A phase I study of topotecan/paclitaxel alternating with etoposide/cisplatin and thoracic irradiation in patients with limited small cell lung cancer.
OBJECTIVE
Topotecan and paclitaxel are promising cytotoxic drugs with novel mechanisms of action relative to other chemotherapies used in the treatment of small cell lung cancer (SCLC). In an effort to integrate paclitaxel and topotecan into the treatment of limited disease (LD) SCLC, we conducted a Phase I study of these agents administered as initial induction therapy.


METHODS
Escalating doses of topotecan (0.8-1.4 mg/m(2) d1-5) and paclitaxel (110-175 mg/m(2) d1) were administered i.v. every 21 days for two cycles to determine the maximum tolerated dose (MTD) in patients with LD SCLC. This was followed by two cycles of etoposide (120 mg/m(2) d1-3) and cisplatin (60 mg/m(2) d1) with thoracic radiotherapy. The first 5 subjects received 1.8 Gy once daily x 25 fractions, while subsequent subjects received 1.5 Gy twice daily x 30 fractions. Two additional cycles of chemotherapy (topotecan and paclitaxel, followed by etoposide and cisplatin) were given.


RESULTS
Common toxicities included grade >/=3 neutropenia in 67% of courses of topotecan and paclitaxel and grade >/=2 esophagitis in 71% of patients. The MTD was based on toxicity during the first two cycles of chemotherapy and defined after accrual of 18 patients to four dose levels. Two of three patients developed grade 3 nonhematological toxicity (pneumonia) at the fourth dose level. Thus, the third dose level (topotecan 1.2 mg/m(2), paclitaxel 160 mg/m(2)) was defined as the MTD recommended for Phase II studies. One subject died suddenly on day 2 of cycle 1 without autopsy confirmation of the etiology. A second subject died during cycle 3 due to thrombocytopenia, gastrointestinal bleeding, and respiratory failure. Response rates after induction of topotecan and paclitaxel: 16 of 18 (88.8%) partial response, 1 of 18 (5.5%) complete response. Response rates after completion of therapy: 10 of 18 (55.5%) partial response, 7 of 18 (38.8%) complete response.


CONCLUSIONS
Induction topotecan and paclitaxel before chemoradiotherapy in patients with LD SCLC is feasible and results in expected toxicities. The outcome of a recently closed Cancer and Leukemia Group B Phase II study of similar design (CLB-39808) should help determine whether or not this approach warrants testing in a randomized setting.
Lu
Charles
C
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Komaki
Ritsuko
R
Lee
Jin Soo
JS
Shin
Dong M
DM
Palmer
J Lynn
JL
Coldman
Brenda J
BJ
Pisters
Katherine M
KM
Kurie
Jonathan M
JM
Fossella
Frank V
FV
Glisson
Bonnie S
BS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage
D005047:Etoposide; D019772:Topotecan; D017239:Paclitaxel; D002945:Cisplatin