Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. PATIENTS AND METHODS: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression. RESULTS: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05). CONCLUSIONS: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease.

PEACE V - Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): a study protocol for a randomized controlled phase II trial.

BACKGROUND: Pelvic nodal recurrences are being increasingly diagnosed with the introduction of new molecular imaging techniques, like choline and PSMA PET-CT, in the restaging of recurrent prostate cancer (PCa). At this moment, there are no specific treatment recommendations for patients with limited nodal recurrences and different locoregional treatment approaches are currently being used, mostly by means of metastasis-directed therapies (MDT): salvage lymph node dissection (sLND) or stereotactic body radiotherapy (SBRT). Since the majority of patients treated with MDT relapse within 2 years in adjacent lymph node regions, with an estimated median time to progression of 12-18 months, combining MDT with whole pelvic radiotherapy (WPRT) may improve oncological outcomes in these patients. The aim of this prospective multicentre randomized controlled phase II trial is to assess the impact of the addition of WPRT to MDT and short-term androgen deprivation therapy (ADT) on metastasis-free survival (MFS) in the setting of oligorecurrent pelvic nodal recurrence. METHODS & DESIGN: Patients diagnosed with PET-detected pelvic nodal oligorecurrence (≤5 nodes) following radical local treatment for PCa, will be randomized in a 1:1 ratio between arm A: MDT and 6 months of ADT, or arm B: WPRT added to MDT and 6 months of ADT. Patients will be stratified by type of PET-tracer (choline, FACBC or PSMA) and by type of MDT (sLND or SBRT). The primary endpoint is MFS and the secondary endpoints include clinical and biochemical progression-free survival (PFS), prostate cancer specific survival, quality of life (QoL), toxicity and time to castration-resistant prostate cancer (CRPC) and to palliative ADT. Estimated study completion: December 31, 2023. DISCUSSION: This is the first prospective multicentre randomized phase II trial assessing the potential of combined WPRT and MDT as compared to MDT alone on MFS for patients with nodal oligorecurrent PCa. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03569241, registered June 14, 2018, ; Identifier on Swiss National Clinical Trials Portal (SNCTP): SNCTP000002947, registered June 14, 2018.

Availability of prostate cancer exercise rehabilitation resources and practice patterns in Belgium: Results of a cross-sectional study.

Exercise is recommended for prostate cancer (PCa) patients treated with androgen deprivation therapy. The goal of the study was to assess the availability of hospital-based rehabilitation resources and national practice patterns for PCa in Belgium. A questionnaire was conducted with rehabilitation physical therapists in all Belgian hospital with urology and rehabilitation departments. Practice patterns were compared with the American College of Sports Medicine guidelines. PCa prevalence data were obtained from the Belgian Cancer Registry and attitude of physicians towards physical activity was documented. We included 98 Belgian hospitals. Only 25% of the PCa population had access to PCa-specific programmes. The occupancy rate of PCa-specific rehabilitation slots was 69%. The main perceived barriers to organise PCa-specific rehabilitation were existence of general programmes (40%) and low referrals (18%). All PCa programmes consisted of aerobic and resistance exercise and 62% included flexibility. Minimal criteria for frequency and duration per session were followed in 83%. The majority (89%) of physicians believed in the positive effects of supervised exercise programmes. The majority of PCa programmes follow the evidence-based guidelines except for flexibility exercises. The minority of PCa patients has access to specific programmes, although not all treatment slots are occupied.

Dynamic contrast-enhanced imaging has limited added value over T2-weighted imaging and diffusion-weighted imaging when using PI-RADSv2 for diagnosis of clinically significant prostate cancer in patients with elevated PSA.

AIM: To determine the added value of dynamic contrast-enhanced imaging (DCE) over T2-weighted imaging (T2-WI) and diffusion-weighted imaging (DWI) for detection of clinically significant prostate cancer (csPC) in patients with elevated prostate-specific antigen (PSA). METHODS AND MATERIALS: Two hundred and forty-five patients with elevated PSA underwent multiparametric (mp) magnetic resonance imaging (MRI) of the prostate before biopsy. mpMRI was performed using a 3 T MRI system without an endorectal coil. Patients underwent transrectal ultrasound-guided systematic 12 core biopsy followed by radical prostatectomy (n=68), radiation therapy (n=91), or clinical follow-up for at least 2 years (n=86). csPC was defined as Gleason score ≥3+4 and/or tumour volume of ≥0.5 ml, and/or tumour stage ≥T3a. The MRI findings were scored according to the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and an alternative overall assessment category (PI-RADSv2Alt) based on only T2-WI and DWI. RESULTS: In 144 patients (58.8%), csPC was found within 2 years after MRI. With scoring according to the PI-RADSv2 guidelines, DCE was not needed for determination of the overall assessment category in 80.8% (198/245) of patients. Receiver operating characteristic (ROC) analysis showed an area under the curve of 0.79 (95% confidence interval [CI]: 0.74-0.85) for PI-RADSv2 and 0.79 (95% CI: 0.73-0.85) for PI-RADSv2Alt. CONCLUSION: The added value of DCE over T2-WI and DWI is limited when using PI-RADSv2 for diagnosis of csPC in patients with elevated PSA before biopsy. An alternative overall assessment score using only T2-WI and DWI yielded similar performance to PI-RADSv2.

