Flutamide reduced prostate cancer development and prostate stem cell antigen mRNA expression in high grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (HGPIN) appears to represent an ideal target for chemoprevention of prostate cancer (PCa). HGPIN responds to androgen ablation and has prostate stem cell antigen (PSCA) mRNA expression. One hundred and seventy two patients with isolated HGPIN were randomized in a double-blind manner to receive flutamide 250 mg/day (86 cases) or a placebo (86 cases) for 12 months and were rebiopsied at 12 and 60 months. PSCA mRNA expression was assessed in the prestudy and 12-month biopsies by in situ hybridization. The incidence of subsequent PCa was 11.6% in the flutamide group when compared with 30.2% in the placebo group over a follow-up period of 5 years (p = 0.0027). PSCA mRNA expression levels were significantly declined after treatment compared with that before treatment (p < 0.001). After treatment, 66 patients had reduced PSCA mRNA expression, in whom none was found with cancer on follow-up, however, 13 cases had increased PSCA mRNA expression levels, in whom 11 were found with cancer. Cox regression analysis demonstrated that HGPIN with increased PSCA mRNA expression after flutamide had an increased relative risk of 4.33 to develop subsequent cancer (95% confidence intervals: 2.48-7.36; p < 0.001). Seventeen (19.8%) cases had the flutamide-associated side effects, which were graded as mild, but all did not discontinue study. Flutamide can effectively and safely reduce PCa development and significantly suppress PSCA mRNA expression in men with isolated HGPIN, whereas the increased PSCA mRNA expression after therapy may be a clinically adverse predictor for cancer onset.     

Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues: implications for prostate carcinogenesis and progression of prostate cancer

OBJECTIVE: Prostate stem cell antigen (PSCA) is a recently defined homolog of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. The objective of the present study was to examine the expression status of PSCA protein and mRNA in clinical specimens of human prostate cancer (PCa) and to validate it as a potential molecular target for diagnosis and treatment of PCa. METHODS: Immunohistochemical (IHC) and in situ hybridization (ISH) analyses of PSCA expression were simultaneously performed on paraffin-embedded sections of 20 benign prostatic hyperplasia (BPH), 20 prostatic intraepithelial neoplasm (PIN) and 48 prostate cancer (PCa) tissues, including 9 androgen-independent prostate cancers. The level of PSCA expression was semiquantitatively scored by assessing both the percentage and intensity of PSCA-positive staining cells in the specimens. We then compared the PSCA expression between BPH, PIN and PCa tissues and analyzed the correlations of PSCA expression level with pathological grade, clinical stage and progression to androgen-independence in PCa. RESULTS: In BPH and low grade PIN, PSCA protein and mRNA staining were weak or negative and less intense and uniform than that observed in high grade PIN (HGPIN) and PCa. Moderate to strong PSCA protein and mRNA expression were noted in 8 of 11 (72.7%) HGPIN and in 40 of 48 (83.4%) PCa specimens examined by IHC and ISH analyses, and their statistical significance was compared with BPH (20%) and low-grade PIN (22.2%) specimens (P < 0.05). The expression level of PSCA increased with a higher Gleason grade, advanced stage and progression to androgen-independence (P < 0.05). In addition, IHC and ISH staining revealed a high degree of correlation between PSCA protein and mRNA overexpression. CONCLUSIONS: Our data demonstrate that PSCA as a new cell surface marker is overexpressed in a majority of cases of human PCa. PSCA expression correlates positively with adverse tumor characteristics, such as increasing pathological grade (poor cell differentiation), worsening clinical stage and androgen-independence and speculatively with prostate carcinogenesis. PSCA may possess prognostic utility and may be a promising molecular target for diagnosis and treatment of PCa.     

