title: Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults.
abstract: We conducted a phase II study of the combination of temozolomide and angiogenesis inhibitors for treating adult patients with newly diagnosed glioblastoma. Patients who had stable disease following standard radiation therapy received temozolomide for 5 days in 28-day cycles, in combination with daily thalidomide and celecoxib. Patients were treated until tumor progression or development of unacceptable toxicity. Four-month progression-free survival (PFS) from study enrollment was the primary end point, and overall survival (OS) was the secondary end point. In addition, we sought to correlate response with O(6)-methylguanine-DNA methyltransferase promoter methylation status and serum levels of angiogenic peptides. Fifty patients with glioblastoma were enrolled (18 women, 32 men). Median age was 54 years (range, 29-78) and median KPS score was 90 (range, 70-100). From study enrollment, median PFS was 5.9 months (95% confidence interval [CI]: 4.2-8.0) and 4-month PFS was 63% (95% CI: 46%-75%). Median OS was 12.6 months (95% CI: 8.5-16.4) and 1-year OS was 47%. Of the 47 patients evaluable for best response, none had a complete response, five (11%) had partial response, four (9%) had minor response, 22 (47%) had stable disease, and 16 (34%) had progressive disease. Analysis of serial serum samples obtained from 47 patients for four angiogenic peptides failed to show a significant correlation with response or survival for three of the peptides; higher vascular endothelial growth factor levels showed a trend toward correlation with decreased OS (p=0.07) and PFS (p=0.09). The addition of celecoxib and thalidomide to adjuvant temozolomide was well tolerated but did not meet the primary end point of improvement of 4-month PFS from study enrollment.
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology, 44 Binney St., SW430D, Boston, MA 02115, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: John W
authors.initials: JW
authors.lastname: Henson
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.forename: Debra C
authors.initials: DC
authors.lastname: Gigas
authors.forename: Lisa
authors.initials: L
authors.lastname: Doherty
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Janina A
authors.initials: JA
authors.lastname: Longtine
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Susan
authors.initials: S
authors.lastname: Weaver
authors.forename: Andrea
authors.initials: A
authors.lastname: Laforme
authors.forename: Naren
authors.initials: N
authors.lastname: Ramakrishna
authors.forename: Peter McL
authors.initials: PM
authors.lastname: Black
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: Abigail
authors.initials: A
authors.lastname: Ciampa
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Mark
authors.initials: M
authors.lastname: Kieran
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D000068579:Celecoxib; D019175:DNA Methylation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D043169:Endostatins / Q000097:blood / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000187:drug effects; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects; D000077204:Temozolomide; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects; D019699:Thrombospondins / Q000097:blood / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D011720:Pyrazoles; D013449:Sulfonamides; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000068579:Celecoxib; D000077204:Temozolomide