testing prior to treatment with EGFR inhibitors since KRAS mutation status±wild type (WT) or mutant (MT)±predicts the response to anti- EFGR therapies [15, 16]. Recently, the testing was expanded to RAS testing (both KRAS and NRAS) [17]. KRAS and NRAS mutations serve as predictive biomarkers for anti-EGFR thera- pies, only patients with RAS wild-type tumors benefit from these therapies. No positive predic- tive biomarkers exist yet, that identify eligible patients rather than exclude ineligible patients. No other molecular marker is part of routine clinical practice when deciding optimized and tailored treatment regimens for mCRC patients. However, irinotecan is a biomarker-directed PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 2 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC chemotherapy for treating mCRC, which unlike molecularly targeted therapies, is a cytotoxic drug given to get rid of or control cancer cells. UGT1A1 testing showed clinical benefits for the administration of irinotecan [18]. All these predictive biomarkers are currently used in clinical settings to make treatment decisions for the safe and effective use of targeted therapies in treating mCRC. Third-party payers often prioritize competing interventions by assessing cost-effectiveness using cost-effectiveness (CEA) and cost-utility analysis (CUA) [19]. The former is often assessed per additional life-years gained (LYs), and the latter per additional quality-adjusted life-year (QALY). Incremental differences in costs and benefits between alternative interven- tions are the main focus of economic evaluations and thus, the primary study outcome is usu- ally to estimate the incremental cost-effectiveness ratio (ICER) per LYs or QALYs [19]. The comparison of alternative courses of action for cancer biomarkers for targeted therapies can be broadly categorised into two forms: `test-treat' strategy (patients are treated with new interven- tion guided by biomarker status) and `treat-all' strategy (all patients are treated without bio- marker testing) [20]. To sum up, the use of biomarkers may permit optimising regimens without compromising health outcomes. This has significant implications for healthcare payers in containing expendi- tures that provide no or minimal benefits to patients. Despite such high expectations, the cost- effectiveness of cancer biomarkers remains unclear given that they are often co-assessed as part of high cost targeted therapy. This study systematically reviews economic evaluations of biomarker-guided therapies and aims to determine the impact of companion biomarkers on the cost-effectiveness of the corresponding therapies in mCRC. Materials and methods Literature search A systematic literature search on the cost-effectiveness of cancer biomarkers for targeted thera- pies in mCRC was performed using Medline (Ovid), Embase (Ovid), EconLit, and the National Health Service Economic Evaluation Database (NHSEED) in June 2018. The search terms (S2 Table) were validated by an information specialist. The reference lists of relevant articles were scrutinized, and the grey literature was hand-searched. The electronic search was performed using Medical subject heading (MeSH) terms and keywords that were developed based on patients (mCRC), intervention (cancer biomarkers for targeted therapies), and outcome (ICERs). These were combined with free-word texts using relevant economic terms (e.g. ªcost-effectivenessº) and the drug names of targeted therapies both in brand and generic terms. Targeted therapies granted a marketing authorization with companion biomarkers by the European Medicines Agency (EMA) or US Food and Drug Administration (FDA) were included in the literature search strategy [13]. Studies published in English were searched from 2000 until June 2018. Study selection The study selection was based on the inclusion and exclusion criteria formulated by the PICOS framework i.e., population, intervention, comparator, outcome, study type (S3 Table). Given the companion nature of predictive biomarkers for targeted therapies, their cost-effec- tiveness is interconnected with clinical effectiveness and costs of corresponding therapies as well as biomarker tests. Hence, the cost-effectiveness of biomarker testing as well as corre- sponding agents were included in this review. Selection of papers followed the eligibility crite- ria below: PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 3 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC 1. Population: the intervention is being applied to adult patients with a diagnosis of mCRC. 2. Intervention: cancer biomarkers for targeted therapies (predictive/companion biomarkers). These biomarkers are used as diagnostic tools to guide treatment or select patients respon- sive to subsequent corresponding therapies. Cancer biomarkers without market authoriza- tions co-licensed with targeted therapies were excluded. 3. Comparator: conventional treatments or targeted therapies with or without use of bio- marker tests. 4. Outcome: ICERs for LYs, ICERs for QALYs. Studies merely reporting costs or effectiveness were excluded. 5. Study type: economic evaluations including model or trial-based analyses. Studies merely reporting on methodological issues, reviews, comments, letters or editorials were excluded. The study selection had three main stages. Firstly, search hits from the electronic databases were imported into EndNote and duplicate citations were removed. Secondly, the titles and abstracts of the identified articles were screened independently by two reviewers. Studies clearly indicated as irrelevant were excluded. Thirdly, the full articles retrieved that met the inclusion criteria were screened by two reviewers, with any disagreements between reviewers resolved by discussion. Data extraction A data extraction form was created based on the Cochrane Handbook of Systematic Reviews of Interventions and the CHEERS statement [21, 22]. The following items were extracted: pub- lication details, target patients, interventions, comparators, outcomes (ICERs), study designs. Data extraction was performed by the first assessor (MKS) using Microsoft Excel1 and any ambiguities were resolved by discussion with the second reviewer (JC). Quality assessment The methodological quality of the included studies was assessed using the Quality of Health Economic Studies (QHES) scales [23]. The QHES has been validated and shown to be useful in discriminating higher quality economic evaluation studies from poorer ones [24]. The qual- ity assessment was conducted by two assessors (MKS, JC). Since no standardized interpreta- tion of QHES scores exist, we assigned QHES scores to three quality groups; above 70 scores as high quality, between 50 and 70 as fair quality, and below 50 as poor quality studies. Final QHES score per study was resolved by discussion. Synthesizing data The cost-effectiveness results of included studies divided into two groups: 1) the cost-effective- ness of cancer biomarkers for targeted therapies (predictive/companion biomarkers), 2) the cost-effectiveness of targeted therapies licensed with companion biomarkers. ICERs for com- panion biomarkers are the primary outcome of this study and those for targeted therapies are a secondary outcome. To enhance the comparability of heterogeneous cost-effectiveness studies especially for the primary outcome of this review, the cost-effectiveness results for companion biomarkers were qualitatively synthesized by the strategies compared in economic evaluations as described below. PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 4 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC a. `Test-treat' strategy: Biomarker test performed, and therapy guided by the biomarker results; for example, RAS wild-type patients receive new intervention (i.e. targeted thera- pies) and RAS mutant patients receive standard care (i.e. existing therapies/best supportive care (BSC)/chemotherapy) b. `Treat-all' with new therapy strategy: No biomarker test performed, and all patients treated with new intervention c. `Treat-all' with standard care strategy: No biomarker test performed, all patients treated with standard care Results Literature search and study selection The electronic search located 2893 publications, and reference tracking identified two addi- tional articles. Duplicates (228 papers) were removed, resulting in 2667 unique studies. The titles and abstracts were then assessed according to the pre-determined eligibility criteria, and 2489 papers were excluded. A total of 178 papers were selected for full-text assessment. Main reasons for exclusion were the type of intervention studied (i.e. not related to cancer biomark- ers for targeted therapies) and the study type (i.e. not economic evaluations or cost-effective- ness analyses). Fifteen papers were excluded because the results were reported in another paper or insufficient information was reported in abstract only. Fourteen papers were excluded as they did not report ICERs as their study outcome. Eight papers were additionally excluded because they did not target patients with mCRC. Altogether, 46 publications were included in the review, consisting of 30 studies reported in full text and 16 reported in abstract only. Study selection is presented in a PRISMA flow diagram (Fig 1) Overview of included studies The modelling designs, the intervention strategies, and the comparator strategies of the included cost-effectiveness studies were heterogeneous. The majority of studies were model- based economic evaluations except for three trial-based studies. Analyses involved compari- sons between two and seven strategy arms. Most studies employed the perspective of third party payers (79%), while only a small proportion of studies adopted a societal perspective (8%) and patient or hospital perspectives. The type of perspective was not disclosed in three studies [25±27]. Most of the included studies were modelled for lifetime or more than 10-year time horizons (66%), while trial-based analyses were modelled only for their trial periods, i.e. 1.5 or 2 years. Most of the studies were set in Europe (40%) and North America (35%), except for six in Latin America, five in Asia, and one in the Middle East. Manufacturer sponsorship was declared by 13 studies, while most studies were either funded by public or academic resources (nine studies from public resources, eight studies from either academic resources or no external funding). Most abstracts did not declare funding source for their projects. More- over, three full papers did not declare their source of funding. Study characteristics are synthe- sized in Fig 2 and detailed characteristics for each study are provided in S4 Table. No