Abstract 5225: Pemetrexed induced thymidylate synthase inhibition in non-small cell lung cancer in vivo: a pilot study with 18F-FLT PET

Abstract

Abstract Objectives Thymidylate synthase (TS) is a key enzyme for de novo synthesis of DNA and as such a target for anticancer drugs. In a mouse model, effective TS inhibition resulted in a 1.8 fold increase of 3′-deoxy-3′-[(18)F]fluorothymidine (18F-FLT) cellular uptake (Cancer Res 2006;66:8558-64). Here we investigated changes in 18F-FLT uptake 4 hours after the first dose of pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods Twelve NSCLC patients (mean age 64 yrs, 4 male) treated with pemetrexed (in combination with cisplatin, carboplatin or monotherapy) were included. Patients underwent dynamic 18F-FLT PET at baseline and 4 hours after the first therapeutic dose of pemetrexed. For primary tumors, regions of interest (ROI) were defined with a 41, 50 and 70% threshold of the maximum pixel, and the maximum standardized uptake value (SUVmax) was determined (as well as full kinetic analysis). One, 2, 3, 4 and 6 hours after pemetrexed administration, blood samples were collected to measure deoxyuridine levels using LCMSMS. After six weeks, RECIST was used to evaluate tumor response. Association between 18F-FLT uptake and RECIST was tested with a chi-square test. Results According to RECIST 3 patients had PR, 7 SD and 2 PD. Four hours after administration of pemetrexed, two patients had increased 18F-FLT uptake (beyond test-retest borders, 22% for SUVmax), while three patients had a significantly decreased uptake (see Table). In 7 out of 12 patients, the change in 18F-FLT uptake was within the test-retest variability. In all patients deoxyuridine levels raised after administration of pemetrexed with a average maximum at 4 hours. There was no significant association between 18F-FLT uptake and RECIST. Conclusions Measuring TS inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in 18F-FLT uptake. The association with response measurement on CT was not significant.18F-FLT PET and RECIST per patientPt No.Baseline 18F-FLT uptake (SUVmax)18F-FLT uptake 4 hours after pemetrexed (SUVmax)Change 18F-FLT in uptake (%)RECIST after 6 weeks14.74.94.1SD24.44.75.0SD34.12.3−44.7SD44.04.411.0PD53.54.528.6PR63.42.2−33.3SD74.85.05.7SD812.57.9−36.6PR911.312.17.1PD105.67.228.3SD115.15.35.7PR124.73.7−21.5SD Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5225.