A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma

作者：Gilbert Mark R^*; Gonzalez Javier; Hunter Kathy; Hess Kenneth; Giglio Pierre; Chang Eric; Puduvalli Vinay; Groves Morris D; Colman Howard; Conrad Charles; Levin Victor; Woo Shaio; Mahajan Anita; de Groot John; Yung W K Alfred

来源：Neuro-Oncology, 2010, 12(11): 1167-1172.

DOI：10.1093/neuonc/noq100

• dose-dense
• glioblastoma
• glioma
• radiotherapy
• temozolomide

External beam radiation therapy (XRT) with concomitant temozolomide and 6 cycles of adjuvant temozolomide (5/28-day schedule) improves survival in patients with newly diagnosed glioblastoma compared with XRT alone. Studies suggest that dose-dense. temozolomide schedules and addition of cytostatic agents may further improve efficacy. This factorial design phase I/II protocol tested dose-dense temozolomide alone and combined with cytostatic agents. Patients with newly diagnosed glioblastoma received fractionated XRT to 60 Gy concomitant with temozolomide (75 mg/m(2)/day for 42 days). In the phase I portion, patients with stable disease or radiologic response 1 month after chemoradiation were randomized to adjuvant temozolomide alone (150 mg/m(2)/day, 7/14-day schedule) or with doublet combinations of thalidomide (400 mg/day), isotretinoin (100 mg/m(2)/day), and/or celecoxib (400 mg twice daily), or all 3 agents. Toxicity was assessed after 4 weeks. Among 54 patients enrolled (median age, 52 years; median Karnofsky performance status, 90), adjuvant treatment was not administered to 12 (22%), primarily because of disease progression (n = 10). All combinations were well tolerated. Grade 3/4 lymphopenia developed in 63% of patients, but no related infections occurred. One patient treated with temozolomide plus isotretinoin plus thalidomide had dose-limiting grade 3 fatigue and rash, and 1 patient receiving all 4 agents had dose-limiting grade 4 neutropenia. Venous thrombosis occurred in 7 patients, 4 of whom received thalidomide. From study entry, median survival was 20 months and the 2-year survival rate was 40%. Multiple cytostatic agents can be safely combined with dose-dense temozolomide. The factorial-based phase II portion of this study is currently ongoing.

• 出版日期2010-11