economic evaluations of cancer biomarkers for targeted therapies in mCRC were published before 2005. Many studies were published in recent years, 60% after 2012. Four studies appeared between 2005±08, 14 studies in 2009±12, and 28 studies in 2013±18. Likewise, recent years were used in costing years of assessments; the years of 2005±08 in five studies, 2009±12 in nine studies, and 2013±18 in sixteen studies. However, a considerable number of assess- ments did not specify a base year for pricing (17 studies). PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 5 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Fig 1. PRISMA flow diagram of study selection. https://doi.org/10.1371/journal.pone.0204496.g001 Primary synthesis Cost-effectiveness of predictive biomarkers in mCRC. Seventeen studies investigated the cost-effectiveness of cancer biomarkers for targeted therapies (Tables 1±3) (detailed results of ICERs per study are provided in S5 Table). These studies assessed the cost-effectiveness of predictive (companion) biomarkers aside from that of the corresponding therapies. Overall, all studies showed favourable results toward predictive biomarkers. Thirteen studies found bio- marker testing to be cost-effective [28±40], of which four studies reported biomarker testing to be dominant [33±36]. Five studies showed cost-saving [41±45] compared to that of `no-test- ing'. Wen et al. [32] evaluated cost-effectiveness of RAS screening prior to monoclonal anti- bodies and found that RAS testing before cetuximab is more cost-effective compared to KRAS-testing with cetuximab. After re-calculating their ICERs, we concluded that all strategies they used were well beyond the acceptable willingness to pay thresholds in China, but RAS testing appeared to be more favourable than KRAS testing for patients with mCRC. Some PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 6 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Fig 2. Overview of study characteristics. https://doi.org/10.1371/journal.pone.0204496.g002 studies reported conflicting results of cost-effectiveness between predictive biomarkers and corresponding therapies; the biomarkers were cost-effective, but their corresponding therapies were not [41±43, 34]. Existing predictive biomarkers (or companion diagnostics) co-licensed with targeted therapies in mCRC included KRAS and RAS approved for the use of panitumu- mab and cetuximab, and UGT1A1 genotyping approved for the administration of irinotecan. KRAS and RAS testing was the most frequently evaluated in economic evaluations (KRAS test- ing in eight studies; RAS testing in seven studies) and UGT1A1 testing in four studies. Cost-effectiveness of KRAS testing. All studies reported favourable cost-effectiveness for KRAS testing prior to the administration of the corresponding targeted therapies, while four corresponding therapies were not cost-effective (Table 1). KRAS testing for targeted therapies was assessed mostly to pre-select eligible patients before administering EGFR therapies such as cetuximab or panitumumab. As shown in Table 1, all studies suggested favourable cost-effec- tiveness for the use of KRAS testing in administering EGFR therapies. Although 50% of these studies reported the corresponding targeted therapies as not cost-effective [41±43, 34], they found that KRAS testing was cost-effective (n = 4) or at least cost-saving (n = 4) prior to the provision of corresponding therapies. Although all studies suggested favourable cost-effectiveness of KRAS testing before provid- ing EGFR therapies, the inclusion of KRAS biomarker testing did not necessarily ensure the cost-effectiveness of the costly corresponding targeted therapies. For example, Behl et al. [41] evaluated the cost-effectiveness of KRAS testing to select patients responsive to cetuximab compared to administering cetuximab to all patients without testing. We re-calculated their PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 7 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Table 1. Cost-effectiveness finding of KRAS testing for corresponding targeted therapies. Study Strategy comparison Model type, ICER/LYs (re- ICER/QALYs Currency, Conclusion based on outcome time caculated if (re-caculated if year horizon necessary) necessary) 'Test-treat' strategy compared to 'treat-all' patients with standard care without testing Behl et al. 2012 KRAS testing plus Cmab vs. Treat all Markov 672,216 NA US$, 2010 The use of KRAS testing was cost- [41] with BSC model, saving prior to Cmab however, Cmab 10-year plus KRAS testing was not cost- effective. Blank et al. 2011 KRAS testing plus Cmab vs. Treat all Markov NA 63,647 Euro, NR KRAS testing prior to Cmab is [28] with BSC model, clinically appropriate and economically Lifetime favourable. Carlson J.J. 2010 KRAS testing plus Cmab vs. Treat all Decision NA 264,644 US$, NR KRAS testing was cost-saving but [42] with BSC analytic Cmab plus KRAS testing was not cost- model, NR effective. Health Quality KRAS testing plus Cmab vs. Treat all Markov NA 54,802 CA$, 2009 KRAS testing was cost-effective for all Ontario 2010 [29] with BSC model, strategies considered. Lifetime KRAS testing plus Pmab vs. Treat all NA 47,795 CA$, 2009 with BSC KRAS testing plus Cmab + Irinotecan NA 42,710 CA$, 2009 vs. Treat all with BSC Shiroiwa et al. 2010 KRAS testing plus Cmab vs. No- Markov 120,000 180,000 US$, 2010 KRAS testing strategy was dominant [34] KRAS testing (Treat all with BSC) model, compared to no-KRAS testing strategy. 2.5- years However, Cmab (with or without KRAS testing) was not cost-effective. 'Test-treat' strategy compared to 'treat-all' patients with new treatment without testing Niedersuess-Beke KRAS testing + Pmab or Cmab vs. NR, NR 26,276 NA EU€, 2013 Testing predictive biomarkers is cost- D. et al. 2015 [44] No predictive biomarker testing saving. (Cmab/Pmab all) 'Treat-all' patients with new treatment without testing compared to 'test-treat' strategy Behl et al. 2012 Treat all with Cmab vs. KRAS testing Markov 2,932,767 NA US$, 2010 Treating all patients with Cmab [41] plus Cmab model, without testing was not cost-effective; 10-years no-testing is not cost-effective. Blank et al. 2011 Treat all with Cmab vs. KRAS testing Markov NA 314,588 Euro, NR Treating all patients with Cmab [28] plus Cmab model, without testing was not cost-effective. Lifetime Health Quality Treat all with Cmab vs. KRAS testing Markov NA Dominated CA$, 2009 No-testing was not cost-effective. Ontario 2010 [29] plus Cmab model, Lifetime Treat all with Cmab vs. KRAS testing NA 308,236 CA$, 2009 plus Pmab Treat all with Cmab vs. KRAS testing NA 163,396 CA$, 2009 plus Cmab + Irinotecan Vijayaraghavan Treat all with Cmab/Pmab/ Markov Higher costs, NA US$, 2009; No-testing was not cost-effective et al. 2012 [35] Combination therapy vs. KRAS model, same EU€ 2009 (dominated). testing plus Cmab/Pmab/ Lifetime effectiveness Combination therapy Pre-defined genetic population (KRAS WT patients) Harty et al. 2015 Cmab + FOLFIRI vs. FOLFIRI; NR, NR NA 72,053 GB£, NR Cmab plus chemotherapy was not cost- [43] strategies compared between effective in a subgroup of patients with different cohorts of patients stratified KRAS WT. However, the stratification by different biomarker status of patients by genetic biomarker status including KRAS WT group does improve the cost-effectiveness of corresponding therapies. ICERs were re-calculated using total costs and effects provided in the pertinent paper. AB; abstract, NA; not available, NR; not reported https://doi.org/10.1371/journal.pone.0204496.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 8 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC ICERs in order to evaluate cost-effectiveness using an appropriate strategy comparison such as `test-treat' strategy against `treating all patients with BSC without testing' strategy. KRAS test- ing plus administering cetuximab had a lower ICER ($672,216) than treating all patients with cetuximab with no KRAS testing ($827,913), when both strategies were compared against the reference strategy of not providing cetuximab at all. It confirms that KRAS testing saved some costs by restricting cetuximab to particular patients, however cetuximab is yet far beyond the acceptable cost-effectiveness thresholds of USA. Carlson[42] compared two intervention strategies (1. Cetuximab for all patients, 2. Cetuxi- mab for KRAS wild-type and BSC for KRAS mutant patients based on biomarker testing) compared to BSC for all patients without biomarker testing. Neither intervention strategy was cost-effective. However, the KRAS testing strategy saved $10,037 with a negligible decrease in QALYs compared to the cetuximab for all patients strategy. Likewise, Shiroiwa and colleagues [34] conducted a comparative analysis using the same strategies; 1) KRAS-testing strategy, 2) No KRAS-testing strategy (cetuximab for all), 3) No cetuximab strategy (BSC for all). They found the KRAS-testing strategy dominated the no-KRAS-testing (cetuximab for all) strategy, however, the ICER for cetuximab (with or without KRAS testing) was too high even if treat- ments were limited to KRAS wild-type patients. Meanwhile, Harty and colleagues [43] investi- gated the cost-effectiveness of cetuximab in combination with irinotecan when patients were stratified into different genetic biomarker groups and suggested that the use of a biomarker improved the cost-effectiveness of cetuximab but its ICER was beyond acceptable thresholds for UK. To sum up, targeted therapies were never cost-effective when a `no-testing strategy (treating all patients with new therapy)' was compared to a `test-treat' strategy. This confirms that KRAS testing is a better use of resources than `no-testing' prior to the administration of tar- geted therapies. However, when a `test-treat' strategy was compared to `treat all with BSC/ SOC', there were conflicting results; three studies not cost-effective [41, 42, 34] and two studies favourable [28, 29]. This implies a positive impact of KRAS testing in improving the cost-effec- tiveness of its companion therapies however; it does not necessarily mean that KRAS testing can ensure the cost-effectiveness of subsequent targeted therapy. Cost-effectiveness of RAS testing. Seven studies evaluated the cost-effectiveness of RAS testing and most of them found favourable results for RAS biomarker testing (Table 2). Of these, two studies assessed the cost-effectiveness of RAS screening compared with that of KRAS testing with targeted therapies [32, 36]. Both studies were performed from a Chinese health care system perspective and found that RAS testing was cost-effective compared to KRAS testing with cetuximab. However, Wu et al. [40] found that RAS testing with