PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges

Abstract

Background: Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies.

Methods: A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa.

Results: Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease.

Conclusions: However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.

Figure 1

Chemical structures of (a) ⁶⁸Ga-PSMA-HBED-CC, the most common ⁶⁸Ga-labeled PSMA radiotracer and two ¹⁸F-labeled agents, (b) ¹⁸F-DCFBC and (c) ¹⁸F-DCFPyL. Note the urea moiety common to all three radiotracers that allows for high-affinity binding to the active site of PSMA. PSMA, prostate-specific membrane antigen. HBED-CC, N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N′-diacetic acid.

Figure 2

(a) Axial ¹⁸F-DCFBC PET and (b) PET/CT images through the pelvis at the level of the prostate in a patient with Gleason 4+5 = 9 PCa in the anterior apex (red arrowheads, maximum SUV 4.1 (lean body mass corrected)). In a small series of patients, the degree of uptake of this radiotracer was shown to positively correlate to Gleason score. (c) Axial T2-weighted images demonstrate a correlating low-signal abnormality in the same location (red arrowheads). The apparent diffusion coefficient MRI sequence acquisition had a great deal of intrinsic noise in this case and was of limited diagnostic utility (not shown). CT, computed tomography; MRI, magnetic resonance imaging; PCa, prostate cancer; PET, positron emission tomography; SUV, standardized uptake value.

Figure 3

(a) Axial pre-operative ¹⁸F-DCFPyL PET and (b) PET/CT images through the pelvis in a patient with NCCN high-risk primary PCa (cT2c, PSA = 125.5 ng ml⁻¹, Gleason 3+5 = 8) and no definitive evidence of pelvic lymph node metastases on CECT. Red arrowheads indicate intense radiotracer uptake in a 6-mm short axis diameter left external iliac lymph node that was subsequently proven to be disease involved following radical prostatectomy and pelvic lymph node dissection. The patient's primary disease was also radiotracer-avid but is below the level of this image. At midline, a large amount of radioactivity is present within the urinary bladder lumen. CECT, contrast-enhanced computed tomography; CT, computed tomography; NCCN, National Comprehensive Cancer Network; PCa, prostate cancer; PET, positron emission tomography.

Figure 4

(a) ¹⁸F-DCFPyL PET and (b) ¹⁸F-DCFPyL PET/CT images from a patient with biochemical recurrence following radical prostatectomy (PSA 0.3 ng dl⁻¹ at the time of imaging). Subtle increased radiotracer uptake is seen in the right prostate bed (red arrowheads) compatible with local recurrence of disease (uptake in the urinary bladder is present anteromedial to the local recurrence). The patient subsequently underwent salvage radiotherapy with a boost to the region of ¹⁸F-DCFPyL uptake and PSA level became undetectable. The lack of radiotracer uptake outside of the typical salvage pelvic radiation field increased the confidence level of the treating clinicians that salvage radiotherapy was the appropriate course of action in this patient. CT, computed tomography; PET, positron emission tomography.

Figure 5

An unusual case of oligometastatic prostate cancer with treatment guided by PSMA PET. (a) Coronal fused image from ¹⁸F-DCFPyL PET/CT demonstrating intense radiotracer uptake at the left skull base, highly suspicious for a site of metastatic PCa (red arrowhead, maximum SUV 18.4 (lean body mass corrected)). No other abnormal uptake was appreciated on the PET/CT. High uptake within the salivary glands is partly imaged, a known aspect of the normal biodistribution of PSMA-targeted radiotracers. (b) Coronal T1-weighted fat saturation post-contrast MRI demonstrating intense abnormal enhancement at the left skull base (red arrowhead), compatible with metastatic PCa. The patient was treated with stereotactic ablative radiotherapy with subsequent decrease in serum PSA. CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SUV, standardized uptake value.