A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients

Purpose:The topoisomerase I inhibitor topotecan (T) and thetopoisomerase II inhibitor etoposide (E) are active drugs in lungcancer. The complementary functions of their targets may suggest benefitfrom the combined use of these agents but drug scheduling has been shownto play a critical role in preclinical models. To establish the optimalschedule and assess the impact of sequential administration of thecombination of T and E, we conducted a dose finding study of sequentialintravenous T and E in a four-weekly-schedule in relapsed lung cancerpatients.Patients and methods:The importance of drugsequence was assessed in consecutive patients throughout all doselevels; patients received in the first course either T followed by E(the TE group: T on days 1–3 and E on days 4–6) or E beforeT (the ET group: E on days 1–3 and T on days 4–6). Thesequence of T and E was alternated in the successive courses. In thiscross-over design, each patient served as his own control for analysisof hematological toxicity in which TE sequence was compared to that ofthe ET sequence. Moreover, hematological toxicity after the first coursewas compared between the TE and the ET groups. The starting dose was T/E0.75/75 mg/m² at dose level 1 and dose escalation was plannedto T/E 1.00/75 mg/m² at dose level 2, T/E 1.00/100mg/m² at dose level 3, T/E 1.25/100 mg/m² at doselevel 4 and T/E 1.50/100 mg/m² at dose level 5. Nineteenpatients (small-cell lung cancer 7, non-small-cell lung cancer 11,mesothelioma 1 patient) were included.Results:Theprincipal toxicity was myelosuppression, primarily neutropenia andthrombocytopenia. At dose level 3 several grade 4 toxicities wereobserved. DLT (febrile neutropenia) occurred in two patients, one in theTE and one in the ET group and precluded further dose escalation. Therewas no significant difference in WBC and platelet nadirs during thefirst course between the TE and the ET group. The influence of thesequence of administration of topotecan and etoposide was calculated bycomparing the nadir values of cycles I and II for each patient. For noneof the dose levels, a significant sequence-dependent effect could bedetected. The MTD was reached at the doses of 100 mg/m²topotecan and 75 mg/m² etoposide. No objective responses wereseen.Conclusion:Although the combined use oftopoisomerase I and II inhibitors is attractive on theoretical grounds,excessive myelosuppression prevents substantial dose escalation.