Androgen deprivation therapy as adjuvant/neoadjuvant to radiotherapy for high-risk localised and locally advanced prostate cancer: recent developments

Androgen deprivation therapy (ADT) has traditionally formed the mainstay of treatment for advanced/metastatic prostate cancer (PCa); however, it is now also having an increasingly important role in earlier stages of disease. Indeed, in patients with locally advanced or high-risk localised disease, the addition of neoadjuvant and adjuvant hormone therapy is now considered the standard of care for those men treated with radical radiotherapy. Although luteinising hormone-releasing hormone (LHRH) agonists have been used for many years as ADT, they may be associated with clinical flare and testosterone breakthrough. Newer hormonal agents continue to be developed, such as gonadotropin-releasing hormone antagonists, which reduce testosterone and prostate-specific antigen levels more rapidly than LHRH agonists, without testosterone flare. This review examines ADT use in combination with radiotherapy to improve outcomes in localised or locally advanced disease, and examines some of the latest developments in hormonal therapy for PCa.     

Frequency of PSA-mRNA-bearing cells in the peripheral blood of patients after prostate biopsy

Transrectal ultrasound (TRUS) guided prostate biopsy is standard diagnostic procedure for prostate cancer (PCa). However, possibility of dissemination of cancer cells by biopsy is not negligible. To investigate this possibility, we examined prostate specific antigen (PSA)-bearing cells in peripheral blood of the 108 patients before and after prostate biopsy. Peripheral blood samples were obtained from 108 patients with elevated serum PSA (sPSA) levels, who had undergone sextant prostate biopsy using TRUS. The presence of PSA-mRNA bearing cells was examined using the nested RT-PCR method enabling detection of one LNCaP cell diluted in 1 ml of whole blood. Among 108 patients, 62 and 46 were diagnosed with benign prostatic hyperplasia (BPH) and PCa, respectively. PSA-mRNA was detected in 3 PCa cases but in no BPH patients before and after biopsy, and in 16 BPH (25.8%) and in 21 PCa (45.7%) patients only after biopsy (P< 0.01). The patients with positive mRNA before biopsy had higher sPSA (P< 0.001), and those after biopsy had higher sPSA and PSA density (PSAD) levels (P< 0.05). Positive PSA-mRNA cases had more cancer involved biopsy cores than the negative PSA-mRNA cases (P< 0.001). Although further investigations are needed, the present findings suggest that prostate biopsy might scatter prostate cells in the blood stream especially in cases with high sPSA and, thus, might contribute to tumour spreading in the cases of prostate cancer.     

Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy

The role of p53 in the pathogenesis of, and as a predictive biomarker for, localized prostate cancer (PCa) is contested. Recent work has suggested that patterns of p53 nuclear accumulation determined by immunohistochemistry are prognostic, whereas studies using other methods question the role of p53 mutations in predicting outcome. We studied 263 men with localized PCa treated with radical prostatectomy to determine whether p53 nuclear accumulation predicts relapse and disease-specific mortality. We combined two p53 immunohistochemistry scoring systems: (a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x 200 power field was deemed "cluster positive." Analysis was undertaken using chi2, Kruskal-Wallis, and Mann-Whitney tests for clinicopathological variables and the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression modeling for evaluation of contribution to relapse and disease-specific survival. At mean follow-up of 55.1 months (range, 4.9-123.0 months), 39% (102 of 263) of patients had relapsed and 2.3% (6 of 253) had died of PCa. Pretreatment serum prostate-specific antigen concentration, pathological tumor stage, lymph node involvement, Gleason score, and p53 nuclear accumulation, as determined by either percentage score or cluster status, were independent predictors of relapse in multivariate analysis. Clustering of p53-positive cells distinguished between favorable and poor prognosis patients within the lowest p53-positive stratum (>0 to <2%) and was the most discriminatory threshold for predicting relapse in the entire cohort. p53 status predicted outcome in patients with a Gleason score of 5 and above but not those with a score of 4 and below. In patients treated with neoadjuvant hormonal therapy, p53 cluster positivity carried a 90% (19 of 21) risk of relapse by 36 months. All six patients who died from PCa in the period of the study exhibited p53 nuclear accumulation in 20% or more tumor nuclei. This study demonstrates strong relationships between p53 nuclear accumulation and relapse and disease-specific mortality in a large series of localized PCas. Furthermore, the presence of clusters of p53-positive nuclei delineates a group of patients with poor prognosis not identified by traditional scoring methods and supports the hypothesis that p53 dysfunction within PCa may exist in foci of tumor cells that are clonally expanded in metastases.     

