title: The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high-grade astrocytoma.
abstract: OBJECTIVE
  To determine the effects of sequential versus concurrent administration of cranial radiotherapy and cisplatin/carmustine (BCNU) chemotherapy on survival and toxicity in newly diagnosed high-grade astrocytomas.
  
  
  METHODS
  From 1988 to 1996, 101 patients were treated on 2 therapeutic protocols for malignant glioma that used the identical chemotherapy regimen but differed in the timing of cranial radiotherapy. The eligibility criteria for the 2 protocols were identical. In the first protocol (1988-1991, 52 patients), cisplatin 120 mg/BCNU 120 mg i.v. over 72 h, was given for 3 monthly cycles prior to cranial radiotherapy. After a response rate of 42%, with a median survival of 13 months was achieved with this sequential regimen, a successor protocol (1992-1996, 49 patients) was developed in which cranial radiotherapy began concurrently with the start of the identical chemotherapy regimen. Chemotherapy was delayed but not discontinued if prolonged grade III/IV hematologic toxicity was experienced, but protocol therapy was discontinued if disease progression or thromboembolic events occurred. Survival outcome and hematologic toxicity were compared for the patients treated on these protocols.
  
  
  RESULTS
  Seventy-seven percent of sequentially-treated patients and 68% of concurrently-treated patients completed all planned therapy. Kaplan-Meier survival was similar to concurrent or sequential administration of chemotherapy and radiotherapy (median 12.8 months vs. 13.8 months, respectively). Hematologic toxicity was significantly less in sequentially- versus concurrently-treated patients, with median nadir per cycle (2.9 vs. 1.8 x 10(3)/mm3) (p < 0.001), and incidence of grade 3/4 leukopenia 40% versus 77% (p = 0.002). There was also an increase in platelet transfusion requirements in concurrently-treated patients, but no significant worsening of anemia. We postulate that the worsened leukopenia results from the effects of concurrent radiotherapy on circulating stem cells.
  
  
  CONCLUSIONS
  Concurrent radiotherapy with this regimen of cisplatin and BCNU chemotherapy did not improve survival, but did increase hematologic toxicity. Therefore, we do not recommend further testing of the concurrent regimen, whereas the sequential regimen is currently under evaluation in a Phase III trial of the Eastern Cooperative Oncology Group and the Southwest Oncology Group. In addition, these studies demonstrate that relatively small radiotherapy fields can deliver a dose to circulating stem cells sufficient to worsen the hematologic toxicity of concurrent myelosuppressive chemotherapy, a phenomena which should be considered in the design of combined modality protocols for other body sites.
authors.affiliation: Division of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, MD, USA. KLEINLA@JHMZ.EDU
authors.forename: L
authors.initials: L
authors.lastname: Kleinberg
authors.forename: S A
authors.initials: SA
authors.lastname: Grossman
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: M
authors.initials: M
authors.lastname: Zeltzman
authors.forename: M
authors.initials: M
authors.lastname: Wharam
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000209:etiology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002330:Carmustine / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007970:Leukopenia / Q000209:etiology; D008214:Lymphocytes / Q000528:radiation effects; D008875:Middle Aged; D011829:Radiation Dosage; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000209:etiology
chemical_list: D002945:Cisplatin; D002330:Carmustine