title: Prospective, Multicenter Study of 5-Fluorouracil Therapeutic Drug Monitoring in Metastatic Colorectal Cancer Treated in Routine Clinical Practice.
abstract: Studies have demonstrated that body surface area-based dosing of chemotherapy drugs leads to significant individual exposure variability, with a substantial risk of under- or overdosing. The present study was initiated to validate the use of therapeutic drug management (TDM) to personalize 5-fluorouracil (5-FU) dosing in patients with metastatic colorectal cancer treated in routine clinical practice.
  
  
  
  A total of 75 patients with metastatic colorectal cancer from 8 German medical centers received ≤ 6 administrations of infusional 5-FU according to the AIO (folinate, 5-FU; n = 16), FOLFOX6 (leucovorin calcium [folinic acid], 5-FU, and oxaliplatin; n = 26), or FUFOX (oxaliplatin plus 5-FU/folinic acid; n = 33) regimen. Initial infusional 5-FU dosing for all patients was determined by the BSA. Individual 5-FU exposure (area under the curve [AUC]) was measured using an immunoassay of a blood sample taken during each infusion. To achieve a target AUC of 20 to 30 mg × h/L, subsequent infusional 5-FU doses were adjusted according to the previous cycle's 5-FU AUC. The primary objective was to confirm that TDM of infusional 5-FU resulted in an increased proportion of patients in the target AUC range at the fourth versus the first administration. The secondary objective was to determine whether 5-FU TDM reduced the treatment-related toxicities compared with the historical data.
  
  
  
  The average 5-FU AUC at the first administration was 18 ± 6 mg × h/L, with 64%, 33%, and 3% of the patients below, within, or above the target AUC range, respectively. By the fourth administration, the average 5-FU AUC was 25 ± 7 mg × h/L (P < .001), with 54% of patients within the target 5-FU AUC range (P = .0294). The incidence of 5-FU-related grade 3 and 4 diarrhea (4.6%), nausea (3.4%), fatigue (0.0%), and mucositis (0.2%) was reduced compared with the historical data, despite 55% of the patients receiving increased doses.
  
  
  
  Personalization of 5-FU dosing using TDM in routine clinical practice resulted in significantly improved 5-FU exposure and suggested a lower incidence of 5-FU-related toxicities.
authors.affiliation: Department of Hematology and Medical Oncology, Paracelsus Medical University, Nuremberg, Germany. Electronic address: Martin.Wilhelm@klinikum-nuernberg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Wilhelm
authors.affiliation: Outpatient Clinic, Leer, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Mueller
authors.affiliation: Saladax Biomedical Inc., Bethlehem, PA.
authors.forename: M Craig
authors.initials: MC
authors.lastname: Miller
authors.affiliation: Outpatient Clinic, Lueneburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Link
authors.affiliation: Institute for Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.affiliation: Central Laboratory, Paracelsus Medical University, Nuremberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertsch
authors.affiliation: University Clinic of Wuerzburg, Wuerzburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Kunzmann
authors.affiliation: Hemato-Oncologic Clinic, Munich, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Stoetzer
authors.affiliation: Oncological Center, Munich, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Suttmann
authors.affiliation: Clinic Barmherzige Brueder, Regensburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.affiliation: Department of Hematology and Medical Oncology, Paracelsus Medical University, Nuremberg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Birkmann
authors.affiliation: CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.
authors.forename: Max
authors.initials: M
authors.lastname: Roessler
authors.affiliation: CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.
authors.forename: Berta
authors.initials: B
authors.lastname: Moritz
authors.affiliation: Pharmaceutical Institute, University Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kraff
authors.affiliation: Outpatient Clinic, Lueneburg, Germany.
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Salamone
authors.affiliation: Pharmaceutical Institute, University Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaehde
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine; D011446:Prospective Studies
chemical_list: D005472:Fluorouracil
keywords: 5-FU; Colorectal cancer; Dosing; Therapeutic drug monitoring