Pharmacokinetic Analysis of Dynamic 18F-Fluoromisonidazole PET Data in Non-Small Cell Lung Cancer

Abstract

Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic analysis (PKA) of ¹⁸F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static ¹⁸ F-FDG and a dynamic ¹⁸F-FMISO scan lasting 168 ± 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estimated for the volumes of interest determined using coregistered ¹⁸F-FDG images for both the volume of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived average values of ¹⁸F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate (k₃) and delivery rate (K₁), influx rate (K_i ) constants, and tissue-to-blood activity concentration ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on average, than those of normal lung and 4.4 times larger than those in muscle. Additionally, for almost all cases, k₃ and K_i had a significant strong correlation for all tissue types. The TBR-k₃ correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K₁-k₃ voxelwise correlations for tumors were varied, but negative for 76% of lesions, globally exhibiting a weak inverse relationship (average R = -0.23 ± 0.39). However, both normal tissue types exhibited significant positive correlations for more than 60% of patients, with 41% having moderate to strong correlations (R > 0.5). Conclusion: All lesions showed distinct ¹⁸F-FMISO uptake. Variable ¹⁸F-FMISO delivery was observed across lesions, as indicated by the variable values of the kinetic rate constant K₁ Except for 3 cases, some degree of hypoxia was apparent in all lesions based on their nonzero k₃ values.

Keywords: 18F-fluoromisonidazole; compartmental analysis; hypoxia; non-small cell lung cancer; pharmacokinetic analysis.

FIGURE 1.

Examples of aortic arch VOI (A) and VOI_Tumor (black), VOI_Normal (blue), and VOI_Muscle (red) (B) time–activity curves (C) corresponding to IF (green), time–activity curve_Avg (black), time–activity curve_Normal (blue), and time–activity curve_Muscle (red).

FIGURE 2.

Total and compartment time–activity curves for patient 1 VOIs determined by PKA: C_model(t) (A), C₁(t) (B), and C₂(t) (C) for time–activity curve_Avg (black), time–activity curve_Normal (blue), and time–activity curve_Muscle (red).

FIGURE 3.

Comparison between kinetic parameters determined for the average time–activity curves of the 3 VOIs investigated (VOI_Tumor, VOI_Normal, and VOI_Muscle): (A) vB, (B) K₁, (C) K₁/k₂, and (E) K_i. Points are labeled as outliers (+) if they are farther than $1.5\times \left(Q_3-Q_1\right)$from the median (midline), where Q₁ and Q₃ are the 25th and 75th percentiles of the sample data, respectively.

FIGURE 4.

Scatterplots of k₃ versus vB (A), K₁/k₂ (B), K₁ (C), K_i (D), and TBR (E), for average time–activity curves: time–activity curve_Avg (black), time–activity curve_Normal (blue), and time–activity curve_Muscle (red). Each point represents 1 lesion (some patients had multiple lesions).

FIGURE 5.

Scatterplot of K₁–k₃ voxelwise correlation versus average k₃ in VOI_Tumor. Each point represents 1 lesion.

FIGURE 6.

Scatterplot of TBR for VOI_Tumor versus K₁–k₃ decile correlation coefficient. Each point represents 1 lesion.