Abstract
Thymidylate synthase (TS) remains a major target for cancer therapy. TS inhibition elicits increases in DNA salvage pathway activity, detected as a transient compensatory "flare" in 3'-deoxy-3'-[(18)F]fluorothymidine positron emission tomography ((18)F-FLT PET). We determined the magnitude of the (18)F-FLT flare in non-small cell lung cancer (NSCLC) patients treated with the antifolate pemetrexed in relation to clinical outcome. METHOD: Twenty-one patients with advanced/metastatic non-small cell lung cancer (NSCLC) scheduled to receive palliative pemetrexed ± platinum-based chemotherapy underwent (18)F-FLT PET at baseline and 4 h after initiating single-agent pemetrexed. Plasma deoxyuridine (dUrd) levels and thymidine kinase 1 (TK1) activity were measured before each scan. Patients were then treated with the combination therapy. The (18)F-FLT PET variables were compared to RECIST 1.1 and overall survival (OS). RESULTS: Nineteen patients had evaluable PET scans at both time points. A total of 32% (6/19) of patients showed (18)F-FLT flares (>20% change in SUVmax-wsum). At the lesion level, only one patient had an FLT flare in all the lesions above (test-retest borders). The remaining had varied uptake. An (18)F-FLT flare occurred in all lesions in 1 patient, while another patient had an (18)F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (p < 0.001) and (18)F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (p = 0.004 each). Notably, 83% (5/6) of patients who exhibited (18)F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit (18)F-FLT flares (15 m). Baseline plasma TK1 was prognostic of survival but its activity remained unchanged following treatment. CONCLUSIONS: The better radiological response and longer survival observed in patients with an (18)F-FLT flare suggest the efficacy of the tracer as an indicator of the early therapeutic response to pemetrexed in NSCLC.