Machine learning-based analysis of [¹⁸F]DCFPyL PET radiomics for risk stratification in primary prostate cancer

PURPOSE: Quantitative prostate-specific membrane antigen (PSMA) PET analysis may provide for non-invasive and objective risk stratification of primary prostate cancer (PCa) patients. We determined the ability of machine learning-based analysis of quantitative [18F]DCFPyL PET metrics to predict metastatic disease or high-risk pathological tumor features. METHODS: In a prospective cohort study, 76 patients with intermediate- to high-risk PCa scheduled for robot-assisted radical prostatectomy with extended pelvic lymph node dissection underwent pre-operative [18F]DCFPyL PET-CT. Primary tumors were delineated using 50-70% peak isocontour thresholds on images with and without partial-volume correction (PVC). Four hundred and eighty standardized radiomic features were extracted per tumor. Random forest models were trained to predict lymph node involvement (LNI), presence of any metastasis, Gleason score ≥ 8, and presence of extracapsular extension (ECE). For comparison, models were also trained using standard PET features (SUVs, volume, total PSMA uptake). Model performance was validated using 50 times repeated 5-fold cross-validation yielding the mean receiver-operator characteristic curve AUC. RESULTS: The radiomics-based machine learning models predicted LNI (AUC 0.86 ± 0.15, p < 0.01), nodal or distant metastasis (AUC 0.86 ± 0.14, p < 0.01), Gleason score (0.81 ± 0.16, p < 0.01), and ECE (0.76 ± 0.12, p < 0.01). The highest AUCs reached using standard PET metrics were lower than those of radiomics-based models. For LNI and metastasis prediction, PVC and a higher delineation threshold improved model stability. Machine learning pre-processing methods had a minor impact on model performance. CONCLUSION: Machine learning-based analysis of quantitative [18F]DCFPyL PET metrics can predict LNI and high-risk pathological tumor features in primary PCa patients. These findings indicate that PSMA expression detected on PET is related to both primary tumor histopathology and metastatic tendency. Multicenter external validation is needed to determine the benefits of using radiomics versus standard PET metrics in clinical practice

Development and Internal Validation of a Novel Nomogram Predicting the Outcome of Salvage Radiation Therapy for Biochemical Recurrence after Radical Prostatectomy in Patients without Metastases on Restaging Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography

BACKGROUND AND OBJECTIVE: Owing to the greater use of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after robot-assisted radical prostatectomy (RARP), patient selection for local salvage radiation therapy (sRT) has changed. Our objective was to determine the short-term efficacy of sRT in patients with BCR after RARP, and to develop a novel nomogram predicting BCR-free survival after sRT in a nationwide contemporary cohort of patients who underwent PSMA PET/CT before sRT for BCR of PCa, without evidence of metastatic disease.METHODS: All 302 eligible patients undergoing PCa sRT in four reference centers between September 2015 and August 2020 were included. We conducted multivariable logistic regression analysis using a backward elimination procedure to develop a nomogram for predicting biochemical progression of PCa, defined as prostate-specific antigen (PSA) ≥0.2 ng/ml above the post-sRT nadir within 1 yr after sRT.KEY FINDINGS AND LIMITATIONS: Biochemical progression of disease within 1 yr after sRT was observed for 56/302 (19%) of the study patients. The final predictive model included PSA at sRT initiation, pathological grade group, surgical margin status, PSA doubling time, presence of local recurrence on PSMA PET/CT, and the presence of biochemical persistence (first PSA result ≥0.1 ng/ml) after RARP. The area under the receiver operating characteristic curve for this model was 0.72 (95% confidence interval 0.64-0.79). Using our nomogram, patients with a predicted risk of &gt;20% had a 30.8% chance of developing biochemical progression within 1 yr after sRT.CONCLUSIONS: Our novel nomogram may facilitate better patient counseling regarding early oncological outcome after sRT. Patients with high risk of biochemical progression may be candidates for more extensive treatment.PATIENT SUMMARY: We developed a new tool for predicting cancer control outcomes of radiotherapy for patients with recurrence of prostate cancer after surgical removal of their prostate. This tool may help in better counseling of these patients with recurrent cancer regarding their early expected outcome after radiotherapy.</p

Development and Internal Validation of a Novel Nomogram Predicting the Outcome of Salvage Radiation Therapy for Biochemical Recurrence after Radical Prostatectomy in Patients without Metastases on Restaging Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography

