Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Michael Xiang
Ting Martin Ma
Ricky Savjani
Erqi L Pollom
R Jeffrey Karnes
Tristan Grogan
Jessica K Wong
Giovanni Motterle
Jeffrey J Tosoian
Bruce J Trock
Eric A Klein
Bradley J Stish
Robert T Dess
Daniel E Spratt
Avinash Pilar
Chandana Reddy
Rebecca Levin-Epstein
Trude B Wedde
Wolfgang A Lilleby
Ryan Fiano
Gregory S Merrick
Richard G Stock
D Jeffrey Demanes
Brian J Moran
Hartwig Huland
Phuoc T Tran
Santiago Martin
Rafael Martinez-Monge
Daniel J. Krauss, Beaumont Health
Eyad I Abu-Isa
Ridwan Alam
Zeyad Schwen
Thomas M Pisansky
C Richard Choo
Daniel Y Song
Stephen Greco
Curtiland Deville
Todd McNutt
Theodore L DeWeese
Ashley E Ross
Jay P Ciezki
Paul C Boutros
Nicholas G Nickols
Prashant Bhat
David Shabsovich
Jesus E Juarez
Natalie Chong
Patrick A Kupelian
Matthew B Rettig
Nicholas G Zaorsky
Alejandro Berlin
Jonathan D Tward
Brian J Davis
Robert E Reiter
Michael L Steinberg
David Elashoff
Eric M Horwitz
Rahul D Tendulkar
Derya Tilki
Johannes Czernin
Andrei Gafita
Tahmineh Romero
Jeremie Calais
Amar U Kishan


Importance: 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.

Objectives: 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.

Design, Setting, and Participants: 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.

Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy.

Main Outcomes and Measures: 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.

Results: 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.

Conclusions and Relevance: 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.