The Role of Prostate-specific Membrane Antigen Positron Emission Tomography for Assessment of Local Recurrence and Distant Metastases in Patients with Biochemical Recurrence of Prostate Cancer After Definitive Treatment: A Systematic Review and Meta-analysis

Background and objective: Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) radioligands has an established role in the assessment of recurrence of prostate cancer (PC) after primary treatment. However, an updated understanding of its diagnostic utility is warranted, particularly in the context of emerging targeted and systemic treatment options for recurrent PC. Our aim was to evaluate the diagnostic performance of PSMA PET for staging and detection of local or metastatic disease in patients with biochemical recurrence (BCR) following definitive treatment for PC. Methods: We conducted a systematic review (Web of Science/MEDLINE, Cochrane Library, and EMBASE from inception to April 25, 2024) and meta-analysis. Eligible retrospective and prospective studies had extractable data on PSMA PET for patients with BCR after radical prostatectomy (RP) or radiation therapy (RT). Risk of bias was assessed using the QUADAS-2 tool. Random-effects models were used to evaluate PSMA PET positivity rates across clinical subgroups stratified by PSA, primary treatment, PSMA PET radioligand, and anatomic lesion sites. Key findings and limitations: A total of 43 studies (8119 patients) were included. PSMA PET positivity rates varied substantially among patients with BCR after primary definitive treatment, with significant study heterogeneity (τ2 = 0.6; p < 0.001), which was mitigated in part after stratification by PSA category. Positivity rates were significantly higher after RT (92%) than after RP (60%; p < 0.001). PSMA PET positivity by anatomic location was 23% for local recurrence, 32% for pelvic nodes, 14% for extrapelvic nodes, 16% for bone metastases, and just 1% for visceral metastases. The positivity rate increased with PSA, from 48% at PSA 0.2–0.5 ng/ml to >90% at PSA >2 ng/ml. Gleason score (GS) at RP did not significantly influence the positivity rate (50% for GS ≤7 vs 62% for GS 8–10; p = 0.08). Heterogeneity limits the generalisability of our findings. Conclusions and clinical implications: We observed substantial variability in PSMA PET positivity rates in BCR because of significant study heterogeneity, mostly related to differences in treatment type, PSA, and anatomic sites. In post-RP BCR, approximately half of patients undergoing PSMA PET had positive findings, even at low PSA (0.2–0.5 ng/ml). In the post-RT setting, PSMA PET use was generally aligned with the Phoenix criterion for BCR, with most studies performing PSMA PET at PSA ≥2 ng/ml. Further research is needed to refine PSA thresholds for PSMA PET, particularly in the post-RT setting, and to assess its role in guiding salvage treatment decisions.