Advanced High-risk Prostate Cancer Research Articles

PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients (pts) with localized or locally advanced high-risk prostate cancer (PC).

TPS285 Background: In pts with localized high-risk PC, disease recurrence rate following RP is ̃50% (Kane et al. J Urol. 2007). Treatment (tx) with androgen blockade before RP can reduce tumor burden post RP (Taplin et al. J Clin Oncol. 2014; McKay et al. Prostate Cancer Prostatic Dis. 2018; Efstathiou et al. Eur Urol. 2019). This study examines if 12 months of perioperative APA + ADT tx before and after RP with pelvic lymph node dissection (pLND) in localized/locally advanced high-risk PC improves pathologic complete response (pCR) rate and metastasis-free survival (MFS) vs PBO + ADT. Methods: PROTEUS, an international multicenter study, is enrolling ̃2000 pts with localized/locally advanced high-risk/very high-risk PC who are candidates for RP with pLND over 3 years at > 203 sites in 18 countries. Stratification variables: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization: 1:1 to APA (240 mg/d) + ADT or PBO + ADT. Pts receive 6-month neoadjuvant tx followed by RP and then 6 months’ adjuvant tx. Primary end points: pCR rate and MFS. In addition to MFS based on conventional imaging, MFS based on PSMA PET or conventional imaging will be assessed as a separate end point. Both pCR and MFS are assessed by blinded independent central review. Conventional imaging by CT or MRI and bone scan are done at screening, within 4 weeks after RP, at biochemical failure (BCF), and then every 6 months after BCF until distant metastasis or death. During the direct perioperative period, APA/PBO is stopped 2 weeks prior to planned RP and then resumed 4 weeks after RP if post-RP imaging has been conducted to assess for lymphocele and disease progression and resolution to grade ≤ 1 of any clinically significant adverse events considered related to RP. To reflect evolving standard of care, the following protocol amendments were added: PSMA-PET imaging at 3 months post adjuvant tx, at BCF, and every 6 months until distant metastasis or death; cardiovascular and thrombotic risk assessment at screening, prior to, and after RP; and guidance for standard thrombotic prophylaxis in the perioperative setting. An independent data monitoring committee will review trial data. Clinical trial information: NCT03767244.

Обследование пациентов с раком предстательной железы высокого риска: реальная практика в России

Introduction. Approaches to the diagnosis and staging of localized and locally advanced high-risk prostate cancer (PCa-НR) continue to be actively researched and improved. Materials and methods. In order to understand some of the controversial and controversial issues regarding the diagnosis of PCа-НR, a survey was conducted, in which 250 specialists took part – oncourologists, urologists, andrologists, specializing in the treatment / observation of patients with prostate cancer (PCа). The survey was conducted within the urological information portal Uroweb.ru by filling out a questionnaire. Results. The results obtained indicate that the most significant differences were obtained in views on the role of positron emission tomography combined with computed tomography (PET/CT) in the primary diagnosis of non-metastatic PCа and the importance of local prevalence in determining the risk of progression, while the attitude to genetic testing, primary local staging and prognosis criteria after radical prostatectomy in the majority respondents were similar. Conclusions. Most Russian oncourologists specialists involved in the treatment of PCа do not recommend that patients with PCа-HR perform PET/CT with prostate specific membrane antigen (68Ga-PSMA) and do not prescribe geneticist consultation and genetic counseling for non-metastatic PCа. To assess the local prevalence of the process in prostate cancer, based on the results of MRI, digital rectal examination and the percentage of tumor tissue in the biopsy sample. Most specialists determine the prognosis of a patient after RP by summing up the pathomorphological (PSA + radiological diagnostics + the result of histological examination) and clinical (PSA + radiological diagnostics + biopsy) indicators, which quite correlates with the global data.