Physiological performance of quails that underwent dietary and pharmacological manipulation of cholesterol.

The present work evaluated whether dietary and pharmacological interference on cholesterol synthesis were capable of inducing alterations in blood and yolk cholesterol levels and the secretion of corticosterone metabolites. Forty-five 40-day-old quails were divided into three experimental groups: vegetal fat diet, 2% beef fat (tallow) diet and vegetal fat diet with simvastatin administration (3.13 mg/kg/day). During all experiments, the animal weights and food consumption were recorded and blood and faecal samples (days 0, 15, 30, 45 and 60), as well as eggs (days 30, 45 and 60), were collected. Analysis of serum and yolk cholesterol was performed and faecal corticosterone levels were measured. No differences were observed on blood cholesterol or faecal corticosterone between all treatments, despite a tendency of increased cholesterol in the group with the animal fat diet. However, quails submitted to an animal fat diet displayed an increase in yolk cholesterol at day 30 of the treatment and the egg yolks of quails treated with simvastatin exhibited a decrease in cholesterol content by the end of the treatment at 60 days. These results improved the knowledge regarding the physiology of quails and offered support to other studies concerning the consequences of the pharmacological treatment and the dietary manipulation of cholesterol levels.

Moderate hypofractionated radiotherapy for prostate cancer: 3-year toxicity results of a multicentre randomized phase 3, non-inferiority trial.

BACKGROUND AND PURPOSE: Moderate hypofractionated radiotherapy (HFRT) is a standard treatment for prostate cancer patients. We compared 2 moderate HFRT regimens, with a biologically equivalent dose of 80 Gy in 2 Gy fractions, with a modest simultaneous integrated boost to the dominant intraprostatic lesion. MATERIAL AND METHODS: This is a multicenter, non-inferiority, randomized phase 3 trial with acute toxicity as the primary endpoint, comparing: 56 Gy in 4 weeks (16x3.5 Gy, 4 days/week, Arm A) with 67 Gy in 5 weeks (25x2.68 Gy, 5 days/week, Arm B). The H0 hypothesis is that both regimens are equivalent in terms of acute grade ≥ 2 gastro-intestinal toxicity, defined as a difference in acute grade ≥ 2 gastro-intestinal toxicity of ≤ 10 %. Here we report on acute and late toxicity. RESULTS: We included 170 patients in Arm A and 172 patients in Arm B. The median follow-up time for all patients was 42 months. Acute grade ≥ 2 gastrointestinal toxicity was reported by 24 % of patients in both groups. Acute grade 2 and 3 urinary toxicity was observed in 52 % and 9 % of patients in Arm A and 53 % and 7 % in Arm B. Late grade 2 and grade ≥ 3 gastrointestinal toxicity occurred in 19 % and 4 % of patients in Arm A compared with 15 % and 4 % in Arm B. Late grade 2 and grade ≥ 3 urinary toxicity was observed in 37 % and 10 % of patients in Arm A and 36 % and 6 % in Arm B. CONCLUSION: This analysis confirms that both HFRT regimens are safe and equivalent in terms of acute grade ≥ 2 gastrointestinal toxicity.

Imaging treated prostate cancer.

In patients with a clinical suspicion of recurrence after treatment for prostate cancer, imaging can be used to distinguish between local recurrence and metastatic disease. Multiparametric magnetic resonance imaging (mpMRI) of the prostate may be a valuable imaging modality for the detection and localization of local recurrence in patients treated for prostate cancer. In mpMRI, morphological T2-weighted images are combined with functional MRI techniques including diffusion-weighted imaging, dynamic contrast-enhanced imaging, and magnetic resonance spectroscopic imaging to improve accuracy. In this paper, the current status of imaging techniques used to detect and to localize tumor recurrence in patients treated for prostate cancer will be reviewed, with emphasis on mpMRI for local prostate cancer recurrence.

Adjuvant Radiotherapy After Radical Cystectomy for Patients with High-risk Muscle-invasive Bladder Cancer: Results of a Multicentric Phase II Trial.

