Context
There is an urgent need to develop novel treatment strategies in patients with unfavorable intermediate- and high-risk localized prostate cancer (PCa) to optimize the outcome of these ...patients. Androgen receptor signaling inhibitors (ARSI) have demonstrated a survival benefit in metastatic hormonesensitive and castration-resistant PCa. A similar benefit might be expected in the localized setting.
Objective
To perform a systematic review about the role of neoadjuvant ARSI in unfavorable intermediate and high-risk localized PCa.
Evidence acquisition
We performed a systematic review of the following databases: MEDLINE (PubMed), EMBASE, Cochrane Library and Web of Science. Publications of ASCO were consulted to identify meeting abstract with early results of ongoing trials. This systematic review was performed and reported in accordance with the PRISMA guidelines.
Evidence synthesis
Pathological complete response (pCR) following neoadjuvant ARSI treatment was observed in 4%–13% of the patients. Minimal residual disease response ranged from 36% to 73.9% when defined as residual cancer burden < 0.25 cm
3
at final pathology and from 8% to 20% when defined as the diameter of the remaining tumor < 5 mm. Despite intense neoadjuvant ARSI treatment, residual pT3 disease was observed in 48%–76% of the patients. In contrast, positive surgical margins (PSM) were present in only 5%–22%. Only one trial reported BCR following neoadjuvant ARSI therapy (44% BCR at a median follow-up of 4 years).
Conclusion
Despite intense neoadjuvant ARSI therapy, pCR is rarely attained and high proportions of pT3 disease are still observed at final pathology. In contrast, promising results are obtained in terms of PSMs. Long-term survival outcomes are eagerly awaited.
Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being ...frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.
Abstract Background To date, no data have been available from large, well-designed trials comparing on demand and nightly dosing of phosphodiesterase type 5 (PDE5) inhibitors on recovery of erectile ...function in postprostatectomy patients with erectile dysfunction (ED). Objective To investigate the effect of early postoperative dosing with vardenafil, administered either nightly or on demand, compared with placebo on recovery of erectile function in men with ED following bilateral nerve-sparing radical prostatectomy (NSRP) surgery. Design, setting, and participants A randomised, double-blind, double-dummy, multicentre, parallel group study conducted at 87 centres across Europe, Canada, South Africa, and the United States. For inclusion, patients had to be scheduled to undergo bilateral NSRP within 1 mo of screening and have a normal International Index of Erectile Function erectile function domain (IIEF-EF) score of ≥26 at screening. A total of 628 men, aged 18–64 yr, were randomised to treatment. Study design consisted of a 9-mo double-blind treatment period, a 2-mo single-blind washout period, and an optional 2-mo open-label period. Intervention Patients received placebo, nightly vardenafil, or on demand vardenafil. Measurements Primary outcome measure was the percentage of subjects with an IIEF-EF score of ≥22 after the 2-mo washout period. Secondary variables included mean per-patient success rates for Sexual Encounter Profile (SEP) questions 2 and 3. Results and limitations No statistically significant differences were observed among treatment groups in the proportion of patients with an IIEF-EF score of ≥22 or in SEP3 success rates after the washout period. On-demand vardenafil treatment resulted in significantly greater IIEF-EF scores and better SEP3 response rates than placebo over the entire treatment period. Conclusions In this study of men with ED following bilateral NSRP, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on demand dosing with PDE5 inhibitors in this patient group. Trial registration European clinical trials database (EudraCT; available at http://eudract.emea.europa.eu/ ). Trial registration number: 11336.
Salvage lymph node dissection (SLND) represents a possible treatment option for prostate cancer patients affected by nodal recurrence after local treatment. However, SLND may be associated with ...intra- and postoperative complications, and the oncological benefit may be limited to specific groups of patients.
To identify the optimal candidates for SLND based on preoperative characteristics.
The study included 654 patients who experienced prostate-specific antigen (PSA) rise and nodal recurrence after radical prostatectomy (RP) and underwent SLND at nine tertiary referral centers. Lymph node recurrence was documented by positron emission tomography/computed tomography (PET/CT) scan using either 11C-choline or 68Ga-labeled prostate-specific membrane antigen ligand.
SLND.
The study outcome was early clinical recurrence (eCR) developed within 1 yr after SLND. Multivariable Cox regression analysis was used to develop a predictive model. Multivariable-derived coefficients were used to develop a novel risk calculator. Decision-curve analysis was used to evaluate the net benefit of the predictive model.
