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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1781-1782 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.7769
Defining the Optimal Schedule of Drug Administration: Art or Science?Section of Oncology and Clinical Research, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom 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 al1 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 fluorouracil2 or paclitaxel3 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.4 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,5 and there may be substantial interspecies variability in drug metabolism and pharmacokinetics.6 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,7 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,8 leading to the assertion that administering chemotherapy at an increased "dose density" will be more effective than standard therapy.9 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.10,11 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/m2/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 clinic1 as well as in murine models.11 The 7-day schedule, however, does have a similar dose-intensity to 2,000 mg/m2/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 also an intermittent schedule. Because of the theoretical benefits for patients of a "drug holiday,"12,13 both schedules were studied with and without a fixed dose of leucovorin.14 These phase I trials ran simultaneously, with similar designs and the same definitions of dose-limiting toxicity to establish three different potential recommended doses for subsequent evaluation. Antitumor activity was seen with each of the regimens, which is unusual in phase I trials. In this situation, where more than one schedule has been evaluated but no single schedule has demonstrated sufficiently better tolerability, greater activity, more favorable pharmacokinetics, or delivery of a substantially higher dose-intensity, the choice of the best schedule to take forward is difficult. A pragmatic decision may be made on the basis of convenience or the scheduling of potential combination partners. A more objective approach is to conduct additional clinical trials in limited numbers of patients treated at the recommended dose(s) with clearly defined efficacy or pharmacodynamic primary end points. A randomized phase II study of the three recommended doses/schedules was performed with capecitabine as first-line therapy for patients with advanced colorectal cancer.15 The study was not powered to detect differences among the three arms in terms of efficacy or toxicity, but capecitabine 2,500 mg/m2/d for 14 days repeated every 3 weeks achieved a higher dose-intensity and possibly longer time to tumor progression, and so was selected for phase III trials. This "pick the winner" phase II design presupposes sufficient evidence of antitumor activity to make such a judgment. Where this is not so, schedule selection may be aided by a phase Ib or phase II study incorporating molecular or imaging biomarkers that were identified and characterized in preclinical models, then carefully validated both technically and biologically. To answer the first question posed above, this single study should not be interpreted as showing that earlier trials identified the wrong schedule for capecitabine; however, the 7-day schedule is a reasonable alternative to the more widely used 14-day schedule. The authors suggest that additional evaluation of this schedule will be undertaken in a phase II combination with bevacizumab, reflecting the evolving treatment of advanced breast cancer. This may, however, preclude formal evaluation of the efficacy of the new schedule compared with that usually employed, which would be unfortunate. The recent demonstration that capecitabine (and fluorouracil) are indeed less well-tolerated in the United States population16 has further emphasized the need to optimize capecitabine administration. The second question was whether this modeling of preclinical data could be applied more widely to the rational selection of treatment schedules in early clinical trials of anticancer drugs. This approach is attractive, and the current study should encourage additional investigation of more systematic approaches to incorporating data on scheduling from improved preclinical models into phase I trial design. If this proves more effective than current approaches, focusing on such rationally defined schedules may substantially streamline drug development. It is too early to say whether this will be the case, but the question is important and warrants thorough clinical evaluation. Traina et al present us with an intriguing glimpse of what might be possible by rational selection of the optimal schedule of administration for anticancer drugs, both old and new. Until definitive clinical studies are undertaken to validate this approach, selection of the appropriate schedule for additional clinical development will often remain both an art and a science. However, there are grounds to believe that better use of improved tumor models may lead to the more effective identification of optimal drug schedules. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Chris J. Twelves, Roche advisory boards (C) Stock Ownership: None Honoraria: Chris J. Twelves, Roche speaker's bureau Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Traina TA, Theodoulou M, Feigin K, et al: Phase I study of a novel capecitabine schedule based upon the Norton-Simon mathematical model in patients with metastatic breast cancer. J Clin Oncol 26:1797-1802, 2008 2. de Gramont A, Bosset JF, Milan C, et al: Randomised trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997 3. Verril MW, Lee J, Cameron D, et al: Anglo-Celtic IV: First results of a UK National Cancer Res Network pharmacogenetic trial of weekly versus 3 weekly paclitaxel in locally advanced or metastatic breast cancer (MBC). J Clin Oncol 25:33S, 2007 (suppl; abstr LBA1005) 4. Martin DS, Balis ME, Fisher B, et al: Role of murine tumour models in cancer treatment research. Cancer Res 46:2189-2192, 1988 5. Steel, GG: Growth and survival of tumour stem cells in growth kinetics of tumours, in GG (ed): Growth Kinetics of Tumours. Oxford, United Kingdom, Clarendon Press, 1977, pp 217-262 6. Gianni L, Vigani L, Surbone A, et al: Pharmacology and clinical toxicity of 4'-iodo-4'deoxydoxorubicin: An example of successful application of pharmacokinetics to dose escalation in phase I trials. J Natl Cancer Inst 82:469-477, 1990 7. Furman WL, Stewart CF, Poquette CA, et al: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815-1824, 1999 8. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986[Medline] 9. Norton L: Conceptual and practical implications of breast tissue geometry: Toward a more effective, less toxic therapy. Oncologist 10:370-381, 2005 10. Norton L, Dugan U, Young D, et al: Optimising chemotherapeutic dose-schedule (CDS) by Norton-Simon modelling: Capecitabine (Xeloda). Presented at the 96th Annual Meeting of American Association for Cancer Research, Anaheim, CA, April 16-20, 2005 (abstr 5007) 11. Traina TA, Theodoulou M, Higgins B, et al: In vivo activity of a novel regimen of capecitabine (C) in a breast cancer xenograft model. The 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 (abstr 6071) 12. Budman DR, Meropol NJ, Reigner B, et al: Preliminary studies of a novel oral fluropyrimidine carbamate: Capecitabine. J Clin Oncol 16:1795-1802, 1998[Abstract] 13. Mackean M, Planting A, Twelves C, et al: Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16:2977-2985, 1998 14. Cassidy J, Dirix L, Bissett D, et al: A phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res 4:2755-2761, 1998[Abstract] 15. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluropyrimidine carbamate with substantial activity in advanced colorectal cancer: Results of a randomised phase II study. J Clin Oncol 18:1337-1345, 2000 16. Haller JG, Cassidy J, Clarke S, et al: Potential regional differences for the tolerability profiles of fluouropyrimidines. J Clin Oncol doi:10.1200/JCO.2007.15.2090
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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