cetuximab is only cost-effective when a patient assistance programme is available in China. However, Wen et al. [32] found that bevacizumab with RAS testing was not cost-effective compared to bevacizumab with KRAS testing. They reported $74,600 which is far more than three times Chinese GDP per capita ($24,000 [46]). However, most of these studies did not use an appropriate strategy comparison such as evaluating a `test-treat' strategy in comparison to a `treat all with existing standard therapy'. Two studies were compared against `treat all with new therapy', and four studies were per- formed in a pre-defined genetic population. Only one recent study employed a comparative strategy of chemotherapy alone without mutation testing [40], however, this economic evalua- tion was of relatively low quality. Thus, the evidence on cost-effectiveness of RAS testing is still inconclusive. Further evaluation is required using an appropriate comparator strategy of `treat all patients with standard care without testing' instead of `treating all with new therapy without testing'. PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 9 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Table 2. Cost-effectiveness finding of RAS testing for corresponding targeted therapies. Study Comparison Model type, ICER/LYs (re- ICER/QALYs Currency, Conclusion based on outcome time caculated if (re-caculated if year horizon necessary) necessary) 'Test-treat' strategy compared to 'treat-all' patients with standard care without testing Wu et al. [40] Cmab + FOLFIRI vs. FOLFIRI Markov $12,107 $14,049 US$, 2016 RAS testing with Cmab is cost-effective when model, patient assistance programme is available in 10-year China. 'Test-treat' strategy compared to 'treat-all' patients with new treatment without testing Niedersuess- RAS testing + Pmab or Cmab NR, NR 9,686 NA EU€, Predictive biomarker testing were cost-saving; Beke D. et al. vs. No predictive biomarker 2013 RAS testing scenario showed lower ICERs 2015 [44] testing (Cmab/Pmab all) than KRAS testing scenario. Saito et al. 2017 RAS testing vs. No testing Markov 2,574,111 3,049,132 JP¥, NR RAS testing was cost-effective compared to [31] before EGFR therapies model, no-testing; however, comprehensive profiling 5-year is more cost-effective than RAS testing only. Pre-defined genetic population (RAS WT patients) Harty et al. 2015 Cmab + FOLFIRI vs. FOFIRI NR, NR NA 44,184 GB£, NR Stratification of patients by genetic biomarker [43] for patients stratified into RAS status improved cost-effectiveness of Cmab; WT group however, its ICERs was yet beyond the £20,000-£30,000 thresholds for UK. Recently however, NICE committees accepted that it was a life-extending end-of-life treatment and approved under the exceptional thresholds of £50,000 in UK[47]. Souza et al. 2017 Cmab + Chemotherapy vs. Markov NA 56,750 BRL$, NR The addition of Cmab to the standard [39] Chemotherapy alone model, chemotherapy is a cost-effective therapy for 20-year RAS WT patients with liver-limited disease. Wen et al. 2015 RAS-Cmab vs.KRAS-Cmab Markov NA 17710 US$, 2014 Patients treated with Cmab and RAS-testing [32] model, was more cost-effective against the strategy of 10-years KRAS-testing and treated with Cmab. RAS-Bmab vs. KRAS-Bmab NA 71079 Patients with RAS-testing and treated with Bmab was not cost-effective compared to KRAS testing and treated with Bmab. Zhou et al. 2016 RAS-Cmab vs.KRAS-Cmab Markov NA (22450) US$, NR RAS screening was dominant over KRAS [36] model, (2016 testing. RAS-Bmab vs. KRAS-Bmab NA (3966) Lifetime assumed) ICERs were re-calculated using total costs and effects provided in the pertinent paper. AB; abstract, NA; not available, NR; not reported https://doi.org/10.1371/journal.pone.0204496.t002 Cost-effectiveness of UGT1A1 testing. The four studies assessing UGT1A1 genotyping for the administration of irinotecan found that the genotyping was either cost-saving or cost- effective (Table 3). However, Obradovic et al. [45] reported that UGT1A1 genotyping in com- bination with a reduced dose of irinotecan was not cost-effective for Asian population groups, reporting very high ICERs at $6,818,000. Since all studies were conducted for populations in Europe or USA, further research on Asian populations to confirm this difference in cost-effec- tiveness of UGT1A1 testing may be required before deciding to reduce irinotecan doses. All studies compared alternative strategies correctly, between `test-treat' with new interven- tion and `treat all' patients with standard care without testing. For example, Gold and col- leagues [37] assessed the comparative analysis of UGT1A1 testing and no testing prior to irinotecan administration, using different scenarios of dose reduction efficacy of irinotecan. They reported that, assuming no reduction in treatment efficacy, the average cost savings of the genotyping test were $272.34 with 0.073 quality-adjusted days saved. Most recently, Butzke et al. [33] evaluated the UGT1A1 genotyping from a German statutory health insurance PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 10 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Table 3. Cost-effectiveness of UGT1A1 testing. Study Comparison Model type, ICER/LYs (re- ICER/QALYs (re- Currency, Conclusion based on outcome time horizon calculated if calculated if year necessary) necessary) 'Test-treat' strategy versus 'treat all' patients with standard care without testing Butzke 2016 UGT1A1 genotyping and dose Markov NA Dominant EU€, 2013 UGT1A1 testing dominates the strategy of [33] reduction vs. the current model, no-testing strategy in treating patients with standard of no testing Lifetime irinotecan-based chemotherapy. Gold et al. UGT1A1 testing and dose Decision- NA Favorable US$, 2007 UGT1A1 testing could be cost-effective if 2009 [37] reduction of irinotecan vs. the analytic irinotecan dose reduction does not reduce current standard of no testing model, 5-year efficacy. Obradovic UGT1A1 testing and dose Decision Cost-saving NA US$, 2006 Genotyping with dose reduction of et al. 2008 reduction of irinotecan vs. No analytic (African, irinotecan was cost-saving for the population [45] UGT1A1 testing and standard model, Caucasian) of African/Caucasian however, not cost- care of irinotecan Lifetime effective for Asian populations. 6,818,203 NA (Asian) Pichereau UGT1A1 genotyping before Decision tree, 942.8±1090.1 NA EU€, 2006 Genotyping strategy was cost-effective et al. 2010 irinotecan vs. no genotyping Lifetime compared to no-testing strategy. [30] strategy NA; not available or not applicable https://doi.org/10.1371/journal.pone.0204496.t003 perspective and found that genotyping prior to irinotecan-based chemotherapy dominates non-guided colon cancer care in Germany. However, this study also reported that there is sub- stantial structural uncertainty in relation to the degree of dose-reduction in heterozygotic patients and suggested to validate it in clinical practice whether physicians indeed chose to reduce dosing in both heterozygote and homozygote patients. Overall, UGT1A1 testing appears to be cost-effective prior to the administration of irinote- can, especially in relation to dose reduction and prevention of adverse events. However, two studies used narrow health outcome measures such as neutropenia avoided [45, 30] and one study suggested a conditional cost-effectiveness of UGT1A1 testing depending on the treat- ment efficacy of irinotecan dose reduction. Secondary synthesis Cost-effectiveness of targeted therapies licensed with companion biomarkers. In 29 studies, the cost-effectiveness of targeted therapies was evaluated [48±56, 25, 57±60, 26, 27]. This secondary synthesis analyses economic evaluations of targeted therapies which did not explicitly analyse the value of predictive biomarkers as part of assessing the cost-effectiveness of biomarker-guided therapies. Fifty-nine percent of these economic evaluations reported favourable cost-effectiveness findings for targeted therapies licensed with companion bio- markers in treating mCRC (n = 17). 41% reported that targeted therapies were not cost-effec- tive (n = 12). 76% of these studies (n = 22) performed their comparative analyses in a pre-defined genetic population such as biomarker-positive patients and often, no differences in the value of predic- tive biomarkers were modelled. These studies frequently assumed that the study population (in all strategy arms) was tested before entering the economic models. However, all studies related to UGT1A1 testing considered the intrinsic value of UGT1A1 testing as an integral part of their comparative analysis in administering irinotecan-based chemotherapies. Among the remaining seven studies, treatment decisions in four studies [48, 61, 62, 25] depended on biomarker mutational status, but in three studies [63±65] the comparative strategies employed were not clear. PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 11 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Overall, this secondary synthesis found that the inclusion of predictive biomarkers improved the cost-effectiveness of targeted therapies, but the improvement was insufficient to make the corresponding targeted therapies cost-effective. It may imply that the impact of their high drug costs on the cost-effectiveness of targeted therapies is much greater than that of the health benefits gained from pre-selection of responsive patients guided by biomarkers. Table 4 presents the cost-effectiveness results for targeted therapies labelled with predictive biomarkers (the ICERs are reported in S5 Table). In the case of bevacizumab, which has not yet an established biomarker in clinical settings, it was often assessed as a comparator strategy (n = 8) and not often as an intervention strategy. But two studies compared all three therapies (cetuximab, panitumumab and bevacizumab) and found bevacizumab to be cost-effective [66, 67]. Both studies were conducted in a pre-defined group of patients with KRAS wild-type sta- tus. All 29 studies included either cetuximab or panitumumab in their comparative assessments. Cetuximab was assessed in the most studies (n = 24). More studies found cetuximab not to be cost-effective (14 versus 10 studies finding it cost-effective). Among the studies reporting cetuximab as cost-effective, seven studies (78%) were conducted in a pre-defined genetic pop- ulation either KRAS wild-type or RAS wild-type, and two not [48, 25]. Moreno and colleagues [25] evaluated weekly and biweekly administration of cetuximab compared to panitumumab, where patients in both arms receive biomarker-guided therapies (either cetuximab or panitu- mumab) when KRAS wild-type and receive bevacizumab when KRAS mutant. They found that biweekly