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The diagnostic pathway is often protracted and resource-intensive, with little known about the costs involved. The primary aims of this study were to (a) determine time-to-treatment-decision (pathway duration) and (b) estimate resources incurred and direct healthcare costs within the UK\u2019s diagnostic pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A microcosting analysis was conducted on 370 patients with CUP. For relevant context, a comparison cohort of 216 patients with stage IV cholangiocarcinoma (CCA) was selected. Pathways were mapped from the first cancer-related investigation until treatment decision. Analyses estimated pathway duration and cost, and explored the significance of prognostic variables on the CUP pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Median pathway duration in CUP was 40% longer than CCA (2.8 months vs 2.0 months, respectively,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Mean per-patient cost of the CUP pathway was 62% higher than CCA (\u00a33902 vs \u00a32403 respectively,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Performance status 0-1 and squamous-cell histology were predictive of higher costs in CUP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Direct healthcare costs were significantly higher in CUP. Improvements are required to rationalise investigations and facilitate patients receiving treatment in an appropriate timeframe.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s44276-026-00252-8","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T10:19:22Z","timestamp":1792750762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Cost of Uncertainty: A Microcosting Analysis of the Cancer of Unknown Primary Diagnostic Pathway"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4152-5068","authenticated-orcid":false,"given":"Laura","family":"Spurgeon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia-Marie","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Gavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"252_CR1","unstructured":"UK CR. 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NC has received consulting fees from Roche Pharmaceuticals, Servier and REDX Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche Pharmaceuticals; support for attending meetings and\/or travel from Roche Pharmaceuticals; research funding to research team from AstraZeneca, Orion, F.Hoffmann-La Roche Ltd, Taiho, Novartis, Starpharma, Bayer, Eisai, UCB, RedX Pharmaceuticals, LOXO-oncology, Avacta, Boehringer Ingelheim, Merck and Tarveda Therapeutics; participated in data safety monitoring board or advisory board at Roche Pharmaceuticals and Cancer Research UK. AMC has received support for attending meetings and\/or travel from Roche Products Limited, Servier Laboratories Ltd. and Novartis Pharmaceuticals UK Ltd; has been the named investigator on a patent registered by \u201cCancer Research Technology Ltd\u201d; has received payment or honoraria for lectures or presentations from Servier Laboratories Ltd.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Approval was gained from the Quality Insurance and Clinical Audit Committee at The Christie NHS Foundation Trust (reference 4582). All patients included in the study provided written informed consent for all investigations and treatments received. The study was performed in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"49"}}