{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T16:24:06Z","timestamp":1764433446706,"version":"build-2065373602"},"reference-count":26,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T00:00:00Z","timestamp":1635811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01CA233169"],"award-info":[{"award-number":["U01CA233169"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2021,12,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease\u2013free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient\u2010reported outcomes (PROs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All\u2010grade and high\u2010grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE\u2010related and any\u2010reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy\u2013Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>More than half of all AEs (57.5%) were low\u2010grade. A cluster of patients with broad and mixed AE (all\u2010grade) trajectory grades was significantly associated with any\u2010reason early treatment discontinuation (odds ratio [OR], 2.87; <jats:italic>P<\/jats:italic> = .01) as well as AE\u2010related discontinuation (OR, 4.14; <jats:italic>P<\/jats:italic> = .001). This cluster had the highest count of all\u2010grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well\u2010being in comparison with a trajectory of no or few AEs (<jats:italic>P<\/jats:italic> &lt; .01). A high\u2010grade AE trajectory did not predict discontinuations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A sustained and cumulative burden of across\u2010the\u2010board toxicities, which were not necessarily all recognized as high\u2010grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all\u2010grade AEs may require additional attention for preventing deterioration in their physical well\u2010being.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.33992","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T17:16:08Z","timestamp":1635873368000},"page":"4546-4556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2\u2013negative breast cancer: A trajectory analysis of adverse events"],"prefix":"10.1002","volume":"127","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4811-4205","authenticated-orcid":false,"given":"Edward H.","family":"Ip","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Data Science Wake Forest School of Medicine Winston\u2010Salem North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santiago","family":"Saldana","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science Wake Forest School of Medicine Winston\u2010Salem North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathy D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology Division Department of Medicine Indiana University School of Medicine Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-7662","authenticated-orcid":false,"given":"Ruth C.","family":"Carlos","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Michigan Comprehensive Cancer Center Ann Arbor Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilana F.","family":"Gareen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Center for Statistical Sciences Brown University School of Public Health Providence Rhode Island"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph A.","family":"Sparano","sequence":"additional","affiliation":[{"name":"Department of Oncology Montefiore Medical Center Albert Einstein College of Medicine Bronx New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah","family":"Graham","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9826-3703","authenticated-orcid":false,"given":"Fengmin","family":"Zhao","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute Boston Massachusetts"},{"name":"Department of Biostatics Harvard T. 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Chan School of Public Health Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju\u2010Whei","family":"Lee","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathaniel S.","family":"O\u2019Connell","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science Wake Forest School of Medicine Winston\u2010Salem North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Cella","sequence":"additional","affiliation":[{"name":"Department of Medical Social Sciences Feinberg School of Medicine Northwestern University Chicago Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-7881","authenticated-orcid":false,"given":"John D.","family":"Peipert","sequence":"additional","affiliation":[{"name":"Department of Medical Social Sciences Feinberg School of Medicine Northwestern University Chicago Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Gray","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute Boston Massachusetts"},{"name":"Department of Biostatics Harvard T. 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Chan School of Public Health Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9685-4796","authenticated-orcid":false,"given":"Lynne I.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Social Sciences and Health Policy Wake Forest School of Medicine Winston\u2010Salem North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,2]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_8_2_1","DOI":"10.1200\/JCO.2018.79.2028"},{"doi-asserted-by":"publisher","key":"e_1_2_8_3_1","DOI":"10.1200\/JCO.2008.21.6457"},{"doi-asserted-by":"publisher","key":"e_1_2_8_4_1","DOI":"10.1200\/JCO.2010.28.0982"},{"doi-asserted-by":"publisher","key":"e_1_2_8_5_1","DOI":"10.1016\/j.ejca.2016.09.024"},{"doi-asserted-by":"publisher","key":"e_1_2_8_6_1","DOI":"10.1016\/S1470-2045(14)70439-5"},{"doi-asserted-by":"publisher","key":"e_1_2_8_7_1","DOI":"10.1200\/JCO.2010.34.1255"},{"doi-asserted-by":"publisher","key":"e_1_2_8_8_1","DOI":"10.1056\/NEJMoa072113"},{"doi-asserted-by":"publisher","key":"e_1_2_8_9_1","DOI":"10.1158\/1078-0432.CCR-10-1791"},{"doi-asserted-by":"publisher","key":"e_1_2_8_10_1","DOI":"10.21037\/tcr.2018.10.17"},{"doi-asserted-by":"publisher","key":"e_1_2_8_11_1","DOI":"10.1200\/PO.17.00059"},{"doi-asserted-by":"publisher","key":"e_1_2_8_12_1","DOI":"10.1023\/A:1012278023233"},{"doi-asserted-by":"publisher","key":"e_1_2_8_13_1","DOI":"10.1080\/01621459.2013.770307"},{"doi-asserted-by":"publisher","key":"e_1_2_8_14_1","DOI":"10.1002\/sim.5719"},{"doi-asserted-by":"publisher","key":"e_1_2_8_15_1","DOI":"10.1056\/NEJMoa1110294"},{"doi-asserted-by":"publisher","key":"e_1_2_8_16_1","DOI":"10.1345\/aph.1L426"},{"doi-asserted-by":"publisher","key":"e_1_2_8_17_1","DOI":"10.1177\/1758835919864236"},{"doi-asserted-by":"publisher","key":"e_1_2_8_18_1","DOI":"10.1002\/onco.13527"},{"doi-asserted-by":"publisher","key":"e_1_2_8_19_1","DOI":"10.1016\/S2352-3026(20)30067-3"},{"doi-asserted-by":"publisher","key":"e_1_2_8_20_1","DOI":"10.1093\/jnci\/djp386"},{"doi-asserted-by":"publisher","key":"e_1_2_8_21_1","DOI":"10.1200\/JCO.2012.42.5967"},{"doi-asserted-by":"publisher","key":"e_1_2_8_22_1","DOI":"10.1016\/j.clinthera.2016.03.011"},{"doi-asserted-by":"publisher","key":"e_1_2_8_23_1","DOI":"10.1200\/JCO.2014.57.9334"},{"doi-asserted-by":"publisher","key":"e_1_2_8_24_1","DOI":"10.1016\/S1470-2045(06)70910-X"},{"doi-asserted-by":"publisher","key":"e_1_2_8_25_1","DOI":"10.1001\/jama.2019.19970"},{"doi-asserted-by":"publisher","key":"e_1_2_8_26_1","DOI":"10.1016\/j.jval.2017.09.009"},{"doi-asserted-by":"publisher","key":"e_1_2_8_27_1","DOI":"10.1016\/j.jclinepi.2004.01.012"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.33992","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.33992","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.33992","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T21:37:42Z","timestamp":1760305062000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.33992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,2]]},"references-count":26,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2021,12,15]]}},"alternative-id":["10.1002\/cncr.33992"],"URL":"https:\/\/doi.org\/10.1002\/cncr.33992","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"type":"print","value":"0008-543X"},{"type":"electronic","value":"1097-0142"}],"subject":[],"published":{"date-parts":[[2021,11,2]]},"assertion":[{"value":"2021-06-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}