Dual time point imaging in locally advanced head and neck cancer to assess residual nodal disease after chemoradiotherapy
Authors: Soffers Frederik , Helsen Nils , Van den Wyngaert Tim , Carp Laurens , Hoekstra Otto S. , Goethals Laurence , Martens Michel , Deben Kristof , Spaepen Karoline , De Bree Remco , De Geeter Frank , Zwezerijnen G. J. C. , Van Laer Carl , Maes Alex , Lenssen Olivier , Stroobants Sigrid ,   the ECLYPS Investigators, Beels Laurence , Cambier Jean-Philippe , Carp Laurens , Deben Kristof , De Bree Remco , Debruyne Philip , De Geeter Frank , Goethals Laurence , Hakim Sara , Helsen Nils , Hoekstra Otto S. , Homans Filip , Hutsebaut Isabel , Lenssen Olivier , Maes Alex , Maes Annelies , Martens Michel , Spaepen Karoline , Specenier Pol , Stroobants Sigrid , van den Weyngaert Daniëlle , Van den Weyngaert Tim , Vanderveken Olivier , van Dinther Joost , Van Laer Carl , Zwezerijnen G.J.C. 
Published: June 2022

Abstract
Background
FDG-PET/CT has a high negative predictive value to detect residual nodal disease in patients with locally advanced squamous cell head and neck cancer after completing concurrent chemoradiotherapy (CCRT). However, the positive predictive value remains suboptimal due to inflammation after radiotherapy, generating unnecessary further investigations and possibly even surgery. We report the results of a preplanned secondary end point of the ECLYPS study regarding the potential advantages of dual time point FDG-PET/CT imaging (DTPI) in this setting. Standardized dedicated head and neck FDG-PET/CT images were obtained 12 weeks after CCRT at 60 and 120 min after tracer administration. We performed a semiquantitative assessment of lymph nodes, and the retention index (RI) was explored to optimize diagnostic performance. The reference standard was histology, negative FDG-PET/CT at 1 year, or > 2 years of clinical follow-up. The time-dependent area under the receiver operator characteristics (AUROC) curves was calculated.

Results
In total, 102 subjects were eligible for analysis. SUV values increased in malignant nodes (median SUV1 = 2.6 vs. SUV2 = 2.7; P = 0.04) but not in benign nodes (median SUV1 = 1.8 vs. SUV2 = 1.7; P = 0.28). In benign nodes, RI was negative although highly variable (median RI = − 2.6; IQR 21.2), while in malignant nodes RI was positive (median RI = 12.3; IQR 37.2) and significantly higher (P = 0.018) compared to benign nodes. A combined threshold (SUV1 ≥ 2.2 + RI ≥ 3%) significantly reduced the amount of false-positive cases by 53% (P = 0.02) resulting in an increased specificity (90.8% vs. 80.5%) and PPV (52.9% vs. 37.0%), while sensitivity (60.0% vs. 66.7%) and NPV remained comparably high (92.9% vs. 93.3%). However, AUROC, as overall measure of benefit in diagnostic accuracy, did not significantly improve (P = 0.62). In HPV-related disease (n = 32), there was no significant difference between SUV1, SUV2, and RI in malignant and benign nodes, yet this subgroup was small.

Conclusions
DTPI did not improve the overall diagnostic accuracy of FDG-PET/CT to detect residual disease 12 weeks after chemoradiation. Due to differences in tracer kinetics between malignant and benign nodes, DTPI improved the specificity, but at the expense of a loss in sensitivity, albeit minimal. Since false negatives at the 12 weeks PET/CT are mainly due to minimal residual disease, DTPI is not able to significantly improve sensitivity, but repeat scanning at a later time (e.g. after 12 months) could possibly solve this problem. Further study is required in HPV-associated disease.