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Abstract
Introduction The early detection of pancreatic cancer is an important step in reducing mortality by offering patients curative treatment. Screening strategies in risk populations and by means of different detection methods have been economically evaluated. However, a synthesis of screening studies to inform resource allocation towards early detection within the disease area has not been done. Therefore, studies evaluating the cost-effectiveness and costs of screening for pancreatic cancer should be systematically reviewed.
Methods and analysis A systematic review of economic evaluations reporting the cost-effectiveness or costs of pancreatic cancer screening will be conducted. The electronic databases Medline, Web of Science and EconLit will be searched without geographical or time restrictions. Two independent reviewers will select eligible studies based on predefined criteria. The study quality will be assessed using the Consolidated Health Economic Evaluation Reporting Standards statement and the Bias in Economic Evaluation checklist. One reviewer will extract relevant data and a second reviewer will cross-check compliance with the extraction sheet. Key items will include characteristics of screened individuals, the screening strategies used, and costs, health effects and cost-effectiveness as study outputs. Differences of opinion between the reviewers will be solved by consulting a third reviewer.
Ethics and dissemination Ethics approval is not required for this study since no original data will be collected. The results will be disseminated through presentations at conferences and publication in a peer-reviewed journal. The results of the systematic review will inform future economic evaluations of pancreatic screening, which provide guidance for decision-making in healthcare resource prioritisation.
PROSPERO registration number CRD42023475348.
- Systematic Review
- Health economics
- Gastrointestinal tumours
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This protocol increases transparency regarding the methods applied in a systematic review of economic evaluations of pancreatic cancer screening.
The protocol is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines.
The search strategy was developed in collaboration with a librarian and uses a validated search filter.
Heterogeneity in study methodology and inconsistency in study quality may limit the results of the systematic review.
The review will only include studies written in English, which will cause language bias.
Introduction
Pancreatic cancer was diagnosed in around 495 000 individuals globally, and nearly as many people died as a result of it in 2020.1 In Europe, pancreatic cancer is likely to establish itself as one of the top three causes of cancer death.2 The 5-year survival rate for pancreatic cancer has improved over the past decades, but this improvement has been modest compared with other cancer types.3 Pancreatic cancer is therefore gaining in importance within the overall mortality due to cancer. The high lethality of pancreatic cancer is due to its diagnosis at predominantly advanced stages, which underlines the importance of early detection. Screening strategies in population subgroups at increased risk of pancreatic cancer may help to treat the cancer earlier.4 The economic evaluation of such strategies is necessary to guide decision-making in the optimal allocation of healthcare resources.
Current screening modalities for pancreatic cancer include imaging, blood tests and biopsy. The American Gastroenterological Association, for instance, recommends a combination of MRI and endoscopic ultrasonography to detect pancreatic neoplasms at a resectable stage.5 CT is acknowledged as a widely available and rapid method to scan for pancreatic neoplasms.6 Furthermore, modified imaging techniques exist that affect the sensitivity, specificity and accuracy of tests.7 Due to the asymptomatic course of early pancreatic cancer, a combination of routine screening methods complemented with more advanced procedures for more accurate diagnosis is often applied. Expectations are currently placed on the development of more accurate and easier-to-administer testing methods using, for example, biomarkers in human blood.8
Pancreatic cancer screening is only advisable in individuals with an elevated risk compared with the general population, where the prevalence is relatively low. Due to technologically limited modalities, screening high numbers of standard-risk patients would currently lead to high costs per detected case and an ethically unacceptable number of false-positive patients. A recent model-based study showed substantial increases in false-positive results alongside high costs when lowering the sensitivity and specificity of a screening strategy in the general population.9 Thus, current guidelines only advise screening of high-risk individuals who have elevated pancreatic cancer risk.10 There is consensus regarding Peutz-Jeghers syndrome, hereditary pancreatitis, Lynch syndrome and mutations in specific genes as indications for pancreatic cancer screening.11 The elevated risk in these subgroups could result in screening to be cost-effective. An economic evaluation study has reported the cost-effectiveness of screening in familial pancreatic cancer kindreds.12