Pathologic response to neoadjuvant therapy of high risk prostate cancer

Background. The role of pathological response, which develops as a result of systemic therapy for localized and locally advanced high risk prostate cancer, is not still fully understood. There are no clear indications for neoadjuvant therapy and no data on the relationship between neoadjuvant therapy and median of overall or progression free survival. According to increasing interest for neoadjuvant chemohormonal therapy followed by radical prostatectomy, we evaluated the features of pathological response and its effects on overall and progression free survival rates.Objective. Estimating residual disease and pathologic response to neoadjuvant therapy of high risk prostate cancer and its relationship with oncological results.Materials and methods. This was a prospective randomized study: patients with prostate cancer of high and very high-risk groups (prostate specific antigen levels >20 ng/ml and/or Gleason score ≥8 and/or clinical stage ≥T2c) were treated with neoadjuvant chemohormonal therapy followed by radical prostatectomy (n = 36). The neoadjuvant course included the intravenous administration of docetaxel once every 21 days (75 mg/m2 up to 6 cycles) and the antagonist of the gonadotropin releasing hormone degarelix according to the standard scheme (6subcutaneous injections every 28 days). The prostate tissue was evaluated for the residual disease, features of pathological response according to the ABC system. Additionally, the expression of IHC markers (p53, bcl-2, p16, Ki-67, androgen receptors, c-MYC, ERG, PTEN) was evaluated on postoperative material using tissue microarray.Results. A totally of 480 H&Epostoperative and 775 H&E biopsy slides were analyzed. Group A included 10 (32.3 %) cases, group B — 16 (51.6 %), and group C — 5 (16.1 %). The variance analysis revealed a significant difference in the frequency of more localized forms of prostate cancer in group B (43.7 %) (p = 0.028). During assessment we did not found any relationship ABC system assignment and preoperative prostate specific antigen level, the presence of a positive surgical margin, the pathological stage of diseases or regional lymph nodes involvement. However, the values of relapse-free survival vary sharply between groups: the highest median of relapse-free survival was found in group B — 23.02 ± 12.61 months, patients of groups A/C could not achieve the level of median relapse-free survival — 11.7 ± 6.43 and 16.19 ± 16.54 months respectively.Conclusion. The effectiveness of neoadjuvant chemohormonal therapy for high risk prostate cancer can be assessed by the features of pathologic response through ABC system which has demonstrated own versatility and reproducibility in presented material. Neoadjuvant therapy with docetaxel and degarelix can improve the treatment outcomes of prostate cancer patients at high and very high risk of disease progression. The data on changes in the prostate tissue can be helpful in predicting the duration of the effect after chemohormonal therapy with subsequent surgery.

Erratum to: Oncological outcome of neoadjuvant low-dose estramustine plus LHRH agonist/antagonist followed by extended radical prostatectomy for Japanese patients with high-risk localized prostate cancer: a prospective single-arm study.

Background Patients with advanced high-risk prostate cancer (PCa) are prone to have worse pathological diagnoses of positive surgical margins and/or lymph node invasion, resulting in early biochemical recurrence (BCR) despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether patients with high-risk PCa should undergo RP. The purpose of this study was to evaluate the efficacy of neoadjuvant chemohormonal therapy (NAC) followed by RP. Methods A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6 months of estramustine phosphate (EMP) 140 mg twice daily, along with a luteinizing hormone-releasing hormone agonist/antagonist. We developed our surgical technique to reduce the rate of positive surgical margins. We aimed to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum was exposed. Results More than 1 year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7 months. The 3-year BCR-free survival was 74.9%. Multivariate Cox-regression analysis revealed that a positive core ratio of 50% or greater and pathological stage of pT3 or greater were independent predictors for BCR. About 17 of 23 cases received salvage androgen deprivation therapy and concurrent external beam radiotherapy, and showed no progression after the salvage therapies. Conclusions NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

Detection and dynamics of circulating tumor cells in patients with high-risk prostate cancer treated with radiotherapy and hormones: a prospective phase II study

