828217 research-article2019 TAE0010.1177/2042018819828217Therapeutic Advances in Endocrinology and MetabolismE Grande, A Díaz Therapeutic Advances in Endocrinology and Metabolism Systematic Review Economics of gastroenteropancreatic Ther Adv Endocrinol Metab neuroendocrine tumors: a systematic review 2019, Vol. 10: 1–12 DOI: 10.1177/ https://doi.org/10.1177/2042018819828217 https://doi.org/10.1177/2042018819828217 2042018819828217 © The Author(s), 2019. Enrique Grande, Ángel Díaz, Carlos López, Javier Munarriz, Juan-José Reina, Article reuse guidelines: sagepub.com/journals- Ruth Vera, Beatriz Bernárdez, Javier Aller, Jaume Capdevila, Rocio Garcia-Carbonero, permissions Paula Jimenez Fonseca and Marta Trapero-Bertran Abstract Background: Despite current interest, enthusiasm and progress in the development of Correspondence to: therapies for gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), there are Marta Trapero-Bertran Research Institute for substantial gaps in the published literature regarding cost-of-illness analyses, economic Evaluation and Public evaluation and budget impact analyses. Compounding the issue is that data on resource Policies (IRAPP), Universitat Internacional utilization and cost-effectiveness of different diagnostic and therapeutic modalities for GEP- de Catalunya (UIC), Carrer de la Immaculada, 22, NETs are scarce. Barcelona, 08017, Spain Methods: A systematic review on the economic impact of GEP-NETs was carried out using mtrapero@uic.es four databases: EMBASE, PubMed, the National Health Service Economic Evaluation Database Enrique Grande Department of Medical and Cochrane review. Fully published articles from January 2000 to May 2017, in English and Oncology, Hospital Universitario Ramón y Spanish, were included. All articles that satisfied the inclusion criteria were included in the Cajal, Madrid, Spain systematic review; summary descriptive statistics were used to describe the methodological Ángel Díaz Department of Medical characteristics. Oncology, Hospital Results: The 14 studies selected included cost-of-illness analyses (n = 4), economic Universitario Clínico San Carlos, Madrid, Spain evaluations (n = 7) and budget impact analyses (n = 3). Almost all studies were performed Carlos López in the United States. Healthcare costs for patients with NETs included medication, outpatient Department of Medical Oncology, Hospital visits, hospitalizations, and check-ups/tests. Reducing adverse events is an area where cost Universitario Marqués savings could be achieved; however, there was not enough evidence on the cost impact of de Valdecilla, Santander, Spain adverse events. Javier Munarriz Conclusion: There is a lack of data related to resource utilization in the field of GEP- Department of Medical Oncology, Hospital NETs. Therefore, cost-effectiveness and budget impact studies of existing and emerging Provincial de Castellón, treatments are urgently needed to help the decision-making process for patients with Castellón, Spain Juan-José Reina NETs. Department of Medical Oncology, Hospital Virgen Macarena, Sevilla, Spain Keywords: budget impact, cost-of-illness, costs, economic burden, economic evaluation, Ruth Vera Department of Medical gastroenteropancreatic neuroendocrine tumors, resource utilization, systematic review Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain Received: 19 October 2018; revised manuscript accepted: 13 January 2019. Beatriz Bernárdez Department of Pharmacy, Complejo Hospitalario Universitario de Santiago, Introduction NETs localized to the gastrointestinal tract Santiago de Compostela, Spain Neuroendocrine tumors (NETs) are neoplasms (GI-NETs) or pancreas (P-NETs) are collec- Javier Aller arising from neuroendocrine cells which are dis- tively referred to as gastroenteropancreatic (GEP)- Department of tributed widely throughout the body.1 These NETs. Endocrinology, Hospital Universitario Puerta de tumors can cause clinical conditions, including Hierro, Madrid, Spain Zollinger–Ellison syndrome, hypoglycemia and The incidence of GI-NETs has consistently and Jaume Capdevila Vall d’Hebron University watery diarrhea hypokalemia-achlorhydria significantly increased over the past three dec- Hospital, Vall d’Hebron (WDHA) syndrome, bronchospasms, flushing ades.2,3 During this time, estimates in the United Institute of Oncology (VHIO), Universitat and other symptoms due to the release of specific States (US) have shown a 6.4-fold increase in Autònoma de Barcelona, hormones and neuroamines into the bloodstream. incidence from 1973 to 2012 across all sites, stage Barcelona, Spain journals.sagepub.com/home/tae 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Endocrinology and Metabolism 10 Rocio Garcia-Carbonero and grades.4 In some European countries, the undoubtedly useful for purchasers, it does not Oncology Department, Hospital Universitario 12 annual GEP-NET incidence has reached 5.83 address the issue of affordability, which is an de Octubre, IIS