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© 2003 American Society for Clinical Oncology
Boosting Bioavailability to Topotecan: What Do We Gain?Division of Medical Oncology, New York University School of Medicine, New York, NY To the Editor:The Editorial by Gary Hudes1 on "Boosting bioavailability of topotecan: What do we gain?" is unduly negative about the possibility that prolonged exposure to topotecan lactone will result in superior antitumor effects. A major hurdle in studying continuous intravenous infusions has been the impracticality of the schedule coupled with its frequent subjective intolerance by patients undergoing such treatment. The absence of phase II trials indicating superior activity may, in fact, reflect the paucity of experience with this schedule. The interest in intermittent schedules belies the considerable preclinical data2 and some clinical trials showing little activity even in tumor types such as ovarian cancer,3,4 in which more activity was shown by the same groups on the conventional daily x 5 schedule. It should be noted that the continuous exposure schedules may, as is claimed for the intermittent schedules, be safely used in combinations with radiation5 or with cisplatin,6,7 while not compromising on optimal antitumor activity. Therefore, reliable oral bioavailability constitutes an important step forward in exploring how to further enhance the usefulness of topotecan and related topoisomerase I inhibitors. References
1. Hudes G: Boosting bioavailability of topotecan: What do we gain? (Editorial). J Clin Oncol 20:2918–2919, 2002 2. O’Leary J, Muggia FM: Camptothecins: A review of their development and schedules of administration. Eur J Cancer 34:1500–1508, 1998[CrossRef][Medline] 3. Miller DS, Blessing JA, Lentz SS, et al: Phase II evaluation of three-day topotecan in recurrent platinum-sensitive ovarian or primary peritoneal cancer: A Gynecologic Oncology Group study. Gynecol Oncol 84:507, 2002 (abstr 49)[CrossRef] 4. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 16:2233–2237, 1998[Abstract] 5. Chachoua A, Hochster H, Steinfeld A, et al: Feasibility of seven weeks concomitant topotecan continuous infusion with thoracic radiation. Proc Am Soc Clin Oncol 18:1684a, 1999 (abstr 1873) 6. Speyer J, Hochster H, Runowicz C, et al: First line therapy of ovarian cancer with cisplatin and prolonged infusion topotecan. Proc Am Soc Clin Oncol 17:350a, 1998 (abstr 1352) 7. Lilenbaum RC, Miller AA, Batist G, et al: Phase I and pharmacologic study of continuous infusion topotecan in combination with cisplatin in patients with advanced cancer: A Cancer and Leukemia Group B study. J Clin Oncol 16:3302–3309, 1998[Abstract]
In Reply:Genitourinary Malignancies Program, Fox Chase Cancer Center, Philadelphia, PA Dr. Muggia and I agree that there is much preclinical data showing better antitumor activity with longer exposure to topotecan lactone and that the limited clinical experience with prolonged continuous administration of topotecan has not shown a clear advantage over shorter dosing schedules. We also agree that having an oral formulation of topotecan with reliable bioavailability will facilitate additional studies to determine the value of prolonged administration. In my editorial, I argue that the current oral formulation is up to this task; augmenting the already adequate bioavailability of topotecan with a second agent will not likely improve the results and may introduce new toxicities by altering the pharmacokinetics of other drugs taken by the patient. It is unclear whether single weekly doses of topotecan are more or less active than 5-day or longer treatment schedules. For example, in the randomized phase II ovarian carcinoma trial reported by Hoskins et al1 for the National Cancer Institute of Canada’s Clinical Trials Group, a weekly 24-hour intravenous topotecan infusion was compared with the conventional 5-day, every 3-week schedule. Although the partial response rate was better for the latter arm, the median survivals and the proportion of patients with stable disease or objective response on each schedule were equivalent. The two arms were not equitoxic, with significantly less myelotoxicity in patients receiving the weekly treatment.1 Thus, in addition to studies of longer topotecan exposure, there continues to be interest in the less myelosuppressive weekly infusion schedule, substituting bolus for 24-hour infusion. On the basis of the limited clinical experience with any of these alternative schedules, it seems clear that additional randomized trials will be needed to determine a winner. Reference 1. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topitecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 18:2233–2237, 1998
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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