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Sequencing Topotecan and Etoposide Plus Cisplatin to Overcome Topoisomerase I and II Resistance

A Pharmacodynamically Based Phase I Trial

Section of Developmental Therapeutics, Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and Cancer Institute of New Jersey, New Brunswick, New Jersey 08903

Purpose: Resistance to topoisomerase (TOP) 1 and 2 inhibitors is a potentially important reason for treatment failure, and may be related, in part, to a down-regulation of the specific TOP target. Investigators in our laboratories previously noted such a down-regulation of the target, along with a reciprocal up-regulation of the alternate TOP. Therefore, sequencing TOP inhibitors may provide a means for overcoming resistance to the TOP I and II inhibitors. Furthermore, point mutations in TOP I, which confer resistance to TOP I inhibitors, were associated with collateral sensitivity to cisplatin.

Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m²/day) on days 1 to 3 with etoposide (70–80 mg/m²/day) and cisplatin (20–25 mg/m²/day) on days 8 to 10. The timing of the drug sequence was based on the prior Phase I pharmacokinetic and pharmacodynamic studies of camptothecin and etoposide, and the level of the TOP targets in peripheral blood monocytes.

Results: Fifteen patients (7 males and 8 females) received 40 courses of therapy across three dose levels. The median age was 56 (range, 39–77), and the median performance status was 1 (range, 0–2). The diagnoses included: non-small cell lung cancer (7) , head and neck cancer (2) , cancer of unknown primary (2) , and 1 each of ovarian cancer, prostate cancer, gastric cancer, and renal cancer. Level 1 (topotecan 1.0 mg/m²/day; etoposide 80 mg/m²/day; and cisplatin 25 mg/m²/day) produced severe and prolonged febrile neutropenia in the first patient treated, and the subsequent patients were then entered onto a reduced dose level (cohort 2: topotecan 0.75 mg/m²/day; etoposide 70 mg/m²/day; and cisplatin 20 mg/m²/day). Three of 6 patients on cohort 2 experienced grade IV neutropenia >5 days, and a decision was then made to add filgrastim at 5 µg/kg rather than additionally reduce the dosages (cohort 3). Eight patients were then treated on cohort 3, and 1 of the 8 patients experienced a grade 4 neutropenia. Thus, cohort level three was considered the recommended dose for Phase II studies. Twelve of the 15 patients had disease assessable for response to therapy. Seven achieved stable disease for 2 months, whereas 5 showed continued progression of their disease.

Conclusions: These data show that sequencing TOP 1 and 2 inhibitors is feasible, and topotecan 0.75 mg/m²/day days 1–3; etoposide 70 mg/m²/day days 8–10; and cisplatin 20 mg/m²/day days 8–10 with filgrastim at 5 µg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

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