imas12, per 100,000 people.5 This may reflect a true increasing concern.7 Healthcare purchasers are UCM, CNIO, CIBERONC, Madrid, Spain increase in the number of new cancers, or the not only concerned with maximizing efficiency Paula Jimenez Fonseca impact of new or improved diagnostic tests and but also with remaining within their annual budg- Department of Medical technologies. This increase in prevalence has ets. These two objectives are not always consist- Oncology, Hospital Central de Asturias, resulted in a higher financial burden of this dis- ent. Therefore, there is a role for both economic Oviedo, Spain ease in European countries. According to the sur- evaluation and budget impact analyses to inde- veillance, epidemiology and end results (SEER) pendently inform healthcare decision-making. program registry data, prevalence of GEP-NETs The complementary role of these approaches has is among the highest incidence rate, with 3.56 per already been recognized by some decision-making 100,000 people in GEP sites and 0.84 per 100,000 bodies.8,9 people in NETs.4 The aim of this paper was to review the recent GEP-NETs are diagnosed at all stages; approxi- literature on the pharmacoeconomics of GEP- mately 45.1% of diagnoses occur at the localized NET diagnostics and management strategies, as stage, 23.1% of diagnoses occur when the patient such, the cost-of-illness, economics and budget has metastases, while 16.5% occur when the impact evaluations and to identify gaps in knowl- patient has regional lymph node involvement.4 In edge to guide decision-making in the manage- patients with P-NETs, advanced disease is par- ment of these tumors. ticularly common at diagnosis; approximately 60% of patients are diagnosed at a metastatic stage.6 Clinical management of GEP-NETs is Methods also challenging due to the heterogeneous nature, The systematic literature review used four data- anatomical location, and clinical course of these bases: EMBASE, PubMed, the National Health tumors. Clinical interest in GEP-NETs has sub- Service (NHS) Economic Evaluation Database and stantially increased in recent decades, possibly Cochrane reviews. The articles were searched in due to the development of novel diagnostic and these databases by title and abstract using two therapeutic modalities, including targeted agents. different groups of keywords. In order to select Despite the current interest and enthusiasm for the search terms, we considered the Health classical and newly developed therapies for GEP- Information Research Unit at McMaster NETs, data on economics, including cost-of-ill- University (Hamilton, ON, Canada), which spec- ness, budget impact and economic evaluations of ified the search filters for MEDLINE (in Ovid different diagnostic and therapeutic modalities syntax) and the PubMed translation, and the NHS are scarce. Centre for Reviews and Dissemination, which also specified the recommended search terms in a In an era of healthcare budget restrictions, this systematic search. Therefore, the following search information is crucial for decision-making of terms were used: [(neuroendocrine AND tumor) patient management and resource allocation. In OR (neuroendocrine AND tumo*) OR (neuroen- an increasing number of countries, new healthcare docrine AND neoplas*) OR (carcinoid AND interventions must show clinical efficacy and cost- tumo*) OR (carcinoid AND syndrom*)) AND effectiveness before reimbursement or addition to ((cost AND benefit*) OR (cost AND effect*) OR formularies. This increased emphasis on demon- (cost AND utilit*) OR (cost AND minim*) OR strating value for money using economic evalua- cost* OR (economic AND evaluation*) OR eco- tion has arisen because of the increased pressures nomic* OR (budget AND impact) OR (economic on healthcare expenditure in health services, AND impact) OR (resource AND util*)]. Grey driven largely by demographic changes, increased literature was included from a search in Google patient expectations and the rapid development of Scholar; in addition, other papers were included technology. Economic evaluation to assess the using citation tracking from the retrieved and cost-effectiveness of medicines has been widely selected papers. labeled as the ‘fourth hurdle’ to market, in addi- tion to the traditional three hurdles of safety, The systematic review followed recommendations efficacy and quality, required for the licensing of the Preferred Reporting Items for Systematic of a new medicine. While pharmacoeconomics is Reviews and Meta-Analyses (PRISMA) guidelines 2 journals.sagepub.com/home/tae E Grande, A Díaz et al. on reporting systematic reviews.10 Papers pub- The number of publications about the economics lished from January 2000 to May 2017, in English of GEP-NET diagnostics and therapies trended and Spanish, were included. Exclusion criteria upwards from 2012, with five out of eight included comprised studies that were: neither cost-of-illness studies published since 2015. Details