A phase I dose escalation study of multicyclic, dose-intensive chemotherapy with peripheral blood stem cell support for small cell lung cancer.
A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs) was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000-9000 mg/m2, 24-h infusion), carboplatin (300-400 mg/m2), and etoposide (300 mg/m2) followed by subcutaneous filgrastim (75 microg/day) from day 4 to the day of PBSC collection. PBSC were harvested when the WBC count reached >/=5 x 109/l. The leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle, which was started 48 h after the last PBSC collection. The ifosfamide dose was escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2 (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45 Gy and MTD, defined separately. Patients were evaluated for hematologic and non-hematologic toxicity, actual dose intensities, as well as response to therapy. The maximum-tolerated dose (MTD) was defined as the dose level at which more than 5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4 and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as ataxia. Tumor responses were seen in all patients, with 14 patients showing a complete response. The actual total dose-intensity at the recommended dose level was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose escalation of ifosfamide with a mean interval of 16-17 days. We conclude that this regimen is well tolerated, with acceptable hematological and non-hematological toxicity. Bone Marrow Transplantation (2000) 25, 5-11.
Takahashi
M
M
Department of Medicine (II), Niigata University Medical School, Niigata, Japan.
Yoshizawa
H
H
Tanaka
H
H
Tanaka
J
J
Kagamu
H
H
Ito
K
K
Shimbo
T
T
Chou
D
D
Wakabayashi
M
M
Suzuki
E
E
Sakai
K
K
Arakawa
M
M
Gejyo
F
F
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007937:Leukapheresis; D008175:Lung Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011878:Radiotherapy; D011994:Recombinant Proteins; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D016190:Carboplatin; D000069585:Filgrastim; D007069:Ifosfamide