Reproducibility of 18F-fluoromisonidazole intratumour distribution in non-small cell lung cancer

Abstract

Background: Hypoxic tumours exhibit increased resistance to radiation, chemical, and immune therapies. ¹⁸F-fluoromisonidazole (FMISO) positron emission tomography (PET) is a non-invasive, quantitative imaging technique used to evaluate the presence and spatial distribution of tumour hypoxia. To facilitate the use of FMISO PET for identification of individuals likely to benefit from hypoxia-targeted treatments, we investigated the reproducibility of FMISO PET spatiotemporal intratumour distribution in patients with non-small cell lung cancer (NSCLC).

Methods: Ten patients underwent ¹⁸F-fluorodeoxyglucose (FDG) PET/CT scans, followed by two FMISO PET/CT scans 1-2 days apart. Nineteen lesions in total were segmented from co-registered FDG PET image sets. Volumes of interest were also defined on normal contralateral lung and subscapularis muscle. The Pearson correlation coefficient r was calculated for mean standardized uptake values (SUV) within investigated volumes of interest and for voxels within tumour volumes (r _TV). The reproducibility of FMISO voxelwise distribution, SUV- and tumour-to-blood ratio (TBR)-derived indices was assessed using correlation and Bland-Altman analyses.

Results: The SUV_max, SUV_mean, TBR_max, and TBR_mean were highly correlated (r ≥ 0.87, p < 0.001) and were reproducible to within 10-15 %. The mean r _TV was 0.84 ± 0.10. 77 % of voxels identified as hypoxic on one FMISO scan were confirmed as such on the other FMISO scan. Mean voxelwise differences between TBR values as calculated from pooled data including all lesions were 0.9 ± 10.8 %.

Conclusions: High reproducibility of FMISO intratumour distribution in NSCLC patients was observed, facilitating its use in determining the topology of the hypoxic tumour sub-volumes for dose escalation, in patient stratification strategies for hypoxia-targeted therapies, and in monitoring response to therapeutic interventions.

Trial registration: Current Controlled Trials NCT02016872.

Keywords: 18F-fluoromisonidazole; Hypoxia; Non-small cell lung cancer; Quantification; Reproducibility.

Fig. 1

Reproducibility of FMISO intratumor distribution in patients with NSCLC. Voxelwise scatter plots of tumour-to-blood ratio in FMISO1 (x-axis) vs. FMISO2 (y-axis) are presented for all 19 lesions. Black, blue, and red voxels represent normoxic, hypoxia-ambiguous, and hypoxic tumour sub-volumes, respectively, as based on the TBR ≥ 1.2 threshold (dashed lines). Equality lines (dotted) and r _TV are also displayed for all scatter plots. r _TV values were significant in all cases

Fig. 2

FMISO PET images of two patients with non-small cell lung cancer. From left to right: coronal, axial, and sagittal slices showing the first (upper row) and second (lower row) FMISO PET scans of a patient #2 (lesion #2) and b patient #5 (lesion #7). PET images are windowed at 0–1.8 (a) and 0–1.4 (b) tumour-to-blood ratio, respectively

Fig. 3

Bland-Altman analysis results for pooled data from all 19 lesions. Relative differences in voxelwise TBR values are shown against the average value combined from the two FMISO scans. Mean and both upper and lower limits of agreement (LoA) are displayed as red and blue lines, respectively