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Annals of Oncology Advance Access originally published online on July 1, 2009
Annals of Oncology 2009 20(11):1886-1894; doi:10.1093/annonc/mdp210
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

sarcomas

Response to imatinib plus sirolimus in advanced chordoma

S. Stacchiotti1,*, A. Marrari1, E. Tamborini2, E. Palassini1, E. Virdis2, A. Messina3, F. Crippa4, C. Morosi3, A. Gronchi5, S. Pilotti2 and P. G. Casali1

1 Department of Cancer Medicine
2 Department of Pathology and Molecular Biology
3 Department of Radiology
4 Department of Nuclear Medicine
5 Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

* Correspondence to: Dr S. Stacchiotti, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. Tel: +390223902803; Fax: +390223902804; E-mail: silvia.stacchiotti{at}istitutotumori.mi.it

Background: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma.

Patients and methods: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis.

Results: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (≥10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD ≥6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off.

Conclusion: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.

Key words: chordoma, imatinib, mTOR, rapamycin, sarcoma, sirolimus

Received for publication January 30, 2009. Revision received March 4, 2009. Accepted for publication March 11, 2009.


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