For Those On Xeloda(capecitabine)-- Dosing Schedule Affects Efficacy

[Lani]

ABSTRACT: Phase I Study of a Novel Capecitabine Schedule Based on the Norton-Simon Mathematical Model in Patients With Metastatic Breast Cancer
[Journal of Clinical Oncology]
Purpose: This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling.
Patients and Methods: Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks.
Results: Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily.
Conclusion: As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.
OPEN ACCESS: EDITORIAL: Defining the Optimal Schedule of Drug Administration: Art or Science?
[Journal of Clinical Oncology]
The optimal use of the oral fluoropyrimidine carbamate capecitabine (Xeloda; Hoffman-Roche, Nutley, NJ) has been the subject of much debate, with empirical exploration of both doses and schedules different from those approved. In the current issue of the Journal, Traina et al describe a phase I trial of a 7-day capecitabine schedule derived rationally from mathematical modeling of preclinical data. This study has potentially important implications for the use of capecitabine but also more widely for how we should select and evaluate drug schedules in early clinical trials. It raises two important questions: should the 7-day capecitabine schedule be considered a new standard, and can this modeling approach be applied more widely to the rational selection of treatment schedules in early clinical trials of anticancer drugs.
Although determining both the optimal dose and schedule of new anticancer drugs are key goals of early clinical trials, less emphasis is generally placed on schedule than on dose. Arguably, modest changes in the schedule of administration are unlikely to turn a good drug into a bad one (or vice versa), so refining the schedule might be considered a legitimate part of postlicensing drug development. This is, however, inherently inefficient, not least of all from the perspective of the patients who may have benefited from the earlier use of fluorouracil or paclitaxel in the most effective manner.
In phase I trials of anticancer drugs, schema for deciding the starting dose are well established, if not always ideal. By contrast, the selection of different schedules of drug administration is much less well defined. Schedule dependency of antitumor activity in preclinical models may suggest whether a drug should be administered more or less frequently. Likewise, a short half-life for the active compound in preclinical pharmacokinetic studies encourages either daily administration (intravenous or oral) or the use of an intravenous infusion.