Topotecan: What Dose, What Schedule, What Route?1

Vol. 5, 3–5, January 1999 Clinical Cancer Research 3

Editorial Topotecan: What Dose, What Schedule, What Route?1

Seamus O’Reilly2 schedule is being evaluated by some investigators. A recently Waterford Regional Hospital, Waterford, Ireland completed randomized study compared the approved schedule with a 24-h infusion schedule administered once a week for 4 weeks every 6 weeks (7). In this well-conducted study of Topotecan is a semisynthetic water soluble analogue of women with relapsed ovarian cancer, the response rate in the camptothecin, which exerts its cytotoxic effects through inhibi- approved schedule arm was 22.6%, compared to 3.1% in the tion of the enzyme topoisomerase I. This enzyme relaxes super- investigational arm. A similarly conducted trial comparing a coiled DNA by covalently binding to it, leading to transient 21-day infusion schedule of topotecan with the approved sched- single-strand breaks that are resealed by topoisomerase I after ule would also be worthwhile, particularly because recently strand passage. These breaks allow topological shifts in DNA conducted xenograft studies have demonstrated that intermittent strands and are essential steps in permitting DNA replication, exposure schedules maybe the most efficacious (8). repair, and transcription. Topotecan binds to the topoisomerase Questions concerning the optimal dose of topotecan were I-DNA complex and prevents the religation step. Consequently raised following its approval for clinical use. In clinical practice, permanent strand breaks are created, and cell death ensues. the hematological toxicity associated with the recommended Given such S-phase specificity, it is likely that topotecan’s Phase II dose of topotecan has been an area of concern, partic- activity should be schedule dependent. ularly in patients with renal impairment or those who have In Phase I trials of the i.v. formulation of topotecan, a variety of received extensive prior alkylating agent therapy, both of which schedules were evaluated (1). On the basis of the schedule-dependent are common clinical scenarios in patients with relapsed ovarian nature of topotecan’s mechanism of action, its relatively short plasma cancer (9, 10). Hematological toxicity has also been an issue half-life (2 h), and the antitumor activity observed in Phase I testing, a with the development of combination regimens incorporating 30-min infusion schedule administered every 3 weeks was most ex- topotecan with alkylating agents or taxanes (e.g., Refs. 11 and tensively evaluated and was selected for pivotal, disease-specific stud- 12). Dose reductions in therapy or hematopoietic growth factors ies. Antitumor activity in these Phase II and III studies resulted in the have been used to circumvent these effects, the latter strategy approval of this agent for patients with relapsed ovarian cancer in 1996 adding considerably to the expense of therapy. In patients with (2). Nonetheless, 2 years later, clinical investigators are still assessing renal impairment, dose reductions are required to compensate the optimal dose and schedule for this agent. for reduced renal clearance. Anecdotal evidence suggests that Questions concerning the optimal schedule of topotecan antitumor activity is not compromised in these patients by this were raised by investigators at New York University, who strategy (13). However, it is unknown whether efficacy is com- evaluated the use of ambulatory infusion schedules of topotecan promised by dose reductions in extensively pretreated patients. administered for 21 days every 4 weeks (3, 4). Although it was Population studies using limited sampling pharmacokinetics to cumbersome due to the requirements for central venous cathe- assess the relationships between dose, drug exposure, and anti- ters, this schedule was felt to more optimally exploit the sched- tumor response (as have been performed with carboplatin; Ref. ule-dependent nature of topotecan’s effects. Correlative cellular 14) would be helpful to clarify these issues. Indeed, dose inten- pharmacodynamic studies demonstrated down-regulation of the sification using granulocyte colony-stimulating factor to double topotecan target topoisomerase I over the 3 weeks of drug the dose intensity of topotecan therapy in minimally pretreated exposure, followed by recovery to normal in the week off patients with fluorouracil-refractory colorectal cancer did not treatment. Significant antitumor activity was demonstrated in impact on antitumor response rates (15). patients with a variety of refractory solid tumor malignancies. Questions concerning the optimal dose and schedule of an Subsequent Phase II evaluations of this protracted schedule in oral formulation of topotecan are presented in the article by patients with refractory ovarian cancer have produced response Gerrits et al. (16) elsewhere in this issue of Clinical Cancer rates of 43% in one study (5) but only 10.5% in another (6). At Research. On the basis of observations that the i.v. formulation this time, the optimal i.v. schedule of topotecan therapy is of topotecan was orally bioavailable and on the basis of efforts unknown. The most commonly used daily times 5 schedule is to mimic the continuous infusion schedule of topotecan that inconvenient for patients, and a less protracted daily times 3 appeared most active, without the need for infusional pumps and central venous catheters, an oral formulation of topotecan was developed. In the article by Gerrits and colleagues (16), pharmacokinetic and pharmacodynamic relationships from Phase I Received 9/29/98; accepted 10/14/98. studies of oral topotecan are presented and discussed. Four The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked schedules were evaluated: once daily for 5 days every 21 days, advertisement in accordance with 18 U.S.C. Section 1734 solely to once daily for 10 days every 21 days, twice daily for 10 days indicate this fact. every 21 days, and twice daily for 21 days every 28 days. 1 S. O. has received speaker’s honoraria from SmithKline Beecham (the Several interesting observations were made. (a) With the more manufacturers of topotecan). 2 To whom requests for reprints should be addressed, at Waterford protracted schedules of oral administration, diarrhea rather than Regional Hospital, Dunmore Road, Waterford, Ireland. Phone: hematological toxicity was dose limiting. This toxicity appeared 35351873321; Fax: 35351850406; E-mail: [email protected]. more severe than has been observed with the other camptothecin Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 1999 American Association for Cancer Research. 4 Editorial