Critical assessment of tools to predict clinically insignificant prostate cancer at radical prostatectomy in contemporary men

BACKGROUND: Overtreatment of prostate cancer (PCa) is a concern, especially in patients who might qualify for the diagnosis of insignificant prostate cancer (IPCa). The ability to identify IPCa prior to definitive therapy was tested. METHODS: In a cohort of 1132 men a nomogram was developed to predict the probability of IPCa. Predictors consisted of prostate-specific antigen (PSA), clinical stage, biopsy Gleason sum, core cancer length and percentage of positive biopsy cores (percent positive cores). IPCa was defined as organ-confined PCa (OC) with tumor volume (TV) <0.5 cc and without Gleason 4 or 5 patterns. Finally, an external validation of the most accurate IPCa nomogram was performed in the same group. RESULTS: IPCa was pathologically confirmed in 65 (5.7%) men. The 200 bootstrap-corrected predictive accuracy of the new nomogram was 90% versus 81% for the older nomogram. However, in cutoff-based analyses of patients who were qualified by our and the older nomograms as high probability for IPCa, respectively 63% and 45% harbored aggressive PCa variants at radical prostatectomy (Gleason score 7-10, ECE, SVI, and/or LNI). CONCLUSIONS: Despite a high accuracy, currently available models for prediction of IPCa are incorrect in 10% to 20% of predictions. The rate of misclassification is even further inflated when specific cutoffs are used. As a consequence, extreme caution is advised when statistical tools are used to assign the diagnosis of IPCa.     

Significant associations of prostate cancer susceptibility variants with survival in patients treated with androgen-deprivation therapy

Androgen-deprivation therapy (ADT) is the most common therapy for advanced prostate cancer, but the prognosis significantly differs among individuals. In this study, we evaluated recently identified 19 prostate cancer susceptibility variants as prognostic predictors for the survival after ADT. A total of 601 prostate cancer patients treated with ADT were enrolled in this study cohort. The prognostic significance of the prostate cancer risk variants on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Two polymorphisms, rs16901979 and rs7931342, were significantly associated with PCSM (p = 0.005 for rs16901979 and p = 0.038 for rs7931342), and rs16901979 was also associated with ACM (p = 0.003) following ADT. Although the effect of rs7931342 was attenuated after controlling for other known clinical prognostic factors, rs16901979 remained a significant predictor for PCSM and ACM after ADT (p = 0.002). Moreover, the addition of the rs16901979 status in current clinical staging system further enhanced the risk prediction on PCSM and ACM particularly for the high-risk patients with distant metastasis (p < 0.017). In conclusion, this is the first study showing that prostate cancer risk variants, such as rs16901979, might improve outcome prediction following ADT, thus allowing identification of high-risk patients who might benefit from appropriate adjuvant therapy.     

Androgen deprivation therapy in nonmetastatic prostate cancer patients: Indications,treatment effects,and new predictive biomarkers

Men with prostate cancer with positive margins, extraprostatic extension, positive lymph nodes, high prostate‐specific antigen, or high Gleason Score are at high risk of recurrence following primary therapy. Androgen deprivation therapy (ADT), which includes medical/surgical castration, antiandrogen therapy, and combined androgen blockade, can be combined with primary therapy to shrink the tumor, reduce margin positivity, and reduce the risk of recurrence. However, many problems still remain, such as optimizing the application of ADT in the treatment of prostate cancer, for example, ideal patient population and optimal timing and duration of therapy. To investigate these problems, we searched PubMed for relevant publications on clinical studies of deprivation therapy for nonmetastatic prostate cancer. In this review, we discuss our findings on the role of ADT in the treatment of castrate‐sensitive nonmetastatic prostate cancer and the adverse effects associated with ADT. We also examine the recent advances in new predictive biomarkers for ADT, many of which are currently in the exploratory phase. Overall, the addition of ADT to primary therapy improves outcomes for patients with intermediate‐ or high‐risk prostate cancer.     

