68Ga-PSMA Cerenkov luminescence imaging in primary prostate cancer: first-in-man series

Abstract

Purpose: Currently, approximately 11-38% of prostate cancer (PCa) patients undergoing radical prostatectomy have a positive surgical margin (PSM) on histopathology. Cerenkov luminescence imaging (CLI) using ⁶⁸Ga-prostate-specific membrane antigen (⁶⁸Ga-PSMA) is a novel technique for intraoperative margin assessment. The aim of this first-in-man study was to investigate the feasibility of intraoperative ⁶⁸Ga-PSMA CLI. In this study, feasibility was defined as the ability to distinguish between a positive and negative surgical margin, imaging within 45 min and low radiation exposure to staff.

Methods: Six patients were included in this ongoing study. Following perioperative i.v. injection of ~ 100 MBq ⁶⁸Ga-PSMA, the prostate was excised and immediately imaged ex vivo. Different acquisition protocols were tested, and hotspots on CLI images from the intact prostate were marked for comparison with histopathology.

Results: By using an acquisition protocol with 150 s exposure time, 8 × 8 binning and a 550 nm shortpass filter, PSMs and negative surgical margins (NSMs) were visually correctly identified on CLI in 3 of the 5 patients. Two patients had a hotspot on CLI from cancer < 0.1 mm from the excision margin.

Conclusion: Overall, the study showed that ⁶⁸Ga-PSMA CLI is a feasible and low-risk technique for intraoperative margin assessment in PCa. The remaining patients in this ongoing study will be used to assess the diagnostic accuracy of the technique.

Trial registration: NL8256 registered at www.trialregister.nl on 04/11/20109.

Keywords: 68-Gallium-PSMA intraoperative assessment; Cerenkov imaging; Positive surgical margin; Primary prostate cancer.

Fig. 1

Workflow of the current CLI study, a A preoperative ⁶⁸Ga-PSMA PET-CT and MRI scan are acquired 3–4 weeks prior to surgery as per standard of care, based on the result of these images patients are included. b During surgery ⁶⁸Ga-PSMA is administered i.v. after the da Vinci® surgical system is docked. Radiation dose to all surgical staff is monitored. Note the position of the scrub nurse in close proximity to the patient. Once removed, the prostate is rinsed with NaCl to clear any radioactive urine and blood that could be present on the surface. c The prostate is positioned in a disposable specimen tray. d Images of all six sides of the prostate using the different settings are acquired in the CLI device. e Unfiltered Cerenkov image of the intact prostate specimen. f Upon image completion of the intact prostate, the prostate is inked and cleaved ~ 1 cm from the apex by a trained person. g Image of the cleaved prostate and the corresponding CLI image acquired with the same settings as the intact specimen to confirm tumour uptake and quantify the intensity in benign and cancerous tissue

Fig. 2

Overview of the image analysis and quantification methods. a Intraoperative Cerenkov image of the specimen after median and Gaussian filtering. This image is used for visual identification of PSMs and NSMs. b A Cerenkov image of an empty background. Note the presence of the defective pixel (green arrow). c Post-processed Cerenkov image after background subtraction. Note that the background subtraction removes the defective pixel on the post-processed image. d The PSMA PET/CT scan. The green line on the maximum intensity profile (MIP) image indicates the location where the prostate is cleaved. The transverse image of the fused PET/CT scan highlights the location of the tumour (red ROI) and benign tissue (blue ROI). e Intraoperative CLI image of the prostate from patient 2 after the specimen was cleaved at the apex, showing the tumour (red ROI) and the benign tissue (blue ROI). f CLI image of intact prostate specimen from patient 2. Two hotspots, corresponding with a histopathological PSM, can be identified (ROI 1 and ROI 3). Areas with no increased signal, corresponding with benign tissue from a NSM, can also be seen (ROI 2). For clarity, each ROI is also highlighted with a green arrow. For this patient the TBR was calculated by dividing the radiance from ROI 1 and ROI in 2. The dotted white line represents the location where the prostate was cleaved. g Histopathology image of the area corresponding with ROI 3 on the intact CLI image. A PSM can be identified (green arrow)

Fig. 3

Results of protocol optimisation process with different acquisition settings. The images in the upper row are from patient 1 who had a histopathological PSM at the apex. All images were acquired with 8 × 8 pixel binning and 550 nm shortpass filter but with different exposure times of 30 s (TBR:1.10), 60 s (TBR:1.18), 150 s (TBR:1.85) and 300 s (TBR:1.98). The images in the centre row are also from patient 1and were acquired with 150 s exposure time and filter, but different pixel binning 2 × 2 (TBR:1.06), 4 × 4 (TBR:1.26) and 8 × 8 (TBR:1.85). The bottom row images are from patient 3 and were acquired with 150 s exposure time and 8 × 8 binning, but without a filter (TBR:4.33) and with filter (TBR:1.85), respectively. Note that the area of increased signal with the green arrow appears in all non-background subtracted images; this is an artefact from a defect pixel in the camera of the CLI system, and can be ignored. The colour bar indicates the scale of counts

Fig. 4

An overview of the PET/CT scans and CLI images of all five patients. a The MIP of the PSMA PET-scan. Note that these scans were obtained using ⁶⁸Ga-HBEDCC-PSMA (patient 5) and ¹⁸F-DCFPyl (patient 1, 2, 3, 4), hence the difference in PSMA-tracer distribution. b The transverse image of the fused PSMA PET/CT-scan at the level of the prostate lesion. c Non-filtered CLI images of intact prostate specimen. Note that patient one did not have a non-filtered image taken. d Filtered CLI images of intact prostate specimen. e Non-filtered CLI images of the cleaved prostate. The prostate specimen was cleaved at ~ 1 cm from the apex. Note that in patient 3, it was not located in the apex region but in the base, and therefore no tumour signal is visible on the CLI image. Scaling of the PET-scans was performed based on the intensity of the liver; CLI images were scaled visually based on the benign background signal. The displayed CLI images are the intraoperative images that are not corrected for background which explains the presence of the defective pixel. All CLI images were acquired with 150 s exposure time and 8 × 8 binning. *The patient numbers marked with a star had a PSM based on histopathology