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Introduction: To evaluate the oncological outcome of high dose rate (HDR) brachytherapy (BRT) as monotherapy for clinically localised prostate cancer (PCA).
Material and Methods: Between January 2002 and February 2004, 141 consecutive patients with clinically localised PCA were treated with HDR-BRT monotherapy. The cohort comprised 103 (73%) low-, 32 (22.7%) intermediate- and 6 (4.3%) high risk patients according to D’Amico classification or 104 (73.8%) low-, 24 (17.0%) intermediate favourable-, 12 (8.5%) intermediate unfavourable- and one (0.7%) very high risk patient according to National Comprehensive Cancer Network (NCCN) one. Patients received four fractions of 9.5 Gy delivered within a single implant up to a total physical dose of 38 Gy. Catheter-implantation was transrectal ultrasound-based whereas treatment planning CT-based. Thirty-three patients (23.4%) received ADT neoadjuvantly and continued concurrently with BRT. Biochemical relapse-free survival (BRFS) was defined according to the Phoenix Consensus Criteria and genitourinary (GU)/gastrointestinal (GI) toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 5.0.
Results: Median age at treatment and median follow-up time was 67.2 and 15.2 years, respectively. Twenty-three (16.3%) patients experienced a biochemical relapse and 5 (3.5%) developed distant metastases, with only one patient dying of PCA. The BRFS was 85.1% at 15 years and 78.7% at 18 years. The corresponding overall survival, metastases-free survival, and prostate cancer specific mortality at 15- and 18-years was 73.9%/59.1%, 98.3%/90.6%, and 100%/98.5% respectively. Late grade 3 GI and GU toxicity was 4.2% and 5.6% respectively. Erectile dysfunction grade 3 was reported by 27 (19%) patients. From the prognostic factors evaluated, tumor stage (≤T2b compared to ≥T2c) along with the risk group (low-intermediate vs. high) when using the D’Amico classification but not when the NCCN one was taken into account, correlated significantly with BRFS.
Conclusion: Our long-term results confirm HDR-BRT to be a safe and effective monotherapeutic treatment modality for low- and intermediate risk PCA.
The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
Focal therapy is a modern alternative to selectively treat a specific part of the prostate harboring clinically significant disease while preserving the rest of the gland. The aim of this therapeutic approach is to retain the oncological benefit of active treatment and to minimize the side-effects of common radical treatments. The oncological effectiveness of focal therapy is yet to be proven in long-term robust trials. In contrast, the toxicity profile is well-established in randomized controlled trials and multiple robust prospective cohort studies. This narrative review summarizes the relevant evidence on complications and their management after focal therapy. When compared to whole gland treatments, focal therapy provides a substantial benefit in terms of adverse events reduction and preservation of genito-urinary function. The most common complications occur in the peri-operative period. Urinary tract infection and acute urinary retention can occur in up to 17% of patients, while dysuria and haematuria are more common. Urinary incontinence following focal therapy is very rare (0–5%), and the vast majority of patients recover in few weeks. Erectile dysfunction can occur after focal therapy in 0–46%: the baseline function and the ablation template are the most important factors predicting post-operative erectile dysfunction. Focal therapy in the salvage setting after external beam radiotherapy has a significantly higher rate of complications. Up to one man in 10 will present a severe complication.
Background: We aimed to determine the concordance between the radiologic stage (rT), using multiparametric magnetic resonance imaging (mpMRI), and pathologic stage (pT) in patients with high-risk prostate cancer and its influence on nerve-sparing surgery compared to the use of the intraoperative frozen section technique (IFST). Methods: The concordance between rT and pT and the rates of nerve-sparing surgery and positive surgical margin were assessed for patients with high-risk prostate cancer who underwent radical prostatectomy. Results: The concordance between the rT and pT stages was shown in 66.4% (n = 77) of patients with clinical high-risk prostate cancer. The detection of patients with extraprostatic disease (≥pT3) by preoperative mpMRI showed a sensitivity, negative predictive value and accuracy of 65.1%, 51.7% and 67.5%. In addition to the suspicion of extraprostatic disease in mpMRI (≥rT3), 84.5% (n = 56) of patients with ≥rT3 underwent primary nerve-sparing surgery with IFST, resulting in 94.7% (n = 54) of men with at least unilateral nerve-sparing surgery after secondary resection with a positive surgical margin rate related to an IFST of 1.8% (n = 1). Conclusion: Patients with rT3 should not be immediately excluded from nerve-sparing surgery, as by using IFST some of these patients can safely undergo nerve-sparing surgery.