Median follow-up was 30 (interquartile range, 16–50) mo among patients without clinical recurrence (CR), and 334 patients developed CR after SLND. In particular, eCR at 1 yr after SLND was observed in 150 patients, with a Kaplan-Meier probability of eCR equal to 25%. The development of eCR was significantly associated with an increased risk of cancer-specific mortality at 3 yr, being 20% versus 1.4% in patients with and without eCR, respectively (p<0.0001). At multivariable analysis, Gleason grade group 5 (hazard ratio HR: 2.04; p<0.0001), time from RP to PSA rising (HR: 0.99; p=0.025), hormonal therapy administration at PSA rising after RP (HR: 1.47; p=0.0005), retroperitoneal uptake at PET/CT scan (HR: 1.24; p=0.038), three or more positive spots at PET/CT scan (HR: 1.26; p=0.019), and PSA level at SLND (HR: 1.05; p<0.0001) were significant predictors of CR after SLND. The coefficients of the predictive model were used to develop a risk calculator for eCR at 1 yr after SLND. The discrimination of the model (Harrel'sC index) was 0.75. At decision-curve analysis, the net benefit of the model was higher than the “treat-all” option at all the threshold probabilities.
We reported the largest available series of patients treated with SLND. Roughly 25% of men developed eCR after surgery. We developed the first risk stratification tool to identify the optimal candidate to SLND based on routinely available preoperative characteristics. This tool can be useful to avoid use of SLND in men more likely to progress despite any imaging-guided approach.
The risk of early recurrence after salvage lymph node dissection (SLND) was approximately 25%. In this study, we developed a novel tool to predict the risk of early failure after SLND. This tool will be useful to identify patients who would benefit the most from SLND from other patients who should be spared from surgery.
We reported the largest available series of patients treated with salvage lymph node dissection (SLND), and we developed the first risk stratification tool to identify the optimal candidate to SLND based on routinely available preoperative characteristics. This tool can be useful to avoid use of SLND in men more likely to progress despite any imaging-guided approach.
Background
Salvage radiotherapy (RT) (± androgen deprivation therapy (ADT)) is often used as a treatment in patients with biochemical recurrence (BCR) following radical prostatectomy (RP). ...Unfortunately, even after RT ± ADT, a significant number of patients will develop ‘second’ BCR. The aim of this study was to investigate the impact of postoperative treatments (adjuvant/salvage radiotherapy (RT) ± androgen deprivation therapy) on the recurrence pattern in patients with BCR following RP assessed by 11C-Choline PET/CT or 68 Ga-PSMA PET/CT.
Methods
Patients who developed BCR following RP and who had at least one positive lesion on PET/CT were retrospectively assessed. Positive spots were mapped as local, lymph node (LN), skeletal or visceral recurrence. A distinction was made between locoregional (prostate bed and pelvic LN) and extrapelvic recurrence (skeletal, visceral and/or extrapelvic LN). Patients were categorized according to postoperative treatment received in three subgroups (RT, ADT and RT + ADT) and compared with the reference group (RP only). The impact of the radiation field was also investigated.
Results
We identified 200 patients assessed by
68
Ga-PSMA-11 (80%) or
11
C-Choline PET/CT (20%). Patients who received postoperative RT + ADT had less LN recurrence distal to the common iliac bifurcation (26.7% vs 66.6%;
p
= 0.0004), but more recurrence to retroperitoneal LN than the reference group (38% vs. 14.4%,
p
= 0.02). Moreover, the RT + ADT subgroup had more extrapelvic recurrence compared to the reference group (66.2% vs 40.8%,
p
= 0.02). Patients who received RT to the prostate bed had more recurrence distal to the common iliac bifurcation compared to those who received RT to the prostate bed + pelvic LN (51.6% vs 26.1%,
p
= 0.0069).
Conclusion
Post-prostatectomy treatments (ADT and/or RT) and the postoperative radiation field (prostate bed vs. prostate bed + pelvis) have a significant impact on the recurrence pattern. This knowledge can help clinicians to counsel their patients on their chances of being eligible for (locoregional) metastasis-directed therapies.
Abstract Background The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era. Objective ...To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC. Design, setting, and participants Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25–82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC. Intervention Metastasis resection from various anatomic sites with the aim of completely removing detected lesions. Outcome measurements and statistical analysis Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan-Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The α error for statistical significance was set at 0.05. Results and limitations Multivariable analysis revealed that primary tumour T stage ≥3 (hazard ratio HR: 2.8; p < 0.01), primary tumour Fuhrman grade ≥3 (HR: 2.3; p < 0.03), nonpulmonary metastases (HR: 3.1; p < 0.03), disease-free interval ≤12 mo (HR: 2.3; p < 0.058), and multiorgan metastases (HR: 2.5; p < 0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log-rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% ( p < 0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites. Conclusions LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC.