Dose‐escalated radiation therapy for intermediate‐risk prostate cancer

BACKGROUND:

Randomized trials supported the use of androgen deprivation therapy (ADT) with radiation therapy (RT) for intermediate‐risk prostate cancer. However, the value of concurrent ADT was less certain with dose‐escalated RT. Better methods of stratifying patients in this risk group may help select patients who are most likely to benefit.

METHODS:

A total of 238 men with intermediate‐risk (prostate specific antigen [PSA] 10‐20, Gleason 7, or stage T2b‐c) adenocarcinoma of the prostate were treated with external beam RT between 1989 and 2006. Patients had Gleason≤6 (39%) or 7 (61%) tumors; median PSA was 10.5 ng/mL. A median of 37.5% of biopsy cores were positive from a median of 9 biopsy cores sampled. The median RT dose was 74 Gy to the prostate. A total of 112 patients (47%) received neoadjuvant and concurrent ADT (median, 4 months). Median follow‐up period was 49 months.

RESULTS:

The freedom from biochemical failure (FFBF, nadir + 2 definition) was 93% at 3 years, 86% at 4 years, and 80% at 5 years. On univariate analysis, the only factor associated with FFBF was percentage of positive cores (PPC, P = .0340). The prognostic value of PPC≥50 was not evident in patients receiving ADT (FFBF at 4 years 90% vs 91%, P = .3015). For patients not receiving ADT, the impact of PPC≥50 (FFBF at 4 years 76% vs 93%, P = .0844) was more pronounced. On multivariate analysis, PPC (P = .0388) was significantly associated with FFBF, whereas Gleason sum, ADT, RT dose, PSA, and T‐stage were not.

CONCLUSIONS:

After dose‐escalated external beam RT, intermediate‐risk prostate cancer patients with PPC≥50 had the highest risk for biochemical failure and may be most likely to derive a benefit from ADT. Cancer 2009. © 2009 American Cancer Society.     

Obesity and mortality in men with locally advanced prostate cancer: analysis of RTOG 85-31

BACKGROUND: Greater body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure following radical prostatectomy and radiation therapy (RT). Whether BMI is associated with prostate cancer-specific mortality (PCSM) was investigated in a large randomized trial of men treated with RT and androgen deprivation therapy (ADT) for locally advanced prostate cancer. METHODS: Between 1987 and 1992, 945 eligible men with locally advanced prostate cancer were enrolled in a phase 3 trial (RTOG 85-31) and randomized to RT and immediate goserelin or RT alone followed by goserelin at recurrence. Height and weight data were available at baseline for 788 (83%) subjects. Cox regression analyses were performed to evaluate the relations between BMI and all-cause mortality, PCSM, and nonprostate cancer mortality. Covariates included age, race, treatment arm, history of prostatectomy, nodal involvement, Gleason score, clinical stage, and BMI. RESULTS: The 5-year PCSM rate for men with BMI <25 kg/m(2) was 6.5%, compared with 13.1% and 12.2% in men with BMI > or =25 to <30 and BMI > or =30, respectively (Gray's P = .005). In multivariate analyses, greater BMI was significantly associated with higher PCSM (for BMI > or =25 to <30, hazard ratio [HR] 1.52, 95% confidence interval [CI], 1.02-2.27, P = .04; for BMI > or =30, HR 1.64, 95% CI, 1.01-2.66, P = .04). BMI was not associated with nonprostate cancer or all-cause mortality. CONCLUSIONS: Greater baseline BMI is independently associated with higher PCSM in men with locally advanced prostate cancer. Further studies are warranted to evaluate the mechanism(s) for increased cancer-specific mortality and to assess whether weight loss after prostate cancer diagnosis alters disease course.     

