The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high- grade astrocytoma

Lawrence R Kleinberg, Stuart A Grossman, Steven Piantadosi, Michel Zeltzman, Moody Wharam

Research output: Contribution to journalArticle

Abstract

Purpose: 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 and Materials: 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 103/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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)535-543
Number of pages9
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume44
Issue number3
DOIs
StatePublished - Jun 1 1999

Fingerprint

Astrocytoma
chemotherapy
toxicity
radiation therapy
grade
Radiotherapy
Drug Therapy
Carmustine
Survival
leukopenia
Cisplatin
stem cells
Leukopenia
therapy
Stem Cells
transfusion
anemias
Platelet Transfusion
cycles
axioms

Keywords

  • Anaplastic astrocytoma
  • BCNU
  • Chemotherapy
  • Cisplatin
  • Combined modality therapy
  • Glioblastoma
  • Leukopenia
  • Radiotherapy
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

@article{ec3b03b4b1ad46a3b7e0d281afb5d9f5,
title = "The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high- grade astrocytoma",
abstract = "Purpose: 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 and Materials: 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 103/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. Conclusion: 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.",
keywords = "Anaplastic astrocytoma, BCNU, Chemotherapy, Cisplatin, Combined modality therapy, Glioblastoma, Leukopenia, Radiotherapy, Toxicity",
author = "Kleinberg, {Lawrence R} and Grossman, {Stuart A} and Steven Piantadosi and Michel Zeltzman and Moody Wharam",
year = "1999",
month = "6",
day = "1",
doi = "10.1016/S0360-3016(99)00060-7",
language = "English (US)",
volume = "44",
pages = "535--543",
journal = "International Journal of Radiation Oncology Biology Physics",
issn = "0360-3016",
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TY - JOUR

T1 - The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high- grade astrocytoma

AU - Kleinberg, Lawrence R

AU - Grossman, Stuart A

AU - Piantadosi, Steven

AU - Zeltzman, Michel

AU - Wharam, Moody

PY - 1999/6/1

Y1 - 1999/6/1

N2 - Purpose: 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 and Materials: 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 103/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. Conclusion: 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.

AB - Purpose: 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 and Materials: 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 103/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. Conclusion: 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.

KW - Anaplastic astrocytoma

KW - BCNU

KW - Chemotherapy

KW - Cisplatin

KW - Combined modality therapy

KW - Glioblastoma

KW - Leukopenia

KW - Radiotherapy

KW - Toxicity

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JO - International Journal of Radiation Oncology Biology Physics

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