Pemetrexed induced thymidylate synthase inhibition in non-small cell lung cancer patients: a pilot study with 3'-deoxy-3'-[¹⁸F]fluorothymidine positron emission tomography.

Abstract

OBJECTIVES:

Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on ¹⁸F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients.

METHODS:

Fourteen NSCLC patients underwent dynamic ¹⁸F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined.

RESULTS:

Eleven patients had evaluable ¹⁸F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased ¹⁸F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients ¹⁸F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. ¹⁸F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0-7.4 months); median OS was 13.0 months (range 5.1-30.8 months). Changes in ¹⁸F-FLT uptake were not predictive for tumor response, TTP or OS.

CONCLUSIONS:

Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in ¹⁸F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed.

• Authors: Virginie Frings, Astrid A M van der Veldt, Ronald Boellaard, Gerarda J M Herder, Elisa Giovannetti, Richard Honeywell, Godefridus J Peters, Erik Thunnissen, Otto S Hoekstra, Egbert F Smit
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e63705 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23717468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Dideoxynucleosides
• Glutamates
• Pemetrexed
• Guanine
• MTHFR protein, human
• Methylenetetrahydrofolate Reductase (NADPH2)
• Thymidylate Synthase
• alovudine
• Deoxyuridine

Topics

• Adult
• Aged
• Antimetabolites, Antineoplastic (administration & dosage, pharmacology)
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging, metabolism, pathology)
• Deoxyuridine (blood, metabolism)
• Dideoxynucleosides (pharmacokinetics)
• Female
• Glutamates (administration & dosage, pharmacology)
• Guanine (administration & dosage, analogs & derivatives, pharmacology)
• Humans
• Lung Neoplasms (diagnostic imaging, metabolism, pathology)
• Male
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics, metabolism)
• Middle Aged
• Neoplasm Metastasis
• Outcome Assessment, Health Care
• Pemetrexed
• Polymorphism, Genetic
• Positron-Emission Tomography
• Prognosis
• Thymidylate Synthase (antagonists & inhibitors, genetics, metabolism)
• Time Factors
• Tissue Distribution