BACKGROUND AND OBJECTIVE: Owing to the greater use of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after robot-assisted radical prostatectomy (RARP), patient selection for local salvage radiation therapy (sRT) has changed. Our objective was to determine the short-term efficacy of sRT in patients with BCR after RARP, and to develop a novel nomogram predicting BCR-free survival after sRT in a nationwide contemporary cohort of patients who underwent PSMA PET/CT before sRT for BCR of PCa, without evidence of metastatic disease.METHODS: All 302 eligible patients undergoing PCa sRT in four reference centers between September 2015 and August 2020 were included. We conducted multivariable logistic regression analysis using a backward elimination procedure to develop a nomogram for predicting biochemical progression of PCa, defined as prostate-specific antigen (PSA) ≥0.2 ng/ml above the post-sRT nadir within 1 yr after sRT.KEY FINDINGS AND LIMITATIONS: Biochemical progression of disease within 1 yr after sRT was observed for 56/302 (19%) of the study patients. The final predictive model included PSA at sRT initiation, pathological grade group, surgical margin status, PSA doubling time, presence of local recurrence on PSMA PET/CT, and the presence of biochemical persistence (first PSA result ≥0.1 ng/ml) after RARP. The area under the receiver operating characteristic curve for this model was 0.72 (95% confidence interval 0.64-0.79). Using our nomogram, patients with a predicted risk of &gt;20% had a 30.8% chance of developing biochemical progression within 1 yr after sRT.CONCLUSIONS: Our novel nomogram may facilitate better patient counseling regarding early oncological outcome after sRT. Patients with high risk of biochemical progression may be candidates for more extensive treatment.PATIENT SUMMARY: We developed a new tool for predicting cancer control outcomes of radiotherapy for patients with recurrence of prostate cancer after surgical removal of their prostate. This tool may help in better counseling of these patients with recurrent cancer regarding their early expected outcome after radiotherapy.</p

Lutetium-177-PSMA-I&amp;T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. Trial registration: Clinicaltrials.gov identifier: NCT04443062

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer:the BULLSEYE trial

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration: ClinicalTrials.gov NCT04443062. First posted: June 23, 2020

The Actual Value of the Surgical Margin Status as a Predictor of Disease Progression in Men with Early Prostate Cancer

Objectives: The surgical margin status after radical prostatectomy for prostate cancer has long been considered a powerful prognostic factor, as well as an important risk factor for local recurrent disease after radical prostatectomy. In this study, a critical analysis of the predictive value of the surgical margin status was performed. Methods: A well-described cohort of 281 participants of a population-based randomized screening trial who underwent radical prostatectomy between 1994 and 2000 was analyzed. Besides pathologic tumor stage, Gleason score, percentage of high-grade cancer, and tumor volume, the prognostic value of the surgical margin status for disease outcome (prostate-specific antigen [PSA] relapse, local recurrence) was statistically evaluated. Specifically, site ('apical' or 'circumferential') and extent of surgical margin negativity ('negative', or 'close') or positivity ('focal' or 'extensive') was assessed. Results: At a median follow-up of 7 yr (range, 5-120 mo), 39 (13.9%) and 7 (2.5%) men had biochemical failure (PSA ≥0.1 ng/ml), and local relapse, respectively. The surgical margin status was positive in 66 (23.5%), with 26 (9.3%) at the prostatic apex. The margin status was an independent statistically significant risk factor for biochemical relapse, though not for local relapse. Of those with positive margins, 22 (33.3%) had PSA relapse and 4 (6.1%) had local recurrence, whereas these figures were 17 (7.9%) and 3 (1.4%) for those with a negative surgical margin, respectively. The extent of margin positivity was not predictive of PSA relapse nor was the site of the surgical margin. Conclusions: In surgically treated prostate cancer, the surgical margin status has, although being a statistically significant prognostic factor, only limited predictive value for PSA relapse and local recurrent disease. The majority of men with (extensive) positive surgical margins will not experience PSA relapse nor local disease progression, even in absence of adjuvant radiotherapy. So, cases with a positive margin of resection may still be cured, although the procedure in itself was not 'radical'

Comment on Rosenzweig et al. Very Low Prostate PET/CT PSMA Uptake May Be Misleading in Staging Radical Prostatectomy Candidates. J. Pers. Med. 2022, 12, 410

With interest, we read the article by Rosenzweig et al. [...

Prostate cancer development is not affected by statin use in patients with elevated psa levels

Background: The role of statins in prostate cancer (PCa) remains unclear. Conflicting evidence has been found concerning risk reduction with the use of statins on biochemical recurrence (BCR). In this study, we evaluated whether statin use decreases the incidence of advanced PCa in males with elevated prostate-specific antigen (PSA; ≥4.0 ng/mL) levels and determined whether statin use reduces the risk of BCR after radical prostatectomy (RP). Methods: Patients visiting the outpatient urology clinic of the VU Medical Center between 2006 and 2018 with elevated PSA were retrospectively analyzed. Biochemical recurrence after RP was defined as a PSA level of ≥0.2 ng/mL (measured twice). Results: A total of 1566 patients were included, of which 1122 (72%) were diagnosed with PCa. At the time of diagnosis, 252 patients (23%) used statins compared to 83 patients (19%) in the non-malignancy group (p = 0.10). No differences were found in the use of statins between the different risk groups. No correlation was found between the risk of BCR after RP and the use of statins in the total (p = 0.20), the intermediate-risk group (p = 0.63) or the high-risk group (p = 0.14). Conclusion: The use of statins does not affect PCa development/progression in patients with elevated PSA levels, nor the development of BCR after RP