Diagnostic efficacy of C-X-C motif chemokine receptor 4-directed PET/CT in newly diagnosed head and neck squamous cell carcinoma- a head-to-head comparison with [18F]FDG

Background: The aim of this study was to determine the read-out capabilities of the novel C-X-C motif chemokine receptor 4 (CXCR4)-targeting radiotracer [Ga-68]Ga-PentixaFor compared to the reference radiotracer [F-18]FDG in untreated individuals with head and neck squamous cell carcinoma (HNSCC). Material and Methods: 12 patients with histologically confirmed HNSCC were scheduled for [F-18]FDG and [Ga-68]Ga-PentixaFor PET/CT. Maximum standardized uptake values (SUVmax) and target-to-background ratios (TBR) were applied with vena cava superior serving as reference. In addition, we compared [Ga-68]Ga-PentixaFor-PET findings with immunohistochemical (IHC) results of CXCR4 expression. Results: On visual assessment, [F-18]FDG identified more sites of disease, with increased detection rates for both the primary tumor ([F-18]FDG, 12/12 [100%] vs. [Ga-68]Ga-PentixaFor, 10/12 [83%]) and LN metastases ([F-18]FDG, 9/12 [75%] vs. [Ga-68]Ga-PentixaFor, 8/12 [67%]). Indicative for improved image contrast using [F-18]FDG, quantification showed a higher TBR for the latter radiotracer, when compared to [Ga-68]Ga-PentixaFor for all lesions ([F-18]FDG, 11.7 +/- 8.5 vs. [Ga-68]Ga-PentixaFor, 4.3 +/- 1.3; P=0.03), primary tumors ([F-18]FDG, 13.6 +/- 8.7 vs. [Ga-68]Ga-PentixaFor, 4.4 +/- 1.4; P<0.01), and LN lesions ([F-18]FDG, 9.3 +/- 10.6 vs. [Ga-68] Ga-PentixaFor, 4.7 +/- 1.5; P=0.3). IHC showed variable CXCR4 expression in the primary and LN, along with no associations between ex-vivo CXCR4 upregulation and [Ga-68]Ga-PentixaFor-based TBR (R=0.33, P=0.39) or SUVmax (R=0.44, P=0.2). Of note, IHC also revealed heterogeneous expression of CXCR4 in immune cells in the tumor microenvironment and in germinal centers, indicative for inflammatory reactions. Conclusions: In HNSCC, [F-18]FDG demonstrated superior diagnostic performance relative to [Ga-68]Ga-PentixaFor, in particular for assessment of the primary. Based on the IHC analyses, these findings may be explained by CXCR4 upregulation not only by tumor but also by immune cells in the tumor microenvironment.