Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks

Jann N. Sarkaria, Eva Galanis, Wenting Wu, Allan B. Dietz, Timothy J. Kaufmann, Michael P. Gustafson, Paul D. Brown, Joon H. Uhm, Ravi D. Rao, Laurence Doyle, Caterina Giannini, Kurt Jaeckle, Jan C. Buckner

Research output: Contribution to journalArticle

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Abstract

Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.

Original languageEnglish (US)
Pages (from-to)5573-5580
Number of pages8
JournalClinical Cancer Research
Volume16
Issue number22
DOIs
StatePublished - Nov 15 2010

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temozolomide
Glioblastoma
Radiation
Antibiotic Prophylaxis
Chemoradiotherapy
Regulatory T-Lymphocytes
Sirolimus
Natural Killer Cells
temsirolimus
Appointments and Schedules
Infection
1-Phosphatidylinositol 4-Kinase
Mycoses
Virus Diseases
Therapeutics
Helper-Inducer T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Sarkaria, Jann N. ; Galanis, Eva ; Wu, Wenting ; Dietz, Allan B. ; Kaufmann, Timothy J. ; Gustafson, Michael P. ; Brown, Paul D. ; Uhm, Joon H. ; Rao, Ravi D. ; Doyle, Laurence ; Giannini, Caterina ; Jaeckle, Kurt ; Buckner, Jan C. / Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 22. pp. 5573-5580.
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title = "Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks",
abstract = "Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.",
author = "Sarkaria, {Jann N.} and Eva Galanis and Wenting Wu and Dietz, {Allan B.} and Kaufmann, {Timothy J.} and Gustafson, {Michael P.} and Brown, {Paul D.} and Uhm, {Joon H.} and Rao, {Ravi D.} and Laurence Doyle and Caterina Giannini and Kurt Jaeckle and Buckner, {Jan C.}",
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Sarkaria, JN, Galanis, E, Wu, W, Dietz, AB, Kaufmann, TJ, Gustafson, MP, Brown, PD, Uhm, JH, Rao, RD, Doyle, L, Giannini, C, Jaeckle, K & Buckner, JC 2010, 'Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks', Clinical Cancer Research, vol. 16, no. 22, pp. 5573-5580. https://doi.org/10.1158/1078-0432.CCR-10-1453

Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. / Sarkaria, Jann N.; Galanis, Eva; Wu, Wenting; Dietz, Allan B.; Kaufmann, Timothy J.; Gustafson, Michael P.; Brown, Paul D.; Uhm, Joon H.; Rao, Ravi D.; Doyle, Laurence; Giannini, Caterina; Jaeckle, Kurt; Buckner, Jan C.

In: Clinical Cancer Research, Vol. 16, No. 22, 15.11.2010, p. 5573-5580.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks

AU - Sarkaria, Jann N.

AU - Galanis, Eva

AU - Wu, Wenting

AU - Dietz, Allan B.

AU - Kaufmann, Timothy J.

AU - Gustafson, Michael P.

AU - Brown, Paul D.

AU - Uhm, Joon H.

AU - Rao, Ravi D.

AU - Doyle, Laurence

AU - Giannini, Caterina

AU - Jaeckle, Kurt

AU - Buckner, Jan C.

PY - 2010/11/15

Y1 - 2010/11/15

N2 - Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.

AB - Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed.

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U2 - 10.1158/1078-0432.CCR-10-1453

DO - 10.1158/1078-0432.CCR-10-1453

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SP - 5573

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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