title: A phase II study of ifosfamide in combination with etoposide and cisplatin in the treatment of extensive small cell lung cancer.
abstract: The combination of etoposide and cisplatin has become one of the standard treatments for small cell lung cancer. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent antitumor activity comparable with that of the most active agents used to treat small cell lung cancer. Because ifosfamide is relatively nonmyelosuppressive and its principal dose-limiting toxicity, urotoxicity, has largely been eliminated with the introduction of the uroprotective agent mesna, we undertook a phase II study of the combination of all three agents (etoposide/ifosfamide/cisplatin) in good-performance-status, extensive-disease patients 70 years of age or younger. Twenty-five patients (17 men and eight women; median age, 58 years) were treated with 75 mg/m2 etoposide, 20 mg/m2 cisplatin, and 1.0 g/m2/d ifosfamide administered intravenously for 5 days. Mesna (200 mg/m2) was given as a bolus prior to the first day of chemotherapy and then daily by continuous infusion (900 mg/m2 over 24 hours) between administrations of chemotherapy. Mesna was continued for 12 hours after the last dose of ifosfamide. Treatment cycles were planned every 4 weeks for four cycles. Due to severe toxicities in the first eight patients, subsequent patients received only 4 days of treatment (20% dose reduction). Of the 25 extensive-disease patients studied, 23 are evaluable for response. Seven (30%) achieved a complete response and 10 (43%) had a partial response (overall response rate, 73%). Five patients (22%) had stable disease (< 50% decrease and no evidence of disease progression for at least 4 weeks), and disease progressed in 1 patient (4%). The median survival time was 42 weeks (range, 2 to 160+ weeks). Granulocytopenia was dose-limiting: median granulocyte count was 0.486 x 10(9)/L, 21% of cycles had a granulocyte nadir below 0.2 x 10(9)/L, and four patients died of sepsis. Three patients required platelet transfusion and nine needed blood transfusion. Microscopic hematuria occurred in eight patients (11% of treatment cycles) but was reversible in all cases. A number of central nervous system symptoms were reported but could not be definitely attributed to ifosfamide/mesna. Gastrointestinal toxicity was generally mild, which is attributed to the use of an aggressive antiemetic program. The etoposide/ifosfamide/cisplatin regimen is active and produced a complete response rate of 30% in extensive small cell lung cancer; the duration of response and survival appears similar to that of other standard regimens. The 5-day schedule produced excessive toxicity in this patient population, necessitating a 20% dose reduction (by using a 4-day schedule). The method of administration required a minimum of 5 hospital days per cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Medicine, University of Ottawa, Ontario, Canada.
authors.forename: W K
authors.initials: WK
authors.lastname: Evans
authors.forename: D
authors.initials: D
authors.lastname: Stewart
authors.forename: D
authors.initials: D
authors.lastname: Logan
authors.forename: J
authors.initials: J
authors.lastname: Maroun
authors.forename: G
authors.initials: G
authors.lastname: Goss
authors.forename: F A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: J
authors.initials: J
authors.lastname: Latreille
authors.forename: E
authors.initials: E
authors.lastname: Warner
authors.forename: S
authors.initials: S
authors.lastname: Dahrouge
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
chemical_list: D005047:Etoposide; D002945:Cisplatin; D007069:Ifosfamide