title: 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: OBJECTIVE
  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.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands. v.frings@vumc.nl
authors.forename: Virginie
authors.initials: V
authors.lastname: Frings
authors.forename: Astrid A M
authors.initials: AA
authors.lastname: van der Veldt
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
authors.forename: Gerarda J M
authors.initials: GJ
authors.lastname: Herder
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Richard
authors.initials: R
authors.lastname: Honeywell
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.forename: Otto S
authors.initials: OS
authors.lastname: Hoekstra
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D003857:Deoxyuridine / Q000097:blood / Q000378:metabolism; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017063:Outcome Assessment, Health Care; D000068437:Pemetrexed; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography; D011379:Prognosis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D015224:Dideoxynucleosides; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C002854:alovudine; D003857:Deoxyuridine