analogue CPT-11, in that loperamide therapy was ineffective. REFERENCES The pathophysiology of these effects is unknown. These effects 1. Takimoto, C. H., and Arbuck, S. Camptothecins. In: B. A. Chabner may relate to intestinal damage due to unabsorbed drug. (b) and D. L. Longo (eds.), Cancer Chemotherapy and Biotherapy: Princi- Hematological toxicity was the predominant toxicity associated ples and Practice, Ed. 2, pp. 463–484. Philadelphia: Lippincott-Raven Publishers, 1996. with shorter administration schedules. However, with all sched- 2. ten Bokkel Huninink, W., Gore, M., Carmichael, J., Gordon, A., ules, this toxicity was less severe than that observed with the Malfetano, J., Hudson, I., Broom, C., Scarabelli, C., and Davidson, N. intravenous formulation. (c) Substantial intra- and interpatient Topotecan versus paclitaxel for the treatment of recurrent epithelial variability in the pharmacokinetics of topotecan was observed. ovarian cancer. J. Clin. Oncol., 15: 2183–2193, 1997. 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Hochster, H., Liebes, L., Speyer, J., Sorich, J., Taubes, B., Oratz, gest that protocols for dose escalation should be incorporated R., Wernz, J., Chachoua, A., Blum, R. H., and Zelenuich-Jacquotte, A. into clinical trials of this formulation. On the basis of observa- Effect of prolonged topotecan infusion on topoisomerase I levels: a tions from this study, a daily times 5 schedule has been selected Phase I and pharmacodynamic study. Clin. Cancer Res., 3: 1245–1252, 1997. for further clinical development of oral topotecan. 6. Johnson, S., Pyle, L., King, K., et al. A Phase II study of topotecan Answers as to whether this 5-day oral schedule will replace given as a continuous 21 day infusion every 28 days in platinum the 5-day i.v. schedule will come from recently completed Phase pre-treated ovarian carcinoma. Eur. J. Cancer, 33 (Suppl. 8): S120, II and III studies in women with relapsed ovarian cancer (18). In 1997. addition, these studies will address whether the favorable im- 7. 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16. Gerrits, C. J. H., Schellens, J. H. M., Burris, H., Eckardt, J. R., Clarke Pearson, D., Ross, G. A., Dane, G. C., and Fields, S. Z. A Planting, A. S. T., van der Burg, M. E. L., Rodriguez, G. I., Loos, multicenter randomized Phase III study of topotecan administered in- W. J., van Beurden, V., Hudson, I., von Hoff, D. D., and Verweij, J. travenously or orally for advanced epithelial ovarian carcinoma. Proc. A comparison of clinical pharmacodynamics of different administra- Am. Soc. Clin. Oncol., 17: 349a, 1998. tion schedules of topotecan (Hycamtin). Clin. Cancer Res., 5: 69–75, 19. Arbuck, S. G., Canetta, R., and Onetto, N. Current dosage and 1999. schedule issues in the development of paclitaxel (Taxol). Semin. Oncol., 17. Schellens, J. H. M., Creemers, G. J., Beijnen, J. H., Rosing, H., de 20 (Suppl. 3): 31–39, 1993. Boer-Dennert, M., McDonald, M., Davies, B., and Verweij, J. Bioavail- 20. O’Reilly, S., and Rowinsky, E. K. The clinical status of irinotecan ability and pharmacokinetics of oral topotecan: a new topoisomerase I (CPT-11), a novel water soluble camptothecin analogue: 1996. Crit. inhibitor. Br. J. Cancer, 73: 1268–1271, 1996. Rev. Oncol. Hematol., 24: 47–70, 1996. 18. Gore, M., Rustin, G., Calvert, H., Bezwoda, W., Carmichael, J., 21. DeMario, M. D., and Ratain, M. J. Oral chemotherapy: rationale Oza, A., Kaye, S., ten Bokkel Huinink, W., Malfetano, J., Falkson, G., and future directions. J. Clin. Oncol., 16: 2557–2567, 1998.

Seamus O'Reilly

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