BACKGROUND: High-risk muscle-invasive bladder cancer (MIBC) has a poor prognosis. Old trials showed that external beam radiotherapy (EBRT) after radical cystectomy (RC) decreases the incidence of local recurrences but induces severe toxicity. OBJECTIVE: To evaluate the toxicity and local control rate after adjuvant EBRT after RC delivered with volumetric arc radiotherapy. DESIGN, SETTING, AND PARTICIPANTS: This is a multicentric phase 2 trial. From August 2014 till October 2020, we treated 72 high-risk MIBC patients with adjuvant EBRT after RC. High-risk MIBC is defined as ≥pT3-MIBC ± lymphovascular invasion, fewer than ten lymph nodes removed, pathological positive lymph nodes, or positive surgical margins. INTERVENTION: Patients received 50 Gy in 25 fractions with intensity-modulated radiotherapy to the pelvic lymph nodes ± cystectomy bed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is acute toxicity. We report on local relapse-free rate (LRFR), clinical relapse-free survival (CRFS), overall survival (OS), and bladder cancer-specific survival (BCSS). RESULTS AND LIMITATIONS: The median follow-up is 18 mo. Forty-two patients (61%) developed acute grade 2 gastrointestinal (GI) toxicity. Four patients (6%) had acute grade 3 GI toxicity. One patient had grade 5 diarrhea and vomiting due to obstruction at 1 mo. Two-year probabilities of developing grade ≥3 and ≥2 GI toxicity were 17% and 76%, respectively. Urinary toxicity, assessed in 17 patients with a neobladder, was acceptable with acute grade 2 and 3 urinary toxicity reported in 53% (N = 9) and 18% (N = 3) of the patients, respectively. The 2-yr LRFR is 83% ± 5% and the 2-yr CRFS rate is 43% with a median CRFS time of 12 mo (95% confidence interval: 3-21 mo). Two-year OS and BCSS are 52% ± 7% and 62% ± 7%, respectively. Shortcomings are the nonrandomized study design and limited follow-up. CONCLUSIONS: Adjuvant EBRT after RC can be administered without excessive severe toxicity. PATIENT SUMMARY: In this report, we looked at the incidence of toxicity and local control after adjuvant external beam radiotherapy (EBRT) following radical cystectomy (RC) in high-risk muscle-invasive bladder cancer patients. We found that adjuvant EBRT was feasible and resulted in good local control. We conclude that these data support further enrollment of patients in ongoing trials to evaluate the place of adjuvant EBRT after RC.

Is There a Benefit of Combining Immunotherapy and Radiotherapy in Bladder Cancer?

Immune checkpoint inhibitors have transformed the management of patients with metastatic urothelial cancer, by leading to long-term response and prolongation of survival in a subset of patients. Unfortunately, only one in five patients with metastatic urothelial cancer responds to anti-programmed death ligand-1 ([AQ1]anti-PD-1) monotherapy. Preclinical and early clinical evidence indicates that radiotherapy not only acts locally, but also exerts systemic anti-tumour effects by modulating the immune system. It is hypothesised that combining checkpoint inhibitors with radiotherapy might enhance an anti-tumour immune response and increase response rates. So far, a handful of early phase clinical trials have been performed seeking to answer this question in urothelial cancer patients. The current review summarises the available preclinical and clinical evidence on radiotherapy/immunotherapy combinations in locally advanced and metastatic bladder cancer and suggests future avenues worthy of exploration.

Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study.

BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

Pattern of Progression after Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Nodal Recurrences.

AIMS: To report the relapse pattern of stereotactic body radiotherapy (SBRT) for oligorecurrent nodal prostate cancer (PCa). MATERIALS AND METHODS: PCa patients with ≤3 lymph nodes (N1/M1a) at the time of recurrence were treated with SBRT. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a biological effective dose of at least 80 Gy to all metastatic sites. Distant progression-free survival was defined as the time interval between the first day of SBRT and appearance of new metastatic lesions, outside the high-dose region. Relapses after SBRT were recorded and compared with the initially treated site. Secondary end points were local control, time to palliative androgen deprivation therapy and toxicity scored using the Common Terminology Criteria for Adverse Events v4.0. RESULTS: Overall, 89 metastases were treated in 72 patients. The median distant progression-free survival was 21 months (95% confidence interval 16-25 months) with 88% of patients having ≤3 metastases at the time of progression. The median time from first SBRT to the start of palliative androgen deprivation therapy was 44 months (95% confidence interval 17-70 months). Most relapses (68%) occurred in nodal regions. Relapses after pelvic nodal SBRT (n = 36) were located in the pelvis (n = 14), retroperitoneum (n = 1), pelvis and retroperitoneum (n = 8) or in non-nodal regions (n = 13). Relapses after SBRT for extrapelvic nodes (n = 5) were located in the pelvis (n = 1) or the pelvis and retroperitoneum (n = 4). Late grade 1 and 2 toxicity was observed in 17% (n = 12) and 4% of patients (n = 3). CONCLUSION: SBRT for oligometastatic PCa nodal recurrences is safe. Most subsequent relapses are again nodal and oligometastatic.