BackgroundCirculating tumor cells (CTCs) are an established prognostic marker in castration-resistant prostate cancer but have received little attention in localized high-risk disease. We studied the detection rate of CTCs in patients with high-risk prostate cancer before and after androgen deprivation therapy and radiotherapy to assess its value as a prognostic and monitoring marker.Patients and methodsWe performed a prospective analysis of CTCs in the peripheral blood of 65 treatment-naïve patients with high-risk prostate cancer. EpCAM-positive CTCs were enumerated using the CELLSEARCH system at 4 timepoints. A cut off of 0 vs ≥ 1 CTC/7.5 ml blood was defined as a threshold for negative versus positive CTCs status.ResultsCTCs were detected in 5/65 patients (7.5%) at diagnosis, 8/62 (12.9%) following neoadjuvant androgen deprivation and 11/59 (18.6%) at the end of radiotherapy, with a median CTC count/7.5 ml of 1 (range, 1–136). Only 1 patient presented a positive CTC result 9 months after radiotherapy. Positive CTC status (at any timepoint) was not significantly associated with any clinical or pathologic factors. However, when we analyzed variations in CTC patterns following treatment, we observed a significant association between conversion of CTCs and stages T3 (P = 0.044) and N1 (P = 0.002). Detection of CTCs was not significantly associated with overall survival (P > 0.40).ConclusionsOur study showed a low detection rate for CTCs in patients with locally advanced high-risk prostate cancer. The finding of a de novo positive CTC count after androgen deprivation therapy is probably due to a passive mechanism associated with the destruction of the tumor. Further studies with larger samples and based on more accurate detection of CTCs are needed to determine the potential prognostic and therapeutic value of this approach in non-metastatic prostate cancer.Trial registrationClinicalTrials.gov ID: NCT01800058.

Oncological outcome of neoadjuvant low-dose estramustine plus LHRH agonist/antagonist followed by extended radical prostatectomy for Japanese patients with high-risk localized prostate cancer: a prospective single-arm study.

Patients with advanced high-risk prostate cancer (PCa) are prone to have worse pathological diagnoses of positive surgical margins and/or lymph node invasion, resulting in early biochemical recurrence (BCR) despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether patients with high-risk PCa should undergo RP. The purpose of this study was to evaluate the efficacy of neoadjuvant chemohormonal therapy (NAC) followed by "extended" RP. A total of 87 patients with high-risk PCa prospectively underwent extended RP after NAC; most of the patients underwent 6months of estramustine phosphate (EMP) 140mg twice daily, along with a luteinizing hormone-releasing hormone agonist/antagonist. We developed our surgical technique to reduce the rate of positive surgical margins. We aimed to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum was exposed. More than 1year had elapsed after surgery in all 86 patients, with a median follow-up period of 37.7months. The 3-year BCR-free survival was 74.9%. Multivariate Cox-regression analysis revealed that a positive core ratio of 50% or greater and pathological stage of pT3 or greater were independent predictors for BCR. About 17 of 23 cases received salvage androgen deprivation therapy and concurrent external beam radiotherapy, and showed no progression after the salvage therapies. NAC concordant with extended RP is feasible and might provide good cancer control for patients with high-risk PCa.

3-D transperitoneal laparascopic radical prostatectomy in locally advanced high-risk prostate cancer: a prospective evaluation.

3-D transperitoneal laparascopic radical prostatectomy in locally advanced high-risk prostate cancer: a prospective evaluation.

Improved survival with the addition of radiotherapy to androgen deprivation: questions answered and a review of current controversies in radiotherapy for non-metastatic prostate cancer.

The contemporary standard of care for locally advanced high-risk prostate cancer includes a combination of dose-escalated radiotherapy (RT) plus androgen-deprivation therapy (ADT). However, 20 years ago, at the inception of the National Cancer Institute of Canada (NCIC) led study (NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110), the survival impact of prostate RT for high-risk disease was uncertain. Recently, Mason, Warde and colleagues presented the final results of this NCIC/MRC study (PMID: 25691677) randomizing 1,205 high-risk prostate cancer patients to ADT + RT vs. ADT alone. These updated results confirm substantial improvements with the addition of RT to ADT for the endpoints of overall survival (OS), disease-free survival (DFS), and biochemical recurrence. Close examination of subtleties of this trial's design highlight some of the most salient controversies in the field of prostate RT, including the risk-stratified roles of ADT, optimal ADT duration, and RT field design in the dose-escalated and intensity-modulated radiotherapy (IMRT) era.

