Abstract
Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.
Highlights
High- and very high-risk prostate cancer has a heterogeneous disease course, perhaps due to a wide spectrum of intrinsic aggressiveness and an inability to evaluate the true extent of disease at initial diagnosis.[1,2,3,4] Metastatic failures occur more commonly than local failures, suggesting that a substantial number of patients harbor occult spread at presentation.[5]
Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. These findings suggest that Prostate-specific membrane antigen (PSMA) upstage probability is associated with long-term, clinically meaningful end points
We evaluated the significance of the PSMA nomogram on long-term, clinically meaningful end points using internal validation, external validation, and comparison with existing risk-stratification models
Summary
High- and very high-risk prostate cancer has a heterogeneous disease course, perhaps due to a wide spectrum of intrinsic aggressiveness and an inability to evaluate the true extent of disease at initial diagnosis.[1,2,3,4] Metastatic failures occur more commonly than local failures, suggesting that a substantial number of patients harbor occult spread at presentation.[5]. We developed a PSMA nomogram to calculate the probability of finding nonlocalized disease on PSMA PET/CT in patients who appear to have cN0M0 disease on conventional imaging.[8,9] In this study, we evaluated the significance of the PSMA nomogram (and, by proxy, PSMA PET/CT itself) on long-term, clinically meaningful end points (including distant metastasis [DM], prostate cancer–specific mortality [PCSM], and overall survival [OS]) using internal validation, external validation, and comparison with existing risk-stratification models. We hypothesized that the PSMA nomogram would provide more accurate prognostication than existing risk-stratification tools in high-risk patients based on the underlying hypothesis that previously occult, PSMA PET/CT– detectable nonlocalized disease may be the primary reason for treatment failures and underlie the heterogeneity in clinical outcomes
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