Abstract
Objective: To determine the feasibility and maximum tolerated dose of dose-dense topotecan as induction chemotherapy before standard therapy (carboplatin plus etoposide alone or in combination with radiotherapy) in patients with small cell lung cancer (SCLC).
Patients and methods: Chemotherapy-naive patients with SCLC and good performance status were eligible. Three 2-week cycles of dose-dense topotecan administered on days 1–3 with granulocyte colony-stimulating factor support were followed by four cycles of standard carboplatin plus etoposide therapy alone (extensive-stage SCLC) or with radiotherapy (limited-stage SCLC). The dose of topotecan was escalated from 1.5 mg/m2/day to 2.5 mg/m2/day in increments of 0.25 mg/m2/day within cohorts of 3–5 patients each. Dose-limiting toxicity was defined as any grade 3 or 4 toxicity resulting in a treatment reduction or a delay of >3 days.
Results: Twenty-two patients with SCLC (5 limited-stage, 17 extensive-stage) were enrolled. Treatment was well tolerated. The dose-limiting toxicities were thrombocytopenia and neutropenia, and the maximum tolerated dose of dose-dense topotecan induction therapy was 2.25 mg/m2/day. Overall, topotecan-related grade 3/4 haematological toxicities included neutropenia (n = 4), thrombocytopenia (n = 3) and febrile neutropenia (n = 1). No grade 4 non-haematological toxicities occurred. Grade 3 adverse events included nausea (n = 2), renal toxicity (n = 1) and anorexia (n = 1). Toxicity during the carboplatin plus etoposide ± radiotherapy phase of therapy was consistent with that reported in previous trials. The overall response rate was 80% for limited-stage and 76% for extensive-stage SCLC. Median survival was 8 months in patients with limited-stage SCLC and 13.5 months for patients with extensive-stage SCLC.
Conclusion: The results of this phase I study suggest that a regimen of sequential dose-dense topotecan and carboplatin plus etoposide is feasible, and the preliminary activity observed in patients with SCLC warrants further investigation at a starting dose of topotecan 2.25 mg/m2/day.
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Acknowledgements
This study was supported by a grant from Glaxo-SmithKline.
Jennifer Garst is a co-investigator on a Federal R21 grant and a Federal R02×2 grant. Diana M. Maravich-May is an employee of GlaxoSmithKline and holds stock in the company.
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Garst, J., Herndon, J.E., Shafman, T. et al. A Phase I Study of Dose-Dense Topotecan Given Upfront to Standard Therapy in Patients with Small Cell Lung Cancer. Clin. Drug Investig. 26, 257–266 (2006). https://doi.org/10.2165/00044011-200626050-00003
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DOI: https://doi.org/10.2165/00044011-200626050-00003