{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:05:06Z","timestamp":1784199906105,"version":"3.55.0"},"reference-count":21,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100015268","name":"Ministerio de Sanidad, Consumo y Bienestar","doi-asserted-by":"publisher","award":["FIS PI 13\/01659"],"award-info":[{"award-number":["FIS PI 13\/01659"]}],"id":[{"id":"10.13039\/501100015268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Since real\u2010world data lack information on treatment assignment (usually the only information available is treatment prescription\/administration) and early outcomes can happen in advanced cancer, some design choices may introduce immortal time due to selection or due to treatment strategy misclassification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To illustrate design choices that would biassedly introduce immortal time and propose unbiased alternatives, using as a case study the estimation of the effects of different monoclonal antibody (mAb) sequencing strategies on overall survival in colorectal cancer patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We specified a target trial to estimate the effect on overall survival of initiating mAb within 8\u2009weeks of starting first line chemotherapy versus initiating mAb with second line chemotherapy. The first biased design choice would be requiring the initiation of second line chemotherapy for eligibility. This was avoided by aligning eligibility with the initiation of first line chemotherapy. The second biased design choice would be excluding from the first line mAb strategy those who die during the grace period without starting mAb. This was avoided separately via cloning, censoring and weighting and by sequential emulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>There were 1014 eligible patients in GEMCAD 1401. The CCW approach estimated a 4\u2010year survival difference (second\u2014first line mAb) of 4.3% (95% CI) (\u22123.3%; 10.0%) and a risk ratio (RR) of 0.95 (0.88; 1.04). Sequential trial emulation estimated a survival difference of \u22122.8% (\u22127.5%; 1.2%) and a RR of 1.04 (0.98; 1.10). Biased analyses that introduced immortal time estimated an implausible early survival benefit for mAb initiation with second\u2010line (6\u2010month RR of 0.13 (0.03; 0.28)).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results are compatible with no effect on survival by mAb sequencing. Misalignment of time zero, treatment assignment, and eligibility introduced immortal time.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71950","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:36:01Z","timestamp":1781926561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Studying When to Add Biological Therapy to Cytotoxic Therapy in Advanced Cancer Care Using Real World Data: How to Avoid Design Choices That Generate Immortal Time"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9814-2343","authenticated-orcid":false,"given":"Xabier","family":"Garcia\u2010Albeniz","sequence":"first","affiliation":[{"name":"RTI Health Solutions  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Vila\u2010Guilera","sequence":"additional","affiliation":[{"name":"RTI Health Solutions  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Zamparini","sequence":"additional","affiliation":[{"name":"RTI Health Solutions  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Oliveres","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Alonso\u2010Orduna","sequence":"additional","affiliation":[{"name":"Medical Oncology Service Hospital Universitario Miguel Servet  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4867-1420","authenticated-orcid":false,"given":"Jaime","family":"Feliu","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz. Instituto de Investigaci\u00f3n Hospital Universitario La Paz (IdiPAZ) Universidad Aut\u00f3noma de Madrid. Centro de Investigaci\u00f3n Biom\u00e9dica en Red C\u00e1ncer (CIBERONC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4630-5830","authenticated-orcid":false,"given":"Ana","family":"Fern\u00e1ndez\u2010Montes","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Complexo Hospitalario Universitario de Ourense  Ourense Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mart\u00edn\u2010Richard","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Hospital de la Santa Creu i Sant Pau  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"G\u00e1lvez\u2010Munoz","sequence":"additional","affiliation":[{"name":"Medical Oncology Hospital General Universitario de Elda Virgen de la Salud  Elda Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ruiz\u2010Casado","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario Puerta de Hierro\u2010Majadahonda IDIPHISA  Majadahonda Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Yubero\u2010Esteban","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Hospital Clinico Universitario Lozano Blesa  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Aparicio","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Hospital Universitari i Polit\u00e8cnic La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Alcaide\u2010Garcia","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Costa del Sol Marbella. Hospital Regional Universitario de M\u00e1laga, IBIMA  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier Gallego","family":"Plazas","sequence":"additional","affiliation":[{"name":"Medical Oncology Hospital General Universitario de Elche  Elche Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Fernandez\u2010Martos","sequence":"additional","affiliation":[{"name":"Medical Oncology IVO\u2014Fundaci\u00f3n Instituto Valenciano de Oncolog\u00eda  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Gallego\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Oncology Department Hospital General de Granollers  Granollers Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica Guillot","family":"Morales","sequence":"additional","affiliation":[{"name":"Medical Oncology Hospital Universitario Son Espases  Palma De Mallorca Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Leno","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Hospital Virgen Del Puerto  Plasencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Esposito","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Lopez\u2010Prades","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS)  Barcelona Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut Universitat de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00edriam","family":"Cuatrecasas","sequence":"additional","affiliation":[{"name":"Pathology Department, Hospital Cl\u00ednic Barcelona University of Barcelona. 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