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Editorial |
Waterford Regional Hospital, Waterford, Ireland
Topotecan is a semisynthetic water soluble analogue of camptothecin, which exerts its cytotoxic effects through inhibition of the enzyme topoisomerase I. This enzyme relaxes supercoiled DNA by covalently binding to it, leading to transient single-strand breaks that are resealed by topoisomerase I after strand passage. These breaks allow topological shifts in DNA strands and are essential steps in permitting DNA replication, repair, and transcription. Topotecan binds to the topoisomerase I-DNA complex and prevents the religation step. Consequently permanent strand breaks are created, and cell death ensues. Given such S-phase specificity, it is likely that topotecan’s activity should be schedule dependent.
In Phase I trials of the i.v. formulation of topotecan, a variety of schedules were evaluated (1) . On the basis of the schedule-dependent nature of topotecan’s mechanism of action, its relatively short plasma half-life (2 h), and the antitumor activity observed in Phase I testing, a 30-min infusion schedule administered every 3 weeks was most extensively evaluated and was selected for pivotal, disease-specific studies. Antitumor activity in these Phase II and III studies resulted in the approval of this agent for patients with relapsed ovarian cancer in 1996 (2) . Nonetheless, 2 years later, clinical investigators are still assessing the optimal dose and schedule for this agent.
Questions concerning the optimal schedule of topotecan were raised by investigators at New York University, who evaluated the use of ambulatory infusion schedules of topotecan administered for 21 days every 4 weeks (3 , 4) . Although it was cumbersome due to the requirements for central venous catheters, this schedule was felt to more optimally exploit the schedule-dependent nature of topotecan’s effects. Correlative cellular pharmacodynamic studies demonstrated down-regulation of the topotecan target topoisomerase I over the 3 weeks of drug exposure, followed by recovery to normal in the week off treatment. Significant antitumor activity was demonstrated in patients with a variety of refractory solid tumor malignancies. Subsequent Phase II evaluations of this protracted schedule in patients with refractory ovarian cancer have produced response rates of 43% in one study (5) but only 10.5% in another (6) . At this time, the optimal i.v. schedule of topotecan therapy is unknown. The most commonly used daily times 5 schedule is inconvenient for patients, and a less protracted daily times 3 schedule is being evaluated by some investigators. A recently 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 women with relapsed ovarian cancer, the response rate in the approved schedule arm was 22.6%, compared to 3.1% in the investigational arm. A similarly conducted trial comparing a 21-day infusion schedule of topotecan with the approved schedule would also be worthwhile, particularly because recently conducted xenograft studies have demonstrated that intermittent exposure schedules maybe the most efficacious (8) .
Questions concerning the optimal dose of topotecan were raised following its approval for clinical use. In clinical practice, the hematological toxicity associated with the recommended Phase II dose of topotecan has been an area of concern, particularly in patients with renal impairment or those who have received extensive prior alkylating agent therapy, both of which are common clinical scenarios in patients with relapsed ovarian cancer (9 , 10) . Hematological toxicity has also been an issue with the development of combination regimens incorporating topotecan with alkylating agents or taxanes (e.g., Refs. 11 and 12 ). Dose reductions in therapy or hematopoietic growth factors have been used to circumvent these effects, the latter strategy adding considerably to the expense of therapy. In patients with renal impairment, dose reductions are required to compensate for reduced renal clearance. Anecdotal evidence suggests that antitumor activity is not compromised in these patients by this strategy (13) . However, it is unknown whether efficacy is compromised by dose reductions in extensively pretreated patients. Population studies using limited sampling pharmacokinetics to assess the relationships between dose, drug exposure, and antitumor response (as have been performed with carboplatin; Ref. 14 ) would be helpful to clarify these issues. Indeed, dose intensification using granulocyte colony-stimulating factor to double the dose intensity of topotecan therapy in minimally pretreated patients with fluorouracil-refractory colorectal cancer did not impact on antitumor response rates (15) .
