A prospective clinical study of the influence of oral protein intake on [18F]FET-PET uptake and test-retest repeatability in glioma

Abstract

Background: O-(2-[¹⁸F]fluoroethyl)-L-tyrosine positron emission tomography ([¹⁸F]FET PET) scanning is used in routine clinical management and evaluation of gliomas with a recommended 4 h prior fasting. Knowledge of test-retest variation of [¹⁸F]FET PET imaging uptake metrics and the impact of accidental protein intake can be critical for interpretation. The aim of this study was to investigate the repeatability of [¹⁸F]FET-PET metrics and to assess the impact of protein-intake prior to [¹⁸F]FET PET scanning of gliomas.

Results: Test-retest variability in the non-protein group was good with absolute (and relative) upper and lower limits of agreement of + 0.15 and - 0.13 (+ 9.7% and - 9.0%) for mean tumour-to-background ratio (TBR_mean), + 0.43 and - 0.28 (+ 19.6% and - 11.8%) for maximal tumour-to-background ratio (TBR_max), and + 2.14 cm³ and - 1.53 ml (+ 219.8% and - 57.3%) for biological tumour volume (BTV). Variation was lower for uptake ratios than for BTV. Protein intake was associated with a 27% increase in the total sum of plasma concentration of the L-type amino acid transporter 1 (LAT1) relevant amino acids and with decreased standardized uptake value (SUV) in both healthy appearing background brain tissue (mean SUV - 25%) and in tumour (maximal SUV - 14%). Oral intake of 24 g of protein 1 h prior to injection of tracer tended to increase variability, but the effects on derived tumour metrics TBR_mean and TBR_max were only borderline significant, and changes generally within the variability observed in the group with no protein intake.

Conclusion: The test-retest repeatability was found to be good, and better for TBR_max and TBR_mean than BTV, with the methodological limitation that tumour growth may have influenced results. Oral intake of 24 g of protein one hour before a [¹⁸F]FET PET scan decreases uptake of [¹⁸F]FET in both tumour and in healthy appearing brain, with no clinically significant difference on the most commonly used tumour metrics.

Keywords: Amino acid positron emission tomography; Brain tumour; Glioma; Neuro-oncology; Test–retest.

Fig. 1

Inclusion flow diagram of the study population

Fig. 2

The influence of protein intake on [¹⁸F]FET PET uptake in tumour and extracerebral tissue. Left to right: post contrast T1 weighted MRI, baseline [¹⁸F]FET PET and intervention [¹⁸F]FET PET. Images are normalized to mean activity of a cortical background region. Repeat [¹⁸F]FET PET without oral protein intervention is shown in panel A and [¹⁸F]FET PET with and without oral protein intervention are shown in panel B-D. Note markedly relatively higher uptake in extracranial soft-tissue (yellow arrows), and also higher vascular activity in the post–protein intervention scans. A Patient #11, a 68-year-old female with oligodendroglioma, WHO grade 2. Baseline [¹⁸F]FET PET showed mild uptake in the left occipital region indicating active residual tumour with TBR_max of 1.75 and BTV of 1.06 ml. Seven days later a fasting intervention [¹⁸F]FET PET showed stable metrics (TBR_max 1.86 and BTV 0.66 ml). B Patient #2, a 65-year-old male with glioblastoma, WHO grade 4. Baseline [¹⁸F]FET PET showed mild-to-moderate uptake in left posterior frontal region with TBR_max of 1.99 and BTV of 8.0 ml. The protein intervention scan after consumption of 24 g of protein three days prior showed only slightly higher TBR_max of 2.18 and BTV of 9.2 ml. C Patient #1, a 56-year-old male with glioblastoma, WHO grade 4. Baseline [¹⁸F]FET PET showed mild uptake in splenium with TBR_max of 1.99 and BTV of 1.0 ml. The protein intervention scan after consumption of 48 g of protein three days later showed markedly higher TBR_max of 2.70 and BTV of 7.6 ml. D [¹⁸F]FET-PET with and without oral protein intervention: Patient #5, a 42-year-old male with astrocytoma, IDH mutant, WHO grade 3. [¹⁸F]FET PET showed uptake in the right frontoparietal region (TBR_max 4.56 and BT 34.4 ml). For the intervention scan seven days later scan 24 g of protein was consumed yielding an increase in TBR_max to 4.69 and BTV to 47.3 ml. The patient died two weeks after the intervention scan and increasing volume could reflect both protein-intake and tumour growth

Fig. 3

Plasma LAT1-relevant AMAs after protein intake. Sum of LAT1-relevant AMAs (TYR, LEU, ILE, VAL, PHE, TRP, MET and HIS) acid in five patients in the PC group measured at baseline (t = 0) and again after 30, 60 and 100 min

Fig. 4

Test–retest repeatability. Scatter and Bland–Altman plots of TBR_max and BTV in the NP group (open circles). Observations from the PC group are shown superimposed (filed circles and + for single patient with double protein intake). In scatter plots dotted lines shows line of identity and coloured dashed lines show regression lines for the NP (green) and the 24g PC (red) groups. Dashed lines represent line of identity in scatter plot bias (black) and limits of agreement of the NP group (green) in Bland–Altman plots. Limits of agreement of groups combined are also shown (red)

Fig. 5

Relative change in [¹⁸F]FET PET metrics and PET-RANO criteria. Plots shows relative (%) change from baseline to intervention in patients with BTV above (hollow circles) and below (filled circles) PET RANO target lesion threshold in non-protein (NP) protein-consumption (PC) group. Dashed lines show PET RANO limits for stable disease