Admir Mulita, Eleni Bekou, Pipitsa Valsamaki, Ioannis M. Koukourakis, Francesk Mulita, Elias Liolis, Athanasios Zissimopoulos, Alexandra Giatromanolaki, Koukourakis Mi
Background/Objectives: Precise staging and tumor delineation are essential for optimizing treatment and enhancing outcomes of radiotherapy (RT). While computed tomography (CT)-based RT remains standard, fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) offers improved detection of primary and nodal disease. This study investigates the role of PET/CT in RT planning of HNSCC. Methods: Fifty-one HNSCC patients underwent radical volumetric modulated arc RT with concurrent cisplatin chemotherapy in a prospective study. Two RT plans per patient were sequentially created by a single oncologist using CT-only and PET/CT data, respectively. Planning target volumes (PTVs) for primary and nodal regions were independently defined, and dose–volume histograms were analyzed and compared. Results: PET/CT significantly affected TNM staging, increasing the T-stage in 11.8% of patients and the N-stage in 33.3%. Distant metastases were found in 9.8% of patients, leading to a redefinition of the overall treatment policy. PET/CT-based planning improved primary tumor PTV coverage (PTV4) in 37.2% (19/51) of cases. The tumor areas excluded from the CT-based planning received an average of 85.6% of the prescribed PTV4 dose (range 18–93%), while in PET/CT planning, they received 95.4% (range 93–99%) (p < 0.0001). Nodal PTV areas requiring a booster dose (PTV2) were adjusted in 33.3% (17/51) of patients during PET-CT planning. These nodal areas received an average of 85.6% of the prescribed dose for PTV2 (range 18–93%) during CT planning, compared to 95.4% (range 93–99%) during PET/CT planning. There was no statistically significant difference in the dose received by organs at risk between CT- and PET/CT-RT planning. Conclusions: PET/CT improves target delineation for primary tumors and lymph nodes, also allowing for dose escalation in metabolically highly active lesions in patients with HNSCC. The method also reveals occult distant metastases in a subset of patients, enabling personalized treatment strategies.