Phase I dose-escalation trial of gemcitabine and cisplatin for advanced non-small-cell lung cancer: usefulness of mathematic modeling to determine maximum-tolerable dose

• Published in: Journal of clinical oncology Vol. 14; no. 5; p. 1656
• Main Authors: Shepherd, F A, Burkes, R, Cormier, Y, Crump, M, Feld, R, Strack, T, Schulz, M
• Format: Journal Article
• Language: English
• Published: United States 01.05.1996
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Adult; Aged; Antimetabolites, Antineoplastic - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cisplatin - administration & dosage; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Middle Aged; Models, Theoretical
• DOI: 10.1200/JCO.1996.14.5.1656
• ISSN: 0732-183X

This study was undertaken to determine the maximum-tolerated doses of gemcitabine and cisplatin, each given weekly for 3 weeks with a 1-week rest. Patients less than 75 years of age were eligible if they had stage III/IV non-small-cell lung cancer (NSCLC), life expectancy > or = 12 weeks, hemoglobin level > or = 10 g/dL, granulocyte count > or = 2 x 10(9)/L, platelet count > or = 100 x 10(9)/L, hepatic enzymes < or = three times the upper limit of normal, and creatinine concentration < or = 130 mumoles/L. The starting doses for gemcitabine and cisplatin were 1,000 mg/m2 and 25 mg/m2 per week for 3 weeks. At dose level 2, cisplatin was increased to 30 mg/m2/wk for 3 weeks, and thereafter only gemcitabine was increased by 250 mg/m2/wk at each dose level to a maximum of 2,250 mg/m2/wk. There were 33 men and 17 women, with a median age of 62 years. Pathology included adenocarcinoma in 35 patients, squamous in eight, large cell in six, and mixed histology in one. Sixteen patients had stage III and 34 had stage IV tumors. The median nadir granulocyte and platelet counts decreased with each dose level, but cycle 1 dose-limiting toxicity (DLT) in > or = two patients was not encountered in cycle 1, even at the highest dose level. Cumulative marrow toxicity was seen at all levels, which resulted in frequent dose reductions or omissions. A mathematic model of all toxicities over time suggested that dose level 4 (cisplatin 30 mg/m2/wk and gemcitabine 1,500 mg/m2/wk) would be the maximum dose at which grade 4 toxicity would be expected in < or = 33% of patients over four cycles. Of 47 assessable patients, 14 achieved a partial response (30%; confidence interval, 17% to 43%). The median duration was 16 weeks and the median survival time was 24 weeks (range, 3.5-64+). Weekly gemcitabine and cisplatin are active against NSCLC, and the recommended phase II doses are 30 and 1,500 mg/m2/wk for 3 weeks, respectively.