of the cost- analyses, nor economic evaluations, nor budget of-illness, economic evaluations and budget impact analyses; economic evaluations that were impact analyses are summarized in Tables 1, 2, not completed (and therefore did not include the and 3, respectively. Almost all studies (seven out incremental cost-effectiveness ratio); reviews; not of eight) were conducted in the US, except one focused on the disease of interest; and only pub- economic evaluation which was conducted in lished as an abstract. A data extraction form Mexico. The average age, weighted by sample included questions on the studies’ context (e.g. size, of populations included was 53 years, geographical study location), sampling and sample although only two out of eight studies reported characteristics (e.g. disease), methods and results age. All studies specified the diagnosed disease of (e.g. type of costs, measure of outcome, perspec- patients included, which were: carcinoid syn- tive) and conclusions (e.g. results summary, study drome (CS; n = 3), NETs in general (n = 2), funding). The first screening was conducted by P-NETs (n = 2), GI-NETs (n = 2), lung NETs two researchers. Subsequently, each abstract and (n = 2), and pancreatic islet cell tumors (n = 1). paper selected was reviewed by two investigators Half the studies indicated the degree of severity of and data extraction was performed independently. diagnosed diseases. None of the economic evalu- The decision for inclusion of an article in the ations and cost-of-illness studies specified whether review was made by agreement among other expe- or not patients included in the study had received rienced investigators. Whenever there was a disa- previous treatments. Overall, two of three eco- greement, the papers were reviewed by another nomic evaluations and three of four cost-of-illness investigator. Microsoft Excel was used to summa- analyses were based on clinical trials. rize the results from the systematic literature review. Cost-of-illness analysis After all articles that satisfied the inclusion crite- In terms of economic burden or cost-of-illness ria were collected, summary descriptive statistics analysis, four studies were found.12–15 Overall, were used to describe the methodological charac- two articles investigated the resource utilization teristics. Costs were converted to 2017 Euros (€) or economic burden generated in patients treat- using country-specific or country-group-specific ed for NETs;12,13 two articles examined the eco- inflation on average consumer prices.11 The nomic impact of reduction of adverse events, such annual costs and mean unit values were adjusted as diarrhea, in patients with CS (Table 1).14,15 by the interannual inflation rate from the price year to 2017. If required, the unit and annual Both studies that analyzed treatments for NETs costs from 2015 were multiplied by the European also evaluated pharmacological and chemother- Central Bank’s 2017 exchange rates. For papers apy treatments; the economic burden was not cal- not reporting the year in which the costs were cal- culated using a decision analysis because the time culated, the publication year was used. horizons for the analyses were 1 and 3.5 years. Therefore, there was no need to do complex long- term cost estimations. Strosberg and colleagues12 Results reported primary data and carried out a deter- The search identified a total of 288 studies. Of ministic and probabilistic sensitivity analysis, but those, 30 studies were duplicates and were did not report the perspective of analysis, whereas excluded. Of the remaining studies (n = 258), Chuang and colleagues13 reported secondary 222 were excluded because they were congress data, used the National Health System and abstracts, or not associated with NETs. A total of patient perspectives, but did not report the per- 36 articles that met the initial inclusion criteria spective of the analysis. In both studies, the costs were included in the full-text review. Finally, included were medication, outpatient visits, hos- eight studies were selected, which consisted of pitalizations, and diagnostic tests. Stroberg and cost-of-illness analyses (n = 4); economic evalua- colleagues12 concluded that advanced NET pro- tions (n = 3) and budget impact analyses (n = 1), gression had an impact on resource utilization shown in Figure 1. regardless of tumor site, particularly with respect journals.sagepub.com/home/tae 3 Therapeutic Advances in Endocrinology and Metabolism 10 Figure 1. Flow chart search strategy. to hospitalizations, surgeries, imaging and lab and colleagues14 evaluated a retrospective data- tests, chemotherapy and somatostatin analogs base with a time horizon of 10 years and Huynh (SSAs). The authors also suggested that more and colleagues15 analyzed data for a 1-year follow research was necessary to elucidate differences in up. The latter study also conducted a determin- adverse event reporting between patients receiv- istic