Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Abstract

Purpose : The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [ 18 F]fluoromethyl-(1,2- 2 H 4 ) choline ([ 18 F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design : [ 18 F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) scans. Results : Oxidation of [ 18 F]D4-FCH to [ 18 F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [ 18 F]D4-FCH-derived uptake (SUV 60max ) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [ 18 F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [ 18 F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions : [ 18 F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

“…We performed [ 18 F]-D4-FCH dynamic PET scans in mice to gain an understanding of the tumour kinetics and modulation by ABC transporters. Given that the human dynamic scans for this radiotracer are reported in lung cancer [ 14 ], the ABCB4-rich PC-9 human non-small cell lung cancer (NSCLC) xenograft model was used [ 44 ]. Mice were treated with a clinically approved drug in this setting, the epidermal growth factor receptor antagonist (EGFR) gefitinib.…”

“…The recently reported dynamic PET data from the NSCLC patients ( n = 17) scanned with 18 F-D4-FCH were reassessed to investigate the efflux of the [ 18 F]-D4-FCH kinetics [ 14 ]. The pretherapy ~1 h dynamic [ 18 F]-D4-FCH PET/CT scans (maximum dose of 370 MBq) were analysed with graphical and compartmental methods.…”

“…The study cohort was reported recently [ 12 ] and included seventeen patients (mean age ± SD were 64 ± 11 y; age range 39–84 y; weight ± SD, 68.9 ± 15 kg; weight range, 49.7–93.3 kg) with confirmed NSCLC who underwent [ 18 F]-D4-FCH PET/CT [ 14 ]. The parent plasma input function was generated by normalisation to the plasma-over-blood ratio and correcting for metabolites.…”

“…When PET scans with radiolabelled choline tracers, including [ 11 C]choline, are conducted dynamically over time, however, almost all tumours exhibit a rapid radiotracer uptake phase followed by a nearly unchanged time versus radioactivity (TAC) curve, regardless of their stability in oxidation [ 12 , 13 ]. This suggests that other mechanisms may influence the tumour radiolabelled choline biodistribution dynamics [ 14 ].…”

“…Using [ 18 F]-D4-FCH as an exemplar choline radiotracer (from its availability within our lab, representativeness for choline phosphorylation and to avoid a confound of oxidation), the aim of our study was to investigate how hypoxia or HIF-1α regulates the choline radiotracer dynamics and extend the findings to an understanding of the dynamics of radiolabelled choline localisation in mouse xenografts and human NSCLC recently reported by Dubash et al [ 14 ].…”