Defining the Optimal Schedule of Drug Administration: Art or Science?
Authors: Chris J. Twelves
Journal: Journal of Clinical Oncology (2008)

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. It is generally accepted that preclinical models reflect or reliably predict clinical outcomes to only a limited extent, and the need for better models to guide drug development is widely acknowledged. Even those who argue for the wider use of such models acknowledge that they have not reliably provided specific guidelines for scheduling in the clinic. This is not surprising given that activity in preclinical models will be determined by the growth kinetics of human xenografts that generally have higher growth fractions than clinical tumors, and there may be substantial interspecies variability in drug metabolism and pharmacokinetics. For example, though irinotecan was most effective in preclinical neuroblastoma models when administered daily for two consecutive 5-day cycles, and is also well-tolerated and active clinically using the same schedule, it is unclear whether this particular schedule is more effective than others. The 7-day capecitabine schedule reported by Traina et al was derived from novel mathematical modeling and xenograft experiments. The mathematical modeling is predicated on breast cancers having a Gompertzian growth pattern, leading to the assertion that administering chemotherapy at an increased “dose density” will be more effective than standard therapy. Preclinical xenograft studies, so far reported only in abstract form, suggest that the optimal cycle duration for capecitabine is 7 days, with more prolonged administration adding to toxicity but not efficacy. Notwithstanding skepticism about extrapolating directly from murine models to the clinical setting, there is, therefore a sound rationale for a phase I trial of capecitabine given for 7 days repeated every 2 weeks rather than the usual 14 days repeated every 3 weeks. The current study defined capecitabine 2,000 mg twice daily for 7 days as the dose and schedule recommended for additional study. It is suggested that this regimen schedule may be better tolerated than the licensed capecitabine regimen of 2,500 mg/m/d, and that it achieves a higher dose-intensity. It is difficult to compare the tolerability and activity of capecitabine across phase I trials in which the patient populations and trial designs differ. Nevertheless, the 7-day schedule did seem well to be tolerated, although activity was modest (one of 18 assessable patients achieved a partial response; 6%) in a population that had mostly received only adjuvant chemotherapy, albeit regimens often containing an anthracycline and a taxane. Dose-intensities can be compared, although this is complicated by the use of “flat-dosing” (ie, not adjusted for body-surface area [BSA]) in the current study, whereas earlier phase I trial dosing did incorporate BSA. At the recommended dose, during a 6-week period the 7-day regimen delivers 84 g of capecitabine compared with 112 g using the approved dose and schedule (assuming a BSA of 1.6). This is contrary to the authors’ assertion that the 7-day regimen achieves a higher dose-intensity in the clinic as well as in murine models. The 7-day schedule, however, does have a similar dose-intensity to 2,000 mg/m/d capecitabine for 14 days repeated every 3 weeks, which is widely used in the United States (90 g over 6 weeks). Before judging whether this study establishes the 7-day schedule as the schedule for capecitabine, or simply another schedule, it is helpful to recall the studies leading to the approval of capecitabine. Based on evidence that prolonged exposure is beneficial with fluorouracil, and because oral administration is convenient, the initial capecitabine phase I studies investigated continuous administration and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 11 APRIL 1