Biochemical recurrence (BCR) occurs in 20–50% of patients with localized prostate cancer (PC) after radical prostatectomy (RP). Conventional imaging often fails to detect early local or systemic recurrences at low PSA levels. Positron emission tomography/computed tomography (PET/CT) with 18F-DCFPyL PSMA offers improved sensitivity and specificity for detecting recurrent disease. This study evaluates the diagnostic capability of 18F-DCFPyL PET/CT in early BCR of PC following RP and its impact on therapeutic decision-making and clinical management. Methods: In a prospective study, 85 patients with BCR (PSA 0.2–2.0 ng/mL) and negative conventional imaging underwent 18F-DCFPyL PET/CT. Detection rates (DRs) were analyzed against clinical variables, including PSA levels and PSA doubling time (DT-PSA). Lesions were classified into local recurrence, lymph node involvement, bone, and visceral disease. Therapeutic decisions were adjusted based on PET/CT findings. Results: 18F-DCFPyL PET/CT identified lesions in 53% of patients, with DRs of 31.3%, 60%, and 77.8% for PSA levels <0.5, 0.5–1, and >1 ng/mL, respectively. DRs were significantly associated with shorter DT-PSAs (<6 months: 61.5%). The lesions detected included 22.2% local recurrences, 51.1% lymph node disease, 20% bone, and 6.7% visceral involvement. ROC analysis determined optimal PSA and DT-PSA cutoffs of 0.55 ng/mL and 9.2 months, respectively. Therapeutic strategies were modified in 84.4% of PET-positive cases. Conclusions: 18F-DCFPyL PET/CT demonstrates high sensitivity for detecting recurrent PC at low PSA levels, significantly impacting therapeutic decisions and optimizing clinical management. These findings support its integration into guidelines for managing early BCR of PC.
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