New Frontiers in Prostate Cancer Imaging: Clinical Utility of Prostate-Specific Membrane Antigen Positron Emission Tomography - Beyond the Abstract

The diagnosis, staging, and management of prostate cancer (PCa) are largely imaging dependent. Current guidelines recommend using multiparametric MRI (mpMRI) and planar bone scintigraphy. Because of the limitations of these tests, the diagnosis and follow-up of PCa continue to remain challenging. Recently, positron emission tomography (PET) CT has had an increasing role in PCa management. Prostate-specific membrane antigen (PSMA) is a glycoprotein overexpressed in PCa cells. PET scanning using Gallium 68 (68Ga) radiolabeled agents targeting PSMA leads to higher sensitivity for the detection of PCa and its metastases.

PCa patients have a risk of developing recurrent disease after radical treatment, evidenced by a rising serum PSA. The clinical need for a more sensitive tool for early detection of recurrence exists because current modalities struggle to identify disease at a low PSA level successfully and because early detection of recurrent disease allows optimal treatment. Compared with choline PET, PSMA has been found superior in disease detection. Higher Gleason grade tumors express more PSMA receptors and hence why a higher Gleason score and unfavorable PSA kinetics correlate with positive PSMA imaging.

While multiparametric MRI is currently the gold standard for the staging of primary PCa, the accuracy of MRI reduces with small-volume and low-grade disease. Early data on primary tumor evaluation suggest the superiority of PSMA PET over MRI, including a lack of impact on the uptake after a biopsy. However, false-negative results may occur because up to 10% of PCa may be PSMA-negative. Tumors located adjacent to areas of high physiological tracer uptake, small tumors, and those with neuroendocrine differentiation seen in high-grade and high-stage disease may offer false-negative results as well. Overall, there is an increase in sensitivity and specificity when using 68Ga-PSMA PET and mpMRI together.

Most PCa lymph node metastases demonstrate very high levels of PSMA, with a sensitivity of 65.9% and specificity of 98.9% for nodal staging with PSMA PET scans. These rates compare well with the sensitivity of choline PET (49.2%, specificity of 95%) and the even more reduced sensitivity and specificity for CT (42 and 82%) and MRI (39 and 82%). Although micrometastatic nodal disease may still escape detection, PSMA appears to be the most accurate method available of imaging-based nodal assessment, especially in combination with mpMRI.

Although planar bone scintigraphy has long been the standard for diagnosing bone metastases, whole-body MRI is more accurate. The combination of PSMA with whole-body MRI to detect nodal, bone and other sites of disease detection offer a possible one-stop approach to staging. 68Ga-PSMA PET/MRI is superior to 68Ga-PSMA PET/CT for PCa diagnosis and node and bone lesion detection even though bone metastases tend to demonstrate less avid 68Ga-PSMA uptake than nodal sites of disease.

Possible future applications of  68Ga-PSMA PET for diagnosis and treatment of advanced disease include guidance towards treatment options including chemotherapy or radionuclide therapy. Semiquantitative assessment of metastatic sites may offer a method for assessing response to treatment. PSMA ligands labeled with 188Re (Rhenium) or 177Lu (Lutetium) and can act as theranostic agents for radio-guided surgery or endo-radiotherapy.

Newer agents are under development. These include 18F (Fluorine) labeled compound which could be mass-produced via cyclotrons and become more widely available. 18F-DCFBC has been evaluated and shown to identify more bone metastases than bone scintigraphy or CT and also distinguish between high- and low-grade primary PCa. A second-generation 18F-labelled agent, 18F-DCFPyLhas been shown to demonstrate greater metastatic and primary lesion conspicuousness than 18F-DCFBC or  68Ga-PSMA. Future work may include modification of the PSMA molecule itself, which could alter the function and increase sensitivity.

Written by: Asim Afaq, MD, Deepak Batura, MBBS, MS, MCh, FRCS, and Jamshed Bomanji, MD, PhD, FRCR, FRCP,

Institute of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, Euston Road, London, UK., Department of Urology, London North West Healthcare NHS Trust, Watford Road, London, UK. 

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