Tumor Delineation and Quantitative Assessment of Glucose Metabolic Rate within Histologic Subtypes of Non–Small Cell Lung Cancer by Using Dynamic ¹⁸F Fluorodeoxyglucose PET

Abstract

Purpose To assess whether dynamic fluorine 18 (F) fluorodeoxyglucose (FDG) positron emission tomography (PET) has added value over static F-FDG PET for tumor delineation in non-small cell lung cancer (NSCLC) radiation therapy planning by using pathology volumes as the reference standard and to compare pharmacokinetic rate constants ofF-FDG metabolism, including regional variation, between NSCLC histologic subtypes. Materials and Methods The study was approved by the institutional review board. Patients gave written informed consent. In this prospective observational study, 1-hour dynamic F-FDG PET/computed tomographic examinations were performed in 35 patients (36 resectable NSCLCs) between 2009 and 2014. Static and parametric images of glucose metabolic rate were obtained to determine lesion volumes by using three delineation strategies. Pathology volume was calculated from three orthogonal dimensions (n = 32). Whole tumor and regional rate constants and blood volume fraction (V) were computed by using compartment modeling. Results Pathology volumes were larger than PET volumes (median difference, 8.7-25.2 cm; Wilcoxon signed rank test, P < .001). Static fuzzy locally adaptive Bayesian (FLAB) volumes corresponded best with pathology volumes (intraclass correlation coefficient, 0.72; P < .001). Bland-Altman analyses showed the highest precision and accuracy for static FLAB volumes. Glucose metabolic rate and F-FDG phosphorylation rate were higher in squamous cell carcinoma (SCC) than in adenocarcinoma (AC), whereas V was lower (Mann-Whitney U test or t test, P = .003, P = .036, and P = .019, respectively). Glucose metabolic rate, F-FDG phosphorylation rate, and V were less heterogeneous in AC than in SCC (Friedman analysis of variance). Conclusion Parametric images are not superior to static images for NSCLC delineation. FLAB-based segmentation on static F-FDG PET images is in best agreement with pathology volume and could be useful for NSCLC autocontouring. Differences in glycolytic rate and V between SCC and AC are relevant for research in targeting agents and radiation therapy dose escalation. RSNA, 2016 Online supplemental material is available for this article.

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

“…Squamous cell carcinomas are phenotypically characterized by a hypoxic tumor microenvironment, a microenvironmental characteristic associated with radioresistance . Squamous cell NSCLCs have a poor vascularization, more often show necrosis, demonstrate GLUT1 and MCT4 expression in a hypoxia‐related pattern, and show a higher rate constant of cytoplasmic phosphorylation of 18 F‐FDG and lower blood volume fraction on dynamic 18 F‐FDG‐PET . This hypoxic tumor microenvironment activates the hypoxia‐inducible factor 1 (HIF‐1) pathway.…”

“…41 These results support the linkage between oncogenicmutated KRAS and EGFR signaling and aerobic glycolysis and glutamine metabolism in adenocarcinomas, 38,40,42 and are in agreement with tumor microenvironmental characteristics: adenocarcinomas show better vascularization relative to squamous cell carcinomas, GLUT1 and MCT4 expression in a nonhypoxia-related pattern, and a lower rate constant of cytoplasmic phosphorylation of 18 F-FDG and higher blood volume fraction on dynamic 18 F-FDG-PET. [17][18][19] However, a limitation is the descriptive character of this study. These associations between mutations and expression of metabolismrelated markers do not necessarily imply that these mutations regulate metabolism of lung adenocarcinoma.…”

“…Our previous analyses showed differences in GLUT1, CAIX, and MCT1 expression, vascular density and 18-fluoro-2-deoxyglucose ( 18 F-FDG) uptake between adeno-and squamous cell NSCLCs, supporting differences in glucose tumor metabolism among NSCLC histological subtypes. [17][18][19] In view of the association between glucose metabolism and aggressive tumor behavior, and the worse prognosis in predominantly micropapillary and solid adenocarcinomas, we further explored glucose and glutamine metabolism-related markers in this study within squamous cell NSCLC and subclassifications of adenocarcinomas. Furthermore, expression of metabolism-related markers was correlated with mutational status to examine oncogenic mutations that are associated with reprogrammed tumor metabolism in NSCLC.…”

CD147‐mediated glucose metabolic regulation contributes to the predictive role of 18F‐FDG PET/CT imaging for EGFR‐TKI treatment sensitivity in NSCLC

“…Among the multiple underlying molecular mechanisms of such resistance, secondary mutations in the EGFR kinase domain, particularly the T790M mutation, have been found in approximately 50% of refractory tumors in patients . Moreover, EGFR‐TKIs have also been found to be effective in 10‐20% of patients without EGFR mutations …”

“…Given the limitations in determining EGFR activity and EGFR mutation status due to tissue availability and tumor heterogeneity, a noninvasive, direct radiographic method for the early detection of EGFR‐TKI sensitivity is needed. Deoxy‐2‐[ 18 F]‐fluoro‐D‐glucose positron emission tomography with computed tomography ( 18 F‐fluorodeoxyglucose [ 18 F‐FDG] PET/CT) is an effective means for staging NSCLC patients and is now part of routine staging protocols . Furthermore, 18 F‐FDG PET/CT has also been illustrated as a reliable tool for detecting early molecular responses to erlotinib in NSCLC .…”