title: 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.
abstract: 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/m²)/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/m²/day, 7/14-day schedule) or with doublet combinations of thalidomide (400 mg/day), isotretinoin (100 mg/m²/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.
authors: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Unit 431, 1515 Holcombe Blvd., Houston, TX 77030, USA. mrgilbert@mdanderson.org
authors: Mark R
authors: MR
authors: Gilbert
authors: Javier
authors: J
authors: Gonzalez
authors: Kathy
authors: K
authors: Hunter
authors: Kenneth
authors: K
authors: Hess
authors: Pierre
authors: P
authors: Giglio
authors: Eric
authors: E
authors: Chang
authors: Vinay
authors: V
authors: Puduvalli
authors: Morris D
authors: MD
authors: Groves
authors: Howard
authors: H
authors: Colman
authors: Charles
authors: C
authors: Conrad
authors: Victor
authors: V
authors: Levin
authors: Shaio
authors: S
authors: Woo
authors: Anita
authors: A
authors: Mahajan
authors: John
authors: J
authors: de Groot
authors: W K Alfred
authors: WK
authors: Yung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068579:Celecoxib; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D015474:Isotretinoin / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011878:Radiotherapy; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000077204:Temozolomide; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D013449:Sulfonamides; D013792:Thalidomide; D003606:Dacarbazine; D015474:Isotretinoin; D000068579:Celecoxib; D000077204:Temozolomide