The detection of pancreatic cancer at the resectable cancer stage ideally allows physicians to offer their patients curative treatment. Surgical resection combined with adjuvant therapy is the only curative treatment option for pancreatic cancer patients.13 Prolonging survival is thus an important objective in pancreatic cancer surgery. However, <20% of patients are classified as surgically resectable, so the large majority of patients rely on other forms of oncological and palliative care, which do not prolong survival as much.14 Thus, besides survival, another important endpoint for evaluating the effects of pancreatic cancer care is health-related quality of life (HRQoL). It can be measured using disease-specific instruments such as the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 or via generic scales such as the 5-dimension EuroQol questionnaire (EQ-5D).15 The EQ-5D index as well as other comparable preference-based indices are common ways of calculating quality-adjusted life years (QALYs). The EQ-5D score converts intoQALYs, which is a well-established measure of health effects in the economic evaluation of healthcare. One QALY represents 1 year in perfect health whereas zero value represents death. Managing HRQoL matters to all pancreatic cancer patients and includes controlling pain symptoms, for example.16
The incidence of pancreatic cancer increases with age and is defined as a disease of older populations.17 Thus, in ageing societies, pancreatic cancer will incur increasing costs in the future. The development of cost-effective screening strategies could be of help in controlling these costs. The 2020 direct costs of pancreatic cancer in Germany were €1.2 billion—exceeding €722 million in 2015.18 Direct costs include medicines, staff hours and other healthcare resources. Particularly in high-income countries, an increasing disease burden due to demographic change is expected.19 A recent Swedish study predicts a rise in total costs from €125 million in 2018 to €225 million in 2030 for pancreatic cancer.20 This prediction is largely due to increasing indirect costs related to mortality. Indirect costs account for lost productivity due to premature death or morbidity. The costs of pancreatic cancer have been studied methodologically in different ways, leading to high variability in average costs.21 This study focuses on a specific aspect of pancreatic cancer care. Reviewing economic aspects of pancreatic cancer screening may support resource allocation towards early detection by synthesising cost-effective strategies.
This study will complement existing reviews of benefits through screening in patients at risk by including economic aspects.22 Health economic evaluations relate the cost of an intervention to its effectiveness and compare at least two interventions against each other.23 This is referred to as cost-effectiveness analysis. Health technology assessment agencies recommend this method to inform decisions for healthcare resource allocation. A recent systematic review of economic evaluations in pancreatic cancer analysed the studies from 2000 to 2015 and included four screening and eight studies evaluating diagnostic procedures.24 However, a review focusing exclusively on early detection strategies of pancreatic cancer and their economic outcomes has not been conducted yet. A preliminary count of studies that have been published since then gives rise to the preparation of an updated systematic review of cost-effectiveness and costing studies in pancreatic cancer screening. This will serve as a reference for future studies evaluating screening strategies.
Objective
This paper provides a protocol for a systematic review of studies evaluating the cost-effectiveness or costs of screening interventions in pancreatic cancer. Following a qualitative approach, this systematic review will synthesise economic evaluations of screening interventions for the early detection of pancreatic cancer in adult patients and present those in tabular form. The studies will be assessed using respective checklists for reporting completeness and risk of bias in economic evaluations. The aim of the systematic review will be studying the following research question: how have early detection strategies for pancreatic cancer been economically evaluated?
Methods and analysis
The protocol was developed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement (online supplemental appendix 1).25 The study was registered in the PROSPERO International Prospective Register of Systematic Reviews (ID: CRD42023475348). The results will be presented in accordance with the PRISMA statement and changes to this protocol will be reported.
