吉西他滨和顺铂用于晚期非小细胞肺癌的I期剂量递增试验：数学建模在确定最大耐受剂量中的应用

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.

作者信息

Shepherd F A, Burkes R, Cormier Y, Crump M, Feld R, Strack T, Schulz M

机构信息

Department of Medicine, Toronto Hospital, Ontario, Canada.

出版信息

J Clin Oncol. 1996 May;14(5):1656-62. doi: 10.1200/JCO.1996.14.5.1656.

DOI:10.1200/JCO.1996.14.5.1656

PMID:8622085

Abstract

PURPOSE

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 AND METHODS

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.

RESULTS

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+).

CONCLUSION

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.

摘要

目的

本研究旨在确定吉西他滨和顺铂的最大耐受剂量，两种药物均每周给药1次，共3周，随后休息1周。

患者与方法

年龄小于75岁、患有Ⅲ/Ⅳ期非小细胞肺癌（NSCLC）、预期生存期≥12周、血红蛋白水平≥10g/dL、粒细胞计数≥2×10⁹/L、血小板计数≥100×10⁹/L、肝酶≤正常上限3倍且肌酐浓度≤130μmol/L的患者符合入组条件。吉西他滨和顺铂的起始剂量分别为每周1000mg/m²和25mg/m²，共3周。在剂量水平2时，顺铂增加至30mg/m²/周，共3周，此后仅吉西他滨在每个剂量水平上每周增加250mg/m²，最高至2250mg/m²/周。

结果

共有33例男性和17例女性，中位年龄为62岁。病理类型包括腺癌35例、鳞癌8例、大细胞癌6例、混合组织学类型1例。16例患者为Ⅲ期，34例为Ⅳ期肿瘤。随着剂量水平的增加，中位最低点粒细胞和血小板计数下降，但即使在最高剂量水平，第1周期也未在≥2例患者中出现剂量限制性毒性（DLT）。所有剂量水平均出现累积骨髓毒性，导致频繁减量或漏用。随时间推移的所有毒性数学模型表明，剂量水平4（顺铂30mg/m²/周和吉西他滨1500mg/m²/周）将是在4个周期内≤33%的患者中预期出现4级毒性的最大剂量。在47例可评估患者中，14例获得部分缓解（30%；置信区间，17%至43%）。中位缓解持续时间为16周，中位生存时间为24周（范围，3.5 - 64 +）。