Prognostic Value of Urokinase-Type Plasminogen Activator Receptor PET/CT in Head and Neck Squamous Cell Carcinomas and Comparison with 18F-FDG PET/CT: A Single-Center Prospective Study

Abstract

The aim of this phase II clinical trial (NCT02965001) was to evaluate the prognostic value of urokinase-type plasminogen activator receptor (uPAR) PET/CT with the novel ligand 68Ga-NOTA-AE105 in head and neck cancer and compare it with 18F-FDG. Methods: Patients with head and neck squamous cell carcinoma referred for curatively intended radiotherapy were eligible and prospectively included in this study. 68Ga-uPAR and 18F-FDG PET/CT were performed before initiation of curatively intended radiotherapy, and the SUVmax of the primary tumor was measured on both PET/CT studies by 2 independent readers. Relapse-free survival (RFS) and overall survival (OS) were calculated, and optimal cutoffs were established for 68Ga-uPAR and 18F-FDG PET independently and compared using log rank and Kaplan-Meier statistics, as well as univariate and multivariate analysis in a Cox proportional-hazards model. Results: In total, 57 patients were included and followed for a median of 33.8 mo (range, 2.30-47.2, mo). The median SUVmax of the primary tumors was 2.98 (range, 1.94-5.24) for 68Ga-uPAR and 15.7 (range, 4.24-45.5) for 18F-FDG. The optimal cutoffs for 68Ga-NOTA-AE105 SUVmax in the primary tumor were 2.63 for RFS and 2.66 for OS. A high uptake of 68Ga-NOTA-AE105 (SUVmax above cutoff) was significantly associated with poor RFS and OS (log-rank P = 0.012 and P = 0.022). 68Ga-NOTA-AE105 uptake in the primary tumor was significantly associated with poor RFS in univariate analysis (hazard ratio [HR], 8.53 [95% CI, 1.12-64.7]; P = 0.038), and borderline-associated with OS (HR, 7.44 [95% CI, 0.98-56.4]; P = 0.052). For 18F-FDG PET, the optimal cutoffs were 22.7 for RFS and 22.9 for OS. An 18F-FDG SUVmax above the cutoff was significantly associated with reduced RFS (log-rank P = 0.012) and OS (log-rank P = 0.000). 18F-FDG uptake was significantly associated with reduced RFS (HR, 3.27 [95% CI, 1.237-8.66]; P = 0.017) and OS (HR, 7.10 [95% CI, 2.60-19.4]; P < 0.001) in univariate analysis. In a multivariate analysis including 68Ga-uPAR SUVmax, 18F-FDG SUVmax, TNM stage, and p16 status, only 68Ga-uPAR SUVmax remained significant (HR, 8.51 [95% CI, 1.08-66.9]; P = 0.042) for RFS. For OS, only TNM stage and 18F-FDG remained significant. Conclusion: The current trial showed promising results for the use of 68Ga-uPAR PET SUVmax in the primary tumor to predict RFS in head and neck squamous cell carcinoma patients referred for curatively intended radiotherapy when compared with 18F-FDG PET, TNM stage, and p16 status. 68Ga-uPAR PET could potentially become valuable for identification of patients suited for deescalation of treatment and risk-stratified follow-up schemes.

Keywords: 68Ga-NOTA-AE105; PET/CT; head and neck cancer; prognostication; risk stratification; urokinase-type plasminogen activator receptor.

© 2022 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

Graphical abstract

FIGURE 1.

CONSORT (Consolidated Standards of Reporting Trials) flow diagram of inclusion process. HNC = head and neck cancer; UPT = unknown primary tumor.

FIGURE 2.

Delineated tumor volumes of interest in uPAR PET/CT with 68Ga-NOTA-AE105 and 18F-FDG-PET/CT in two cases with discordant tracer uptake. High 68Ga-uPAR/low 18F-FDG uptake (A) and low 68Ga-uPAR/high 18F-FDG uptake (B). Both cases present with stage 3 oropharyngeal cancer (T3N0M0). High and low refers to above or below the established cutoffs.

FIGURE 3.

Kaplan–Meier plots of RFS for 68Ga-uPAR (A), OS for 68Ga-uPAR (B), RFS for 18F-FDG (C), and OS for 18F-FDG (D) stratified by corresponding 68Ga-uPAR and 18F-FDG SUVmax cutoffs.

FIGURE 4.

Kaplan–Meier plots of RFS (A) and OS (B) for concordant and discordant groups: 68Ga-uPAR and 18F-FDG both low (dark blue); 1 low/1 high (turquoise); and both high (green).