sensitivity analysis. Both studies included ing chemotherapy versus targeted agents. Chuang costs on medication, outpatient visits and hospi- and colleagues13 highlighted the existence of eco- talizations; it was concluded that adverse events, nomic impact among individuals with NETs and such as diarrhea associated with CS, accounted pointed out the importance of investigating the for higher total healthcare spending compared economic burden of patients with longer follow with no adverse events. In addition to these sav- up in the future. ings, the improvement of quality of life should be also taken into account. Therefore, healthcare Of the two studies that examined resource utili- costs could be reduced if effective preventive zation associated with adverse events in patients treatment for adverse events associated with treated for NETs,14,15 neither used a decision pharmacological treatments for NETs could be analysis to estimate the costs generated. Broder used. 4 journals.sagepub.com/home/tae E Grande, A Díaz et al. Table 1. Summary of cost-of-illness studies (n = 4). Reference Publication Average Country Country Study design Perspective Cost Analysis method (authors) year age of author of study typology Strosberg 2013 NS United United Prospective Provider Direct Multivariate and States States healthcare analysis colleagues12 costs Chuang and 2015 54.2 years United United Retrospective Provider Direct Statistical analysis colleagues13 (medical States States healthcare (descriptive group) costs analysis; 51.3 years nonparametric (surgical Wilcoxon test to group) detect differences analysis; etc.) Broder and 2016 51.5 United United Retrospective Provider Direct Statistical analysis colleagues14 States States (insured healthcare (descriptive population) costs analysis; multivariate analysis to compare the risk of overall and carcinoid syndrome-related hospitalizations) Huynh and 2017 NS United United Retrospective Commercial Direct Statistical analysis colleagues15 States States payer healthcare (descriptive (healthcare costs and analysis; two- and patients health- sample Student’s related related t-test with costs) productivity unequal variance, losses Satterthwaite’s method) NS, not stated. Economic evaluation recommended rate in each country. All studies Of eight economic evaluations, seven were on phar- included costs such as medication; outpatient visits macological treatment.16,17,19–22 The remaining study hospitalizations, check-ups and tests. These costs analyzed a surgical strategy (Table 2).18 Only one were the same as those included in studies of eco- study compared pharmacological therapies with nomic burden. The incremental cost-effectiveness or equivalent doses.16 Most studies that evaluated phar- cost-utility ratios were specified in seven studies16–22 macological treatment provided dosing information and were all below the cost-utility threshold recom- of the intervention group, with the exception of Hallet mended for that particular country, which indicated and colleagues.20 Cost-effectiveness was evaluated in the cost-effectiveness of the intervention. A probabil- all analyses, except those conducted by Hallet20 and istic and deterministic sensitivity analysis was per- Ayyagari and colleagues,22 which used cost analysis. A formed in all studies, although the acceptability curve total of four studies used a Markov model to estimate was detailed in only four studies.17–19,21 costs and health outcomes.16–18,21 The time horizons were established as 5 years,22 10 years,16,17,19 and a lifetime18,21 or were not specified.20 Overall survival Budget impact and quality adjusted life years (QALYs) were used Rose and colleagues23 assessed the budget impact of across six studies. Overall, four studies used the everolimus for the treatment of GI-NETs and National Health System perspective,16,17,21,22 whereas advanced or metastatic lung NETs and established two studies used the provider perspective.18,19 All the total population using prevalence data, although costs and outcomes were discounted according to the no data was provided regarding the percentage of journals.sagepub.com/home/tae 5 6 Table 2. Summary of economic evaluations (n = 7). Reference Publication Average Control Treatment Perspective Results Costs Conclusions (authors) year age measure Therapeutic Dose Therapeutic Dose strategy strategy Casciano and 2012 NS Sunitinib 37.5 Everolimus 10 mg/ Payer LYG/ Everolimus: ICER (everolimus colleagues16 mg/day day QALYs US$221/dose; versus sunitinib): US$5768/ US$28,281/LYG and monthly cycle US$41,702/QALYs SUNI: US$230/dose; US$6374/ monthly cycle Ortega and 2012 NS Placebo +BSC NS Sunitinib + 37.5 Payer PFS, OS, Sunitinib+BSC ICER (sunitinib+BSC Therapeutic Advances in Endocrinology and Metabolism 10 colleagues17 BSC mg/day QALYs increases versus placebo+BSC): direct costs in US$17,661.7/OS US$20,854.5 US$42,157.2/PFS (versus US$29,807.9/QALY placebo+BSC) Spolverato and 2015 57 years IAT NS HR