Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma

Mayo/north central cancer treatment group study n0074

Joon H. Uhm, Karla V. Ballman, Wenting Wu, Caterina Giannini, J. C. Krauss, Jan C. Buckner, C. D. James, Bernd W. Scheithauer, Robert J. Behrens, Patrick J. Flynn, Paul L. Schaefer, Shaker R. Dakhill, Kurt Jaeckle

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Abstract

Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.

Original languageEnglish (US)
Pages (from-to)347-353
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Volume80
Issue number2
DOIs
StatePublished - Jun 1 2011

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Astrocytoma
Glioblastoma
grade
cancer
evaluation
Epidermal Growth Factor Receptor
Neoplasms
Radiation
mutations
Exanthema
progressions
genes
Disease-Free Survival
radiation
Therapeutics
intervals
erbB-1 Genes
Cytochrome P-450 CYP3A
Mutation
chemotherapy

All Science Journal Classification (ASJC) codes

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Uhm, Joon H. ; Ballman, Karla V. ; Wu, Wenting ; Giannini, Caterina ; Krauss, J. C. ; Buckner, Jan C. ; James, C. D. ; Scheithauer, Bernd W. ; Behrens, Robert J. ; Flynn, Patrick J. ; Schaefer, Paul L. ; Dakhill, Shaker R. ; Jaeckle, Kurt. / Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma : Mayo/north central cancer treatment group study n0074. In: International Journal of Radiation Oncology Biology Physics. 2011 ; Vol. 80, No. 2. pp. 347-353.
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title = "Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma: Mayo/north central cancer treatment group study n0074",
abstract = "Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2{\%}, which was not statistically different compared with that of historical control population (48.9{\%}, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7{\%}) was also not significantly different to that of historical controls (30.3{\%}). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41{\%}), rash (62{\%}), and loose stools (58{\%}) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.",
author = "Uhm, {Joon H.} and Ballman, {Karla V.} and Wenting Wu and Caterina Giannini and Krauss, {J. C.} and Buckner, {Jan C.} and James, {C. D.} and Scheithauer, {Bernd W.} and Behrens, {Robert J.} and Flynn, {Patrick J.} and Schaefer, {Paul L.} and Dakhill, {Shaker R.} and Kurt Jaeckle",
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Uhm, JH, Ballman, KV, Wu, W, Giannini, C, Krauss, JC, Buckner, JC, James, CD, Scheithauer, BW, Behrens, RJ, Flynn, PJ, Schaefer, PL, Dakhill, SR & Jaeckle, K 2011, 'Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma: Mayo/north central cancer treatment group study n0074', International Journal of Radiation Oncology Biology Physics, vol. 80, no. 2, pp. 347-353. https://doi.org/10.1016/j.ijrobp.2010.01.070

Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma : Mayo/north central cancer treatment group study n0074. / Uhm, Joon H.; Ballman, Karla V.; Wu, Wenting; Giannini, Caterina; Krauss, J. C.; Buckner, Jan C.; James, C. D.; Scheithauer, Bernd W.; Behrens, Robert J.; Flynn, Patrick J.; Schaefer, Paul L.; Dakhill, Shaker R.; Jaeckle, Kurt.

In: International Journal of Radiation Oncology Biology Physics, Vol. 80, No. 2, 01.06.2011, p. 347-353.

Research output: Contribution to journalArticle

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T1 - Phase II evaluation of gefitinib in patients with newly diagnosed grade 4 astrocytoma

T2 - Mayo/north central cancer treatment group study n0074

AU - Uhm, Joon H.

AU - Ballman, Karla V.

AU - Wu, Wenting

AU - Giannini, Caterina

AU - Krauss, J. C.

AU - Buckner, Jan C.

AU - James, C. D.

AU - Scheithauer, Bernd W.

AU - Behrens, Robert J.

AU - Flynn, Patrick J.

AU - Schaefer, Paul L.

AU - Dakhill, Shaker R.

AU - Jaeckle, Kurt

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.

AB - Purpose: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. Methods and Materials: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. Results: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. Conclusions: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.

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