Prostate cancer chemotherapy by intratumoral administration of Docetaxel-Mesoporous silica nanomedicines.

Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route.

Refining clinically relevant cut-offs of prostate specific antigen density for risk stratification in patients with PI-RADS 3 lesions.

BACKGROUND: Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions, identified through multiparametric magnetic resonance imaging (mpMRI), present a clinical challenge due to their equivocal nature in predicting clinically significant prostate cancer (csPCa). Aim of the study is to improve risk stratification of patients with PI-RADS 3 lesions and candidates for prostate biopsy. METHODS: A cohort of 4841 consecutive patients who underwent MRI and subsequent MRI-targeted and systematic biopsies between January 2016 and April 2023 were retrospectively identified from independent prospectively maintained database. Only patients who have PI-RADS 3 lesions were included in the final analysis. A multivariable logistic regression analysis was performed to identify covariables associated with csPCa defined as International Society of Urological Pathology (ISUP) grade group ≥2. Performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and net benefit. Significant predictors were then selected for further exploration using a Chi-squared Automatic Interaction Detection (CHAID) analysis. RESULTS: Overall, 790 patients had PI-RADS 3 lesions and 151 (19%) had csPCa. Significant associations were observed for age (OR: 1.1 [1.0-1.1]; p = 0.01) and PSA density (OR: 1643 [2717-41,997]; p < 0.01). The CHAID analysis identified PSAd as the sole significant factor influencing the decision tree. Cut-offs for PSAd were 0.13 ng/ml/cc (csPCa detection rate of 1% vs. 18%) for the two-nodes model and 0.09 ng/ml/cc and 0.16 ng/ml/cc for the three-nodes model (csPCa detection rate of 0.5% vs. 2% vs. 17%). CONCLUSIONS: For individuals with PI-RADS 3 lesions on prostate mpMRI and a PSAd below 0.13, especially below 0.09, prostate biopsy can be omitted, in order to avoid unnecessary biopsy and overdiagnosis of non-csPCa.

External validation and comparison of magnetic resonance imaging-based risk prediction models for prostate biopsy stratification.

PURPOSE: Magnetic resonance imaging (MRI) is a promising tool for risk assessment, potentially reducing the burden of unnecessary prostate biopsies. Risk prediction models that incorporate MRI data have gained attention, but their external validation and comparison are essential for guiding clinical practice. The aim is to externally validate and compare risk prediction models for the diagnosis of clinically significant prostate cancer (csPCa). METHODS: A cohort of 4606 patients across fifteen European tertiary referral centers were identified from a prospective maintained database between January 2016 and April 2023. Transrectal or transperineal image-fusion MRI-targeted and systematic biopsies for PI-RADS score of ≥ 3 or ≥ 2 depending on patient characteristics and physician preferences. Probabilities for csPCa, defined as International Society of Urological Pathology (ISUP) grade ≥ 2, were calculated for each patients using eight models. Performance was characterized by area under the receiver operating characteristic curve (AUC), calibration, and net benefit. Subgroup analyses were performed across various clinically relevant subgroups. RESULTS: Overall, csPCa was detected in 2154 (47%) patients. The models exhibited satisfactory performance, demonstrating good discrimination (AUC ranging from 0.75 to 0.78, p < 0.001), adequate calibration, and high net benefit. The model described by Alberts showed the highest clinical utility for threshold probabilities between 10 and 20%. Subgroup analyses highlighted variations in models' performance, particularly when stratified according to PSA level, biopsy technique and PI-RADS version. CONCLUSIONS: We report a comprehensive external validation of risk prediction models for csPCa diagnosis in patients who underwent MRI-targeted and systematic biopsies. The model by Alberts demonstrated superior clinical utility and should be favored when determining the need for a prostate biopsy.

The impact of prostate volume estimation on the risk-adapted biopsy decision based on prostate-specific antigen density and magnetic resonance imaging score.

PURPOSE: Utility of prostate-specific antigen density (PSAd) for risk-stratification to avoid unnecessary biopsy remains unclear due to the lack of standardization of prostate volume estimation. We evaluated the impact of ellipsoidal formula using multiparametric magnetic resonance (MRI) and semi-automated segmentation using tridimensional ultrasound (3D-US) on prostate volume and PSAd estimations as well as the distribution of patients in a risk-adapted table of clinically significant prostate cancer (csPCa). METHODS: In a prospectively maintained database of 4841 patients who underwent MRI-targeted and systematic biopsies, 971 met inclusions criteria. Correlation of volume estimation was assessed by Kendall's correlation coefficient and graphically represented by scatter and Bland-Altman plots. Distribution of csPCa was presented using the Schoots risk-adapted table based on PSAd and PI-RADS score. The model was evaluated using discrimination, calibration plots and decision curve analysis (DCA). RESULTS: Median prostate volume estimation using 3D-US was higher compared to MRI (49cc[IQR 37-68] vs 47cc[IQR 35-66], p < 0.001). Significant correlation between imaging modalities was observed (τ = 0.73[CI 0.7-0.75], p < 0.001). Bland-Altman plot emphasizes the differences in prostate volume estimation. Using the Schoots risk-adapted table, a high risk of csPCa was observed in PI-RADS 2 combined with high PSAd, and in all PI-RADS 4-5. The risk of csPCa was proportional to the PSAd for PI-RADS 3 patients. Good accuracy (AUC of 0.69 and 0.68 using 3D-US and MRI, respectively), adequate calibration and a higher net benefit when using 3D-US for probability thresholds above 25% on DCA. CONCLUSIONS: Prostate volume estimation with semi-automated segmentation using 3D-US should be preferred to the ellipsoidal formula (MRI) when evaluating PSAd and the risk of csPCa.