NA Provider QALYs HR: $25,086 ICER (HR versus colleagues18 lifetime cost IAT) (man with IAT: metachronous US$61,252 symptomatic NELM lifetime cost that involved <25% of the liver in absence of extrahepatic disease): US$8,427/QALY Chua and 2018 NS BSC NS Everolimus 10 mg/ Provider Cost per Everolimus ICER: CA$145,670/ colleagues19 + BSC day LYG/ + BSC: QALY QALYs CA$146,137. CA$109,166/LYG BSC alone: CA$56,342 journals.sagepub.com/home/tae Table 2. (Continued) Reference Publication Average Control Treatment Perspective Results Costs Conclusions (authors) year age measure Therapeutic Dose Therapeutic Dose strategy strategy journals.sagepub.com/home/tae Hallet and 2017 This cost analysis compared the cost of NET management with CC management in four phases of care (pre-diagnosis, diagnosis, colleagues20 post-diagnosis and prolonged post-diagnosis). The pre-diagnostic mean NET costs were higher than the CC costs (US$5877 versus US$5368) but was lower in the diagnostic and post-diagnostic phases. In the prolonged post-diagnostic stage, the drug costs were higher for NETs, compared with CC (US$26,788 versus US$7827). Joish and 2018 NS Octreotide 24.32 TE + TE Payer Costs and QALYs: 1.67 colleagues21 mg / octreotide dose = QALYs (octreotide), 2.33 (TE month 21,000 + octreotide) average mg/ Costs: US$495,125 month (octreotide), average US$590,087 (TE + octreotide) Ayyagari and 2017 NS Octreotide 30 mg Lanreotide 120 mg Payer Cost Octreotide was The cost of treatment colleagues22 (long-acting) analysis associated with octreotide 30 (treatment with lower mg is lower than and costs by lanreotide 120 mg adverse US$10,290 for patients with events) (1 year), metastatic GI-NETs US$25,480 (3 years) and US$37,323 (5 years), compared with lanreotide BSC, best supportive care; CA, Canadian dollars; CC, colon cancer; GEP-NETs, gastroenteropancreatic neuroendocrine tumors; GI, gastrointestinal; HR, hepatic resection; IAT, intraarterial therapy; ICER, incremental cost-effectiveness ratio; LYG, life year gained; NELM, neuroendocrine liver metastases; NET, neuroendocrine tumor; NS, not stated; OS, overall survival; PFS, progression-free survival; QALY, quality adjusted life years; TE, telotristat ethyl. 7 E Grande, A Díaz et al. Therapeutic Advances in Endocrinology and Metabolism 10 Table 3. Summary of budget impact evaluations (n = 3). Reference Publication Average Treatment Dose Current scenario Potential Perspective Time (authors) year age scenario horizon Rose and 2017 NS Everolimus 10 mg/day Budget without Budget with Payer 3 years colleagues23 everolimus everolimus (total US managed care health plan and pharmacy budget) Joish and 2017 NS TE 250 mg Budget per Budget with Payer 1, 2 and 3 colleagues24 current TE (+ SSA years treatment LAR) (somatostatin analog LAR) Ortendahl 2018 NS Somatostatin 120 mg Baseline Hypothetical Provider 1 year and analog lanreotide utilization of shift in colleagues25 (octreotide and and 30 mg lanreotide or utilization of lanreotide) octreotide octreotide lanreotide or octreotide LAR, long-acting release; NS, not stated; SSA, somatostatin analog; TE, telotristat ethyl; US, United States. patients diagnosed and treated (Table 3). The and treatment duration, which were expected to authors established a clear comparison between the alter the budget impact by a magnitude of 2.04 cents current scenario without everolimus on the market PMPM and 0.79 cents PMPM in the third year after for GI-NETs and the potential scenario with everoli- launch for GI-NETs and lung NETs, respectively. mus on the market. The same scenarios were built According to the sensitivity analysis of the budget for lung NETs. The total budget impact on a US impact model, the impact of drug costs and treat- managed healthcare plan and a pharmacy budget ment duration is greater for GI-NETs, compared was evaluated. The time horizon for both perspec- with lung NETs.23 tives was 3 years. In the first perspective, costs included drug therapies, other cost of treatment, In the evaluation of the short-term affordability of treatment administration, hospitalizations, physician reimbursing telotristat ethyl for CS diarrhea in visits and monitoring/management of adverse events. patients who were not controlled with long-acting Costs included in the second perspective only release SSAs, the net budget impact of was found included the drug therapy costs. The total budget to be minimal to a US health plan. The incremen- impact and the impact on pharmacy budget were tal cost PMPM of reimbursing telotristat ethyl expected to increase in GI-NETs and lung NETs was US$0.013, US$0.019 and US$0.025 for 1, 2 with the introduction of everolimus, although the and 3 years, respectively.24 changes were minimal. For GI-NETs, in the first 3 years, the difference between having everolimus on Furthermore, a model-predicted per-patient cost the market or not was 0.0568 and 0.1443 cents per for SSAs was US$83,473 and US$89,673, for lan- member per month (PMPM), resulting in a −0.0875 reotide and octreotide, respectively, for patients cent PMPM difference, and for lung NETs 0.0181 with locally advanced or metastatic GEP-NETs.25 cents and 0.0355 cents PMPM, resulting in a −0.0174 cent PMPM difference. A deterministic univariate sensitivity analysis was carried out in order Discussion to study the impact of a 10% variation in drug costs, Despite new treatment approvals, representing treatment duration, number of patients eligible for important therapeutic advances, there are sub- treatment, and new treatment market share. The stantial gaps in the published literature in the most significant impact was caused by drug price understanding of several key domains relevant to 8 journals.sagepub.com/home/tae E Grande, A Díaz et al. the economics of NETs, particularly with respect NETs. This review showed that there was enough to cost-of-illness, economic evaluation and budget published evidence to conduct further research into impact. The present systematic review highlights the effectiveness of these treatments taking in the scarcity of data on resource utilization in account direct healthcare costs, such as the drug- patients with GEP-NETs. related events, direct nonhealthcare related costs and productivity losses. The latter two are impor- A previous systematic review on resource utiliza- tant for this type of disease due to the high degree of tion in NETs was performed to review available dependency on family members and impact on car- data in advanced NETs for cost-of-illness/ egivers, which contributes to the cost of illness from resource utilization, economic studies/health a societal perspective.36 If the differences in terms of technology assessment and quality of life.26 Chau additional health benefits between available treat- and colleagues found a lack of consistent and ments are not significant, this implies that the end comprehensive documentation of resource utili- differences on drug price are going to be relevant in zation in the management of NETs.26 It could be order to convince decision-makers to publicly fund argued that diagnosis and surgical resection (pri- these types of treatments. In this sense, studies on mary treatment) and therapeutics should be the treatment costs for different options37,38 are use- treated as separate categories. However, despite ful in clarifying the direct healthcare costs of these the relevance of separating these categories the treatment options. lack of evidence on the economic burden of NETs still remains a problem. Some research concluded that surgical therapy is the only curative treatment in individuals with There is a lack of studies that quantify the poten- NETs and when adequately indicated, no further tial cost reduction associated with CS symptom treatment is need, thereby reducing future health- resolution or improvement, following treatment care resource use and costs.39 However, with of patients with NETs. In addition, patients with innovative pharmacological treatments, more evi- NETs have significantly higher rates of mortality dence of resource utilization with longer follow and hepatic and gastrointestinal morbidities, up is needed to evaluate and compare healthcare compared with patients without NETs.27 There is resource utilization and the economic burden of a need to quantify this burden economically in surgery and pharmacological treatments. Other order to have a clear picture of the total economic costs such as productivity losses have also not burden. been evaluated.13 Therefore, more research is required to evaluate the overall impact on the Due to the limited number of studies, robust economic burden of NETs. conclusions could not be drawn in terms of effec- tiveness of pharmacological therapies. Further Regarding the limitations of the present review, cost savings may be achieved by reducing adverse its main weaknesses are due to the limited availa- events, however, there is currently not enough ble data included in the identified literature. evidence on the cost of adverse events and more However, the review of existing international data studies are required in this field. The conclusions has resulted in a clearer picture of the current from the economic evaluations in this review burden of the disease that can be useful to inform highlight the lack of data on the estimated utili- clinical and healthcare policy decisions. The limi- ties of different health states among patients with tation of the budget impact study was the availa- NETs. While it is optimal to compare pharmaco- bility of data found only in the US. Costs and logical therapies in head-to-head trials, due to prices may not be generalizable to other countries data restrictions, indirect comparisons may still or health systems. Another limitation included provide useful information. uncertainty surrounding some of the most impor- tant inputs used in this analysis. Prevalence esti- Since 2009, pharmacological treatments of NETs28– mates