Purpose. Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. Methods. Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/ mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. Results. The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. Conclusion. It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.
Bibliographical noteFunding Information:
Both H. H. G. and J. S. M. contributed equally to this work. Supported in part by NIH GCRC RR00046 and a grant from Glaxo Smith Kline. Address correspondence to Heidi H. Gillenwater, M.D., University of Virginia, 6th Floor Multistory Building, Room 6007, Charlottesville, VA 22908-0716, USA; Fax: (434) 243-6086; E-mail: email@example.com
- Extensive stage
- Small cell lung cancer