Validation of [ 18 F]FLT as a perfusion-independent imaging biomarker of tumour response in EGFR-mutated NSCLC patients undergoing treatment with an EGFR tyrosine kinase inhibitor

Abstract

Background

3′-Deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]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 [¹⁸F]FLT as a perfusion-independent PET tracer, by gaining insight in the intra-tumoural relationship between [¹⁸F]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 [¹⁵O]H₂O and [¹⁸F]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 [¹⁵O]H₂O and proliferation measured with [¹⁸F]FLT volume of distribution (V_T ). A multiparametric classification was performed by classifying voxels as low and high perfusion and/or low and high [¹⁸F]FLT V_T 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_T , low perfusion-high V_T , high perfusion-low V_T and high perfusion-high V_T ).

Results

A total of 17 perfusion and 18 [¹⁸F]FLT PET/CT scans were evaluated. The average tumour values across all lesions were 0.53 ± 0.26 mL cm^− 3 min^− 1 and 4.25 ± 1.71 mL cm^− 3 for perfusion and [¹⁸F]FLT V_T , respectively. Multiparametric analysis suggested a shift in voxel distribution, particularly regarding the V_T : from an average of ≥ 77% voxels classified in the "high V_T category" to ≥ 85% voxels classified in the "low V_T 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 [¹⁸F]FLT might be a perfusion-independent PET tracer for measuring tumour response as parametric changes in [¹⁸F]FLT uptake occurred independent from changes in perfusion.

Trial registration

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

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