title: Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM.
abstract: Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1, and irinotecan, 400 mg/m(2) on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1 and irinotecan 75 mg/m(2) Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 C(max) and AUC in EIAC patients receiving 400 mg/m(2) irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m(2), 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.
authors.affiliation: Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA. jaeckle.kurt@mayo.edu
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Schomberg
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: Joon H
authors.initials: JH
authors.lastname: Uhm
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brown
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hammack
authors.forename: Robert
authors.initials: R
authors.lastname: Arusell
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nikcevich
authors.forename: Roscoe F
authors.initials: RF
authors.lastname: Morton
authors.forename: Donald B
authors.initials: DB
authors.lastname: Wender
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000628:therapy*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011878:Radiotherapy / Q000379:methods*; D013223:Statistics as Topic; D013997:Time Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D002330:Carmustine; D002166:Camptothecin