For patients with intermediate and high-risk localized prostate cancer who are being considered for local therapy, pre-treatment staging is important to exclude or at least characterize the burden of metastatic disease. To date, bone scintigraphy and abdominopelvic computed tomography have been utilized even though there are known issues related to poor sensitivity. Prostate-specific membrane antigen (PSMA) based imaging using PET/CT fusion has been increasingly used for patients with recurrent prostate cancer. In the proPSMA study, Dr. Hofman and colleagues set to determine the role of PSMA PET/CT in pre-treatment staging.
They performed a multi-center, two-arm randomized controlled trial among men with histologically confirmed prostate cancer who were being considered for curative intent radical prostatectomy or radiotherapy. To be eligible for inclusion, men must have had at least one high-risk factor including prostate-specific antigen (PSA) greater than or equal to 20 ng/mL, ISUP grade group 3-5, or clinical stage T3 or greater. Patients who had undergoing staging investigations (apart from prostate MRI) within eight weeks prior to randomization were excluded.
Following enrollment, patients were randomly assigned in a 1:1 ratio to either conventional imaging performed using bone scan and CT or PSMA PET/CT. Randomization was stratified according to the center. Patients who were randomized to conventional imaging underwent an abdominopelvic CT scan with contrast as well as a technetium-99m bone scan with SPECT CT of chest, abdomen, and pelvic in keeping with the standard of care. These investigations were assessed in aggregate to determine the presence of findings of interest. For patients randomized to PET/CT, gallium-68 PSMA-11 PET/CT was performed. In patients who had fewer than three unequivocal sites of metastasis, cross-over imaging for confirmation was performed within 14 days. Confirmatory testing following imaging was performed at the discretion of the treating physician and included biopsy confirmation.
The primary study outcome was the accuracy of first-line diagnostic imaging for the identification of either pelvic nodal or distant metastatic disease. Accuracy was assessed using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. The reference standard was a composite panel of histopathology, imaging, clinical, and biochemical characteristics.
The authors estimated a sample size of 300 total patients to achieve a power of 85% to distinguish between conventional imaging with an AUC of 0.65 (sensitivity 0.65 and specificity 0.65) and PET-CT with an AUC of 0.90 (sensitivity 0.90 and specificity 0.90) assuming an event rate of 25% of patients harboring nodal or distant metastatic disease and a two-sided type I error of 0.10.
Between 20017 and 2018, the authors randomly assigned 302 patients of whom 300 received assigned first-line imaging. In keeping with the prostate cancer population, the median age was 68 years, 293 men had ISUP grade 3 or higher, 65 had PSA 20 ng/mL or higher, and 82 had clinical stage T3 or T4. 96% (146) of men assigned to conventional imaging underwent subsequent second-line PSMA PET-CT.
Assessment of the reference standard was possible in 295 (98%) of men, including 87 of whom had evidence of nodal or distant metastasis. Of these, hard criteria were used to define disease in 20 men.
In the primary outcome assessment, PSMA PET-CT had a 27% absolute greater AUC for accuracy compared to conventional imaging (95% confidence interval [CI] 23-31): 92% (95% CI 88-95%) vs. 65% (60-69%). Conventional imaging had both a lower sensitivity (38% vs. 85%) and also a lower specificity (91% vs. 98%).
The authors performed a sensitivity analysis in which all lesions rated as equivocal were considered positive. This changed the results only marginally with an absolute difference of 28% (95% CI 23-33%). These results were also consistent in subgroups of patients with pelvic nodal disease and those with distant metastasis. Further posthoc subgroup analysis showed an incremental benefit for PSMA PET-CT in men with Gleason Grade Group (GGG) 4-5 disease, those with GGG less than or equal to 3, and those with a PSA of 20 ng/mL or greater.
Further, equivocal findings were more common in men undergoing conventional imaging (23%) compared to those undergoing PSMA PET-CT (7%).
Prior to treatment, the results of conventional imaging studies resulted in treatment change for 23 men (15%, 95% CI 10-22) while the results of PSMA PET-CT resulted in treatment change for 41 (28%, 95% confidence interval 21-36). These changes included both a transition from curative intent to palliative intent treatment in 20 patients (14%) and also a change in treatment approach in 22 (14%). These data demonstrate the clinical utility of utilizing PSMA PET-CT in this clinical space.
Further, conventional imaging was associated with a higher radiation dose (19.2 mSv compared to 8.4 mSv; absolute difference 10.9 mSv, 95% CI 9.8-12.0 mSv0. PSMA PET-CT was not associated with any adverse events and reporter agreement was high for both nodal (kappa 0.87, 95% CI 0.81-0.94) and distant metastatic disease (kappa 0.88, 95% CI 0.94-0.92).
Presented by: Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, Professor of Molecular Imaging, The University of Melbourne, Nuclear Medicine Physician, Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Twitter: @WallisCJD at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020
Reference:
1. Hofman, Michael S., Nathan Lawrentschuk, Roslyn J. Francis, Colin Tang, Ian Vela, Paul Thomas, Natalie Rutherford et al. "Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multi-centre study." The Lancet (2020).
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