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

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 SUV_max 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 SUV_max 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 SUV_max in the primary tumor were 2.63 for RFS and 2.66 for OS. A high uptake of ⁶⁸Ga-NOTA-AE105 (SUV_max 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 SUV_max 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 SUV_max, ¹⁸F-FDG SUV_max, TNM stage, and p16 status, only ⁶⁸Ga-uPAR SUV_max 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 SUV_max 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.

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