Transperineal or Transrectal Magnetic Resonance Imaging-targeted Biopsy for Prostate Cancer Detection.

BACKGROUND AND OBJECTIVE: A notable paradigm shift has emerged in the choice of prostate biopsy approach, with a transition from transrectal biopsy (TRBx) to transperineal biopsy (TPBx) driven by the lower risk of severe urinary tract infections. The impact of this change on detection of clinically significant prostate cancer (csPCa) remains a subject of debate. Our aim was to compare the csPCa detection rate of TRBx and TPBx. METHODS: Patients who underwent magnetic resonance imaging (MRI)-targeted and systematic biopsies for clinically localized PCa at 15 European referral centers from 2016 to 2023 were included. A propensity score matching (PSM) analysis was performed to minimize selection biases. Logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). KEY FINDINGS AND LIMITATIONS: Of 3949 patients who met the study criteria, 2187 underwent TRBx and 1762 underwent TPBx. PSM resulted in 1301 matched pairs for analysis. Patient demographics and tumor characteristics were comparable in the matched cohorts. TPBx versus TRBx was associated with greater detection of csPCa, whether defined as International Society of Urological Pathology grade group ≥2 (51% vs 45%; OR 1.37, 95% CI 1.15-1.63; p = 0.001) or grade group ≥3 (29% vs 23%; OR 1.38, 95% CI 1.13-1.67; p = 0.001). Similar results were found when considering MRI-targeted biopsy alone and after stratifying patients according to tumor location, Prostate Imaging-Reporting and Data System score, and clinical features. Limitations include the retrospective nature of the study and the absence of centralized MRI review. CONCLUSIONS: Our findings bolster existing understanding of the additional advantages offered by TPBx. Further randomized trials to fully validate these findings are awaited. PATIENT SUMMARY: We compared the rate of detection of clinically significant prostate cancer with magnetic resonance imaging (MRI)-guided biopsies in which the sample needle is passed through the perineum or the rectum. Our results suggest that the perineal approach is associated with better detection of aggressive prostate cancer.

The Added Value of Side-specific Systematic Biopsy in Patients Diagnosed by Magnetic Resonance Imaging-targeted Prostate Biopsy.

BACKGROUND: Systematic biopsy (SB) combined with magnetic resonance imaging (MRI)-targeted biopsy is still recommended considering the risk of missing clinically significant prostate cancer (csPCa). OBJECTIVE: To evaluate the added value in csPCa detection on side-specific SB relative to MRI lesion and to externally validate the Noujeim risk stratification model that predicts the risk of csPCa on distant SB cores relative to the index MRI lesion. DESIGN, SETTING, AND PARTICIPANTS: Overall, 4841 consecutive patients diagnosed by MRI-targeted biopsy and SB for Prostate Imaging Reporting and Data System score ≥3 lesions were identified from a prospectively maintained database between January 2016 and April 2023 at 15 European referral centers. A total of 2387 patients met the inclusion criteria and were included in the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: McNemar's test was used to compare the csPCa detection rate between several biopsy strategies including MRI-targeted biopsy, side-specific SB, and a combination of both. Model performance was evaluated in terms of discrimination using area under the receiver operation characteristic curve (AUC), calibration plots, and decision curve analysis. Clinically significant prostate cancer was defined as International Society of Urological Pathology grade group ≥2. RESULTS AND LIMITATIONS: Overall, the csPCa detection rate was 49%. Considering MRI-targeted biopsy as reference, the added values in terms of csPCa detection were 5.8% (relative increase of 13%), 4.2% (relative increase of 9.8%), and 2.8% (relative increase of 6.1%) for SB, ipsilateral SB, and contralateral SB, respectively. Only 35 patients (1.5%) exclusively had csPCa on contralateral SB (p < 0.001). Considering patients with csPCa on MRI-targeted biopsy and ipsilateral SB, the upgrading rate was 2% (20/961) using contralateral SB (p < 0.001). The Noujeim model exhibited modest performance (AUC of 0.63) when tested using our validation set. CONCLUSIONS: The added value of contralateral SB was negligible in terms of cancer detection and upgrading rates. The Noujeim model could be included in the decision-making process regarding the appropriate prostate biopsy strategy. PATIENT SUMMARY: In the present study, we collected a set of patients who underwent magnetic resonance imaging (MRI)-targeted and systematic biopsies for the detection of prostate cancer. We found that biopsies taken at the opposite side of the MRI suspicious lesion have a negligible impact on cancer detection. We also validate a risk stratification model that predicts the risk of cancer on biopsies beyond 10 mm from the initial lesion, which could be used in daily practice to improve the personalization of the prostate biopsy.