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Observational Study
. 2021 Dec 1;4(12):e2138550.
doi: 10.1001/jamanetworkopen.2021.38550.

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  1 , Ting Martin Ma  1 , Ricky Savjani  1 , Erqi L Pollom  2 , R Jeffrey Karnes  3 , Tristan Grogan  4 , Jessica K Wong  5 , Giovanni Motterle  3 , Jeffrey J Tosoian  6 , Bruce J Trock  7 , Eric A Klein  8 , Bradley J Stish  9 , Robert T Dess  10 , Daniel E Spratt  10 , Avinash Pilar  11 , Chandana Reddy  12 , Rebecca Levin-Epstein  1 , Trude B Wedde  13 , Wolfgang A Lilleby  13 , Ryan Fiano  14 , Gregory S Merrick  14 , Richard G Stock  15 , D Jeffrey Demanes  1 , Brian J Moran  16 , Hartwig Huland  17 , Phuoc T Tran  18 , Santiago Martin  19 , Rafael Martinez-Monge  19 , Daniel J Krauss  20 , Eyad I Abu-Isa  10 , Ridwan Alam  7 , Zeyad Schwen  7 , Thomas M Pisansky  9 , C Richard Choo  9 , Daniel Y Song  18 , Stephen Greco  18 , Curtiland Deville  18 , Todd McNutt  18 , Theodore L DeWeese  18 , Ashley E Ross  21 , Jay P Ciezki  12 , Paul C Boutros  22 , Nicholas G Nickols  1   23 , Prashant Bhat  1 , David Shabsovich  1 , Jesus E Juarez  1 , Natalie Chong  1 , Patrick A Kupelian  1 , Matthew B Rettig  24   25 , Nicholas G Zaorsky  26 , Alejandro Berlin  11 , Jonathan D Tward  27 , Brian J Davis  9 , Robert E Reiter  28 , Michael L Steinberg  1 , David Elashoff  4 , Eric M Horwitz  5 , Rahul D Tendulkar  12 , Derya Tilki  17   29 , Johannes Czernin  30 , Andrei Gafita  30 , Tahmineh Romero  4 , Jeremie Calais  30 , Amar U Kishan  1
Affiliations
Observational Study

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 et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Savjani reported receiving grants from Varian Medical Systems Research outside the submitted work. Dr Karnes reported delivering an advisory lecture for Telix/Lanteus outside the submitted work. Dr Tosoian reported be cofounder of and holding equity in LynxDx. Dr Trock reported receiving grants from Myriad Genetics and MDxHealth to their institution outside the submitted work. Dr Spratt reported receiving personal fees from Janssen Pharmaceuticals, AstraZeneca, Boston Scientific, and Varian outside the submitted work. Dr Song reported receiving grants from Candel Therapeutics, Bayer, Celgene, BioProtect, Allegheny Health Network, and the National Cancer Institute outside the submitted work. Dr Ross reported receiving personal fees from GenomeDx, Bayer, Astellas, Pfizer, Myovant, and Blue Earth outside the submitted work. Dr Boutros reported serving on the scientific advisory boards of Sage Bionetworks, BioSymetrics, Intersect Diagnostics outside the submitted work. Dr Nickols reported receiving grants from Lantheus during the conduct of the study; receiving grants from Janssen Pharmaceuticals and Bayer outside the submitted work; and receiving personal fees from Oncolinea outside the submitted work. Dr Rettig reported consulting for Amgen, Ambrx, and Roivant; serving as speaker for Bayer and Johnson & Johnson; receiving nonfinancial support from Merck and Novartis outside the submitted work; and having a patent pending for androgen receptor inhibitors. Dr Tward reported serving on the advisory board of Blue Earth Diagnostics during the conduct of the study and receiving grants from Bayer and Myriad Genetics outside the submitted work. Dr Steinberg reported receiving honoraria from Viewray outside the submitted work. Dr Tilki reported receiving personal fees from AAA/Novartis, Apogepha, AstraZeneca, Exact Sciences, Ipsen, Roche, Takeda, and mIR Scientific outside the submitted work. Dr Czernin reported being founder of Sofie Biosciences and Trethera Corporation outside the submitted work. Dr Calais reported receiving personal fees from Advanced Accelerator Applications, Blue Earth Diagnostics, Curium Pharma, GE Healthcare, EXINI, IBA RadioPharma, Janssen Pharmaceuticals, POINT biopharma, Lantheus, Radiomedix, and Telix Pharmaceuticals outside the submitted work. Dr Kishan reported receiving honoraria and consulting fees from Varian Medical Systems; receiving honoraria, consulting fees, and research support from ViewRay; receiving consulting fees from Intelligent Automation; and serving on the advisory board of Janssen Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prognostic Significance of the Prostate-Specific Membrane Antigen Nomogram in the Multi-institutional Cohort
A, Concordance indices of the nomogram for biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) at 3 to 10 years. Error bars are 95% CIs. B-E, Survival curves (freedom from BCR, freedom from DM, freedom from PCSM, and OS) according to nomogram-defined risk groups, corresponding to upstaging risks of 14% or less (group 1), 14.1% to 27% (group 2), 27.1% to 41% (group 3), and greater than 41% (group 4).
Figure 2.
Figure 2.. Prognostic Significance of the Prostate-Specific Membrane Antigen Nomogram in the Registry-Based Cohorts
A, Concordance indices of the nomogram for prostate cancer-specific mortality (PCSM) in Surveillance, Epidemiology, and End Results (SEER) and overall survival (OS) in SEER and the National Cancer Database (NCDB) at 3 to 6 years. Error bars are 95% CIs. B-D, Survival curves (freedom from PCSM in SEER, OS in SEER, and OS in NCDB) according to nomogram-defined risk groups, corresponding to upstaging risks of 14% or less (group 1), 14.1% to 27% (group 2), 27.1% to 41% (group 3), and greater than 41% (group 4). P values are for groups 1-4 only, while outcomes of patients with cN1M0 (group 5) and M1 (group 6) disease are graphed for comparison.
Figure 3.
Figure 3.. Performance of the Prostate-Specific Membrane Antigen (PSMA) Nomogram, Staging Collaboration for Cancer of the Prostate (STAR-CAP) Stage Groups, Cancer of the Prostate Risk Assessment (CAPRA) Risk Groups, and Memorial Sloan Kettering Cancer Center (MSKCC) Nomogram in the Multi-institutional Cohort, as Assessed by the Concordance Indices
End points are biochemical recurrence (BCR) (A), distant metastasis (DM) (B), prostate cancer–specific mortality (PCSM) (C), and overall survival (OS) (D). Error bars represent 95% CIs.
Figure 4.
Figure 4.. Performance of the Prostate-Specific Membrane Antigen (PSMA) Nomogram, Staging Collaboration for Cancer of the Prostate (STAR-CAP) Stage Groups, Cancer of the Prostate Risk Assessment (CAPRA) Risk Groups, and Memorial Sloan Kettering Cancer Center (MSKCC) Nomogram, as Assessed by the Concordance Indices
NCDB indicates National Cancer Database; PCSM, prostate cancer–specific mortality; and SEER, Surveillance, Epidemiology, and End Results. Error bars represent 95% CIs.
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