Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer

Filippo Pietrantonio, Filippo de Braud, Massimo Milione, Claudia Maggi, Roberto Iacovelli, Katia Fiorella Dotti, Federica Perrone, Elena Tamborini, Marta Caporale, Rosa Berenato, Giorgia Leone, Alessio Pellegrinelli, Ilaria Bossi, Fabrizio Festinese, Stefano Federici, Maria Di Bartolomeo

Research output: Contribution to journalArticle

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Abstract

Background: In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Methods: Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. Results: From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p <0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. Conclusions: Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.[MediaObject not available: see fulltext.]

Original languageEnglish
JournalTargeted Oncology
DOIs
Publication statusAccepted/In press - Nov 4 2015

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temozolomide
Colorectal Neoplasms
Immunohistochemistry
Disease-Free Survival
Asthenia
Survival
Patient Selection
Methylation
Neoplasms
Appointments and Schedules
Biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer. / Pietrantonio, Filippo; de Braud, Filippo; Milione, Massimo; Maggi, Claudia; Iacovelli, Roberto; Dotti, Katia Fiorella; Perrone, Federica; Tamborini, Elena; Caporale, Marta; Berenato, Rosa; Leone, Giorgia; Pellegrinelli, Alessio; Bossi, Ilaria; Festinese, Fabrizio; Federici, Stefano; Di Bartolomeo, Maria.

In: Targeted Oncology, 04.11.2015.

Research output: Contribution to journalArticle

Pietrantonio, F, de Braud, F, Milione, M, Maggi, C, Iacovelli, R, Dotti, KF, Perrone, F, Tamborini, E, Caporale, M, Berenato, R, Leone, G, Pellegrinelli, A, Bossi, I, Festinese, F, Federici, S & Di Bartolomeo, M 2015, 'Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer', Targeted Oncology. https://doi.org/10.1007/s11523-015-0397-2
Pietrantonio, Filippo ; de Braud, Filippo ; Milione, Massimo ; Maggi, Claudia ; Iacovelli, Roberto ; Dotti, Katia Fiorella ; Perrone, Federica ; Tamborini, Elena ; Caporale, Marta ; Berenato, Rosa ; Leone, Giorgia ; Pellegrinelli, Alessio ; Bossi, Ilaria ; Festinese, Fabrizio ; Federici, Stefano ; Di Bartolomeo, Maria. / Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer. In: Targeted Oncology. 2015.
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abstract = "Background: In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Methods: Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. Results: From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 {\%} (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p <0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. Conclusions: Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.[MediaObject not available: see fulltext.]",
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T1 - Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer

AU - Pietrantonio, Filippo

AU - de Braud, Filippo

AU - Milione, Massimo

AU - Maggi, Claudia

AU - Iacovelli, Roberto

AU - Dotti, Katia Fiorella

AU - Perrone, Federica

AU - Tamborini, Elena

AU - Caporale, Marta

AU - Berenato, Rosa

AU - Leone, Giorgia

AU - Pellegrinelli, Alessio

AU - Bossi, Ilaria

AU - Festinese, Fabrizio

AU - Federici, Stefano

AU - Di Bartolomeo, Maria

PY - 2015/11/4

Y1 - 2015/11/4

N2 - Background: In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Methods: Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. Results: From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p <0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. Conclusions: Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.[MediaObject not available: see fulltext.]

AB - Background: In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Methods: Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m2 for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. Results: From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p <0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS. Conclusions: Our data confirm the encouraging activity of TMZ in chemorefractory CRC patients selected for MGMT silencing, even in the RAS-BRAF-mutated population. The role of MGMT IHC as a biomarker for improving patient selection warrants further prospective confirmation.[MediaObject not available: see fulltext.]

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