Cognitive factors influencing treatment decision-making in patients with localised prostate cancer: development of a standardised questionnaire.

BACKGROUND: Men diagnosed with localised prostate cancer have to make a well-informed treatment choice between (robot-assisted) radical prostatectomy, external beam radiotherapy and, in selected cases, brachytherapy and active surveillance. We developed and validated a questionnaire to determine the cognitive reasons motivating this choice. MATERIALS AND METHODS: The Prostate Cancer Decision-Making Questionnaire (PC-DMQ) was designed in-house and validated through the Delphi method. Finally, we tested the questionnaire in a cohort of 24 men, recently diagnosed with localised PC, before undergoing RARP (n = 16), EBRT (n = 6), brachytherapy (n = 1) or active surveillance (n = 1). RESULTS: The experts reached consensus after three rounds. In the patient cohort, 75% of men undergoing RARP chose this treatment because 'it provides the best chance of cure'. Reasons to choose EBRT were not as explicit: 33.3% chose this treatment because 'it provides the best chance of cure' and 33.3% because 'the maintenance of potency is important to them'. CONCLUSIONS: The PC-DMQ is a comprehensive and standardised tool that allows further research into cognitive factors that influence treatment decision-making in patients with localised PC.

Screening and early diagnosis of prostate cancer: an update.

Screening for prostate cancer has become a main controversial topic. First the currently used screening tools, PSA (Prostate Specific Antigen) and DRE (Digital Rectal Examination) have a low accuracy in the prediction of prostate cancer. Second, the benefit of screening in reducing the prostate cancer related mortality was not uniformly shown in older screening studies and there was concern about the risk of overdiagnosis and over-treatment of insignificant prostate cancers. Very recently, 3 major prospective, randomized screening studies have been published. This paper aims to provide an overview how the performance of the current screening tools can be ameliorated and evaluates the recently published screening studies with practical considerations for future screening protocols.

A comparison of the acute toxicity profile between two-dimensional and three-dimensional image-guided radiotherapy for postoperative prostate cancer.

AIMS: To compare acute gastrointestinal and genitourinary toxicity for patients positioned with an electronic portal imaging device (EPID) and patients positioned with kilovoltage cone beam computed tomography (CBCT) during postoperative prostate radiotherapy. MATERIALS AND METHODS: Between 1999 and April 2010, 196 prostate cancer patients were referred for postoperative salvage radiotherapy. Patient position was corrected using EPID (1999 to December 2006, n=116) or CBCT (January 2007 to present, n=80). The treatment technique, number of beams, dose prescription, dose computation algorithm and planning target volume margins were not altered over time. Grade 1-3 acute gastrointestinal and genitourinary toxicity were compared between the EPID group and the CBCT group. RESULTS: The incidence of grade 1 and 2 genitourinary toxicity was significantly reduced by 17 and 14%, respectively, in the CBCT group compared with the EPID group (P<0.05). This was mainly attributed to a decrease in the following grade 1 symptoms: frequency (P<0.05), nocturia (P=0.06) and urgency (P=0.07). Grade 2 incontinence (P=0.06) and frequency (P=0.06) were lower in the CBCT group. Grade 3 genitourinary toxicity was comparably low (EPID 3% versus CBCT 1%). There was no significant difference in gastrointestinal grade 1-2 toxicity between both groups. No grade 3 gastrointestinal toxicity was observed. CONCLUSIONS: Patient positioning with CBCT significantly reduces acute genitourinary toxicity compared with positioning with EPID.

Fractures of the calcaneus in racing greyhounds.

Fifty-one calcaneus fractures associated with (41) or without (10) central tarsal bone (Tc) fractures in racing greyhounds were evaluated and categorized. All calcaneal fractures with no Tc fractures had a plantar proximal intertarsal subluxation. No subluxations were found in dogs with both calcaneal and central tarsal fractures. The calcaneal fractures were treated either with coaptation splints or surgical repair. Surgical techniques included a Steinmann pin with a figure eight tension band device or screw or plate fixation as primary techniques supplemented by Kirschner wires and cerclage wires. In all calcaneal fractures associated with plantar proximal intertarsal subluxation, an arthrodesis of the calcaneoquartal joint was performed. All 22 surgically repaired fractures in dogs available for physical and radiographic reexamination had healed within 1 to 6 months. Eight dogs with fractures of the calcaneus associated with fractures of Tc returned to a racing career. None of the dogs with plantar proximal intertarsal subluxation raced again. Based on the orientation of the fracture lines and on dissection of two tarsi with calcaneal fractures, a hypothesis on the pathogenesis of calcaneal fractures in racing greyhounds was formulated.