Abstract
BackgroundA platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule.MethodsFrom February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days.ResultsThe MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively.ConclusionVinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively.Trial Registration NumberNCT00287963.
Highlights
A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status
Patients were recruited based upon the following eligibility criteria: pathologically proven lung cancer, all histologic types of lung cancer were eligible; recurrent or progressive disease after at least one prior chemotherapy +/- radiotherapy regimen; at least 2 weeks after completion of prior radiotherapy; no prior therapy with topotecan or vinorelbine; age ≥ 18 years; ECOG performance status ≤ 2; adequate organ and
Eighteen patients with recurrent NSCLC or SCLC were included in this phase I study between February 2004 and March 2007
Summary
A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. Platinum-based treatment may be associated with significant toxicities, alternative platinum-free combinations should be investigated. In patients with advanced nonsmall cell lung cancer (NSCLC) single agent therapy with cisplatin results in a modest clinical benefit and its use is an independent prognostic variable predicting superior survival[1,3]. In the ECOG 1594 trial, where patients with stage IV NSCLC were treated with four different platinum containing doublets, no significant differences in overall response rates or overall survival between them was observed [4]. In small cell lung cancer (SCLC) combination platinum chemotherapy regimens are commonly utilized in part due to their high response rates as first line therapy, in patients with limited stage disease [5]. Platinum-based treatment is associated with significant toxicities, development of alternative platinum free chemotherapy combinations are warranted
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