Early biochemical outcomes following PSMA guided approach for bIoCHEmical relapse after prostatectomy-PSICHE trial (NCT05022914): preliminary results.
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SUBMITTER: Francolini G
PROVIDER: S-EPMC10113311 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Early biochemical outcomes following PSMA guided approach for bIoCHEmical relapse after prostatectomy-PSICHE trial (NCT05022914): preliminary results.
Francolini Giulio G Ganovelli Michele M Di Cataldo Vanessa V Detti Beatrice B Caini Saverio S Loi Mauro M Simontacchi Gabriele G Desideri Isacco I Greto Daniela D Valzano Marianna M Serni Sergio S Vaggelli Luca L Salvestrini Viola V Visani Luca L Becherini Carlotta C Olmetto Emanuela E Franzese Ciro C Baldaccini Davide D Scorsetti Marta M Sollini Martina M Chiti Arturo A Meattini Icro I Valicenti Richard K RK Livi Lorenzo L
Clinical & experimental metastasis 20230403 2
PSICHE (NCT05022914) is a prospective trial to test a [<sup>68</sup>Ga]Ga- PSMA-11 PET/CT imaging tailored strategy. All evaluable patients had biochemical relapse after surgery and underwent centralized [<sup>68</sup>Ga]Ga-PSMA-11 PET/CT imaging. The treatment was performed according pre-defined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with a negative ...[more]
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Project description:BackgroundSalvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure.ObjectiveThis study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer.MethodsThis multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions.ResultsBaseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram.ConclusionsThe developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions.
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Project description:PurposeThe prognostic value of PSMA intensity on PSMA PET/CT due to underlying biology and subsequent clinical implications is an emerging topic of interest. We sought to investigate whether primary tumour PSMA PET intensity contributes to pre- and post-operative prediction of oncological outcomes following radical prostatectomy.MethodsWe performed a retrospective cohort study of 848 men who underwent all of multiparametric MRI (mpMRI), transperineal prostate biopsy, and 68 Ga-PSMA PET/CT prior to radical prostatectomy. PSMA intensity, quantified as maximum standard uptake value (SUVmax), and other clinical variables were considered relative to post-operative biochemical recurrence-free survival (BRFS) using Cox regression and Kaplan-Meier analysis.ResultsAfter a median follow-up of 41 months, 219 events occurred; the estimated 3-year BRFS was 79% and the 5-year BRFS was 70%. Increasing PSMA intensity was associated with less favourable BRFS overall (Log rank p < 0.001), and within subgroups of Gleason score category (Log rank p < 0.03). PSMA intensity was significantly associated with shorter time to biochemical recurrence, after adjusting for pre-operative (HR per 5-unit SUVmax increase = 1.15) and post-operative (HR per 5-unit SUVmax increase = 1.10) parameters.ConclusionThese results in a large series of patients confirm PSMA intensity to be a novel, independent prognostic factor for BRFS.
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Project description:Background and purposeThe treatment of biochemical recurrence (BCR) after prostatectomy is challenging as the site of the recurrence is often undetectable. Our aim was to test a personalised treatment concept for BCR based on PSA kinetics during salvage radiotherapy (SRT) combined with prostate-specific membrane antigen positron emission tomography (PSMA-PET).Materials and methodsThis phase II trial included 100 patients with BCR. PSMA-PET was performed at baseline. PSA was measured weekly during SRT. Initially, 70 Gy in 35 fractions was prescribed to the prostate bed. Radiotherapy was adapted after 50 Gy. Non-responders (PSA still ≥ 0.15 ng/mL) received sequential lymph node irradiation with a boost to PSMA-PET positive lesions, while responders (PSA < 0.15 ng/mL) continued SRT as planned. PET-findings were only taken into consideration for treatment planning in case of PSA non-response after 50 Gy.ResultsData from 97 patients were eligible for analysis. Thirty-four patients were classified as responders and 63 as non-responders. PSMA-PET was positive in 3 patients (9%) in the responder group and in 22 (35%) in the non-responder group (p = 0.007). The three-year failure-free survival was 94% for responders and 68% for non-responders (median follow-up 38 months). There were no significant differences in physician-reported urinary and bowel toxicity. Patient-reported diarrhoea at end of SRT was more common among non-responders.ConclusionThis new personalised treatment concept with intensified SRT based on PSA response demonstrated a high tumour control rate in both responders and non-responders. These results suggest a clinically significant effect with moderate side effects in a patient group with otherwise poor prognosis. PSMA-PET added limited value. The treatment approach is now being evaluated in a phase III trial.Clinical trial registration numbers: NCT02699424&ISRCTN45905321.