cetuximab for KRAS wild-type and bevacizumab for patients with KRAS mutant status more cost-effective compared to panitumumab-based schedules. Annemans et al. [48] assessed the cost-effectiveness of cetuximab in combination with irinotecan-based chemother- apy compared to current care in Belgium and found that the cetuximab strategy is cost-effec- tive with ICERs between€17000 (6-week treatment scenario) and€40000 (12-week treatment scenario) per LY gained. In this study, all patients in the intervention arm were treated with cetuximab plus irinotecan-based chemotherapy, while patients in the comparator arm were all treated with the current treatment. Nevertheless, none of these studies considered the clinical utility of predictive biomarkers in guiding the optimization of treatments depending on bio- marker status in patients. Among fourteen studies reporting cetuximab as not cost-effective, ten studies were in a pre-defined genetic group and often, this population scoping was used to justify not consider- ing the intrinsic value of predictive biomarkers in the evaluation. Only two studies made the appropriate comparison of a `test-treat' strategy and a `treat all with standard of care'. Both were conducted from a perspective of the English NHS and both found cetuximab not cost- effective [61, 62]. Hoyle et al. [61] assessed the cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for KRAS wild-type patients from the perspective of the English National Health Service (NHS) and found that all three strategies were not cost-effective com- pared to BSC. They modelled that 54% of patients were KRAS wild-type and thus, costing £296 per person for KRAS testing (£160 per test). Most recently, Huxley et al. [62] evaluated cetuximab and panitumumab for patients with RAS wild-type mCRC, using a similar compari- son structure with Hoyle et al., and they also found that cetuximab and panitumumab in com- bination of chemotherapy were poor value for money in the English NHS. Panitumumab assessed in 14 studies, was found to be cost-effective in eight studies [50±52, 56±58, 27, 60] and not cost-effective in six. All studies finding panitumumab to be cost-effec- tive were conducted in a pre-defined genetic group and therefore, further research is required comparing an alternative strategy where all patients receive standard of care without testing rather than that patients in comparator arm are all provided of panitumumab without PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 12 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Table 4. Cost-effectiveness of targeted therapies licensed with companion biomarkers. Study Treatments/Strategies Model type, time Biomarker Outcome Conclusion based on outcome (reference) horizon test measure Annemans et al. 1. Cmab + Irinotecan (6 week Trial-based model, NR NS LYs Cmab + Irinotecan is cost-effective in Belgium. 2007 [48] rule, 12 week rule) 2. Current treatment Asseburg et al. 1. Cmab + FOLIFIRI Patient-level simulation, KRAS LYs First line treatment with Cmab plus FOLFIRI offers a 2011 [49] 2. Bmab + FOLFOX 10-year cost-effective treatment option versus Bmab plus FOLFOX for KRAS WT genotype patients in Germany. Thus, KRAS testing should be performed on all presenting cases of mCRC to ensure access to this treatment option. Carvalho et al. 2017 1. Pmab Markov model, Lifetime RAS LYs Both Pmab and Cmab are not cost-effective in patients [68] 2. Cmab with RAS WT mCRC. 3. BSC Chaugule et al. 1. Cmab + BSC Markov model, Lifetime KRAS QALYs Cmab is not cost-effective in KRAS WT patients with 2012 [69] 2. BSC alone mCRC. Davari et al. 2015 1. FOLFIRI, FOLFOX, CAPOX Unclear, NR KRAS LYs, QALYs Addition of Cmab to FOLFIRI, FOLFOX, CAPOX [63] without the addition of Cmab (Capecitabin+oxaliplati) is not cost effective. 2. FOLFIRI, FOLFOX, CAPOX with the addition of Cmab Dos Santos et al. 1. Pmab + mFOLFOX6 Markov model, Lifetime RAS LYs, QALYs Pmab is clearly cost-effective compared to Bmab for 2015 [50] 2. Bmab + mFOLFOX6 treatment of wild-type RAS mCRC in Brazil. Ewara et al. 2014 1. Bmab + FOLFIRI Markov model, Lifetime KRAS QALYs Bmab+FOLFIRI is cost-effective. Bmab + FOLFIRI [66] 2. Cmab + FOLFIRI found to be dominant over the other two strategies. 3. Pmab + FOLFIRI The other two strategies are dominated by Bmab + FOLFIRI. However, sensivitiy analysis showed that Cmab + FOLIFIRI is being cost-effective under certain range of parameter valuesÐthus, further investigation needed for Cmab. Graham et al. 2014 1. Pmab Semi-Markov model, KRAS, RAS LYs, QALYs Pmab plus mFOLFOX represents good value for [51] 2. Bmab Lifetime money compared to a current SOC Bmab plus mFOLFOX6. Graham et al. 2016 1. Panitumumab in pts with Semi-Markov model, KRAS LYs, QALYs Compared to Cmab, the study suggested that Pmab is [52] KRAS WT status Lifetime favorable. 2. Cetuximab in pts with KRAS WT status Hnoosh et al. 2015 1. Cmab + either FOLFOX, Markov model, 10-year RAS QALYs Cmab is cost-effective and a good use of NHS Wales (AWMSG) [53] FOLFIRI, CAPOX resource through stratifiation of RAS WT patients. 2. FOLFOX 3. FOLFIRI 4. CAPOX Hnoosh et al. 2015 1. Cmab + either FOLFOX, Markov model, 10-year RAS QALYs Cost-effectiveness of Cmab could be deemed (NICE) [70] FOLFIRI, CAPOX favourable when considering it as end-of-life 2. FOLFOX medicine. 3. FOLFIRI Hoyle et al. 2013 1. Cmab Semi-Markov model, 10 KRAS LYs, QALYs All three strategies (Cmab, Cmab+Irinotecan, Pmab) [61] 2. Cmab + Irinotecan years (lifetime) are not cost-effective. 3. Pmab 4. BSC Huxley et al. 2017 1. FOLFOX (reference strategy) Semi-Markov model, 30 RAS QALYs Cmab and Pmab in combination with chemotherapy [62] 2. Cmab + FOLFOX years (lifetime) are likely to be poor value for money. 3. Pmab + FOLFOX Junqueira et al. 1. Cmab + FOLIFIRI Markov model, 10 years RAS LYs Cmab+FOLIFIRI is cost-effective for a subgroup of 2015 (RAS 2. FOLFIRI patients with RAS wild-type. subgroup) [54] Junqueira et al. 1.Cmab+FOLFIRI Markov model, 10 years RAS LYs The use of Cmab shown significant and meaningful 2015 (Cmab and 2.Bmab+FOLFIRI benefits while being cost-saving to HCS in Brazil. Bmab) [55] (Continued ) PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 13 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC Table 4. (Continued ) Study Treatments/Strategies Model type, time Biomarker Outcome Conclusion based on outcome (reference) horizon test measure Kourlaba et al. 1. Pmab + FOLFOX6 Markov model, NR RAS QALYs Pmab + mFOLFOX6 is cost-effective. 2014 [56] 2. Bmab + FOLFOX6 Krol et al. 2015 [71] 1. Cmab + FOLFIRI Markov model, 20-year RAS QALYs ICUR results were close to CET. ICURs strongly 2. FOLFIRI differed from the Netherlands and Belgium. It is 3. Cmab + FOLFOX mainly due to lower drug costs in Belgium. 4. FOLFOX Lawrence et al. 1. FBC (reference) Markov model, Lifetime KRAS QALYs Bmab + FBC offers the best value for money in KRAS 2013 [67] 2. Bmab + FBC (to maximum of 10 WT patient population. 3. Cmab + FBC years) 4. Pmab + FBC Mittmann 2009 1. Cmab + BSC Trial-based model, KRAS LYs, QALYs ICER of Cmab over BSC alone for unselected mCRC [72] 2. BSC Duration of the clinical pts was high and sensitive to drug costs. ICER was trial (18±19 months) lower when the analysis was limited to pts with KRAS WT. Moreno et al. 2012 1. Scenario A: KRAS WT pts Unclear, NR KRAS Response 1st line oxaplatin combinations of biweekly Cmab for [25] receive weekly Cmab rate WT and Bmab for MT optimise cost per additional + FOLFOX response rate rather than Pmab-based schedules. 2. Scenario B. Pmab + FOLFOX 3. Scenario C. Cmab biweekly + FOLFOX Norum J. 2006 [64] 1. 3rd line chemotherapy (Cmab Decision tree, Unclear EGFR LYs Cmab + Irinotecan as 3rd line therapy in mCRC is + Irinotecan) promising, but a very expensive antibody. Reduced 2. No 3rd line chemotherapy drug cost and/or improved overall survival may alter this conclusion. Ortendahl et al. 1. FOLFIRI + Cmab Unclear, Lifetime KRAS, RAS LYs, QALYs Cmab + FOLFIRI improve health outcomes and use 2014 [26] 2. FOLFIRI + Bmab financial resource more efficiently compared to Bmab + FOLFIRI. Riesco-Martinez Strategy 1 (reference strategy: Markov model, 5-year KRAS, RAS QALYs 1st line of EGFRI is not cost-effective at its current 2016 [73] EGFRI monotherapy in 3rd pricing relative to Bmab. line). Strategy 2 (EGFRI and Irinotecan in 3L). Strategy 3 (EGFRI in 1L). Rivera et al. 2017 1. Pmab + mFOLFOX6 Semi-Markov model, RAS LYs, QALYs Pmab+mFOLFOX6 is more cost-effective than Bmab [57] 2. Bmab + mFOLFOX6 Lifetime +mFOLFOX6 for the first line treatment of RAS WT mCRC. Samyshkin et al. 1. Bmab + Chemotherapy semi-Markov model, KRAS QALYs Cmab plus FOLFIRI is the most cost-effective for 2011 [58] 2. Cmab + Chemotherapy Lifetime patients with KRAS WT tumors. ICERs of Cmab 3. Pmab + Chemotherapy + Chemotherapy (CT), Bmab + CT, and Pmab + CT are within the commonly accepted threshold of CE in UK. Shankaran et al. 1. FOLFIRI plus Cmab in Decision tree, 2 years KRAS, RAS LYs, QALYs Results were more favorable for Cmab in RAS-WT 2015 [59] treatment-naïve patients with (trial period) patients. KRAS wt type in mCRC 2. FOLFIRI plus Bmab treatment-naïve patients with KRAS wt type in mCRC Starling et al. 2007 1. Cmab + Irinotecan Trial-based model, EGFR LYs, QALYs ICERs for Cmab+Irinotecan is relatively high [65] 2. Active/best supportive care Lifetime compared to other healthcare interventions. (ASC/BSC) Vargas-Valencia 1. Pmab + FOLFOX Markov model, Lifetime RAS LYs Pmab showed treatment outcomes improvement vs. et al. 2015 [27] 2. Cmab + FOLFIRI Cmab for RAS WT patients at a lower cost per life year. Xu et al. 2016 [60] 1. Pmab Markov model, 3-year NR LYs, QALYs Pmab dominates over Cmab. Pmab has a cost 2. Cmab advantage over Cmab. AB; abstract, ASC/BSC; active/best supportive care, Bmab; bevacizumab, Cmab; cetuximab, Pmab; panitumumab and NR; not reported https://doi.org/10.1371/journal.pone.0204496.t004 PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 14 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC biomarker testing. For example, two studies reported panitumumab as not cost-effective when compared with treating all patients with best supportive care without prior testing [61, 62]. Bevacizumab was evaluated only in three studies [66, 67, 58], two found it to be cost-effec- tive and one not cost-effective. All three studies were in pre-defined patient groups. Ewara et al. [66] assessed first-line treatment strategies for mCRC patients with KRAS wild-type and compared three strategies of bevacizumab, cetuximab, panitumumab respectively combined with FOLFIRI and found that bevacizumab is dominant over both cetuximab and panitumu- mab. Similarly, Samyshkin et al. [58] also assessed three strategies of