Validation of [F]FLT as a perfusion-independent imaging biomarker of tumour response in EGFR-mutated NSCLC patients undergoing treatment with an EGFR tyrosine kinase inhibitor.

Background: 3'-Deoxy-3'-[F]fluorothymidine ([F]FLT) was proposed as an imaging biomarker for the assessment of in vivo cellular proliferation with positron emission tomography (PET). The current study aimed to validate [F]FLT as a perfusion-independent PET tracer, by gaining insight in the intra-tumoural relationship between [F]FLT uptake and perfusion in non-small cell lung cancer (NSCLC) patients undergoing treatment with a tyrosine kinase inhibitor (TKI). Six patients with metastatic NSCLC, having an activating epidermal growth factor receptor (EGFR) mutation, were included in this study. Patients underwent [O]HO and [F]FLT PET/CT scans at three time points: before treatment and 7 and 28 days after treatment with a TKI (erlotinib or gefitinib). Parametric analyses were performed to generate quantitative 3D images of both perfusion measured with [O]HO and proliferation measured with [F]FLT volume of distribution (V ). A multiparametric classification was performed by classifying voxels as low and high perfusion and/or low and high [F]FLT V using a single global threshold for all scans and subjects. By combining these initial classifications, voxels were allocated to four categories (low perfusion-low V , low perfusion-high V , high perfusion-low V and high perfusion-high V ).

Results: A total of 17 perfusion and 18 [F]FLT PET/CT scans were evaluated. The average tumour values across all lesions were 0.53 ± 0.26 mL cm min and 4.25 ± 1.71 mL cm for perfusion and [F]FLT V , respectively. Multiparametric analysis suggested a shift in voxel distribution, particularly regarding the V : from an average of ≥ 77% voxels classified in the "high V category" to ≥ 85% voxels classified in the "low V category". The shift was most prominent 7 days after treatment and remained relatively similar afterwards. Changes in perfusion and its spatial distribution were minimal.

Conclusion: The present study suggests that [F]FLT might be a perfusion-independent PET tracer for measuring tumour response as parametric changes in [F]FLT uptake occurred independent from changes in perfusion.

Trial Registration: Nederlands Trial Register (NTR), NTR3557 . Registered 2 August 2012.