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Project description:PurposeTo evaluate outcomes for men with biochemically recurrent prostate cancer who were selected for transponder-guided salvage radiotherapy (SRT) to the prostate bed alone by 68Ga-labelled prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET).MethodsThis is a single-arm, prospective study of men with a prostate-specific antigen (PSA) level rising to 0.1-2.5 ng/mL following radical prostatectomy. Patients were staged with 68Ga-PSMA-PET and those with a negative finding, or a positive finding localised to the prostate bed, continued to SRT only to the prostate bed alone with real-time target-tracking using electromagnetic transponders. The primary endpoint was freedom from biochemical relapse (FFBR, PSA > 0.2 ng/mL from the post-radiotherapy nadir). Secondary endpoints were time to biochemical relapse, toxicity and patient-reported quality of life (QoL).ResultsNinety-two patients (median PSA of 0.18 ng/ml, IQR 0.12-0.36), were screened with 68Ga-PSMA-PET and metastatic disease was found in 20 (21.7%) patients. Sixty-nine of 72 non-metastatic patients elected to proceed with SRT. At the interim (3-year) analysis, 32 (46.4%) patients (95% CI 34.3-58.8%) were FFBR. The median time to biochemical relapse was 16.1 months. The rate of FFBR was 82.4% for ISUP grade-group 2 patients. Rates of grade 2 or higher gastrointestinal and genitourinary toxicity were 0% and 15.2%, respectively. General health and disease-specific QoL remained stable.ConclusionPre-SRT 68Ga-PSMA-PET scans detect metastatic disease in a proportion of patients at low PSA levels but fail to improve FFBR. Transponder-guided SRT to the prostate bed alone is associated with a favourable toxicity profile and preserved QoL.Trial registration numberACTRN12615001183572, 03/11/2015, retrospectively registered.
| S-EPMC8571130 | biostudies-literature
Project description:PURPOSE:Since the success of prostate-specific membrane antigen-positron emission tomography (PSMA-PET) imaging for patients with oligorecurrent prostate cancer (ORPC), it is increasingly used for radiotherapy as metastasis-directed therapy (MDT). Therefore, we developed a prognostic risk classification for biochemical relapse-free survival (bRFS) for patients after PSMA-PET-guided MDT after radical prostatectomy. METHODS:We analyzed 292 patients with local recurrence (LR) and/or pelvic lymph node (LN) lesions and/or up to five distant LN, bone (BM), or visceral metastases (VM) detected with [68Ga]PSMA-PET imaging. Median follow-up was 16 months (range 0-57). The primary endpoint was bRFS after MDT. Cox regression analysis for risk factors was incorporated into a recursive partitioning analysis (RPA) with classification and regression tree method. RESULTS:PSA at recurrence ??0.8 ng/mL, BM, and VM was significantly associated with biochemical relapse. RPA showed five groups with tenfold cross-validation of 0.294 (SE 0.032). After building risk classes I to IV (p?<?0.0001), mean bRFS was 36.3 months (95% CI 32.4-40.1) in class I (PSA <?0.8 ng/mL, no BM) and 25.8 months (95% CI 22.5-29.1) in class II (PSA ??0.8 ng/mL, no BM, no VM). LR and/or pelvic LNs caused relapse in classes I and II. Mean bRFS was 16.0 months (95% CI 12.4-19.6) in class III (PSA irrelevant, present BM) and 5.7 months (95% CI 2.7-8.7) in class IV (PSA ??0.8 ng/mL, no BM, present VM). CONCLUSION:We developed and internally validated a risk classification for bRFS after PSMA-PET-guided MDT. Patients with PSA <?0.8 ng/mL and local relapse only (LR and/or pelvic LNs) had the most promising bRFS. PSA ??0.8 ng/mL and local relapse only (LR and/or pelvic LNs) indicated intermediate risk for failure. Patients with BM were at higher risk regardless of the PSA. However, those patients still show satisfactory bRFS. In patients with VM, bRFS is heavily decreased. MDT in such cases should be discussed individually.
