title: PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.
abstract: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation.
  
  
  
  Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS).
  
  
  
  Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation.
  
  
  
  PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Elinzano
authors.affiliation: Penn State Hershey Medical Center, Hershey, PA.
authors.forename: Michael
authors.initials: M
authors.lastname: Glantz
authors.affiliation: Department of Neuro-oncology, The University of Washington Medical Center, Seattle, WA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Mrugala
authors.affiliation: UCSD Moores Cancer Center, La Jolla, CA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.affiliation: UCSD Moores Cancer Center, La Jolla, CA.
authors.forename: David E
authors.initials: DE
authors.lastname: Piccioni
authors.affiliation: Department of Neuro-oncology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Kim
authors.affiliation: Department of Neuro-oncology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Edward
authors.initials: E
authors.lastname: Pan
authors.affiliation: Department of Neuro-oncology, University of Massachusetts Memorial Medical Center, Worcester, MA.
authors.forename: Shakeeb
authors.initials: S
authors.lastname: Yunus
authors.affiliation: Department of Neuro-oncology, SUNY Upstate Medical University, Syracuse, NY.
authors.forename: Thomas
authors.initials: T
authors.lastname: Coyle
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Kinsella
authors.initials: K
authors.lastname: Timothy
authors.affiliation: Maine Center for Cancer Medicine, Portland, ME.
authors.forename: Devon
authors.initials: D
authors.lastname: Evans
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Jerrold
authors.initials: J
authors.lastname: Boxerman
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Thomas
authors.initials: T
authors.lastname: DiPetrillo
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: John E
authors.initials: JE
authors.lastname: Donahue
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hebda
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Mitchell
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Kayla L
authors.initials: KL
authors.lastname: Rosati
authors.affiliation: Department of Neuro-oncology, The Brown University Oncology Research Group, Providence, RI.
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
mesh_terms: D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018714:Radiotherapy, Adjuvant; D016037:Single-Blind Method; D016019:Survival Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014481:United States
chemical_list: D025521:Tumor Suppressor Proteins; D011099:Polyglutamic Acid; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D017239:Paclitaxel; C509139:paclitaxel poliglumex