Supplemental material
Eligibility criteria
Pancreatic cancer and its subtypes will be the diagnosis of interest, and adult patients at all cancer stages will be eligible. To obtain a broad overview, studies concerned with the early detection of exocrine or neuroendocrine pancreatic cancer will be included. Strategies with the aim of early diagnosing pancreatic cancer are of interest. Thus, screening strategies that test patients based on risk factors and diagnostic strategies that test based on previous findings will be included. Considered study types will be full economic evaluations comparing at least two alternative strategies by including both the costs and effects of the respective strategies in early pancreatic cancer detection.23 In addition, partial economic evaluations analysing the costs of screening strategies will be considered eligible for review.23 Studies need to be written in English and published in peer-reviewed journals. Non-original research articles (eg, editorials or conference abstracts), systematic reviews, meta-analyses and qualitative research articles will be excluded. Furthermore, evaluations that only assess screening effectiveness will not be included. Economic evaluations that use trial data, apply a model-based study design or other evaluation methods will be included.26 Other than a review that included economic evaluations across all interventions for pancreatic cancer up until December 2015, this review will be restricted to economic evaluations assessing cost-effectiveness or costs in pancreatic cancer screening.24 There will be no restrictions regarding the publication year or geographical context.
Information sources and search strategy
Electronic searches will be conducted in Medline, Web of Science and EconLit starting in mid-April 2024 and we anticipate this work to be completed by 30 June 2024. Search terms will include terms such as “Costs, Economic evaluation, Pancreatic cancer, Screening, Early detection, Diagnosis, Surveillance”. A preliminary strategy for searches in Medline is shown in table 1. The search strategy was developed in collaboration with a librarian. The search terms in row 1 were adapted from the Canadian Agency for Drugs and Technologies in Health Search Filters Database as a previously validated search filter for searching economic evaluations Medline.27 Row 2 contains a list of terms from a previous systematic review and was modified by focusing on titles or abstracts.24 The intervention criteria in row 3 were chosen in accordance with another pancreatic cancer screening review to include a sufficiently broad range of detection strategies.4 If necessary, there will be a modification of search terms in accordance with the requirements of each electronic database. The reference lists of systematic reviews that have been published in pancreatic cancer screening and on the economics of pancreatic cancer will be hand-searched.
Preliminary search strategy in Medline
Study records (data management, selection and collection)
After merging the search results from all databases in one list, the results will be managed using Endnote 21 as a software tool. Duplicates will be removed and two independent reviewers will screen study titles for eligibility. Subsequently, abstract text screening will be performed independently according to the predefined eligibility criteria. Any discrepancies will be resolved by consensus and a third person will be consulted in case of uncertainty. At the final stage, all full-texts will be obtained and independently screened by both reviewers. The excluded articles will be listed in the appendix and reasons will be provided. Relevant data will be extracted using a data extraction sheet with standardised categories. The extraction sheet will be tested on its applicability by using sample studies. The extraction will be performed by one reviewer and validated by the second reviewer. A PRISMA flowchart will visualise the study selection process.
Data items
The review will provide an overview of economic evaluations in pancreatic cancer screening. Key study characteristics, populations at risk, study input data and study results will be the main categories to be extracted. These categories and the respective subcategories are displayed in a data extraction sheet (online supplemental appendix 2). The study type refers to whether a full or partial economic evaluation was conducted and the respective subclassification. Full economic evaluations are expected to be based on either economic modelling or clinical trial data. Single studies applying deviating approaches will be categorised as such. The distribution of economic evaluations in pancreatic cancer screening among these analytic approaches is unknown at this point. Nevertheless, a 2017 systematic review identified two-thirds of the included studies as model-based, and all three screening evaluations followed this approach.24 In addition, the evaluation of medical screening often involves modelling since costs and consequences need to be studied over a long-time horizon.28 Thus, the data extraction categories were selected to capture relevant features of model-based and trial-based economic evaluations. Eligible partial economic evaluations will be reported by their screening approach, the respective costs and any additional information. The measure of health effects will be QALYs, life-years or other study endpoints.
