title: Renal function, body surface area, and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care.
abstract: BACKGROUND
  The objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care.
  
  
  METHODS
  A total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early--i.e. cycle one or two--severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis.
  
  
  RESULTS
  Among 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥ 3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m(2), p = 0.0007), body surface area (BSA) (OR 0.33 per m(2), p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥ 3 toxicity was 0.704 (95% confidence interval 0.666-0.743, optimism-corrected AUC 0.690).
  
  
  CONCLUSIONS
  Renal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: J G Coen
authors.initials: JGC
authors.lastname: van Hasselt
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: ADR
authors.lastname: Huitema
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands. Electronic address: j.schellens@nki.nl.
authors.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
mesh_terms: D000367:Age Factors; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D019540:Area Under Curve; D001830:Body Surface Area; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality / Q000628:therapy; D005260:Female; D006760:Hospitalization; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012372:ROC Curve; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine
keywords: Capecitabine; Fluoropyrimidine-associated toxicity; Safety; Toxicity; adverse events