Academic Background

Prostate cancer is one of the most common cancers in men worldwide, particularly in Western countries. Despite advances in early diagnosis and treatment significantly improving survival rates, cancer recurrence remains a major clinical challenge. This is particularly true for patients with high-risk nonmetastatic hormone-sensitive prostate cancer (nmHSPC). Managing biochemical recurrence (BCR) after primary therapy in such cases is complex. Conventional imaging techniques (e.g., CT and bone scans) have limitations in detecting metastatic disease and may lead to disease understaging. In recent years, prostate-specific membrane antigen–positron emission tomography (PSMA-PET/CT) has emerged as a promising imaging technique showing superior capability in detecting prostate cancer metastases.

The primary aim of this study was to explore the diagnostic performance of PSMA-PET/CT in high-risk nmHSPC patients and its potential impact on disease staging. Through a retrospective analysis, the research evaluated PSMA-PET/CT’s ability to detect metastatic disease in patients classified as nonmetastatic by conventional imaging and examined its potential influence on clinical decision-making.

Source of the Paper

The paper was authored by Adrien Holzgreve, MD, and colleagues from institutions such as the University of California, Los Angeles (UCLA). It was published on January 3, 2025, in the JAMA Network Open journal under the title “PSMA-PET/CT Findings in Patients With High-Risk Biochemically Recurrent Prostate Cancer With No Metastatic Disease by Conventional Imaging.”

Study Design and Methods

Study Design

This was a retrospective cross-sectional study aimed at analyzing the PSMA-PET/CT imaging findings in patients with high-risk nmHSPC. The study included 182 patients from four prospective studies conducted between September 15, 2016, and September 27, 2021. All patients experienced biochemical recurrence after undergoing radical prostatectomy (RP), definitive radiotherapy (DRT), or salvage radiotherapy (SRT). The primary objective was to describe staging information obtained via PSMA-PET/CT in these patients.

Study Population

From a total of 2,002 screened patients, 182 met the inclusion criteria for the EMBARK trial (a phase III randomized study evaluating enzalutamide with or without leuprolide in high-risk nmHSPC). Inclusion criteria included rising prostate-specific antigen (PSA) levels (PSA > 1.0 ng/mL after RP and SRT; PSA > 2.0 ng/mL after DRT), PSA doubling time ≤ 9 months, and serum testosterone level ≥ 150 ng/dL. Exclusion criteria included distant metastatic disease detected on conventional imaging or previous hormone or systemic therapy.

PSMA-PET/CT Imaging

All patients underwent 68Ga-PSMA-11 PET/CT scans. Prior to imaging, a median dose of 5.0 mCi of 68Ga-PSMA-11 was injected, and PET images were recorded after a median uptake time of 61 minutes. CT contrast agents were administered to 98% of patients. PSMA-PET/CT findings, including location, number, and stage of lesions, were interpreted jointly by a certified nuclear medicine physician and a radiologist.

Statistical Analysis

Statistical analysis was conducted using IBM SPSS Statistics 29. Differences in disease distribution among treatment groups were evaluated using the Pearson χ2 test, and results were compared with original data from the EMBARK trial. Statistical significance was established at P < 0.05 for all two-sided tests.

Results

Patient Characteristics

Among the 182 patients included in the study, 91 (50%) underwent RP, 39 (21%) received DRT, and 52 (29%) received RP followed by SRT. Median PSA levels were 2.4 ng/mL after RP, 6.9 ng/mL after DRT, and 2.6 ng/mL after RP and SRT. PSMA-PET/CT findings were positive in 84% of patients (¹⁵³⁄₁₈₂), detected distant metastases (M1 disease) in 46% (⁸⁴⁄₁₈₂), and revealed polymetastatic disease (≥5 lesions) in 24% (⁴³⁄₁₈₂).

Detection Capability of PSMA-PET/CT

PSMA-PET/CT detected distant metastases in 34% of patients after RP, 56% after DRT, and 60% after RP and SRT. Polymetastatic disease was identified in 19% of patients after RP, 36% after DRT, and 23% after RP and SRT.

Discussion

The study suggests that conventional imaging may underestimate metastatic risk in high-risk nmHSPC patients. PSMA-PET/CT identified positive lesions in 84% of patients and detected distant metastases in 46%, challenging current practices based on conventional imaging. These findings highlight the potential role of PSMA-PET/CT in guiding patient selection and treatment strategies.

PSMA-PET/CT could help identify patients eligible for local or stereotactic body radiotherapy, potentially offering a curative approach in some cases. However, the false-positive rate of PSMA-PET/CT (especially in bone metastases) requires further investigation.

Conclusion

PSMA-PET/CT plays a critical role in disease staging for high-risk nmHSPC, detecting metastatic lesions overlooked by conventional imaging. This evidence supports PSMA-PET/CT as a valuable tool in clinical practice and calls for further research to evaluate its independent prognostic value and role in treatment decision-making.

Key Highlights

1. Key Findings: PSMA-PET/CT identified positive lesions in 84% of high-risk nmHSPC patients, detected distant metastases in 46%, and found polymetastatic disease in 24%.
2. Clinical Significance: Results suggest conventional imaging may understage disease burden, while PSMA-PET/CT provides enhanced staging precision.
3. Innovation: This is one of the first systematic evaluations of PSMA-PET/CT in high-risk nmHSPC patients, offering valuable insights for clinical research.

Limitations

1. Sample Size: The study included a relatively small population, particularly fewer patients undergoing SRT, which may limit generalizability.
2. Retrospective Design: The study design may introduce bias and lacks longitudinal follow-up data.
3. False Positives: The potential for false-positive findings in PSMA-PET/CT, especially in bone metastases, needs further clarification.

Future Directions

Future studies should further explore the prognostic significance of PSMA-PET/CT and evaluate its impact on treatment outcomes. Prospective research with larger patient populations will help validate these findings and refine PSMA-PET/CT’s clinical applications.