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.

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.

JAMA network open. 2021 Dec 01*** epublish ***

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, 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

Department of Radiation Oncology, University of California, Los Angeles., Department of Radiation Oncology, Stanford University, Stanford, California., Department of Urology, Mayo Clinic, Rochester, Minnesota., Department of Medicine Statistics Core, David Geffen School of Medicine at UCLA, Los Angeles, California., Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Department of Urology, University of Michigan, Ann Arbor., Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland., Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio., Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota., Department of Radiation Oncology, University of Michigan, Ann Arbor., Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada., Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio., Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway., Schiffler Cancer Center, Wheeling Hospital, Wheeling Jesuit University, Wheeling, West Virginia., Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York City, New York., Prostate Cancer Foundation of Chicago, Westmont, Illinois., Martini-Klinik Prostate Cancer Center, University Hospital Hamburg Eppendorf, Hamburg, Germany., Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland., Department of Oncology, ClĂ­nica Universitaria de Navarra, University of Navarra, Pamplona, Spain., Oakland University William Beaumont School of Medicine, Royal Oak, Michigan., Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Department of Human Genetics, University of California, Los Angeles., Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles., Department of Radiation Oncology, Penn State Cancer Institute, Hershey, Pennsylvania., Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City., Department of Urology, University of California, Los Angeles., Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, UCLA Medical Center, Los Angeles, California.

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