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Multicenter Study
. 2023 May 1;6(5):e2314748.
doi: 10.1001/jamanetworkopen.2023.14748.

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer

Constantinos Zamboglou  1   2   3   4 , Jan C Peeken  5   6   7 , Ali Janbain  8 , Sandrine Katsahian  8 , Iosif Strouthos  9 , Konstantinos Ferentinos  9 , Andrea Farolfi  10 , Stefan A Koerber  11   12 , Juergen Debus  11   12 , Marco E Vogel  5   6   7 , Stephanie E Combs  5   6   7 , Alexis Vrachimis  13   14 , Alessio Giuseppe Morganti  15 , Simon K B Spohn  1   2   3 , Mohamed Shelan  16 , Daniel M Aebersold  16 , Anca-Ligia Grosu  1   2 , Francesco Ceci  17   18 , Christoph Henkenberens  19 , Stephanie G C Kroeze  20   21 , Matthias Guckenberger  20 , Stefano Fanti  10 , Claus Belka  22 , Peter Bartenstein  23 , George Hruby  24 , Sophia Scharl  25 , Thomas Wiegel  25 , Louise Emmett  26   27 , Armelle Arnoux  8 , Nina-Sophie Schmidt-Hegemann  21
Affiliations
Multicenter Study

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer

Constantinos Zamboglou et al. JAMA Netw Open. .

Abstract

Importance: Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer.

Objective: To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT.

Design, setting, and participants: This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022.

Exposures: Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible.

Main outcomes and measures: The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT.

Results: In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort.

Conclusions and relevance: This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Zamboglou reported receiving grants from BMBF-PersoRad and DKTK-ImproRec during the conduct of the study. Dr Katsahian reported receiving grants from the French Ministry of Health and nonfinancial support from Boehringer Ingelheim, Merck, Guerbet, Merit Medical, St Jude Medical, AVF Biomedical, and Xenios AG outside the submitted work. Dr Koerber reported receiving grants from Viewray Inc; and honoraria and travel fees from IBA Dosimetry and Think Wired! outside the submitted work. Dr Debus reported receiving grants from Accuray, Elekta, Siemens, Merck, and Raysearch during the conduct of the study. Dr Combs reported receiving personal fees from Roche, AstraZeneca, Dr. Sennewald Medizintechnik, Elekta, Accuray, BMS, Brainlab, Daiichi Sankyo, Icotec, Zeiss Meditec, and HMG Systems Engineering outside the submitted work. Dr Fanti reported receiving personal fees from AAA, Bayer, Janssen, Novartis, and Telix outside the submitted work. Dr Belka reported receiving grants from the Federal Ministry of Education and Research HMGU during the conduct of the study; personal fees from Merck Darmstadt, BMS, MSD, and AstraZenca outside the submitted work. Dr Wiegel reported receiving personal fees from Janssen, Takeda, and Recordati outside the submitted work. Dr Arnoux reported receiving grants from the French Ministry of Health and nonfinancial support from Boehringer Ingelheim, Merck, Guerbet, Merit Medical, St Jude Medical, AVF Biomedical, and Xenios AG outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Nomogram for Freedom From Biochemical Failure (FFBF) After Prostate-Specific Membrane Antigen Positron-Emission Tomography–Guided Salvage Radiotherapy (sRT)
ADT indicates androgen deprivation therapy; ISUP, International Society of Urological Pathology; PET, positron emission tomography; PSA, prostate-specific antigen; and R status, resection status. Dose to the fossa is given in equivalent dose 2 Gy (EQD2, α/β = 1.6 Gy). SI conversion factor: To convert PSA to to micrograms per liter, multiply by 1.0.
Figure 2.
Figure 2.. Calibration Plots for Internal and External Outlier Validation Sets
A, Internal validation cohort. B, External outlier validation cohort. FFBF indicates freedom from biochemical failure. The error bars indicate 95% CIs.
Figure 3.
Figure 3.. Kaplan-Meier Plot for Freedom From Biochemical Failure (FFBF)
A, Internal validation cohort. B, External outlier validation cohort. The Kaplan-Meier curves show patients stratified by their risk group according to their points on the nomogram. The cutoff value of 229 was defined as the median nomogram value in the training cohort. The groups showed a significant difference in FFBF for the internal validation cohort and a trend toward a significant difference in FFBF in the external outlier cohort using the log-rank test. The dotted lines represent the time points for 50% FFBF.
Figure 4.
Figure 4.. Kaplan-Meier Plot for Freedom From Distant Metastases (FFDM)
A, All imaging modalities in internal validation cohort. B, Prostate-specific membrane antigen positron-emission tomography (PSMA-PET) only in internal validation cohort. C, PSMA-PET only in external outliers cohort. The Kaplan-Meier curves show patients stratified by their risk group according to their points on the nomogram for freedom from biochemical failure prediction. The cutoff value of 229 was defined as the median nomogram value in the training cohort. The groups showed a significant difference in FFDM for the internal validation cohort but not for the external outlier cohort using the log-rank test. The dotted lines represent the time points for 50% FFDM.
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