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Project description:BackgroundGleason scoring represents the standard for diagnosis of prostate cancer (PCa) and assessment of prognosis following radical prostatectomy (RP), but it does not account for patterns in neighboring normal-appearing benign fields that may be predictive of disease recurrence.ObjectiveTo investigate (1) whether computer-extracted image features within tumor-adjacent benign regions on digital pathology images could predict recurrence in PCa patients after surgery and (2) whether a tumor plus adjacent benign signature (TABS) could better predict recurrence compared with Gleason score or features from benign or cancerous regions alone.Design, setting, and participantsWe studied 140 tissue microarray cores (0.6mm each) from 70 PCa patients following surgery between 2000 and 2004 with up to 14 yr of follow-up. Overall, 22 patients experienced recurrence (biochemical [prostate-specific antigen], local, or distant recurrence and cancer death) and 48 did not.InterventionRP was performed in all patients.Outcome measurements and statistical analysisThe top 10 features identified as most predictive of recurrence within both the benign and cancerous regions were combined into a 10-feature signature (TABS). Computer-extracted nuclear shape and architectural features from cancerous regions, adjacent benign fields, and TABS were evaluated via random forest classification accuracy and Kaplan-Meier survival analysis.Results and limitationsTumor-adjacent benign field features were predictive of recurrence (area under the receiver operating characteristic curve [AUC]: 0.72). Tumor-field nuclear shape descriptors and benign-field local nuclear arrangement were the predominant features found for TABS (AUC: 0.77). Combining TABS with Gleason sum further improved identification of recurrence (AUC: 0.81). All experiments were performed using threefold cross-validation without independent test set validation.ConclusionsComputer-extracted nuclear features within cancerous and benign regions predict recurrence following RP. Furthermore, TABS was shown to provide added value to common predictors including Gleason sum and Kattan and Stephenson nomograms.Patient summaryFuture studies may benefit from evaluation of benign regions proximal to the tumor on surgically excised prostate cancer tissue for assessing risk of disease recurrence.
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Project description:BackgroundThe optimal field size of salvage radiotherapy (SRT) for biochemical recurrence, particularly for patients with high-risk prostate cancer, remains undefined. This retrospective analysis was performed to investigate oncological outcomes as well as treatment-related toxicity following salvage intensity-modulated radiotherapy (IMRT) to the whole pelvis and to compare the results with other studies implementing a small field size of the prostate bed.MethodsThe medical records of 170 patients with high-risk prostate cancer who received SRT for biochemical recurrence following prostatectomy were reviewed. Whole-pelvic IMRT was administered with a median dose of 66 Gy in 30 fractions. To improve treatment accuracy, an endorectal balloon device and daily cone-beam computed tomography were utilized. Androgen-deprivation therapy combined with SRT was administered to 97 (57.1%) patients.ResultsEventually, 68 (40.0%) patients showed biochemical progression (BCP) after SRT. With a median follow-up period of 56 months, the 5-year BCP-free survival was 38.6%. The overall and cause-specific survival rates were 90.9% and 96.7%, respectively. Regarding BCP-free survival analysis, pathological T stage, persistent prostate-specific antigen (PSA) elevation after prostatectomy, and preSRT PSA level were significant prognostic factors on univariate analysis. On multivariate analysis, pathological T stage and preSRT PSA value retained their significance. Acute and late grade-3 genitourinary toxicities were observed in one (0.6%) and five (2.9%) patients, respectively. One patient each developed acute and late grade-3 gastrointestinal toxicity.ConclusionSRT to whole pelvis using IMRT and image guidance is as safe as SRT to the prostate bed, but its efficacy should be confirmed in ongoing randomized trials. PreSRT PSA was the only controllable prognostic factor, suggesting the benefit of early SRT.