were not accurate enough in order to do 32 have demonstrated improvements, in progres- fair approximations of the real number of patients sion-free survival and overall survival, compared diagnosed with NETs. The number of patients with placebo,33–35 although some patients had drug- with progressive tumors is not available in the related adverse events, such as diarrhea, fatigue and published literature and there is no available respiratory infections. The use of lanreotide30 and information from real-world studies. Moreover, telotristat ethyl31,32 can improve symptoms of CS in there was a lack of evidence on the estimation of journals.sagepub.com/home/tae 9 Therapeutic Advances in Endocrinology and Metabolism 10 treatment market share and treatment duration. 2. Tsikitis VL, Wertheim BC and Guerrero Specific estimates of healthcare resource utiliza- MA. Trends of incidence and survival of tion associated with each therapy were not avail- gastrointestinal neuroendocrine tumors in the able; therefore, the results might be affected by United States: a SEER analysis. J Cancer 2012; 3: 292–302. the uncertainty of these parameters. The lack of real estimates and data might indicate that the 3. Modlin IM, Lye KD and Kidd M. A 5-decade 10% of variation used to run a deterministic sen- analysis of 13,715 carcinoid tumors. Cancer 2003; sitivity analysis might be not enough in order to 97: 934–959. estimate the potential uncertainty around these 4. Dasari A, Shen C, Halperin D, et al. Trends in model results. the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the In conclusion, management of advanced GEP- United States. JAMA Oncol 2017; 3: 1335–1342. NETs has changed substantially in the past few 5. Sandvik OM, Søreide K, Gudlaugsson E, decades due to improved diagnostic tests and et al. Epidemiology and classification of increased availability of targeted treatments; fur- gastroenteropancreatic neuroendocrine ther economic evaluations are required to inform neoplasms using current coding criteria. Br J Surg healthcare decision-making. 2016; 103: 226–232. 6. Ong S, Garcea G, Pollard C, et al. A fuller Acknowledgements understanding of pancreatic neuroendocrine The authors thank Rudi Subirà Gómez, Sara tumours combined with aggressive management González and Marc Gil Fornaguera for their improves outcome. Pancreatology 2009; 9: 583–600. contribution to this manuscript. The authors also thank Mimi Chan, PhD, of Springer 7. Trueman P, Drummond M and Hutton J. Developing guidance for budget impact analysis. Healthcare Communications, who edited this Pharmacoeconomics 2001; 19: 609–621. manuscript for English language. This medical writing assistance was funded by Novartis 8. Garattini L and van de Vooren K. Budget impact Pharmaceuticals. analysis in economic evaluation: a proposal for a clearer definition. Eur J Health Econ 2011; 12: Funding 499–502. This work was funded by Novartis Pharmaceuticals. 9. Sullivan SD, Mauskopf JA, Augustovski F, et al. The funder had no influence over the conduct of Budget impact analysis—principles of good this study or the drafting of this manuscript. practice: report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force. Conflict of interest statement Value Health 2014; 17: 5–14. E.G. received honoraria as a speaker, and partici- 10. Moher D, Liberati A, Tetzlaff J, et al. Preferred pated in advisory boards at Novartis, Pfizer, reporting items for systematic reviews and meta- IPSE, Adacap and Lexicon. All other authors analyses: the PRISMA statement. Int J Surg have no conflicts of interest to declare. 2010; 8: 336–341. 11. International Monetary Fund. World economic Supplemental material outlook database. Washington: International Supplemental material for this article is available Monetary Fund, https://www.imf.org/ (2017, online. accessed 17 April 2018). ORCID iD 12. Strosberg J, Casciano R, Stern L, et al. United States-based practice patterns and resource Marta Trapero-Bertran https://orcid.org/0000 utilization in advanced neuroendocrine tumor -0002-9233-1776 treatment. World J Gastroentero 2013; 19: 2348–2354. 13. Chuang CC, Bhurke S, Chen SY, et al. Clinical References characteristics, treatment patterns, and economic 1. Ramage J, Davies A, Ardill J, et al. Guidelines burden in patients treated for neuroendocrine for the management of gastroenteropancreatic tumors in the United States: a retrospective neuroendocrine (including carcinoid) tumours. cohort study. J Med Econ 2015; 18: Gut 2005; 54(Suppl. 4): iv1–iv16. 126–136. 10 journals.sagepub.com/home/tae E Grande, A Díaz et al. 14. Broder MS, Chang E, Romanus D, et al. US health plan perspective. Clin Ther 2017; 39: Healthcare and economic impact of diarrhea 2338–2344. in patients with carcinoid syndrome. World J 25. Ortendahl JD, Pulgar SJ, Mirakhur B, et al. Gastroentero 2016; 22: 2118–2125. Budget impact of somatostatin analogs as 15. Huynh L, Totev T, Vekeman F, et al. Cost treatment for metastatic gastroenteropancreatic reduction from resolution/improvement of neuroendocrine tumors in US hospitals. CEOR carcinoid syndrome symptoms following 2017; 9: 495–503. treatment with above-standard dose of octreotide LAR. J Med Econ 2017; 20: 945–951. 