Androgen deprivation therapy does not impact cause-specific or overall survival in high-risk prostate cancer managed with brachytherapy and supplemental external beam

PURPOSE: To determine cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) in high-risk prostate cancer patients undergoing brachytherapy with or without supplemental therapies. METHODS AND MATERIALS: Between April 1995 and July 2002, 204 patients with high-risk prostate cancer (Gleason score > or = 8 or prostate-specific antigen [PSA] >20 ng/mL or clinical stage > or = T2c) underwent brachytherapy. Median follow-up was 7.0 years. The bPFS was defined by a PSA < or = 0.40 ng/mL after nadir. Multiple clinical, treatment, and dosimetric parameters were evaluated for the impact on survival. RESULTS: The 10-year CSS, bPFS, and OS were 88.9%, 86.6%, and 68.6%, respectively. A statistically significant difference in bPFS was discerned between hormone naive, ADT < or = 6 months, and ADT >6 month cohorts (79.7% vs. 95.% vs. 89.9%, p = 0.032). Androgen deprivation therapy (ADT) did not impact CSS or OS. For bPFS patients, the median posttreatment PSA was <0.04 ng/mL. A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS, whereas percent positive biopsies and duration of ADT best predicted for bPFS. The OS was best predicted by Gleason score and diabetes. Thirty-eight patients have died, with 26 of the deaths from cardiovascular/pulmonary disease or second malignancy. Eleven patients have died of metastatic prostate cancer. CONCLUSIONS: The ADT improved 10-year bPFS without statistical impact on CSS or OS. Death as a result of cardiovascular/pulmonary disease and second malignancies were more than twice as common as prostate cancer deaths. Strategies to improve cardiovascular health should positively impact OS.     

前列腺干细胞抗原在前列腺组织的表达及意义

目的演探讨前列腺干细胞抗原(prostatestemcellantigen,PSCA)在前列腺组织中的表达及其意义。眼方法演应用核酸分子原位杂交穴ISH雪技术,对PSCAmRNA在26例前列腺癌、20例良性前列腺增生(BPH)和9例正常前列腺(NP)标本中的表达水平进行检测及定位。眼结果演PSCAmRNA在NP、BPH及前列腺癌组织表达阳性率分别为66.7%、70.0%及84.6%,强阳性率分别为0、10.0%及57.7%。NP与BPH组织表达水平无显著差异(P>0.05),其表达定位于前列腺上皮的基底细胞层;PSCAmRNA在前列腺癌组织主要表达于癌细胞,细胞间质和肌肉组织均无表达。前列腺癌与NP、BPH组织表达水平均有显著差异(P<0.01)。PSCAmRNA表达水平与前列腺癌临床分期、病理分级均无相关性(P>0.05)。眼结论演PSCA高表达是前列腺癌的共同特征;PSCA在前列腺癌早期诊断与免疫靶向治疗方面有良好的开发应用前景。     

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT‐resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT‐resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox‐induced overexpression of any Notch intracellular domains (NICD1‐4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance‐associated phospho‐p38 and Bcl‐2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ‐secretase inhibitor (GSI), DAPT, downregulated both phospho‐p38 and Bcl‐2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.     

Dietary inflammatory index and prostate cancer survival

Systemic inflammatory status has been reported to impact survival of prostate cancer (PCa) patients; however, evidence is lacking on whether the inflammatory potential of diet can influence prognosis of PCa patients. To investigate the association between a dietary inflammatory index (DII) and PCa survival, we conducted a retrospective cohort study including 726 men with PCa originally enrolled, between 1995 and 2002, in an Italian case–control study. Information on diet and Gleason score was collected at PCa diagnosis. DII was derived from a food frequency questionnaire using a validated algorithm. Adjusted hazard ratios (HRs) of death with 95% confidence intervals (CIs) were estimated using a Fine‐Gray model. DII scores were not significantly associated with all‐cause mortality of PCa patients (HR highest vs. lowest DII tertile = 1.25; 95% CI: 0.86–1.83). However, considerable heterogeneity emerged according to Gleason score (p < 0.01): no associations emerged among men with Gleason score 2–6 PCa; whereas, among patients with Gleason score 7–10 PCa, DII was directly associated with both all‐cause and PCa‐specific mortality (HR highest vs. lowest DII tertile: 2.78; 95% CI: 1.41–5.48; and 4.01; 95% CI: 1.25–12.86; respectively). Among patients with Gleason score 7–10 PCa, ten‐year all‐cause survival probabilities were 58% (95% CI: 47–67%) for highest and 78% (95% CI: 67–86%) for lowest DII tertile. Study findings support the hypothesis that diet, through its inflammatory potential, may influence the prognosis of patients with more aggressive PCa. Dietary interventions aimed at decreasing inflammation may be considered to improve survival of men with PCa.     

