Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 260-260
Author(s):  
Nedal Bukhari ◽  
Kylea R. Potvin ◽  
D. Scott Ernst ◽  
Lori Sax ◽  
Eric Winquist
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Median Overall Survival ◽  
High Volume ◽  
Outcome Data ◽  
Resistant Disease ◽  
Docetaxel Resistance ◽  
Docetaxel Treatment ◽  
Psa Progression ◽  
Hormone Sensitive

260 Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were < 0.2, 0.2-4, and > 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was < 0.2 (1 pt), 0.2-4 (2 pts) and > 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1st-line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived > 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.

scholarly journals Prognostic value of alkaline phosphatase in hormone-sensitive prostate cancer: a systematic review and meta-analysis

2019 ◽  
Vol 25 (2) ◽  
pp. 247-257 ◽  
Author(s):  
Keiichiro Mori ◽  
Florian Janisch ◽  
Mehdi Kardoust Parizi ◽  
Hadi Mostafaei ◽  
Ivan Lysenko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Alkaline Phosphatase ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
High Volume ◽  
Free Survival ◽  
Increased Risk ◽  
Hormone Sensitive

Abstract Purpose To assess the prognostic value of alkaline phosphatase in patients with hormone-sensitive prostate cancer. Methods A systematic review and meta-analysis was performed using the PUBMED, Web of Science, Cochrane Library, and Scopus in April 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared hormone-sensitive prostate cancer patients with high vs. low alkaline phosphatase to determine its predictive value for overall survival, cancer-specific survival, and progression-free survival. We performed a formal meta-analysis of these outcomes. Results 42 articles with 7938 patients were included in the systematic review and 28 studies with 5849 patients for the qualitative assessment. High alkaline phosphatase was associated with worse overall survival (pooled HR 1.72; 95% CI 1.37−2.14) and progression-free survival (pooled HR 1.30; 95% CI 1.10−1.54). In subgroup analyses of patients with “high-volume” and “low-volume”, alkaline phosphatase was associated with the overall survival (pooled HR 1.41; 95% CI 1.21−1.64 and pooled HR 1.64; 95% CI, 1.06−2.52, respectively). Conclusions In this meta-analysis, elevated serum levels of alkaline phosphatase were associated with an increased risk of overall mortality and disease progression in patients with hormone-sensitive prostate cancer. In contrast, those were not associated with an increased risk of cancer-specific mortality. Alkaline phosphatase was independently associated with overall survival in both patients with “high-volume” and “low-volume” hormone-sensitive prostate cancer. Alkaline phosphatase may be useful for being integrated into prognostic tools that help guide treatment strategy, thereby facilitating the shared decision making process.

An update on clinical outcome data for a phase II randomized study comparing androgen deprivation therapy plus docetaxel versus androgen deprivation therapy alone in men with locally advanced/metastatic hormone sensitive prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 259-259 ◽  
Author(s):  
Adam Hassani ◽  
John A. Frew ◽  
Rhona Margaret McMenemin ◽  
Ashraf S. Azzabi ◽  
Ian D. Pedley
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Clinical Outcome ◽  
Androgen Deprivation Therapy ◽  
Outcome Data ◽  
Androgen Deprivation ◽  
Line Treatment ◽  
Second Line ◽  
Hormone Sensitive ◽  
Docetaxel Chemotherapy

259 Background: Androgen deprivation therapy has been the standard of care for advanced prostate cancer for many years. However recent studies have reported a survival benefit for upfront docetaxel chemotherapy in men with hormone sensitive prostate cancer. The GenTax trial was a single institution phase II study investigating clinical outcome and gene profiling for patients with treatment naïve prostate cancer treated with either docetaxel chemotherapy plus androgen deprivation therapy (D+ADT) or androgen deprivation therapy alone (ADT). We report on updated clinical outcome data for this trial. Methods: Patients with newly diagnosed T3/T4, PSA ≥ 50ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised to ADT or D+ADT (docetaxel 75mg/m2 q21 days for 6 cycles). Data were analysed for overall survival, toxicities, time to second line treatment and number of subsequent treatments. Results: 30 patients were randomly assigned to ADT (n = 15) or D+ADT (n = 15) between 10/13/2005 and 12/02/2009. 7 patients in each arm had metastatic disease. Grade 3-4 toxicities were infrequent in D+ADT arm and were not noted in the ADT arm. There were no significant differences between treatment arms for overall survival (log rank p = 0.977) or time to second line treatment (log rank p = 0.954). Median overall survival was 98 months (95% CI 72.3 - 123.7) for ADT and 87 months (95% CI 71.5 - 102.5) for D+ADT. Median time to second line treatment was 45 months (95% CI 13.4 - 76.6) for ADT and 46 months (95% CI 13.2 – 78.8) for D+ADT. Number of subsequent treatments ranged from 0-6 (mean 2.40) for ADT-only and 0-5 (mean 2.13) for D+ADT. Conclusions: The combination of docetaxel and ADT in the hormone sensitive setting is well tolerated, as previously reported. This study was not sufficiently powered to detect statistically significant differences in survival. Patients proceeded to receive a number of subsequent lines of therapy although the order in which these were given was variable. There is a need to establish optimal sequencing of treatments in the upfront docetaxel era. Clinical trial information: 2004-004874-96.