The majority of prostate cancers are hormone-dependent at diagnosis highlighting the central role of androgen signalling in this disease. Surprisingly, most forms of castration-resistant prostate ...cancer (CRPC) are still dependent on the androgen receptor (AR) for survival. Therefore, the advent of new AR-targeting drugs, such as enzalutamide, is certainly beneficial for the many patients with metastatic CRPC. Indeed, this compound provides a substantial survival benefit-but it is not curative. This Perspectives article describes the different ways through which cancer cells can become resistant to enzalutamide, such as AR truncation and other mutations, as well as by-pass of the AR dependence of prostate cancer cells through expression of the glucocorticoid receptor. The clinical relevance of these mechanisms and emerging questions concerning new therapeutic regimens in the treatment of metastatic CRPC are being discussed.
Objective
To perform an external validation of the Cancer of the Bladder Risk Assessment (COBRA) score for estimating cancer‐specific survival (CSS) after radical cystectomy (RC) in a large ...bi‐institutional cohort of patients.
Patients and Methods
Patients treated with RC and lymph node dissection (LND) between May 1996 and July 2017 were retrieved from the RC databases of Leuven and Turin. Collected variables were age at RC, tumour stage, lymph node (LN) density, neoadjuvant chemotherapy, the extent of LND, and nodal stage. The primary outcome was CSS visualised using Kaplan–Meier plots. Cox proportional hazard models were used to assess the impact of variables on CSS. We performed a pairwise comparison between the COBRA score levels using a log‐rank test corrected by Bonferroni, and developed a simplified COBRA score with three risk categories. To compare models, we assessed concordance indices (C‐indices), receiver operating characteristic curves with area under the curve (AUC), calibration plots, and decision curve analysis (DCA). Finally, we compared both COBRA and simplified COBRA models with the established American Joint Committee on Cancer (AJCC) model.
Results
A total of 812 patients were included. All COBRA score variables had a significant impact on CSS in a Cox proportional hazard model. However, pairwise comparison of the COBRA subscores could not differentiate significantly between all COBRA score levels. Based on these findings, we developed a simplified COBRA score by introducing three categories within the following COBRA score ranges: low‐ (0–1) vs intermediate‐ (2–4) vs high‐risk (5–7). A pairwise comparison could discriminate significantly between all COBRA risk categories. When finally comparing COBRA and simplified COBRA models with the AJCC model, AJCC performed better than both. C‐indices, AUCs, calibration plots and DCA for AJCC were all better compared with the original and simplified COBRA models.
Conclusion
We performed an external validation of the COBRA score in a large bi‐institutional cohort. We observed that several risk groups had overlapping CSS, demonstrating suboptimal performance of the COBRA score. Therefore, we constructed a simplified model with three COBRA score risk categories. This model resulted in demarcated risk groups with non‐overlapping CSS and good predictive accuracy. However, both COBRA score models were outperformed by the AJCC staging system. Therefore, we conclude that the AJCC staging system should remain the current standard for stratifying patients after RC for CSS.
In 2022, the European Commission updated its recommendation on cancer screening, inviting the Member States (MSs) to explore the feasibility of stepwise implementation of population-based screening ...for prostate cancer (PCa). In line with this recommendation, the PRAISE-U (Prostate Cancer Awareness and Initiative for Screening in the European Union (EU)) project was initiated. As part of the PRAISE-U, we aim to understand the current practice towards early detection in the EU MSs, the barriers to implementing or planning population-based screening programmes, and potential solutions to overcome these barriers. Methods: We adapted the Barriers to Effective Screening Tool (BEST) survey to the PCa context. However, it has not been validated in this context. We translated it into all spoken languages in the EU27 and disseminated it to different stakeholders across the EU using a snowballing approach. Results: We received 410 responses from 55 countries, of which 301 (73%) were from the 27 EU MSs. The most represented stakeholder group was urologists (218 (54%)), followed by general practitioners (GPs) (83 (21%)), patient representatives (35 (9%)), policy stakeholders (27 (7%)), researchers (23 (6%)), oncologists, pathologists, radiologists, nurses, and others (16 (4%)) and one industry representative. Among all respondents, 286 (69%) reported the absence of a population-based screening programme, mainly attributed to resource limitations and a lack of political and medical society support. Out of these 286 respondents, 196 (69%) indicated that opportunistic screening is being applied in their country, and 199 (70%) expressed their support for population-based screening programmes (which was highest amongst patient representatives and urologists and lowest amongst GPs and policy stakeholders). The highest scored barriers were lack of political support, insufficient operational resources, and inadequate participation. Suggested solutions to overcome these included awareness campaigns, consensus meetings, political lobbying and European guidelines (to overcome political support barriers), compatible IT systems (to overcome operational barriers), and easy access (to overcome participation barriers). Conclusions: Participants have noted the presence of opportunistic screening, and particularly urologists and patient representatives expressed their support for the establishment of a population-based PCa screening programme. Nevertheless, successful implementation of population-based screening programmes is complex; it requires political and medical society support, operational resources and capacity, awareness campaigns, as well as the development of protocols, guidelines, and legal frameworks.
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