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

• Published in: European journal of cancer (1990) Vol. 54; pp. 120 - 130
• Main Authors: Meulendijks, Didier, van Hasselt, J.G. Coen, Huitema, Alwin D.R., van Tinteren, Harm, Deenen, Maarten J., Beijnen, Jos H., Cats, Annemieke, Schellens, Jan H.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2016
• Subjects: adverse events; Age Factors; Aged; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Area Under Curve; Body Surface Area; Capecitabine; Capecitabine - administration & dosage; Capecitabine - adverse effects; Drug-Related Side Effects and Adverse Reactions - diagnosis; Drug-Related Side Effects and Adverse Reactions - etiology; Drug-Related Side Effects and Adverse Reactions - mortality; Drug-Related Side Effects and Adverse Reactions - therapy; Female; Fluoropyrimidine-associated toxicity; Hematology, Oncology and Palliative Medicine; Hospitalization; Humans; Kidney - physiopathology; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; ROC Curve; Safety; Severity of Illness Index; Time Factors; Toxicity; Treatment Outcome; Fluoropyrimidine-associated toxicity; Safety; adverse events; Capecitabine; Toxicity
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2015.10.013

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. 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. 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 m2, p = 0.0007), body surface area (BSA) (OR 0.33 per m2, 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). 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. •Fluoropyrimidines are used by approximately 2 million patients worldwide each year.•We examined the factors related to early severe fluoropyrimidine-related toxicity.•In total, 1463 patients treated in routine clinical care were analysed.•Renal function, BSA, DPD deficiency, and age were related to early severe toxicity.•These factors are associated with clinically relevant differences in risk of early severe toxicity.