The article by Drs. Takimoto and Arbuck reviews the chemistry, mechanism of action, pharmacology and clinical trials of topotecan (Hycamtin), one of two topoisomerase I inhibitors approved recently by the FDA. Topotecan was approved for refractory ovarian cancer and irinotecan (Camptosar) for advanced colorectal cancer. These drugs represent a new drug class designed to inhibit topoisomerase I, an enzyme involved in relaxation of torsional strain in supercoiled DNA allowing replication and translation. The authors overview is informative and unbiased.
They point out that topoisomerase I is ubiquitous in mammalian eukaryotic cells. In contradistinction to other enzyme inhibitors, for which upregulation of the enzyme may confer drug resistance, the presence of topoisomerase is critical for the cytotoxic activity of the inhibitors and increasing levels of the enzyme conferenhanced sensitivity in vitro. There is no proof, however, of this correlation in vivo. This point is important, because use of topoisomerase I inhibitors as either single agents or in combination may depend on this association.
The very short section on the mechanism of drug resistance in the review by Takimoto and Arbuck is testimony to how much remains to be learned about these drugs and the factors governing resistance or sensitivity to them. Since topotecan is the active drug and its pharmacology is simpler than, for example, that of irinotecan (no prodrug assay is necessary), future clinical investigators should explore in greater detail such issues as whether intrinsic levels of topoisomerase I are directly correlated with response, the impact of peak plasma or area-under-the-curve (AUC) values as a function of outcome, and the role, if any, of p-glycoprotein in the mediation of resistance. This would be easiest in leukemia (early data suggest activity), in which sequential sampling is feasible.
Topotecan Toxicity Profile
Phase I studies have characterized the major toxicity of topotecan as hematologic. The authors point out, however, that the toxicity profile may chang-in patients with moderate renal impairment (creatinine clearance,
³ 40 mL/min) and also probably for those with mild hepatic dysfuction (serum bilirubin,
£ 3 mg/dL). This information is helpful for guiding therapy in these patients, but caution is still advised because of the small patient numbers. Furthermore, the authors point out the important lack of protein binding by topotecan and the significant penetration of cerebrospinal fluid. These facts make topotecan a potentially excellent compound for treating primary central nervous system (CNS) disease or tumor metastatic to the CNS.
Clinical issues related to topotecan that were not discussed or were covered only briefly in the review or briefand require that further emphasis include the following:
- Topotecan has an apparent lack of cumulative toxicity to granulocytic precursors, making repeated dosing possible in the responding patient.
- Thrombocytopenia becomes dose-limiting in some 5% of patients even with daily × 5 schedules and is not an infrequent cause of discontinuing the drug even in the responding patient, due to the development of platelet transfusion dependency.
Patients developing anemia with topotecan usually do so early in the course of treatment; decrements of hemoglobin
³ 2 g in the first cycle are frequently seen in such patients without laboratory evidence of hemolysis.
- Gastrointestinal toxicity is so uncommon and of such low grade when it occurs, that prophylactic antiemetics are not needed and may actually lead to significant complaints of constipation if serotonin antagonists are used daily for 5 days.
Topotecan as Salvage Therapy
The authors' discussion of ovarian cancer, the only tumor for which topotecan is currently approved as salvage therapy, is fairly complete. The major trials demonstrate that the drug is active, more so in platinum-sensitive than platinum-resistant patients, as has been the case with all drugs entered into clinical trial over the past decade, including paclitaxel (Taxol). This places topotecan into the realm of one of many salvage therapies available to patients who do not respond to primary therapy with a taxane/platinum combination.
The two major positive features of topotecan as salvage therapy are the rather long duration of response seen in sensitive patients and the relative paucity of serious adverse effects. The major drawback is the administration schedule (daily × 5), which is difficult for those who live any distance from a health-care provider. This problem may be solved when an oral form of the drug, which is currently being evaluated in a clinical trial, becomes available.
The data in small-cell lung cancer are also compelling. In this tumor type, topotecan is especially active, and more so in patients who, like those with ovarian cancer, did not progress on first- line therapy. The only concerns are the relatively small number of patients treated, which causes wide confidence intervals around the response rate, and the paucity of complete radiographic responses (~ 7%). Activity in non-small-cell lung cancer is less compelling.
Although few cases are reported, there should also be significant interest in the use of topotecan in pediatric neuroblastoma and rhabdomyosarcoma. in which response rates exceed 35%. Furthermore, very early data on the activity of topotecan in myelodysplasia are interesting, but further work is needed to determine whether reduced doses can preserve efficacy without the excessive toxicity seen in other studies.
Topotecan in Combination Regimens
The article could be more explicit in describing how one might combine topotecan with other agents so as to involve topotecan in primary therapy. After reading this article, one is left with a sense that even doublets containing topotecan and paclitaxel, cisplatin (Platinol), or etoposide (VePesid) are too toxic. Each of these drugs is potentially important for use in combination with topotecan, based on observations of their single-agent activity in ovarian and/or small-cell lung cancer. Further work is needed in this area to determine whether scheduling has any adverse effects or any effect on efficacy. In terms of combining topotecan with drugs such as etoposide or doxorubicin, the preclinical data would strongly suggest that the topoisomerase I inhibitor be adminstered prior to the topoisomerase II inhibitor, since the former drug, by upregulating topoisomerase II levels, makes the subsequent therapy more effective. The combination of paclitaxel and topotecan (topotecan at a dose of 0.75 mg/m2 and paclitaxel at 135 mg/m2 dispensed over 24 hours) was administered in a safe manner with granulocyte colony-stimulating factor (G-CSF [Neupogen] support, and demonstrated significant activity in recurrent ovarian cancer. Consideration should be given to using this combination as front-line therapy, perhaps alternating it with the standard paclitaxel/cisplatin doublet. Furthermore, the combination of topotecan and cisplatin was found to be safe when given with G-CSF in a phase I study, as noted in the article.
In summary, topotecan is an interesting new antineoplastic compound. Topotecan and irinotecan are the first two inhibitors of topoisomerase I to enter clinical practice, with many others to follow. Topotecan appears to have a broad spectrum of antitumor activity and an acceptable toxicity profile in early phase II trials. Further work in the phase II area is needed so as to expand the drug's therapeutic indications. More importantly, combinations with existing agents need to be tested to try to move this drug into primary therapy for tumors in which it already has known efficacysmall-cell lung cancer and ovarian cancer.
1. Whitacre CM, Zobrowska E, Gordon NH, et al: Topotecan increases topoisomerase II alpha levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res 57:1425-1428, 1997.
2. OReilly S, Fleming GF, Barker SD, et al: Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: A Gynecologic Oncology Group study. J Clin Oncol 15:177-186, 1997.