P075 Is neoadjuvant docetaxel chemotherapy and androgen blockage before curative treatment feasible in locally advanced high-risk prostate cancer?

P075 Is neoadjuvant docetaxel chemotherapy and androgen blockage before curative treatment feasible in locally advanced high-risk prostate cancer?

Weekly Neoadjuvant Ixabepilone on Surgical Feasibility and Clinical Outcomes in Locally Advanced High-Risk Prostate Cancer: A Phase II Clinical Trial

Background:Men diagnosed with locally advanced high-risk prostate cancer have up to a 40% risk of biochemical recurrence after prostatectomy. The authors performed a phase II trial of neoadjuvant weekly ixabepilone prior to radical prostatectomy. Methods:Enrollment criteria included patients with high-risk prostate cancer defined by D¢‚¬„¢Amico criteria or high-volume Gleason 4+3 with a palpable nodule. Patients received ixabepilone 20 mg/m2/week or 16 mg/m2/week for 3 weeks every 28 days for 4 cycles followed by surgery 2-8 weeks later. Results:Sixteen patients were enrolled with a mean age of 56.5 years (range 43-70). PSA values decreased by a mean of 47% in 14/16 men with patients receiving a mean of 8.25 weeks of treatment (range 2-12). Nine men experienced an adverse event requiring dose modification or premature cessation of chemotherapy. Pathologic staging in 9 patients showed T3a, 5 with T3b, and 1 with T2c disease; 8 had R1 disease and 2 demonstrated nodal involvement. Mean operative time, blood loss, and hospital stay were 189 minutes, 184 mL, and 1.5 days, respectively. At median follow-up of 32 months (range 15-45), 4 patients experienced biochemical recurrence. Conclusions: Neoadjuvant weekly ixabepilone had a good PSA response and no increased surgical morbidity; however, a higher dose is associated with significant persistent neuropathy. There were no complete pathologic responses, but biochemical recurrence rate is low. Further assessment of time to treatment failure will require continued, planned follow-up to evaluate the long-term potential clinical benefit of this study.

Conformal radiotherapy plus local hyperthermia in patients affected by locally advanced high risk prostate cancer: Preliminary results of a prospective phase II study

Purpose: Hyperthermia has been used in several trials to treat pelvic cancers without excessive toxicity and with positive results. The aim of this study was to evaluate feasibility and results in terms of biochemical recurrence-free, disease-free survival, overall survival, and treatment toxicity profile of hyperthermia combined with radiotherapy in locally advanced high risk prostate cancer.Patients and methods: From November 1998 to December 2004, 144 patients with locally advanced prostate cancer (LAPC) were enrolled in a phase II study. They were treated using conformal radiotherapy (CRT) plus local hyperthermia (LHT) and androgen suppression therapy (AST). Treatment modalities consisted of: 1) CRT with a mean dose of 74 Gy (2 Gy/fraction/5 fractions per week); 2) LHT: one session per week during the first, second, third, and fourth week of the radiotherapy course; 3) AST was administered as neo-adjuvant and adjuvant therapy in more than 60% of patients.Results: The median follow-up time was 51.7 months. Four patients were lost at follow-up. Of 140 evaluated patients, four died because of intercurrent diseases and 12 because of progression of disease. Patients were evaluated in terms of five-year overall survival (87%), and five-year biochemical progression-free survival (49%). No significant side effects, except symptoms related to AST have been reported. No late grade 3 toxicity occurred.Conclusions: In advanced high risk prostatic cancer, hyperthermia is feasible and well tolerated. It may be useful to enhance the radiotherapy efficacy at intermediate dose in order to avoid higher doses of irradiation which increases acute and late sequelae. The advantage of LHT combined with CRT should be confirmed by a randomized phase III trial, comparing irradiation plus AST with or without hyperthermia.