Questions concerning the optimal dose and schedule of an oral formulation of topotecan are presented in the article by Gerrits et al. (16) elsewhere in this issue of Clinical Cancer Research. On the basis of observations that the i.v. formulation of topotecan was orally bioavailable and on the basis of efforts to mimic the continuous infusion schedule of topotecan that 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 studies of oral topotecan are presented and discussed. Four schedules were evaluated: once daily for 5 days every 21 days, once daily for 10 days every 21 days, twice daily for 10 days every 21 days, and twice daily for 21 days every 28 days. Several interesting observations were made. (a) With the more protracted schedules of oral administration, diarrhea rather than hematological toxicity was dose limiting. This toxicity appeared more severe than has been observed with the other camptothecin analogue CPT-11, in that loperamide therapy was ineffective. The pathophysiology of these effects is unknown. These effects may relate to intestinal damage due to unabsorbed drug. (b) Hematological toxicity was the predominant toxicity associated with shorter administration schedules. However, with all schedules, this toxicity was less severe than that observed with the intravenous formulation. (c) Substantial intra- and interpatient variability in the pharmacokinetics of topotecan was observed. Mean intrapatient variations in the area under the plasma concentration versus time curve, ranging from 25.4 to 96.5% with the lowest intrapatient variability, was observed with the daily times 5 schedule. Interpatient variability in area under the concentration versus time curve varied from 40.1 to 73.4%. These results most likely reflect the relatively wide range in topotecan bioavailability reported previously by this group (17) and suggest that protocols for dose escalation should be incorporated into clinical trials of this formulation. On the basis of observations from this study, a daily times 5 schedule has been selected for further clinical development of oral topotecan.
Answers as to whether this 5-day oral schedule will replace the 5-day i.v. schedule will come from recently completed Phase II and III studies in women with relapsed ovarian cancer (18) . In addition, these studies will address whether the favorable improvement in hematological toxicity profile of the oral formulation is at the expense of reduced antitumor activity. Results from such studies will also generate interest in developing combination regimens with oral topotecan, which may circumvent the hematological toxicities observed in combination regimens of the i.v. formulation.
These questions and answers pertaining to the optimal dose, schedule, and route of administration are not unique to topotecan. Similar issues of dose and schedule apply to other approved agents, such as paclitaxel (19) and CPT-11 (20) , whereas issues of interpatient variability also pertain to all orally administered anticancer agents (21) . Indeed, of the available anticancer agents, only carboplatin has been rigorously evaluated in clinical pharmacodynamic models relating drug exposure and antitumor activity. The story of the clinical development of topotecan is important because it emphasises the role of pharmacokinetic and pharmacodynamic studies in guiding drug development. A chapter of this story is elegantly demonstrated in the work of Gerrit et al. (16) , in which pharmacokinetic and pharmacodynamic endpoints were used to determine the optimal schedule. This story emphasises the importance of Phase IV (postapproval) drug studies in which the majority of clinical drug development occurs and the need for both pharmacological evaluations and randomized comparisons as part of this process.
ACKNOWLEDGMENTS
The excellent secretarial assistance of Heretta Stanfield is gratefully acknowledged. I also acknowledge helpful discussions related to topotecan over the past several years with Drs. Eric Rowinsky, Ross Donehower, Louise Grochow, Sharyn Baker, and Deborah Armstrong.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 S. O. has received speaker’s honoraria from SmithKline Beecham (the manufacturers of topotecan). 
2 To whom requests for reprints should be addressed, at Waterford Regional Hospital, Dunmore Road, Waterford, Ireland. Phone: 35351873321; Fax: 35351850406; E-mail: oreillys{at}sehb.ie
Received 9/29/98; accepted 10/14/98.
REFERENCES
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  W. L. Furman, C. F. Stewart, M. Kirstein, J. L. Kepner, M. L. Bernstein, F. Kung, T. J. Vietti, C. P. Steuber, D. L. Becton, S. Baruchel, et al. Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study J. Clin. Oncol., March 15, 2002; 20(6): 1617 - 1624. [Abstract] [Full Text] [PDF]
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