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Project description:OBJECTIVES:The aim of this study was the validation of a recently established comprehensive and compact prediction model for 68Ga-PSMA-11-ligand positron-emission tomography (PET) positivity with an independent subsequent patient series. METHODS:A total of 292 consecutive patients with early biochemical recurrence after radical prostatectomy and PSA values between 0.2 and 1 ng/ml who underwent 68Ga-PSMA-11-ligand PET/computed tomography (CT) between January 2016 and June 2017 were retrospectively included. The cohort was divided into a very low PSA value (0.2-0.5 ng/ml, n = 151) and a low PSA value (> 0.5-1 ng/ml, n = 141) subgroup. First, pre-test positivity probabilities for each patient were calculated according to the previously published comprehensive prediction model using all clinical variables (PSA value, ISUP grade group, T- and N-stage, patient under androgen deprivation therapy (ADT), previous radiation therapy) and the compact model using just the most predictive factors PSA value, ADT, and grade group. Then, all 68Ga-PSMA-11-ligand PET/CTs were analysed by one experienced nuclear medicine physician, and the results were correlated to the calculated pre-test probabilities. RESULTS:In the very low PSA value subgroup, mean pre-test probability for positive findings in 68Ga-PSMA-11-ligand PET/CT was 57% (95% CI 55-60%) according to the compact model and 59% (95% CI 56-61%) according to the comprehensive model. In the low PSA value subgroup, mean pre-test probability was 72% (95% CI 70-74%) in the compact model and 74% (95% CI 72-76%) in the comprehensive model. After image analysis, 59% (89/151) of the patients in the very low PSA value subgroup revealed positive imaging findings. Seventy-nine percent (112/141) of the patients in the low PSA value subgroup presented with positive findings in the 68Ga-PSMA-11-ligand PET/CT. The accuracy (AUC) of the prediction models was 0.71 (95% CI 0.65-0.78) for the compact model and 0.74 (95% CI 0.68-0.80) for the comprehensive model. CONCLUSION:External validation of the recently proposed prediction models showed a high concordance of the calculated pre-test probabilities and actual 68Ga-PSMA-11-ligand PET/CT findings in the validation cohort confirming the prediction models' ability to determine the presence of a positive lesion at 68Ga-PSMA-11-ligand PET. However, the predictive accuracy of the nomogram itself is suboptimal and should be used with caution. Furthermore, the model's generalizability may be hampered due to the study design (in-house validation). Nevertheless, given the limited health resources and the costs of hybrid imaging techniques, prediction models might be a benefit in patient selection.
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Project description:ObjectiveTo derive and evaluate the association of prostate shape distension descriptors from T2-weighted MRI (T2WI) with prostate cancer (PCa) biochemical recurrence (BCR) post-radical prostatectomy (RP) independently and in conjunction with texture radiomics of PCa.MethodsThis retrospective study comprised 133 PCa patients from two institutions who underwent 3T-MRI prior to RP and were followed up with PSA measurements for ≥3 years. A 3D shape atlas-based approach was adopted to derive prostate shape distension descriptors from T2WI, and these descriptors were used to train a random forest classifier (CS ) to predict BCR. Texture radiomics was derived within PCa regions of interest from T2WI and ADC maps, and another machine learning classifier (CR ) was trained for BCR. An integrated classifier CS + R was then trained using predictions from CS and CR . These models were trained on D1 (N = 71, 27 BCR+) and evaluated on independent hold-out set D2 (N = 62, 12 BCR+). CS + R was compared against pre-RP, post-RP clinical variables, and extant nomograms for BCR-free survival (bFS) at 3 years.ResultsCS + R resulted in a higher AUC (0.75) compared to CR (0.70, p = 0.04) and CS (0.69, p = 0.01) on D2 in predicting BCR. On univariable analysis, CS + R achieved a higher hazard ratio (2.89, 95% CI 0.35-12.81, p < 0.01) compared to other pre-RP clinical variables for bFS. CS + R , pathologic Gleason grade, extraprostatic extension, and positive surgical margins were associated with bFS (p < 0.05). CS + R resulted in a higher C-index (0.76 ± 0.06) compared to CAPRA (0.69 ± 0.09, p < 0.01) and Decipher risk (0.59 ± 0.06, p < 0.01); however, it was comparable to post-RP CAPRA-S (0.75 ± 0.02, p = 0.07).ConclusionsRadiomic shape descriptors quantifying prostate surface distension complement texture radiomics of prostate cancer on MRI and result in an improved association with biochemical recurrence post-radical prostatectomy.
