title: A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme.
abstract: BACKGROUND
  Nitrosoureas constitute the main resource of chemotherapy for glioblastoma. However, because of chemoresistance, which is intrinsic or rapidly acquired after the first administration of chemotherapy, there have been few improvements in survival. Because O(6)-alkylguanine-DNA alkyltransferase (AGT) is the main target for increasing cell sensitivity to the nitrosoureas, we postulated that preexposure to other alkylating agents might increase the therapeutic index of the nitrosoureas by saturating all the copies of AGT present in the tumor cells.
  
  
  OBJECTIVE
  To investigate the response rate, toxic effects, time from start of chemotherapy to progression of disease or exit from the study for any reason (TTP), and progression-free survival at 6 months (PFS-6) associated with a multidrug combination that could reverse resistance to carmustine (BCNU) through AGT depletion.
  
  
  METHODS
  We conducted a phase 2 study of patients with glioblastoma at first relapse or progression after surgery and standard radiotherapy. Patients were treated with 100 mg/m(2) of procarbazine on days 1 to 5, 80 mg/m(2) of BCNU on days 3 to 5, and 1.4 mg/m(2) of vincristine on day 3 every 8 weeks.
  
  
  RESULTS
  Fifty-eight patients were enrolled in the study, and all were assessable for response and toxic effects. Six patients (10.3%) had a complete response, 11 (19%) had a partial response, and 17 (29.3%) had stable disease. The median TTP was 4.8 months; 42.3% of patients had PFS-6, and 15.4% had PFS at 12 months. Response to chemotherapy was the only significant prognostic factor for TTP. Neutropenia was grade 3 in 8.6% of patients and grade 4 in 5.2% of patients, and thrombocytopenia was grade 3 in 17.2% of patients and grade 4 in 12% of patients; hepatic and pulmonary toxic effects were grade 3 in 5.2% and 8.6% of patients, respectively.
  
  
  CONCLUSIONS
  This regimen proved active in chemotherapy-naive patients with recurrent glioblastoma even though toxic effects were substantial.
authors.affiliation: Department of Medical Oncology, Azienda Ospedale-Università, Padova, Italy. aabrandes@unipd.it
authors.forename: A A
authors.initials: AA
authors.lastname: Brandes
authors.forename: S
authors.initials: S
authors.lastname: Turazzi
authors.forename: U
authors.initials: U
authors.lastname: Basso
authors.forename: L M
authors.initials: LM
authors.lastname: Pasetto
authors.forename: B
authors.initials: B
authors.lastname: Guglielmi
authors.forename: L
authors.initials: L
authors.lastname: Volpin
authors.forename: P
authors.initials: P
authors.lastname: Iuzzolino
authors.forename: P
authors.initials: P
authors.lastname: Amistà
authors.forename: G
authors.initials: G
authors.lastname: Pinna
authors.forename: R
authors.initials: R
authors.lastname: Scienza
authors.forename: M
authors.initials: M
authors.lastname: Ermani
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002330:Carmustine / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D011344:Procarbazine / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D011344:Procarbazine; D014750:Vincristine; D002330:Carmustine