scholarly journals Three-month early change in prostate-specific antigen levels as a predictive marker for overall survival during hormonal therapy for metastatic hormone-sensitive prostate cancer

2021 ◽  
Author(s):  
Shotaro Nakanishi ◽  
Masato Goya ◽  
Mitsuyoshi Tamaki ◽  
Takuma Oshiro ◽  
Seiichi Saito
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Prostate Specific Antigen ◽  
Characteristic Curve ◽  
Specific Antigen ◽  
Predictive Marker ◽  
Castration Resistant Prostate Cancer ◽  
Pretreatment Level ◽  
Castration Resistant ◽  
Hormone Sensitive

Abstract Objective: To date, there are no useful markers for predicting the prognosis of metastatic hormone-sensitive prostate cancer (mHSPC). We evaluated the effect of early changes in prostate-specific antigen (PSA) levels after androgen deprivation therapy (ADT) on castration-resistant prostate cancer (CRPC) progression and overall survival (OS) in mHSPC patients. Results: In 71 primary mHSPC patients treated with ADT, the median times to CRPC and OS were 15 months and 92 months, respectively. In multivariate analysis, a Gleason score of ≥8 (p = 0.004), an extent of disease value (EOD) of ≥2 (p = 0.004), and a 3-month PSA level >1% of the pretreatment level (p = 0.017) were independent predictors of shorter time to CRPC. The area under the receiver operating characteristic curve was feasible at 0.822. For OS, a 3-month PSA level >1% of the pretreatment level was an independent predictor of time to CRPC (p = 0.004).Three factors were independent predictors of shorter time to CRPC. A 3-month PSA level >1% of the pretreatment level correlated with poor a prognosis.

scholarly journals Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

2015 ◽  
Vol 23 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Jan Kroon ◽  
Martin Puhr ◽  
Jeroen T Buijs ◽  
Geertje van der Horst ◽  
Daniëlle M Hemmer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
Cell Lines ◽  
Chemotherapy Resistance ◽  
Clinical Problem ◽  
Dependent Manner ◽  
Ru 486 ◽  
Docetaxel Resistance ◽  
Docetaxel Treatment

Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

scholarly journals Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial

2018 ◽  
Vol 36 (11) ◽  
pp. 1080-1087 ◽  
Author(s):  
Christos E. Kyriakopoulos ◽  
Yu-Hui Chen ◽  
Michael A. Carducci ◽  
Glenn Liu ◽  
David F. Jarrard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Volume ◽  
Phase Iii ◽  
Cancer Trial ◽  
Term Survival ◽  
Chemohormonal Therapy ◽  
Androgen Ablation ◽  
Hormone Sensitive ◽  
Low Volume

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

scholarly journals Local and systemic morbidities of de novo metastatic prostate cancer in Singapore: insight from 685 consecutive patients from a large prospective Uro-oncology registry

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034331 ◽  
Author(s):  
Yu Guang Tan ◽  
Leonard Pang ◽  
Farhan Khalid ◽  
Randy Poon ◽  
Hong Hong Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Metastatic Prostate Cancer ◽  
Group Performance ◽  
De Novo ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
High Volume ◽  
Secondary Outcome ◽  
Systemic Complications

ObjectiveTo evaluate the incidence and management of local and systemic complications afflicting patients with de novo metastatic prostate cancer (mPCa) in Singapore.DesignRetrospective analysis of a large prospective Uro-oncology registry of mPCa.SettingThis study is carried out in a tertiary hospital in Singapore.ParticipantsWe reviewed our institution’s prospectively maintained database of 685 patients with mPCa over a 20-year period (1995–2014). Patients with non-mPCa or those progressed to metastatic disease after previous curative local treatments were excluded.Primary and secondary outcome measuresThe primary outcome was to evaluate the systemic and local morbidity rates associated with mPCa. Local complication was defined as the need for palliative procedures to relieve urinary obstruction, worsening renal function or refractory haematuria, while systemic complication was related to radiographic evidence of skeletal-related pathological fractures. Secondary outcomes analysed were the management and overall survival patterns over 20 years.Results237 (34.6%) patients required local palliative treatments. 88 (12.8%) patients presented with acute urinary retention, 23 patients (9.7%) required repetitive local palliative treatments. On multivariate analyses, prostate-specific antigen >100 (p=0.02) and prostate volume >50 g (p=0.03) were independent prognostic factors for significant obstruction requiring palliative procedures. 118 (17.2%) patients developed skeletal fractures, with poor Eastern Cooperative Oncology Group Performance (ECOG) status (p=0.01) and high volume bone metastasis (p<0.01) independently predictive of skeletal fractures. Altogether, 653 (95.3%) patients received androgen deprivation therapy (ADT), with the median time to castrate resistance of 21.4 months (IQR 7–27). The median overall survival was 45 months (IQR 20–63), with prostate cancer mortality of 81.4%. Improved overall survival was observed from 41.6 months (1995–1999) to 47.8 months (2010–2014) (p<0.01).ConclusionMorbidities and complications arising from mPCa are more common and debilitating than we thought, often requiring immediate palliative treatments, while many necessitate repeated interventions with progression.

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