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

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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.

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Acknowledgments

The authors thank all patients included in this study and their families.

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Authors and Affiliations

  1. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 - 20133, Milan, Italy

    Filippo Pietrantonio, Filippo de Braud, Claudia Maggi, Roberto Iacovelli, Katia Fiorella Dotti, Marta Caporale, Rosa Berenato, Ilaria Bossi & Maria Di Bartolomeo

  2. Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Massimo Milione, Federica Perrone, Elena Tamborini, Giorgia Leone & Alessio Pellegrinelli

  3. Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Fabrizio Festinese & Stefano Federici

Authors
  1. Filippo Pietrantonio
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  2. Filippo de Braud
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  3. Massimo Milione
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Corresponding author

Correspondence to Filippo Pietrantonio.

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Conflict of Interest

FP, FdB, MM, CM, RI, KFD, FP, ET AND MC declared no conflict of interest.

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Pietrantonio, F., de Braud, F., Milione, M. et al. Dose-Dense Temozolomide in Patients with MGMT-Silenced Chemorefractory Colorectal Cancer. Targ Oncol 11, 337–343 (2016). https://doi.org/10.1007/s11523-015-0397-2

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  • DOI: https://doi.org/10.1007/s11523-015-0397-2

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