Despite recent advances in the treatment of metastatic prostate cancer (PCa), resistance development after taxane treatments is inevitable, necessitating effective options to combat drug resistance. Previous studies indicated antitumoral properties of the natural compound amygdalin. However, whether amygdalin acts on drug-resistant tumor cells remains questionable. An in vitro study was performed to investigate the influence of amygdalin (10 mg/mL) on the growth of a panel of therapy-naïve and docetaxel- or cabazitaxel-resistant PCa cell lines (PC3, DU145, and LNCaP cells). Tumor growth, proliferation, clonal growth, and cell cycle progression were investigated. The cell cycle regulating proteins (phospho)cdk1, (phospho)cdk2, cyclin A, cyclin B, p21, and p27 and the mammalian target of rapamycin (mTOR) pathway proteins (phospho)Akt, (phospho)Raptor, and (phospho)Rictor as well as integrin β1 and the cytoskeletal proteins vimentin, ezrin, talin, and cytokeratin 8/18 were assessed. Furthermore, chemotactic activity and adhesion to extracellular matrix components were analyzed. Amygdalin dose-dependently inhibited tumor growth and reduced tumor clones in all (parental and resistant) PCa cell lines, accompanied by a G0/G1 phase accumulation. Cell cycle regulating proteins were significantly altered by amygdalin. A moderate influence of amygdalin on tumor cell adhesion and chemotaxis was observed as well, paralleled by modifications of cytoskeletal proteins and the integrin β1 expression level. Amygdalin may, therefore, block tumor growth and disseminative characteristics of taxane-resistant PCa cells. Further studies are warranted to determine amygdalin’s value as an antitumor drug.
Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease.
Background: To test the impact of urethral sphincter length (USL) and anatomic variants of prostatic apex (Lee-type classification) in preoperative multiparametric magnet resonance imaging (mpMRI) on mid-term continence in prostate cancer patients treated with radical prostatectomy (RP). Methods: We relied on an institutional tertiary-care database to identify patients who underwent RP between 03/2018 and 12/2019 with preoperative mpMRI and data available on mid-term (>6 months post-surgery) urinary continence, defined as usage 0/1 (-safety) pad/24 h. Univariable and multivariable logistic regression models were fitted to test for predictor status of USL and prostatic apex variants, defined in mpMRI measurements. Results: Of 68 eligible patients, rate of mid-term urinary continence was 81% (n = 55). Median coronal (15.1 vs. 12.5 mm) and sagittal (15.4 vs. 11.1 mm) USL were longer in patients reporting urinary continence in mid-term follow-up (both p < 0.01). No difference was recorded for prostatic apex variants distribution (Lee-type) between continent vs. incontinent patients (p = 0.4). In separate multivariable logistic regression models, coronal (odds ratio (OR): 1.35) and sagittal (OR: 1.67) USL, but not Lee-type, were independent predictors for mid-term continence. Conclusion: USL, but not apex anatomy, in preoperative mpMRI was associated with higher rates of urinary continence at mid-term follow-up.
Insulin-like growth factor-1 (IGF-1)-related signaling is associated with prostate cancer progression. Links were explored between IGF-1 and expression of integrin adhesion receptors to evaluate relevance for growth and migration. Androgen-resistant PC3 and DU145 and androgen-sensitive LNCaP and VCaP prostate cancer cells were stimulated with IGF-1 and tumor growth (all cell lines), adhesion and chemotaxis (PC3, DU145) were determined. Evaluation of Akt/mTOR-related proteins, focal adhesion kinase (FAK) and integrin α and β subtype expression followed. Akt knock-down was used to investigate its influence on integrin expression, while FAK blockade served to evaluate its influence on mTOR signaling. Integrin knock-down served to investigate its influence on tumor growth and chemotaxis. Stimulation with IGF-1 activated growth in PC3, DU145, and VCaP cells, and altered adhesion and chemotactic properties of DU145 and PC3 cells. This was associated with time-dependent alterations of the integrins α3, α5, αV, and β1, FAK phosphorylation and Akt/mTOR signaling. Integrin blockade or integrin knock-down in DU145 and PC3 cells altered tumor growth, adhesion, and chemotaxis. Akt knock-down (DU145 cells) cancelled the effect of IGF-1 on α3, α5, and αV integrins, whereas FAK blockade cancelled the effect of IGF-1 on mTOR signaling (DU145 cells). Prostate cancer growth and invasion are thus controlled by a fine-tuned network between IGF-1 driven integrin-FAK signaling and the Akt-mTOR pathway. Concerted targeting of integrin subtypes along with Akt-mTOR signaling could, therefore, open options to prevent progressive dissemination of prostate cancer.