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Response to imatinib plus sirolimus in advanced chordoma.

AbstractBACKGROUND:
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 (> or =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 > or =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.
AuthorsS Stacchiotti, A Marrari, E Tamborini, E Palassini, E Virdis, A Messina, F Crippa, C Morosi, A Gronchi, S Pilotti, P G Casali
JournalAnnals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 20 Issue 11 Pg. 1886-94 (Nov 2009) ISSN: 1569-8041 [Electronic] England
PMID19570961 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Oncogene Protein v-akt
  • Sirolimus
Topics
  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Benzamides
  • Blotting, Western
  • Chordoma (drug therapy, pathology)
  • Female
  • Humans
  • Imatinib Mesylate
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Oncogene Protein v-akt (biosynthesis, drug effects)
  • Piperazines (administration & dosage, adverse effects)
  • Pyrimidines (administration & dosage, adverse effects)
  • Sacrum (pathology)
  • Sirolimus (administration & dosage, adverse effects)
  • Skull Base Neoplasms (drug therapy, pathology)
  • Spinal Neoplasms (drug therapy, pathology)
  • Treatment Outcome
  • Young Adult

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