The information on screening strategies will include all approaches that were compared to detect pancreatic cancer for the first time in patients. Information on the pancreatic cancer type will be displayed as well. Defining populations at risk is of particular importance in pancreatic cancer because screening the general population is not advisable.29 The risk factors of individuals that economic evaluations focused on will be reported as well as their age and sex. Model-based studies often define hypothetical patient cohorts whereas cost description studies may focus on real patients, which will be included as well. The study input data refers to the cost and effectiveness parameters that were used to calculate costs or cost-effectiveness as study output. In model-based studies, these parameters are often derived from multiple sources, whereas trial-based studies are limited to few sources.23 The included studies are expected to provide information on cost inputs. The types of costs can be divided into direct and indirect costs. The currency and year that were used for calculation will be included in the data extraction table. The input costs for each screening strategy will be extracted. Follow-up costs include all costs that may follow a test result. The main utility values, if used in the study, will be displayed.
Relevant study results will be collected as the final data extraction category. The total costs per screening strategy will be reported. The main types of study outputs will be cost-utility or cost-effectiveness ratios, but costing studies may report another type of output. To account for differences in publication place and year, all costs will be converted and inflated to Euros in the same reference year using the harmonised index of consumer prices and purchasing power parities of the Organisation for Economic Co-operation and Development.30 The assessment of uncertainty is a key component in any economic evaluation and serves to identify study parameters that significantly impact the study output. The type of uncertainty assessment will be reported. In this systematic review, the cost-effectiveness of early detection strategies will be reported as such, if the authors conducted a sufficient assessment of uncertainty and compared their results to a threshold. Otherwise, the author’s conclusion will be reported or no evidence of cost-effectiveness. Where data on cost-effectiveness is missing, only the total costs of the respective strategy will be presented. This descriptive approach was chosen since the studies are expected to be heterogeneous in terms of methodology and output. Thus, a statistical combination of results will not be conducted.
Assessment of study quality
Both reviewers will assess the reporting quality independently in accordance with the Consolidated Health Economic Evaluation Reporting Standards statement.31 The guideline comprises 28 checklist items divided into seven main categories to check the completeness of reporting in economic evaluations. The reporting quality will be judged based on whether and where each checklist item was included to provide an update on reporting quality since the last systematic review.24 Furthermore, identifying economic evaluations that include a broad set of checklist items will guide the future development of cost-effectiveness studies in the area of pancreatic cancer screening. To identify any sources of bias in reviewed economic evaluations, the Bias in Economic Evaluation checklist will be used.32 The list contains 11 general biases in economic evaluations and 11 biases in model-based economic evaluations. Both reviewers will conduct the assessment independently and disagreements will be resolved by consensus.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.
Discussion
This systematic review aims to synthesise information from economic evaluations of pancreatic cancer screening strategies. No previous review has focused on screening as a subset of pancreatic cancer care with respect to its cost-effectiveness and costs. Thus, a limited understanding of cost-effective screening approaches and the resources needed per approach exists. This review will complement this gap in research by analysing studies that have been conducted so far. The literature sample will be restricted to English publications, which may limit the results due to language bias. Although the number of studies that meet the inclusion criteria at this point may be low to moderate, the analysis of publications will likely yield initial findings regarding the type of strategies that have been compared. Furthermore, the study types and quality could point to patterns in methodology. Systematic assessment of these features could be of relevance for future economic evaluations, which are in demand due to an ongoing development in guidelines regarding screening recommendations. The German guideline on pancreatic cancer care, for instance, will provide recommendations for screening patients with a hereditary risk in the next guideline version.33 Future screening evaluations could evaluate whether screening further population groups could be cost-effective. In addition, new methods of detection such as blood-based screening are currently being developed and will require support by cost-effectiveness analysis to be included in healthcare guidelines.
Ethics and dissemination
Ethical approval will not be required because this study will retrieve data from already published research. Patients did not participate in this study. The results of this study will be published in an academic journal and presented at scientific conferences. This work was supported by the European Union (figure 1).
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References
Supplementary materials
Supplementary Data
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Footnotes
X @DrChrisBrett
Contributors All authors contributed to the study protocol. The concept for the protocol was jointly developed by RW, CB and H-HK. RW drafted the study manuscript, and a critical revision was done by CB and H-HK. The search strategy was agreed on by all authors. All authors approved the submitted version of the article. RW is responsible for the overall content as guarantor.
Funding Funded by the European Union (grant agreement ID: 101096309). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authorities can be held responsible for them.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.