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

<b>Purpose:</b> The aim of this phase II 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 to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). <b>Materials and Methods:</b> Patients with head and neck squamous cell carcinoma (HNSCC) referred to curatively intended radiotherapy were eligible and prospectively included in this phase II study. A ⁶⁸Ga-uPAR- and ¹⁸F-FDG-PET/CT were performed before initiation of curatively intended radiotherapy and maximum standardized uptake values (SUV_max) of the primary tumor was measured on both PET/CTs by two independent readers. Relapse-free survival (RFS) and overall survival (OS) were calculated and optimal cut-off values were established for ⁶⁸Ga-uPAR- and ¹⁸F-FDG-PET independently and compared using log rank and Kaplan-Meier statistics, and univariate and multivariate analysis in Cox proportional hazards model. <b>Results:</b> A total of 57 patients were included and followed for a median of 33.8 months (range 2.30-47.2). The median SUV_max of the primary tumors were 2.98 (range 1.94-5.24) for ⁶⁸Ga-uPAR and 15.7 (range 4.24-45.5) for ¹⁸F-FDG. The optimal cut-off points for ⁶⁸Ga-NOTA-AE105 SUV_max in the primary tumor was 2.63 for RFS and 2.66 for OS. A high uptake of ⁶⁸Ga-NOTA-AE105 (SUV_max above cut-off) was significantly associated with poor RFS and OS (log-rank <i>P</i> = 0.012 and <i>P</i> = 0.022). ⁶⁸Ga-NOTA-AE105-uptake in the primary tumor was significantly associated with poor RFS in univariate analysis (HR=8.53 (95% confidence interval (CI) 1.12-64.7), <i>P</i> = 0.038) and borderline associated with OS (HR=7.44 (95% CI 0.98-56.4), <i>P</i> = 0.052). For ¹⁸F-FDG-PET, the optimal cut-off points were 22.7 for RFS and 22.9 for OS. ¹⁸F-FDG SUV_max above cut-off was significantly associated with reduced RFS (log-rank <i>P</i> = 0.012) and OS (log-rank <i>P</i> = 0.000). ¹⁸F-FDG-uptake was significantly associated with reduced RFS and OS in univariate analysis (HR=3.27; 95% CI 1.237-8.66), <i>P</i> = 0.017) and (HR=7.10; 95% CI 2.60-19.4), p&lt;0.001). In a multivariate analysis including ⁶⁸Ga-uPAR SUV_max, ¹⁸F-FDG SUV_max, Tumor, Node and Metastasis (TNM) stage and p16 status, only ⁶⁸Ga-uPAR SUV_max remained significant (HR 8.51 (95%CI 1.08-66.9), <i>P</i> = 0.042) for RFS. For OS, only TNM stage and ¹⁸F-FDG remained significant. <b>Conclusion:</b> The current phase II clinical trial showed promising results for the use of ⁶⁸Ga-uPAR-PET SUV_max in the primary tumor to predict RFS in HNSCC patients referred to curatively intended radiotherapy when compared to ¹⁸F-FDG-PET, TNM stage and p16 status. ⁶⁸Ga-uPAR-PET could potentially become valuable for identification of patients suited for de-escalation of treatment and risk stratified follow-up schemes.

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