Radiation concurrent with gemcitabine for locally advanced head and neck cancer: A phase I trial and intracellular drug incorporation study
Radiation concurrent with gemcitabine for locally advanced head and neck cancer: A phase I trial and intracellular drug incorporation study
复制标题
DOI：
10.1200/jco.2001.19.3.792
复制
发表时间：
2001-02-01
影响因子：
45.3
通讯作者：
Lawrence, TS
中科院分区：
文献类型：
--
作者：
Eisbruch, A;Shewach, DS;Lawrence, TS
目的：研究每周一次吉西他滨在临床前研究中预测的剂量下产生放射增敏的可行性和剂量限制性毒性（DLT），同时进行局部晚期头颈癌的标准放射治疗。测量三磷酸吉西他滨（dFdCTP）的肿瘤掺入情况，以评估在每个剂量水平下是否达到足够的浓度。患者和方法：29例不可切除的头颈癌患者接受一个疗程的放疗（70 Gy / 7周，每周5天），同时每周输注低剂量吉西他滨。第一次吉西他滨输注后（放疗开始前）进行肿瘤活检，并测量细胞内dFdCTP浓度。结果：在连续的患者队列中，严重急性和晚期粘膜和咽部相关性DLT需要降低吉西他滨剂量，剂量水平分别为300 mg/m(2)/周、150 mg/m(2)/周和50 mg/m(2)/周。10 mg/m(2)/周未见DLT。在不同的队列中，内镜检查和活检评估完全肿瘤反应的比率为66%至87%。在接受50至300 mg/m(2)的患者中，肿瘤dFdCTP水平相似（平均1.55 pmol/mg, SD 1.15），但在10 mg/m(2)时几乎检测不到或无法检测到。结论：在50 ~ 300 mg/m的剂量水平下，该方案观察到高的急性和晚期粘膜相关性DLT发生率和高的肿瘤完全缓解率(2)，这也导致了相似的亚细胞毒性细胞内dFdCTP浓度。这些结果表明低剂量吉西他滨对肿瘤和正常组织有显著的放射增敏作用。根据有望提高治疗率的最新临床前数据，应该评估不同的放射和吉西他滨联合方案。(C) 2001年美国临床肿瘤学会。
Purpose: To examine the feasibility and dose-limiting toxicity (DLT) of once-weekly gemcitabine at doses predicted in preclinical studies to produce radiosensitization, concurrent with a standard course of radiation for locally advanced head and neck cancer. Tumor incorporation of gemcitabine triphosphate (dFdCTP) was measured to assess whether adequate concentrations were achieved at each dose level.Patients and Methods: twenty-nine patients with unresectable head and neck cancer received a course of radiation (70 Gy over 7 weeks, 5 days weekly) concurrent with weekly infusions of low-dose gemcitabine. tumor biopsies were performed after the first gemcitabine infusion (before radiation started), and the intracellular concentrations of dFdCTP were measured.Results: Severe acute and late mucosal and pharyngeal-related DLT required de-escalation of gemcitabine dose in successive patient cohorts receiving dose levels of 300 mg/m(2)/wk, 150 mg/m(2)/wk, and 50 mg/m(2)/wk. No DLT was observed at 10 mg/m(2)/wk. The rate of endoscopy- and biopsy assessed complete tumor response was 66% to 87% in the various cohorts. Tumor dFdCTP levels were similar in patients receiving 50 to 300 mg/m(2) (on average, 1.55 pmol/mg, SD 1.15) but were barely or not detectable at 10 mg/m(2).Conclusion: A high rate of acute and late mucosa-related DLT and a high rate of complete tumor response were observed in this regimen at the dose levels of 50 to 300 mg/m(2), which also resulted in similar, subcytotoxic intracellular dFdCTP concentrations. These results demonstrate significant tumor and normal tissue radiosensitization by low-dose gemcitabine. Different regimens of combined radiation and gemcitabine should be evaluated, based on newer preclinical data promising an improved therapeutic ratio. (C) 2001 by American Society of Clinical Oncology.