Prostate-specific antigen response to deferred combined androgen blockade therapy using bicalutamide predicts survival after subsequent oestrogen and docetaxel therapies in patients with castration-resistant prostate cancer.
ABSTRACT Study Type - Prognosis (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? The additional use of anti-androgen (deferred combined androgen blockade [CAB] therapy) for patients with castration-resistant prostate cancer (CRPC) initially treated with androgen deprivation monotherapy (ADMT) can provide a clinical response, although the reported response rates vary widely. Our previous study, which reported a response rate of 66% to deferred CAB therapy, suggested that deferred CAB responders would also respond better to subsequent therapies than non-responders because the difference in cancer-specific survival between the deferred CAB responders and the non-responders was much larger than the progression-free survival rates for the responders. The present study showed that PSA response to deferred CAB therapy predicts clinical outcomes after subsequent oestrogen and docetaxel therapy. We propose that PSA response to deferred CAB be used for planning individualized treatment that includes secondary hormonal therapy and chemotherapy.
• To evaluate whether there is any association between prostate-specific antigen (PSA) response to deferred combined androgen blockade (CAB) therapy using bicalutamide in patients with castration-resistant prostate cancer (CRPC), initially treated with castration monotherapy, and the clinical outcomes after subsequent oestrogen and docetaxel therapies.
• Fifty-six patients with advanced prostate cancer, who were refractory to both initial castration monotherapy and subsequent deferred CAB, received oestrogen therapy (estramustine phosphate 140 or 280 mg/day in 50 patients, diethylstilbestrol diphosphate 100 mg/day orally in six patients). Of the 56 patients, 33 underwent docetaxel therapy (median dose 55 mg/m(2) , every 4-8 weeks, median 6 courses) when they became refractory to oestrogen therapy. • A deferred CAB response was defined as a decrease of >50% in PSA levels after the addition of bicalutamide. The difference in cancer-specific survival (CSS) after confirmation of resistance to initial castration monotherapy between the deferred CAB responders and the non-responders was evaluated, and outcomes after oestrogen and docetaxel therapies were also compared between the two groups.
• A response to deferred CAB was observed in 27 (48%) of the 56 patients. There was no significant difference between the responders and the non-responders in pretreatment clinical variables, including Gleason score, metastatic sites, PSA level at diagnosis, and PSA nadir during castration monotherapy. • A deferred CAB response was a significant predictor of CSS after confirmation of resistance to initial castration monotherapy. • The deferred CAB responders had significantly longer progression-free survival (PFS) (median 3.2 months in the responders, 2.1 month in the non-responders, P= 0.04) and CSS (median 3.0 years in the responders, 1.5 years in the non-responders, P= 0.04) after oestrogen therapy. Likewise, PFS (median 8.2 months in the responders, 2.2 months in the non-responders, P < 0.01) and CSS (median not reached in the responders, 1.4 years in the non-responders, P < 0.01) after docetaxel therapy was significantly longer in the deferred CAB responders.
• PSA response to deferred CAB predicts clinical outcomes after subsequent oestrogen and docetaxel therapies in patients with CRPC, and provides useful information for planning individualized optimum treatment courses that include secondary hormonal therapy and chemotherapy.
- SourceAvailable from: Tsuneharu Miki[show abstract] [hide abstract]
ABSTRACT: One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.Cancer Research 07/2007; 67(11):5117-25. · 8.65 Impact Factor
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ABSTRACT: Some authors have recently reported that maximum androgen block (MAB), in which the nonsteroidal anti-androgen, flutamide, is used together with conventional hormone therapy such as castration or luteinizing hormone-releasing hormone analogue, is more effective for prostate cancer than conventional methods. However, others have reported that the effect of MAB on survival is minimal, and definite conclusions concerning MAB remain unclear. Conversely, using flutamide as a second-line hormone therapy after recurrence is also considered, but few authors have reported whether this therapeutic option is effective or for which patients it is effective. 124 patients with prostate cancer were diagnosed and followed at Kobe City General Hospital between 1995 and 1997. Twenty-two of these cases developed recurrence during first-line hormone therapy, and flutamide was prescribed in these cases. The prognostic value and effectiveness of flutamide were evaluated by measurement of serum prostate-specific antigen (PSA) at diagnosis, posttreatment nadir PSA level, PSA at the time of flutamide use, histological grade, recurrence-free time after firstline hormone therapy and age at the time of diagnosis. Six of 9 cases whose post-treatment nadir PSA levels after initial hormone therapy were within the normal limit (<4 ng/ml) achieved complete remission (CR) with flutamide use, but no patient whose post-treatment nadir PSA level remained elevated achieved CR. PSA at diagnosis and PSA at the start of flutamide use were significantly lower for patients with CR. However, the results of multivariate logistic regression analysis demonstrated that only the post-treatment nadir PSA level was significantly correlated with prognosis of flutamide use. Flutamide use as second-line hormone therapy should be limited to cases in which first-line hormone therapy has been highly effective and for whom the post-treatment nadir PSA level was within normal limits, and other patients should undergo other therapies. By limiting flutamide use to patients in whom the effect of flutamide is considered to be maximal, the incidence of complications and medication costs can be decreased.European Urology 02/2000; 37(2):218-22. · 10.48 Impact Factor
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ABSTRACT: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.Clinical Cancer Research 07/2005; 11(14):5233-40. · 7.84 Impact Factor