cetuximab, bevacizumab, and panitumumab for the first-line treatments for mCRC patients with KRAS wild-type, how- ever, they found cetuximab plus FOLFIRI is the most cost-effective. But bevacizumab and panitumumab-containing regimens were also within the acceptable thresholds in UK. On the other hand, Lawrence et al. [67] found bevacizumab was not cost-effective with ICERs of $131,600 per QALYs, compared to fluoropyrimidine-based chemotherapy (FBC) alone. Quality assessment The quality of the included studies was assessed by the Quality of Health Economic Studies (QHES) instrument. The QHES scale consists of 16 weighted questions, with a range of scores from 0 (worst quality) to 100 (best quality). The QHES tool was used by two independent assessors to rate the quality of the studies. QHES score per study is provided in S6 Table. Eco- nomic evaluations reported in full articles were scored using the QHES instrument (n = 30) and studies reported only in abstract (n = 16) were excluded from quality assessment due to their limited information. In total, 60% of the studies scored above 70 (good quality) and 33% scored between 50 and 70 (fair quality), and only two papers scored below 50 (low quality). These scores were gener- ated based on 16 `yes or no' questions. The quality elements most commonly omitted from economic evaluations of cancer biomarkers for targeted therapies were the direction and mag- nitude of potential biases, the methodology for data abstraction, reliable use or justifications of health outcomes measures and scales. For the question ªDid the author(s) explicitly discuss direction and magnitude of potential biases?º (Question 14), only 13% of articles were posi- tively rated. With regard to health outcome measures (Question 11), only eight studies got pos- itive scores. As for the question, ªWas the methodology of data abstraction (including the value of health states and other benefits) stated?º (Question 7) 43% of articles were scored positively. The study objectives were clearly presented by all studies (Question 1). The perspective of the analysis was not stated by Behl et al. [41] (Question 2). However, it seems plausible that Behl et al. might have used the perspective of US payer since, they briefly discussed the poten- tial cost savings for the payer, chose the mCRC interventions most commonly used in USA and the analysis was commissioned by US National Institutes of Health. We found eleven papers [48, 37, 64, 45, 30, 73, 31, 65, 32, 36, 40] unlikely to have used data from best available source (Question 3). We interpreted this question as meaning that they provided insufficient justification of their choice of data sources. Applying data from another modelling paper or simply using RCT trial data without justifications (i.e. systematic literature review or meta- analysis) was considered insufficient. If estimates came from a subgroup analysis, were the groups pre-specified (Question 4). This item was not applicable for most of the studies since their estimates were not from a subgroup analysis. As for Question 5 on handling uncertainty, we awarded `yes' to studies which performed at least one type of sensitivity analyses. We found that all studies performed one sensitivity analysis or more. However, five studies [30, 31, 35, 36, 68] only performed one-way sensitivity analysis which may be considered insufficient, for PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 15 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC example, the NICE HTA guideline requires probabilistic sensitivity analysis [74]. Two studies did not perform incremental analysis between alternatives (Question 6) [35, 32]. Many studies did not clearly state the methodology for data abstraction of the values of health states and other benefits (n = 17) (Question 7). Four studies did not state the time horizon and discount rates applied in their studies (Question 8) [48, 63, 64, 45]. However, some studies justified that they did not discount their costs and benefits because of short time horizon of trial periods (18±19 months or 2 years) [72, 59], however this is not sufficient reason for not discounting and, to be appropriate methodologically, all costs and benefits beyond 1 year need to be dis- counted. Eight studies [66, 37, 30, 65, 35, 32, 40, 43] did not measure costs appropriately and the methodology for cost estimation was not clearly described (Question 9). Seven studies [49, 41, 63, 64, 59, 32, 36] did not clearly state primary outcome measures or did not provide clear descriptions of how they were measured (Question 10). Only eight studies [33, 51, 52, 62, 72, 29, 57, 65] used valid health outcomes and provided sufficient justifications for the measures and scales used (Question 11). Most other studies did not provide sufficient information on the health utility measures used or simply borrowed utility values from previous literature without justifications on validity of their measures and scales. Meanwhile, another eight stud- ies did not include health outcomes at all and they estimated ICERs per LYs [48, 49, 41, 68, 64, 45, 30, 35]. Four studies were not transparent on their model structure and study methods including how they estimated monetary outcomes of cost-effectiveness (Question 12) [63, 72, 45, 65]. For example, Davari et al.[63] provided almost no information about their study meth- ods and modelling structure. Most studies stated the choice of model and assumptions (n = 22) (Question 13). However, only four studies discussed potential biases in relation to their study results [33, 66, 62, 64] (Question 14). We found three studies did not come to a rea- sonable conclusion based on their study results (Question 15) but the conclusions of all other studies appear to be reasonable following their study results. However, three papers implied or suggested the intervention was cost-effective, while it was not cost-effective given the cost- effectiveness thresholds of the respective countries [48, 67, 32]. For example, Wen et al. calcu- lated monthly estimations and thus, it should conclude that it is not cost-effective given the yearly WTP in China. All but three studies explicitly disclosed their funding source [48, 29, 31] (Question 16), although the Health Quality Ontario report is likely to be commissioned by public resources [29]. Finally, we also examined if there is any influence of commercial sponsorships in terms of the quality of economic evaluations and found that there is no influence. Among all eighteen studies rated as good quality (> = 70), ten studies were in fact funded by commercial sources mainly from manufacturers. However, all studies performed by public sources such as HTA bodies, i.e. NICE or Ontario HTA were very highly rated, above 85 scores [33, 61, 62, 29]. Overall, we found that most of the studies were of good or fair quality except for two papers which scored below 50. Discussion Altogether, 46 papers were included in this systematic review. We identified three systematic reviews previously conducted for targeted therapies in mCRC [75±77], although they are dif- ferent from ours in terms of the interventions focused. We focused on predictive biomarkers (or, companion biomarkers) and thus, targeted therapies with no licensed companion diag- nostics were not included. Our review is more comprehensive than previous studies. We identified and screened a much higher number of papers (n = 2893) and conducted longer periods of literature search (17.5 years between 2000 and June 2018). And finally, we included the highest number of PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 16 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC studies in the review (n = 46) despite the narrower focus on predictive biomarkers with tar- geted therapies, while excluding cost-effectiveness analyses of targeted therapies with no licenced companion biomarkers. Lange et al. [78] which focused on assessing the cost-effectiveness of monoclonal antibodies rather than that of biomarkers, is not directly comparable to our review. However, they provi- sionally suggested that KRAS testing is cost-effective compared to no-testing. They found that treatment with bevacizumab, cetuximab, and panitumumab was generally not cost-effective. They assessed the quality of identified papers but did not synthesize the results even qualita- tively. Frank and Mittendorf [79] focused on pharmacogenomic profiling prior to the adminis- tration of pharmaceuticals in mCRC. They observed that the application of predictive biomarkers prior to EGFR antibodies was cost-effective but the cost-effectiveness of biomark- ers for irinotecan-based chemotherapy remained unclear. They provided qualitative synthesis on key drivers and areas of uncertainty in the included studies. First, they found that bio- marker costs were a driver of cost-effectiveness. Second, the characteristics of biomarkers such as performance accuracy and time of testing influence cost-effectiveness. Third, limited avail- ability of clinical data is a source of uncertainty, especially because the efficacy of biomarkers is determined by the effects of subsequent therapies. Both reviews [78, 79] suggested that the addition of KRAS testing prior to treatment could be more cost-effective than a no-testing strategy. The most recent systematic literature review was done by Guglielmo et. al [77], focus- ing on genetic tests of Lynch syndrome (LS) and KRAS mutation tests. But their search covers a very short period and search strategies were not performed step by step. Overall, none of the studies synthesized the cost-effectiveness results of predictive biomarkers for corresponding therapies even qualitatively, although they assessed the quality of identified studies. To the best of our knowledge, this is the first paper that analysed the cost-effectiveness of predictive bio- markers and corresponding therapies separately and analysed the interactions between them in terms of the influence of predictive biomarkers on the cost-effectiveness of subsequent therapies. We found that most studies used a third-party payer perspective such as health care systems or national health insurances, often taking account of only direct costs in their evaluations. Three studies included both direct and indirect costs from a societal perspective [36, 69, 71]. Zhou et al. [36] stated that they evaluated from a perspective of Chinese health care system, however, we categorised their study as having a societal perspective since they considered indi- rect costs as well i.e., travel fees and absenteeism fees. Although a general view is that it is appropriate to include both direct and indirect costs in cost-effectiveness analyses [19], it is not commonly practised