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01-06-2016 | Original Research Article

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

Authors: 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

Published in: Targeted Oncology | Issue 3/2016

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.

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Title: Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer
Authors: 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
Publication date: 01-06-2016
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 3/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-015-0397-2

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Background

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Conclusions

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