TY - JOUR
T1 - A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with carboplatin and etoposide in extensive stage small cell lung cancer
AU - Gillenwater, Heidi H.
AU - McCune, Jeannine S.
AU - Lindley, Celeste
AU - Faucette, Stephanie
AU - Shord, Stacy
AU - Donahue, Angela
AU - Socinski, Mark A.
AU - Stewart, Clinton F.
AU - Zamboni, William C.
AU - Kirstein, Mark N.
AU - Moore, Dominic
N1 - Funding 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 protected]
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - Carboplatin
KW - Etoposide
KW - Extensive stage
KW - MTSE
KW - Small cell lung cancer
KW - Topotecan
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U2 - 10.1080/07357900500201400
DO - 10.1080/07357900500201400
M3 - Article
C2 - 16203659
AN - SCOPUS:26844574581
SN - 0735-7907
VL - 23
SP - 511
EP - 519
JO - Cancer Investigation
JF - Cancer Investigation
IS - 6
ER -