in performing economic evaluations for pharmaceutical products especially when aimed to get reimbursed. Consequently, few economic evaluations have taken a societal perspective (n = 3) as seen in S4 Table. Without the changes to the HTA guidelines for reimbursement in respective countries, this trend won't be reversed. For example, Krol et al. [71] conducted their study from two perspectives, a HCS perspective for Belgium and societal perspective for Netherlands, following the respective country's HTA guidelines. When conducting a comparative analysis such as cost-effectiveness analyses, it is methodo- logically and ethically important to use the most appropriate alternative therapy as a compara- tor strategy. Standard of care (SOC) is the most widely accepted comparator in economic evaluations according to cost-effectiveness analysis guidelines in many countries. However, we found that a majority of economic evaluations of biomarker-guided therapies were performed in a pre-defined genetic group (n = 23) and by doing so, most studies failed to explicitly con- sider the values of predictive biomarkers in their comparative analyses. Our finding that whether the use of biomarkers makes corresponding therapies more cost- effective is largely driven by the expected impact on health outcomes rather than on costs PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 17 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC contrasts with that of Frank and Mittendorf [79]. This finding also highlights that the cost- effectiveness analyses of targeted therapies should consider the sensitivity and specificity of biomarker testing. Our review showed that only six studies included the clinical characteristics of the biomarker such as performance accuracy [38, 28, 33, 37, 44, 35]. A considerable number of studies did not include this in their evaluations. For example, low sensitivity may lead to not giving targeted therapies to KRAS WT patients, whereas low specificity may lead to treating patients unresponsive to the therapy. Then, some of these patients may experience poorer out- comes owing to adverse events, compared to the comparator strategy of receiving BSC. Or, false negative test results may lead to not treating the responsive patients, which causes an accumulated loss of health benefits compared to the strategy of having all patients treated with the intervention without biomarker testing. Biomarker prevalence (proportion of patients with a biomarker status) was often not considered in evaluations. Some limitations need to be acknowledged with regard to the present review. Systematic reviews are transparent, rigorous and reproducible and thus, are widely used to identify exist- ing literature in many fields including health economics. However, literature searches using an electronic database may be limited by the performance of database filtering algorithms and indexers. Therefore, our review was supplemented by hand-searches using snowballing meth- ods and references from other reviews as well as conference abstracts. Our review relies on published evidence in the public domain and consequently is vulnerable to publication bias. Given that quantitative synthesis of the study results of economic evaluations is not possible owing to heterogeneity across different countries and clinical settings, we performed the data synthesis qualitatively in order to provide a comprehensive view on the cost-effectiveness of predictive biomarkers for targeted therapies. As a typical example, economic evaluations of low income countries such as Chinese studies are not comparable to that of high income coun- tries in terms of willingness to pay thresholds and healthcare systems. In conclusion, companion biomarkers for targeted therapies in mCRC were mostly found to be cost-effective; otherwise, they improved the cost-effectiveness of corresponding therapies by saving some costs. However, they did not necessarily make the corresponding targeted ther- apies cost-effective. Biomarker's clinical and economic inputs captured in economic evalua- tions of targeted therapies were often limited to the cost of tests and these values were frequently omitted especially when the scope of comparative analysis was limited to a pre- defined genetic population. In addition, we observed that there is no consensus on the best practice of strategy comparisons and no consistency in how to compare alternative strategies to estimate the ICERs of cancer biomarkers for targeted therapies in mCRC. Supporting information S1 Table. PRISMA checklist. (DOCX) S2 Table. Search terms. (DOCX) S3 Table. PICOS inclusion and exclusion criteria. (DOCX) S4 Table. Overview of included studies. (DOCX) S5 Table. Cost-effectiveness results of all included papers. (DOCX) PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 18 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC S6 Table. QHES scoring per study. (DOCX) Author Contributions Conceptualization: Mikyung Kelly Seo, John Cairns. Data curation: Mikyung Kelly Seo. Formal analysis: Mikyung Kelly Seo. Investigation: Mikyung Kelly Seo. Project administration: Mikyung Kelly Seo. Supervision: John Cairns. Validation: John Cairns. Writing ± original draft: Mikyung Kelly Seo. Writing ± review & editing: John Cairns. References 1. Stewart B, Wild C. World cancer report 2014. Lyon: International Agency for Research on Cancer, WHO; 2014. 2015. 2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh J, Comber H et al. Cancer inci- dence and mortality patterns in Europe: estimates for 40 countries in 2012. European journal of cancer. 2013; 49(6):1374±403. https://doi.org/10.1016/j.ejca.2012.12.027 PMID: 23485231 3. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014; 64 (1):9±29. 4. Michor F, Iwasa Y, Lengauer C, Nowak MA. Dynamics of colorectal cancer. Seminars in cancer biology. 2005; 15(6):484±93. https://doi.org/10.1016/j.semcancer.2005.06.005 PMID: 16055342 5. Vogelstein B, Kinzler KW. The genetic basis of human cancer. McGraw-Hill; 2002. 6. Zlobec I, Lugli A. Prognostic and predictive factors in colorectal cancer: A critical review. Journal of clini- cal pathology. 2008. 7. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011; 331(6024):1559± 64. https://doi.org/10.1126/science.1203543 PMID: 21436443 8. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Critical reviews in oncogenesis. 2013; 18(1±2):43. PMID: 23237552 9. Holch J, Stintzing S, Heinemann V. Treatment of Metastatic Colorectal Cancer: Standard of Care and Future Perspectives. Visc Med. 2016; 32(3):178±83. https://doi.org/10.1159/000446052 PMID: 10. Ciombor KK, Bekaii-Saab T. A Comprehensive Review of Sequencing and Combination Strategies of Targeted Agents in Metastatic Colorectal Cancer. Oncologist. 2018; 23(1):25±34. https://doi.org/10. 1634/theoncologist.2017-0203 PMID: 29021377 11. Edwards MS, Chadda SD, Zhao Z, Barber BL, Sykes DP. A systematic review of treatment guidelines for metastatic colorectal cancer. Colorectal disease: the official journal of the Association of Coloproctol- ogy of Great Britain and Ireland. 2012; 14(2):e31±47. https://doi.org/10.1111/j.1463-1318.2011.02765. x PMID: 21848897 12. SEO M. Economic evaluations of cancer biomarkers for targted therapies: practices, challenges, and policy implications. In: BAaS R., editor. Cancer biomarkers: ethics, economics and society. Megalo- ceros Press; 2017. p. 25±38. 13. United States Food and Drug Administration. List of cleared or approved companion diagostic devices (in vitro and imaging tools). Available from https://www.fda.gov/MedicalDevices/ ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm [Last accessed 25 June 2018] 14. National Institute for Health and Care Excellence. Managing advaced ad metastatic colorectal cancer. Available from https://pathways.nice.org.uk/pathways/colorectal-cancer#path=view%3A/pathways/ PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 19 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC colorectal-cancer/managing-advanced-and-metastatic-colorectal-cancer.xml&content=view-node% 3Anodes-first-line-biological-therapy-for-metastatic-disease [Last accessed 25 June 2018] 2018. 15. Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a sys- tematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. The lancet oncology. 2008; 9(10):962±72. https://doi.org/10.1016/S1470-2045(08) 70206-7 PMID: 18804418 16. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. The oncologist. 2010; 15(7):699± 731. https://doi.org/10.1634/theoncologist.2010-0025 PMID: 20584808 17. Sforza V, Martinelli E, Ciardiello F, Gambardella V, Napolitano S, Martini G et al. Mechanisms of resis- tance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer. World journal of gastroenterology. 2016; 22(28):6345. https://doi.org/10.3748/wjg.v22.i28.6345 PMID: 27605871 18. Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson WD. Can UGT1A1 genotyping reduce morbid- ity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence- based review. Genetics in Medicine. 2009; 11(1):21±34. https://doi.org/10.1097/GIM. 0b013e31818efd77 PMID: 19125129 19. Drummond MF, Sculpher MJ, Claxton K, Stoddart GL, Torrance GW. Methods for the economic evalua- tion of health care programmes. Oxford university press; 2015. 20. Faulkner E, Annemans L, Garrison L, Helfand M, Holtorf AP, Hornberger J et al. Challenges in the development and reimbursement of personalized medicine-payer and manufacturer perspectives and implications for health economics and outcomes research: a report of the ISPOR personalized medicine special interest group. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2012; 15(8):1162±71. https://doi.org/10.1016/j.jval.2012.05.006 PMID: 21. Shemilt I, Mugford M, Byford S, Drummond M, Eisenstein E, Knapp M et al. Incorporating economics evidence. Cochrane handbook for systematic reviews of interventions. 2008:449±80. 22. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D et al. Consolidated health economic evaluation reporting standards (CHEERS) statement. BMC medicine. 2013; 11(1):1. 23. Chiou C-F, Hay JW, Wallace JF, Bloom BS, Neumann PJ, Sullivan SD et al. Development and valida- tion of a grading system for the quality of cost-effectiveness studies. Medical care. 2003; 41(1):32±44. https://doi.org/10.1097/01.MLR.0000039824.73620.E5 PMID: 12544542 24. Ofman JJ, Sullivan SD, Neumann PJ, Chiou C- F, Henning JM, Wade SW et al. Examining the value and quality of health economic analyses: implications of utilizing the QHES. Journal of Managed Care Pharmacy. 2003; 9(1):53±61. https://doi.org/10.18553/jmcp.2003.9.1.53 PMID: 14613362 25. Moreno VM-A, B.; Barriuso, J.; Mezquita, L.; De Caceres, I. I.; Sacido, A. A.; Pena, J. M.; Perona, R.; Belda-Iniesta, C. Cost-effectiveness analysis of cetuximab and panitumumab as first-line metastatic colorectal cancer therapies in Spain. Journal of Clinical Oncology Conference. 