{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:04:25Z","timestamp":1791921865906,"version":"4.3.4"},"reference-count":30,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2019,5]]},"abstract":"\n Carriers of the genetic\n DPYD<\/jats:italic>\n *2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine\u2010associated toxicity. Upfront\n DPYD<\/jats:italic>\n *2A genotype\u2010based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of\n DPYD<\/jats:italic>\n *2A genotype\u2010guided dosing. A cohort of 40 prospectively identified heterozygous\n DPYD<\/jats:italic>\n *2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair\u2010analysis was performed in which for each\n DPYD<\/jats:italic>\n *2A carrier a matched\n DPYD<\/jats:italic>\n *2A wild\u2010type patient was identified. Overall survival and progression\u2010free survival were compared between the matched groups. The frequency of severe (grade \u2265 3) treatment\u2010related toxicity was compared to 1] a cohort of 1606 wild\u2010type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86\n DPYD<\/jats:italic>\n *2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40\n DPYD<\/jats:italic>\n *2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months\n versus<\/jats:italic>\n 24 months,\n p<\/jats:italic>\n = 0.47) nor progression\u2010free survival (median 14 months\n versus<\/jats:italic>\n 10 months,\n p<\/jats:italic>\n = 0.54). Risk of severe fluoropyrimidine\u2010related toxicity in\n DPYD<\/jats:italic>\n *2A carriers treated with reduced dose was 18%, comparable to wild\u2010type patients (23%,\n p<\/jats:italic>\n = 0.57) and significantly lower than the risk of 77% in\n DPYD<\/jats:italic>\n *2A carriers treated with full dose (\n p<\/jats:italic>\n < 0.001). Our study is the first to show that\n DPYD<\/jats:italic>\n *2A genotype\u2010guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine\u2010based chemotherapy, while resulting in significantly improved patient safety.\n <\/jats:p>","DOI":"10.1002\/ijc.32022","type":"journal-article","created":{"date-parts":[[2018,11,28]],"date-time":"2018-11-28T12:49:36Z","timestamp":1543409376000},"page":"2347-2354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Effectiveness and safety of reduced\u2010dose fluoropyrimidine therapy in patients carrying the\n DPYD<\/i>\n *2A variant: A matched pair analysis"],"prefix":"10.1002","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0141-7927","authenticated-orcid":false,"given":"Linda M.","family":"Henricks","sequence":"first","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Department of Clinical Pharmacology, Division of Medical Oncology The Netherlands Cancer Institute Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisanne N.","family":"van Merendonk","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Department of Clinical Pharmacology, Division of Medical Oncology The Netherlands Cancer Institute Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Meulendijks","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Department of Clinical Pharmacology, Division of Medical Oncology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Dutch Medicines Evaluation Board (CBG\u2010MEB) Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten J.","family":"Deenen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Catharina Hospital Eindhoven The Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos H.","family":"Beijnen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy & Pharmacology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences Faculty of Science, Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonius","family":"de Boer","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences Faculty of Science, Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Cats","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Oncology, Division of Medical Oncology The Netherlands Cancer Institute Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.M.","family":"Schellens","sequence":"additional","affiliation":[{"name":"Division of Pharmacology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Department of Clinical Pharmacology, Division of Medical Oncology The Netherlands Cancer Institute Amsterdam the Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences Faculty of Science, Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,1,4]]},"reference":[{"key":"e_1_2_7_2_1","volume-title":"Scrip world pharmaceutical news","author":"Scrip's Cancer Chemotherapy Report","year":"2002"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2010.511610"},{"key":"e_1_2_7_4_1","first-page":"2295","article-title":"Dihydropyrimidine dehydrogenase (DPD) and clinical pharmacology of 5\u2010fluorouracil (review)","volume":"14","author":"Milano G","year":"1994","journal-title":"Anticancer Res"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2003.12.004"},{"key":"e_1_2_7_6_1","first-page":"1149","article-title":"Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5\u2010fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency","volume":"7","author":"Van Kuilenburg 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