26. Chau I, Casciano R, Willet J, et al. Quality of life, resource utilisation and health economics 16. Casciano R, Chulikavit M, Perrin A, et al. Cost- assessment in advanced neuroendocrine tumours: effectiveness of everolimus vs sunitinib in treating a systematic review. Eur J Cancer Care 2013; 22: patients with advanced, progressive pancreatic 714–725. neuroendocrine tumors in the United States. J Med Econ 2012; 15(Suppl. 1): 55–64. 27. Hess GP, Chen CC, Liu Z, et al. Clinical burden of illness in patients with neuroendocrine tumors. 17. Ortega EM, Chi-Chan A, Peniche-Otero G, et al. Pancreas 2012; 41: 1058–1062. Costo Efectividad del Tratamiento de Tumores Neuroendócrinos Pancreáticos Avanzados no 28. Raymond E, Dahan L, Raoul JL, et al. Operables con Sunitinib en México. Value Health Sunitinib malate for the treatment of pancreatic 2012; 1: 150–155. neuroendocrine tumors. New Engl J Med 2011; 364: 501–513. 18. Spolverato G, Vitale A, Ejaz A, et al. Net health benefit of hepatic resection versus intraarterial 29. Yao JC, Shah MH, Ito T, et al. Everolimus for therapies for neuroendocrine liver metastases: advanced pancreatic neuroendocrine tumors. A Markov decision model. Surgery 2015; 158: New Engl J Med 2011; 364: 514–523. 339–348. 30. Vinik AI, Wolin EM, Liyanage N, et al. 19. Chua A, Perrin A, Ricci JF, et al. Cost- Evaluation of lanreotide depo/autogel efficacy and effectiveness of everolimus for the treatment safety as a carcinoid syndrome treatment (elect): of advanced neuroendocrine tumours of a randomized, double-blind, placebo-controlled gastrointestinal or lung origin in Canada. Curr trial. Endocr Pract 2016; 22: 1068–1080. Oncol 2018; 25: 32–40. 31. Kulke MH, Horsch D, Caplin ME, et al. 20. Hallet J, Law CHL, Cheung M, et al. Patterns Telotristat ethyl, a tryptophan hydroxylase and drivers of costs for neuroendocrine tumor inhibitor for the treatment of carcinoid syndrome. care: a comparative population-based analysis. J Clin Oncol 2017; 35: 14–23. Ann Surg Oncol 2017; 24: 3312–3323. 32. Pavel M, Gross DJ, Benavent M, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy 21. Joish VN, Frech F and Lapuerta P. Cost- in the TELECAST phase 3 trial. Endocr Relat effectiveness analysis of telotristat ethyl for Cancer 2018; 25: 309–322. treatment of carcinoid syndrome diarrhea inadequately controlled with somatostatin 33. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide analogs. J Med Econ 2018; 21: 182–188. in metastatic enteropancreatic neuroendocrine tumors. New Engl J Med 2014; 371: 224–233. 22. Ayyagari R, Neary M, Li S, et al. Comparing the cost of treatment with octreotide long- 34. Caplin ME, Pavel M, Ćwikła JB, et al. Anti- acting release versus lanreotide in patients with tumour effects of lanreotide for pancreatic metastatic gastrointestinal neuroendocrine and intestinal neuroendocrine tumours: the tumors. Am Health Drug Benefits 2017; 10: CLARINET open-label extension study. Endocr- 408–415. Relat Cancer 2016; 23: 191–199. 23. Rose DB, Nellesen D, Neary MP, et al. Budget 35. Rinke A, Muller HH, Schade-Brittinger C, et al. impact of everolimus for the treatment of Placebo-controlled, double-blind, prospective, progressive, well-differentiated, non-functional randomized study on the effect of octreotide neuroendocrine tumors of gastrointestinal or lung LAR in the control of tumor growth in patients origin that are advanced or metastatic. J Med with metastatic neuroendocrine midgut tumors: Econ 2017; 20: 395–404. a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656–4663. 24. Joish VN, Frech F and Lapuerta P. Budgetary impact of telotristat ethyl, a novel treatment for 36. Pearman TP, Beaumont JL, Cella D, et al. patients with carcinoid syndrome diarrhea: a Health-related quality of life in patients with journals.sagepub.com/home/tae 11 Therapeutic Advances in Endocrinology and Metabolism 10 neuroendocrine tumors: an investigation of 38. Orlewska E, Bednarczuk T, Kaminski G, et al. treatment type, disease status, and symptom LanroNET, a non-interventional, prospective burden. Support Care Cancer 2016; 24: 3695– study to assess the resource utilization and cost of 3703. lanreotide autogel 120 mg in Polish patients with neuroendocrine tumors–results of interim analysis. 37. Marty R, Roze S and Kurth H. Decision-tree Contemp Oncol (Pozn) 2014; 18: 442–447. Visit SAGE journals online model for health economic comparison of two journals.sagepub.com/ long-acting somatostatin receptor ligand devices 39. Norton JA, Warren RS, Kelly MG, et al. Aggressive home/tae in France, Germany, and the UK. Med Devices surgery for metastatic liver neuroendocrine tumors. SAGE journals (Auckl) 2012; 5: 39–44. Surgery 2003; 134: 1057–1063. 12 journals.sagepub.com/home/tae