2012;30(15 SUPPL. 1). 26. Ortendahl JDB T. G.; Anene A. M.; Purdum A. G.; Bolinder B. Cost-effectiveness of cetuximab as first- line treatment for metastatic colorectal cancer in the United States. Value in Health. 2014; 17 (3):A86. 27. Vargas-Valencia J, Garcia Perlaza J. Cost-effectiveness analysis of panitumumab + folfox compared to cetuximab + folfiri as first-line treatment for patients with wild-type (WT) RAS (exons 2, 3, and 4 of KRAS and NRAS) metastatic colorectal cancer (MCRC) in Colombia. Value in Health. 2015; 18 (7): A460. 28. Blank PR, Moch H, Szucs TD, Schwenkglenks M. KRAS and BRAF mutation analysis in metastatic colorectal cancer: A cost-effectiveness analysis from a Swiss perspective. Clinical Cancer Research. 2011; 17(19):6338±46. https://doi.org/10.1158/1078-0432.CCR-10-2267 PMID: 21807639 29. Ontario HQ. KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer: An Evidence- Based and Economic Analysis. Ont Health Technol Assess Ser. 2010; 10(25):1±49. PMID: 23074403 30. Pichereau SLL A.; Lecomte T.; Blasco H.; Le Guellec C.; Bourgoin H. Cost-effectiveness of UGT1A1 28 genotyping in preventing severe neutropenia following FOLFIRI therapy in colorectal cancer. Journal of Pharmacy & Pharmaceutical Sciences. 2010; 13(4):615±25. 31. Saito S, Kameyama H, Muneoka Y, Okuda S, Wakai T, Akazawa K. Cost-effectiveness analysis of the use of comprehensive molecular profiling before initiating monoclonal antibody therapy against meta- static colorectal cancer in Japan. Journal of Cancer Policy. 2017; 12:61±6. 32. Wen F, Yang Y, Zhang P, Zhang J, Zhou J, Tang R et al. Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study. Cancer Biology and Therapy. 2015; 16(11):1577±84. https://doi.org/10.1080/15384047.2015.1095398 PMID: PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 20 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC 33. Butzke B, Oduncu FS, Severin F, Pfeufer A, Heinemann V, Giessen-Jung C et al. The cost-effective- ness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance. Acta oncologica (Stockholm, Sweden). 2016; 55(3):318±28. https://doi.org/10.3109/0284186x.2015.1053983 PMID: 26098842 34. Shiroiwa TMY.; Tsutani K. Cost-effectiveness analysis of KRAS testing and cetuximab as last-line ther- apy for colorectal cancer. Molecular Diagnosis and Therapy. 2010; 14(6):375±84. https://doi.org/10. 2165/11587610-000000000-00000 PMID: 21275455 35. Vijayaraghavan A, Efrusy MB, Goke B, Kirchner T, Santas CC, Goldberg RM. Cost-effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany. International Journal of Cancer. 2012; 131(2):438±45. https://doi.org/10.1002/ijc.26400 PMID: 21898389 36. Zhou J, Zhao R, Wen F, Zhang P, Tang R, Chen H et al. Economic evaluation study (CHEER-compli- ant): Cost-effectiveness analysis of RAS screening for treatment of metastatic colorectal cancer based on the CALGB 80405 trial. Medicine (United States). 2016; 95 (27) (no pagination)(e3762). 37. Gold HTHM. J.; Blinder V.; Schackman B. R. Cost effectiveness of pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 before irinotecan administration for metastatic colorectal can- cer. Cancer. 2009; 115(17):3858±67. https://doi.org/10.1002/cncr.24428 PMID: 19517472 38. Berry K, Bensink ME, Musa Z, Shankaran V, Lin EH, Ladabaum U et al. Cost-effectiveness of bio- marker-directed bevacizumab for first-line therapy of persons with metastatic colorectal cancer. Journal of Clinical Oncology Conference. 2012; 30(15 SUPPL. 1). 39. Souza PV, Zanini FE, Biglia LV, Kim HS, Fahham L. Cetuximab in the first-line treatment of ras wild- type metastatic colorectal cancer with liver-limited disease. Value in Health. 2017; 20 (9):A875. http:// dx.doi.org/10.1016/j.jval.2017.08.2578. 40. Wu B, Yao Y, Zhang K, Ma X. RAS testing and cetuximab treatment for metastatic colorectal cancer: a cost-effectiveness analysis in a setting with limited health resources. Oncotarget. 2017; 8(41):71164. https://doi.org/10.18632/oncotarget.17029 PMID: 29050352 41. Behl AS, Goddard KAB, Flottemesch TJ, Veenstra D, Meenan RT, Lin JS et al. Cost-effectiveness anal- ysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer. Journal of the National Cancer Institute. 2012; 104(23):1785±95. https://doi.org/10.1093/jnci/djs433 PMID: 23197490 42. Carlson JJ. Cost-utility of kras mutation testing prior to treatment of metastatic colorectal cancer with cetuximab monotherapy. Value in Health. 2010; 13 (3):A36. 43. Harty GT, Jarrett J, Jofre-Bonet M. Consequences of biomarker analysis on the cost-effectiveness of cetuximab in combination with irinotecan based chemotherapy for first-line treatment of metastatic colo- rectal cancer. Stratified medicine at work? Value in Health. 2015; 18 (7):A456. https://doi.org/10.1016/j. jval.2015.09.1165 PMID: 26532566 44. Niedersuess-Beke D, Schiffinger M, Mader R. Economic impact of biomarker-based anti EGFR thera- pies in metastatic colorectal cancer in Austria. Annals of Oncology. 2015; 26:iv68. 45. Obradovic M, Mrhar A, Kos M. Cost-effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer. Pharmacogenomics. 2008; 9(5):539±49. https://doi.org/10.2217/14622422.214.171.1249 PMID: 18466101 46. World Bank. GDP per capita (current US$). https://data.worldbank.org/indicator/NY.GDP.PCAP.CD. 2016. Accessed November 20 2017. 47. National Institute for Health and Care Excellence. Cetuximab and panitumumab for previously untreated metastatic colorectal cancer: Technology Apprasial Guidance (TA439) 2017. 48. Annemans L, Van Cutsem E, Humblet Y, Van Laethem JL, Bleiberg H. Cost-effectiveness of cetuximab in combination with irinotecan compared with current care in metastatic colorectal cancer after failure on irinotecanÐA Belgian analysis. Acta Clinica Belgica. 2007; 62(6):419±25. https://doi.org/10.1179/ acb.2007.061 PMID: 18351186 49. Asseburg C, Frank M, Kohne CH, Hartmann JT, Griebsch I, Mohr A et al. Cost-effectiveness of targeted therapy with cetuximab in patients with K-ras wild-type colorectal cancer presenting with initially unre- sectable metastases limited to the liver in a German setting. Clinical Therapeutics. 2011; 33(4):482±97. https://doi.org/10.1016/j.clinthera.2011.04.010 PMID: 21635994 50. Dos Santos RF, Coutinho MB, Haas L. Panitumumab + mFOLFOX6 versus bevacizumab + mFOL- FOX6 as firstline treatment of wild-type RAS metastatic colorectal cancer: A cost-effectiveness analysis from the Brazilian private healthcare system perspective. Value in Health. 2015; 18 (7):A821. 51. Graham CN, Hechmati G, Hjelmgren J, De Liege F, Lanier J, Knox H et al. Cost-effectiveness analysis of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer. European Journal of Cancer. 2014; 50 (16):2791±801. https://doi.org/10.1016/j.ejca.2014.08.016 PMID: 25219451 PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 21 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC 52. Graham CN, Maglinte GA, Schwartzberg LS, Price TJ, Knox HN, Hechmati G et al. Economic Analysis of Panitumumab Compared with Cetuximab in Patients with Wild-type KRAS Metastatic Colorectal Cancer That Progressed after Standard Chemotherapy. Clinical Therapeutics. 2016; 38(6):1376±91. https://doi.org/10.1016/j.clinthera.2016.03.023 PMID: 27085587 53. Hnoosh A, Harty GT, Sullivan L, Byrne B, Von Honhorst P. A cost utility analysis of cetuximab for 1st- line treatment of RAS wild-type metastatic colorectal cancer: A summary of the submission to all Wales medicines strategy group (AWMSG). Value in Health. 2015; 18 (7):A454. 54. Junqueira M, De Campos MC, Cardoso AP, Von Hohnhorst P, Fujii RK. Cost-effectiveness of cetuxi- mab+folfiri versus folfiri at the public healthcare system in Brazil-the crystal trial RAS subgroup eco- nomic perspective. Value in Health. 2015; 18 (3):A205. 55. Junqueira M, De Campos MC, Cardoso AP, Von Hohnhorst P, Fujii RK. Cost-effectiveness of cetuxi- mab+folfiri versus bevacizumab+folfiri at the public healthcare system in brazilÐThe fire 3 trial eco- nomic perspective. Value in Health. 2015; 18 (3):A204. 56. Kourlaba G, Boukovinas I, Saridaki Z, Papagiannopoulou V, Tritaki G, Maniadakis N. Cost-effective- ness analysis of panitumumab+mFOLFOX over bevacizumab+mFOLFOX as a first-line treatment for metastatic colorectal cancer patients with wild-type RAS in Greece. Value in Health. 2014; 17 (7):A633. 57. Rivera F, Valladares M, Gea S, Lopez-Martinez N. Cost-effectiveness analysis in the Spanish setting of the PEAK trial of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer. J Med Econ. 2017; 20 (6):574±84. https://doi.org/10.1080/13696998.2017.1285780 PMID: 28107090 58. Samyshkin Y, Hertel N, Griebsch I. Cost-effectiveness of cetuximab, bevacizumab, and panitumumab in first-line treatment of metastatic colorectal cancer (mCRC) for patients with KRAS wild-type (wt) tumors in the United Kingdom. Journal of Clinical Oncology Conference: ASCO Annual Meeting. 2011;29(15 SUPPL. 1). 59. Shankaran VO J. D.; Purdum A. G.; Bolinder B.; Anene A. M.; Sun G. H.; Bentley T. G. K. Cost-Effec- tiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States. American Journal of Clinical Oncology: Cancer Clinical Trials. 2015;22. 60. Xu Y, Hay JW, Lenz HJ, Sadeghi S, Barzi A. Comparative effectiveness of panitumumab (P) and cetuxi- mab (C) in metastatic colorectal cancer (mCRC) with wild-type KRAS (WTKRAS). Journal of Clinical Oncology Conference. 2016; 34(4 SUPPL. 1). 61. Hoyle M, Peters J, Crathorne L, Jones-Hughes T, Cooper C, Napier M et al. Cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer. Value in Health. 2013; 16(2):288±96. https:// doi.org/10.1016/j.jval.2012.11.001 PMID: 23538180 62. Huxley N, Crathorne L, Varley-Campbell J, Tikhonova I, Snowsill T, Briscoe S et al. The clinical effec- tiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumu- mab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation. Health Technol Assess. 2017; 21(38):1±294. https://doi.org/10.3310/hta21380 PMID: 28682222 63. Davari M, Ashrafi F, Maracy M, Aslani A, Tabatabaei M. Cost-effectiveness analysis of cetuximab in treatment of metastatic colorectal cancer in Iranian pharmaceutical market. International Journal of Pre- ventive Medicine. 2015;2015 (JULY) (no pagination)(63). 64. Norum J. Cetuximab in the treatment of metastatic colorectal cancer: A model-based cost-effectiveness analysis. Journal of Chemotherapy. 2006; 18(5):532±7. PMID: 17127231 65. Starling N, Tilden D, White J, Cunningham D. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment. British Journal of Cancer. 2007; 96(2):206±12. https://doi.org/10. 1038/sj.bjc.6603561 PMID: 17242694 66. Ewara EM, Zaric GS, Welch S, Sarma S. Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer. Current Oncology. 2014; 21(4):e541±e50. https://doi.org/ 10.3747/co.21.1837 PMID: 25089105 67. Lawrence D, Maschio M, Leahy KJ, Yunger S, Easaw JC, Weinstein MC. Economic analysis of bevaci- zumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the first-line treat- ment of KRAS wild-type metastatic colorectal cancer (mCRC). Journal of Medical Economics. 2013; 16 (12):1387±98. https://doi.org/10.3111/13696998.2013.852097 PMID: 24102083 68. Carvalho AC, Leal F, Sasse AD. Cost-effectiveness of cetuximab and panitumumab for chemotherapy- refractory metastatic colorectal cancer. PLoS One. 2017; 12(4):e0175409. https://doi.org/10.1371/ journal.pone.0175409 PMID: 28403233 PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 22 / 23 Do cancer biomarkers make targeted therapies cost-effective? SLR in mCRC 69. Chaugule S, Hay J. The cost effectiveness of cetuximab plus best supportive care (BSC) versus BSC alone in last line for kras wild type metastatic colorectal cancer patient population. Value in Health. 2012; 15 (4):A219. 70. Hnoosh A, Harty GT, Sullivan L, Byrne B, Von Honhorst P. Cost effectiveness of cetuximab in first line treatment of ras wild-type metastatic colorectal cancer in the UK: A summary of economic analyses sub- mitted to the national institute for health and care excellence (NICE). Value in Health. 2015; 18 (7): A459. 71. Krol M, Ovcinnikova O, Von Hohnhorst P, Jarrett J. Cost-effectiveness of cetuximab in first-line treat- ment of patients with metastatic colorectal cancer in Belgium and the Netherlands. Value in Health. 2015; 18 (7):A464. 72. Mittmann N, Au HJ, Tu D, O'Callaghan CJ, Isogai PK, Karapetis CS et al. Prospective cost-effective- ness analysis of cetuximab in metastatic colorectal cancer: Evaluation of national cancer institute of canada clinical trials group CO.17 Trial. Journal of the National Cancer Institute. 2009; 101(17):1182± 92. https://doi.org/10.1093/jnci/djp232 PMID: 19666851 73. Riesco-Martinez MC, Berry SR, Ko YJ, Mittmann N, Giotis A, Lien K et al. Cost-effectiveness analysis of different sequences of the use of epidermal growth factor receptor inhibitors for wild-type kras unre- sectable metastatic colorectal cancer. Journal of Oncology Practice. 2016; 12(6):e710±e23. https://doi. org/10.1200/JOP.2015.008730 PMID: 27143148 74. Excellence NIfC. Guide to the methods of technology appraisal. https://wwwniceorguk/process/pmg9/ chapter/the-reference-case#exploring-uncertainty. 2013. 75. Lange A, Prenzler A, Frank M, Kirstein M, Vogel A, Von Der Schulenburg J. A systematic review of cost-effectiveness of monoclonal antibodies for metastatic colorectal cancer. European journal of can- cer. 2014; 50(1):40±9. https://doi.org/10.1016/j.ejca.2013.08.008 PMID: 24011538 76. Frank M, Mittendorf T. Influence of pharmacogenomic profiling prior to pharmaceutical treatment in met- astatic colorectal cancer on cost effectiveness. Pharmacoeconomics. 2013; 31(3):215±28. https://doi. org/10.1007/s40273-012-0017-2 PMID: 23338963 77. Guglielmo A, Staropoli N, Giancotti M, Mauro M. Personalized medicine in colorectal cancer diagnosis and treatment: a systematic review of health economic evaluations. Cost Eff Resour Alloc. 2018; 16:2. https://doi.org/10.1186/s12962-018-0085-z PMID: 29386984 78. Lange A, Prenzler A, Frank M, Kirstein M, Vogel A, von der Schulenburg JM. A systematic review of cost-effectiveness of monoclonal antibodies for metastatic colorectal cancer. Eur J Cancer. 2014; 50 (1):40±9. https://doi.org/10.1016/j.ejca.2013.08.008 PMID: 24011538 79. Frank M, Mittendorf T. Influence of pharmacogenomic profiling prior to pharmaceutical treatment in met- astatic colorectal cancer on cost effectiveness: a systematic review. Pharmacoeconomics. 2013; 31 (3):215±28. doi: 10.1007/s40273-012-0017-2. PMID: 23338963 PLOS ONE | https://doi.org/10.1371/journal.pone.0204496 September 26, 2018 23 / 23
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IDT Corp. IDT, -4.18% said it has terminated its previously announced proposal to acquire ITXC Corp. itxc. The companies have entered an agreement whereby IDT will not acquire shares of ITXC for the next thirty days without ITXC's consent and that the two parties will enter talks. IDT shares closed Wednesday at $14.30, up 3.5 percent, while ITXC's stock finished the session at $1.64, down 3.5 percent.
IDT ends hostile bid for ITXC, will hold talks
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Transition of Autumn
Transition of Autumn
By Nancy Lynn
As we transition from the warm breezes of summer into the changing leaves of autumn, we are reminded of the beauty of change. Every year the leaves on the trees lose their green shade and fade to brilliant arrays of reds, oranges, yellows, and browns. Our lives are much like these leaves as the season changes, so do we as people. We grow and transform ourselves into new versions while shedding our old skin and incorporating the lessons we have learned into the new revision of who we are. We move forward in life and begin to gain a greater awareness of the universe and our place within it.
Autumn holds a great significance to spiritualists, as it is the time of the autumn equinox. On September 22 the day and night will be equal in length, creating a perfect balance of light to dark, masculine to feminine, a balance within ourselves as well as other energies around us. It is a time of inner reflection. Autumn is a season that is shrouded in possibilities. It invites us to release what no longer benefits us in our journey to open our way of furthering our personal development.
Just as a farmer harvests the rich bounty at the end of summer, he looks at autumn as the time to turn over soil and fertilize the earth. Autumn reminds us of the impermanence of everything. We have experienced the growth of life, which is seen in spring, the flowerings and expansion of summer, autumn the rich colors of the leaves and winter the baron branches of what was. All there to remind us of the fleeting beauty of nature in all its glory. We can take advantage of this time of year to reap the possibilities of changes and the insight in the journey.
In order to bring about positive self-change we must learn to release any self-destructive behaviors. Look at what you have accomplished versus what you have not and remember the grass is not always greener on the other side. We should approach this time with realistic expectations, as it is essential to assist in self-change and spiritual growth. Our greatest gift to our self is to create reachable tasks and awards for obtaining our achievements.
Much like the changing colors of the leaves each Autumn we should take this time to reevaluate where we are and where we want to go to. Each season without the other one before, would not be able to complete the cycle of life. The spouting of new life, into the green growth of summer, followed by the shedding of the rich colors of leaves into the transformation and dormancy of winter into a new version of who we will be… Looked at as: Spring creation, Summer development, Autumn reflection, Winter transition.
About the writer: Nancy Lynn
Nancy Lynn is a gifted medium, able to speak with spiritual guides and those who have crossed over. Her mission is to help people reconnect to their own spiritual insight and to their own unique gifts. She provides information on areas of concern in the present that need attention. Nancy founded "Opening to Enlightenment" which provides workshops, training, and self-help sessions that cover a variety of topic areas. She is excited about the opportunity to help you on your journey of personal growth and enlightenment. Visit Nancy's web site at www.nancyote.com to obtain further information about workshops, spirit fests and future events, or email her at [email protected]


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Showing 1–21 of 40 results
49,90 €
Enough space for shoes, towel, clothing and other accessories. Includes a bat sleeve. Perfect for everyday use. Eye catching design. (50 x 24 x 31cm). 37 Litre volume.Add to cart
64,90 €
Offers plenty of space for kit and equipment for larger events. A spacious main compartment and two large outer pockets in an eye catching design. (70 x 34 x 34cm). 80 Litre volume.Add to cart
44,90 €
Attractive rucksack. Perfect for the training hall. Large outer compartment and side mesh pockets. Two adjustable shoulder straps with comfortable padding. (40 x 28 x 12cm). 14 Litre Volume.Add to cart
44,90 €
Eye-catching design. Space for a laptop, documents, and other accessories. Includes a bottle compartment, zip pockets, key hooks and an adjustable shoulder strap. Ideal for the modern coach. (40 x 30 x 16cm). 19 litre volume.Add to cart
129,90 €
Spacious Maxibag with 100 litre volume. Perfect for travel and extended events. Protected bottom compartment, sturdy wheels and an extendable handle. 80x39x39cm.Add to cart
64,90 €
Midi bag for small essentials. Practical outer and inner compartments made from highly durable polyester. 35 litre volume. 55x25x28cmAdd to cart
74,90 €
Designed for all table tennis needs. Multiple inner and outer compartments made from highly durable polyester. Adjustable shoulder strap. 58 litre volume. 60x31x32cmAdd to cart
79,90 €
High mobility with comfortable shoulder straps. Safety compartment on the back. Highly durable polyester. 36 litre volume. 49x36x22cmRead more
59,90 €
Modern Shoulder bag with laptop compartment and bottle holder. Inner compartment with Key anchor. Highly durable polyester. 58 litre volume. 60x31x32cmRead more
119,90 €
Ideal for short trips and fits perfectly as hand luggage for air travel. Sturdy wheels and extendable handle. 51 litre volume. 55x36x20cmRead more
49,90 €
Perfect for training. Will hold shoes, bat case, towel, clothing and a drinks bottle. 55 x 25 x 28cm. Volume 37L. Available in Green or Grey.Select options
64,90 €
Perfect for sporting events of any size. Two end pockets, large inner compartment. Suitable for daily use and multi-day competition. 70 x 31 x 32 cm. Volume 80L. Available in Green or Grey.Select options
129,90 €
Sets a new standard for table tennis players both inside the hall and during travel. Its durable, hard shell, four steering rollers, compatible lock and the cabin size dimensions make it the perfect companion for air travel. (49 × 36 × 23 cm) 42 Litre volume.Add to cart
54,90 €
Duffle bag for essential equipment. Includes two end zipped outer compartments. Easily folds for minimum storage. 50 x 28 x 28cm. Volume 39L. Available in Anthracite only.Add to cart
39,90 €
Courier style rucksack with smart inner compartments. Roll top made from Polyester 420D. 38 x 57 x 13cm. Volume 28L. Available in Anthracite only.Add to cart