Establishment and validation of an individualized cell cycle process-related gene signature to predict cancer-specific survival in patients with bladder cancer.

More accurate models are essential to identify high-risk bladder cancer (BCa) patients who will benefit from adjuvant therapies and thus helpful to facilitate personalized management of BCa. Among various cancer-related hallmarks and pathways, cell cycle process (CCP) was identified as a dominant risk factor for cancer-specific survival (CSS) in BCa. Using a series of bioinformatic and statistical approaches, a CCP-related gene signature was established, and the prognostic value was validated in other independent BCa cohorts. In addition, the risk score derived from the gene signature serves as a promising marker for therapeutic resistance. In combination with clinicopathological features, a nomogram was constructed to provide more accurate prediction for CSS, and a decision tree was built to identify high-risk subgroup of muscle invasive BCa patients. Overall, the gene signature could be a useful tool to predict CSS and help to identify high-risk subgroup of BCa patients, which may benefit from intensified adjuvant therapy

Prognostic risk classification for biochemical relapse-free survival in patients with oligorecurrent prostate cancer after [⁶⁸Ga]PSMA-PET-guided metastasis-directed therapy.

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

Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy—a multicenter retrospective study.

Purpose: Approximately 40–70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases’ site on outcome after metastasis-directed radiotherapy (MDR). Methods: Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA) < post-radiotherapy nadir + 0.2 ng/mL) was assessed using Kaplan-Meier survival and Cox regression analysis. Results: All patients were initially clinically without distant metastases (cM0). Seventy-five patients had local recurrence within the prostatic fossa, 32 patients had pelvic nodal plus local recurrence, 117 patients had pelvic nodal recurrence, 51 patients had paraaortic lymph node metastases with/without locoregional recurrence, and 84 patients had bone or visceral metastases with/without locoregional recurrence. Median PSA before MDR was 1.2 ng/mL (range, 0.04–47.5). Additive androgen deprivation therapy (ADT) was given in 35% (125/359) of patients. Median PSA nadir after MDR was 0.23 ng/mL (range, < 0.03–18.30). After a median follow-up of 16 months (1–57), 239/351 (68%) patients had no biochemical recurrence. Patients with distant lymph node and/or distant metastases, the so-called oligo-body cohort, had an overall in-field control of 90/98 (91%) but at the same time, an ex-field progress of 44/96 (46%). In comparison, an ex-field progress was detected in 28/154 (18%) patients with local and/or pelvic nodal recurrence (oligo-pelvis group). Compared with the oligo-pelvis group, there was a significantly lower BRFS in oligo-body patients at the last follow-up. Conclusion: Overall, BRFS was dependent on patterns of metastatic disease. Thus, MDR of PSMA PET-positive oligo-metastases can be offered considering that about one-third of the patients progressed within a median follow-up of 16 months

Efficacy of PSMA ligand PET-based radiotherapy for recurrent prostate cancer after radical prostatectomy and salvage radiotherapy.

Background: A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT). Methods: We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA < nadir + 0.2 ng/ml or no PSA decline) as well as the androgen deprivation therapy- free survival (ADT-FS) using Kaplan-Meier curves. Log-rank test and multivariate analysis was performed to determine influencing factors. Results: A total of 185 PSMA - PET positive metastases were detected and all lesions were treated with radiotherapy (RT). Concurrent ADT was prescribed in 16.7% (13/78) of patients. The median PSA level before RT was 1.90 ng/mL (range, 0.1-22.1) and decreased statistically significantly to a median PSA nadir level of 0.26 ng/mL (range, 0.0-12.25; p < 0.001). The median PSA level of 0.88 ng/mL (range, 0.0-25.8) at the last follow-up was also statistically significantly lower (p = 0.008) than the median PSA level of 1.9 ng/mL (range, 0.1-22.1) before RT. The median bRFS was 17.0 months (95% CI, 14.2-19.8). After 12 months, 55.3% of patients were free of biochemical progression. Multivariate analyses showed that concurrent ADT was the most important independent factor for bRFS (p = 0.01). The median ADT-FS was not reached and exploratory statistical analyses estimated a median ADT-FS of 34.0 months (95% CI, 16.3-51.7). Multivariate analyses revealed no significant parameters for ADT-FS. Conclusions: RT as MDT based on PSMA - PET of all metastases of recurrent prostate cancer after RP and sRT represents a viable treatment option for well-informed and well-selected patients

The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy-a multicenter retrospective analysis.

PURPOSE: This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific membrane antigen (PSMA-PET) prior to salvage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort. METHODS: Patients who underwent 68 Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS. RESULTS: Two hundred thirty-five patients with a median follow-up (FU) of 24 months were included in the final cohort. Two-year and 4-year BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75% quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1-4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) confirmed these results. CONCLUSION: The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensification or de-intensification. This article is part of the Topical Collection on Oncology-Genitourinary

Metastasis-free survival and patterns of distant metastatic disease after PSMA-PET-guided salvage radiotherapy in recurrent or persistent prostate cancer after prostatectomy.

INTRODUCTION: Prostate specific membrane antigen positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) in prostate cancer (PCa) patients with biochemical recurrence/persistence after prostatectomy. This work examines (i) metastasis-free survival (MFS) following PSMA-PET guided sRT and (ii) the metastatic patterns on PSMA-PET images after sRT. METHODS: This retrospective, multicenter (9 centers, 5 countries) study included patients referred for PSMA-PET due to recurrent/persistent disease after prostatectomy. Patients with distant metastases (DM) on PSMA-PET prior to sRT were excluded. Cox-regression was performed to assess the impact of clinical parameters on MFS. The distribution of PSMA-PET detected DM following sRT and their respective risk factors were analysed. RESULTS: All (n=815) patients received intensity-modulated RT to the prostatic fossa. In case of PET-positive pelvic lymph nodes (PLN-PET, n=275, 34%), pelvic lymphatics had been irradiated. Androgen deprivation therapy had been given in 251 (31%) patients. The median follow-up after sRT was 36 months. The 2-/4-year MFS following sRT were 93%/81%. In multivariate analysis the presence of PLN-PET was a strong predictor for MFS (HR=2.39, p<0.001). Following sRT, DM were detected by PSMA-PET in 128/198 (65%) patients and two metastatic patterns were observed: 43% had DM in sub diaphragmatic paraaortic LNs (abdominal-lymphatic) whereas 45% in bones, 9% in supra diaphragmatic LNs and 6% in visceral organs (distant). Two distinct signatures with risk factors for each pattern were identified. CONCLUSION: MFS in our study is lower compared to previous studies, obviously due to the higher detection rate of DM in PSMA-PET after sRT. Thus, it remains unclear whether MFS is a surrogate endpoint for overall survival in PSMA PET-staged patients in the post sRT setting. PLN-PET may be proposed as a new surrogate parameter predictive of MFS. Analysis of recurrence patterns in PET after sRT revealed risk factor signatures for two metastatic patterns (abdominal-lymphatic and distant), which may allow individualized sRT concepts in the future