| S-EPMC9163353 | biostudies-literature
Project description:ImportanceStratifying patients with biochemical recurrence (BCR) after primary treatment for prostate cancer based on the risk of prostate cancer-specific mortality (PCSM) is essential for determining the need for further testing and treatments.ObjectiveTo evaluate the association of BCR after radical prostatectomy or radiotherapy and its current risk stratification with PCSM.Design, setting, and participantsThis population-based cohort study included a total of 16 311 male patients with 10 364 (64%) undergoing radical prostatectomy and 5947 (36%) undergoing radiotherapy with curative intent (cT1-3, cM0) and PSA follow-up in Stockholm, Sweden, between 2003 and 2019. Follow-up for all patients was until death, emigration, or end of the study (ie, December 31, 2018). Data were analyzed between September 2022 and March 2023.Main outcomes and measuresPrimary outcomes of the study were the cumulative incidence of BCR and PCSM. Patients with BCR were stratified in low- and high-risk according to European Association of Urology (EAU) criteria.ExposuresRadical prostatectomy or radiotherapy.ResultsA total of 16 311 patients were included. Median (IQR) age was 64 (59-68) years in the radical prostatectomy cohort (10 364 patients) and 69 (64-73) years in the radiotherapy cohort (5947 patients). Median (IQR) follow-up for survivors was 88 (55-138) months and 89 (53-134) months, respectively. Following radical prostatectomy, the 15-year cumulative incidences of BCR were 16% (95% CI, 15%-18%) for the 4024 patients in the low D'Amico risk group, 30% (95% CI, 27%-32%) for the 5239 patients in the intermediate D'Amico risk group, and 46% (95% CI, 42%-51%) for 1101 patients in the high D'Amico risk group. Following radiotherapy, the 15-year cumulative incidences of BCR were 18% (95% CI, 15%-21%) for the 1230 patients in the low-risk group, 24% (95% CI, 21%-26%) for the 2355 patients in the intermediate-risk group, and 36% (95% CI, 33%-39%) for the 2362 patients in the high-risk group. The 10-year cumulative incidences of PCSM after radical prostatectomy were 4% (95% CI, 2%-6%) for the 1101 patients who developed low-risk EAU-BCR and 9% (95% CI, 5%-13%) for 649 patients who developed high-risk EAU-BCR. After radiotherapy, the 10-year PCSM cumulative incidences were 24% (95% CI, 19%-29%) for the 591 patients in the low-risk EAU-BCR category and 46% (95% CI, 40%-51%) for the 600 patients in the high-risk EAU-BCR category.Conclusions and relevanceThese findings suggest the validity of EAU-BCR stratification system. However, while the risk of dying from prostate cancer in low-risk EAU-BCR after radical prostatectomy was very low, patients who developed low-risk EAU-BCR after radiotherapy had a nonnegligible risk of prostate cancer mortality. Improving risk stratification of patients with BCR is pivotal to guide salvage treatment decisions, reduce overtreatment, and limit the number of staging tests in the event of PSA elevations after primary treatment.
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