Reardon David A, Quinn Jennifer A, Rich Jeremy N, Desjardins Annick, Vredenburgh James, Gururangan Sridharan, Sathornsumetee Sith, Badruddoja Michael, McLendon Roger, Provenzale James, Herndon James E, Dowell Jeannette M, Burkart Jill L, Newton Herbert B, Friedman Allan H, Friedman Henry S
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer. 2005 Oct 1;104(7):1478-86. doi: 10.1002/cncr.21316.
The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG).
Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum.
CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks.
The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.
作者确定了拓扑异构酶I抑制剂伊立替康（CPT-11）与替莫唑胺联合应用于复发性恶性胶质瘤（MG）患者时的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。
任何复发阶段的MG患者在第1 - 5天接受剂量为200 mg/m²/天的替莫唑胺（TMZ），并在每6周周期的第1、2、4和5周进行90分钟静脉输注CPT-11。患者根据是否同时使用诱导CYP3A4的抗惊厥药（酶诱导抗癫痫药物 [EIAEDs]）进行分层。CPT-11剂量在每个分层的连续患者队列中独立递增。
107例患者接受了剂量范围为40 mg/m²至375 mg/m²的CPT-11与TMZ联合治疗。91例患者（85%）为复发性多形性胶质母细胞瘤（GBM），16例（15%）为复发性间变性胶质瘤。68例患者（%）使用了EIAEDs。同时接受和未接受EIAEDs的患者CPT-11的MTD分别为325 mg/m²和125 mg/m²。DLT为血液学、胃肠道和肝脏毒性。15例患者（14%）在广泛的CPT-11剂量水平上实现了影像学完全缓解（n = 5）或部分缓解（n = 10）。实现影像学缓解的复发性GBM患者的疾病进展中位时间为54.9周。
本研究基于旨在提高拓扑异构酶I抑制剂临床活性的临床前观察。全剂量水平的CPT-11与TMZ联合应用耐受性良好。此外，在这一复发人群中观察到了持久缓解。正在进行的II期研究将评估该方案的疗效及其在其他恶性肿瘤中的应用。