Radical prostatectomy for high-risk prostate cancer

Treatment for high-risk prostate cancer(PCa)(cT3 PCa, Gleason score 8-10 or PSA>20 ng/mL)remains controversial. Radiotherapy with androgen deprivation therapy(ADT)is widely used for high-risk prostate cancer. However, there is a considerable overlap of outcomes among risk groups, suggesting that the so-called high-risk prostate cancer group consists of a heterogeneous population in terms of tumor biology. Actually, the over-staging of cT3a PCa is relatively frequent and occurs in 13-27%of cases. Thus, radical prostatectomy(RP)alone is a reasonable treatment option for selected patients with high-risk prostate cancer. RP can provide an excellent biochemical and clinical progression-free survival for these patients if they have a pathologically organ-confined disease, or their tumors are extirpated completely with a negative surgical margin. A thorough preoperative evaluation, including imaging study and the use of a nomogram, is mandatory for selecting candidates appropriate for RP. Our recent study indicates that a positive biopsy core percentage is a strong independent predictor of organ-confined disease in these high-risk patients. In cases of adverse tumor characteristics, such as positive surgical margin, extraprostatic extension and seminal vesicle invasion, the patient must be informed of the likelihood of a multimodal approach. The use of adjuvant radiotherapy may be reasonable after recuperation from surgery. Immediate ADT may be indicated for those with positive pelvic lymph node.     

Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy

AimsSeveral classes of concomitant medications have been shown to affect oncological outcomes in patients with prostate cancer (PCa). We assessed the association between the use of commonly prescribed concomitant medications and biochemical relapse-free survival (bRFS) in patients with localised PCa treated with radiotherapy and androgen deprivation therapy (ADT).Materials and methodsA secondary pooled analysis of two phase III randomised trials was carried out. In the first trial, patients with localised PCa with clinical stage T1b-T3, prostate-specific antigen <30 ng/ml and Gleason score ≤7 were treated with radical radiotherapy and 6 months of ADT starting 4 months before or concomitantly with radiotherapy. In the second trial, patients with high-risk PCa were treated with radical radiotherapy and 36 months of ADT with randomisation to three-dimensional conformal or intensity-modulated radiotherapy. Information on concomitant medications was collected from the medical record. Univariable and multivariable Cox regression was used to identify factors associated with bRFS.ResultsOverall, 486 patients were evaluable. The median follow-up was 125 months; 10-year bRFS was 83.7%. On univariable analysis, receipt of metformin was significantly associated with worse bRFS. Ten-year bRFS was 73% and 85% for patients with and without concomitant metformin (adjusted hazard ratio 2.11, 95% confidence interval 1.03–4.33). Similar evidence of an association was observed with sulfonamide-based α1-receptor blockers (adjusted hazard ratio 2.72, 95% confidence interval 1.31–5.66). However, no such association was seen with receipt of quinazoline-based α1-receptor blockers (adjusted hazard ratio 1.09, 95% confidence interval 0.42–2.82). There was no significant association between bRFS and receipt of all other medication classes considered.ConclusionsIn this population of patients with localised PCa treated with radiotherapy and ADT, receipt of concomitant metformin and sulfonamide-based α1-receptor blockers was associated with inferior biochemical outcome. Randomised trials are required to assess the true effect of these medications on oncological outcomes in localised PCa.     

Neoadjuvant docetaxel treatment for locally advanced prostate cancer: a clinicopathologic study

BACKGROUND: The objective of the current study was to determine the histologic and molecular changes that occurred in patients with high-risk, localized prostate cancer (PCa) after neoadjuvant docetaxel chemotherapy. METHODS: Patients who had locally advanced PCa (serum preoperative [initial] prostate-specific antigen [iPSA] level >or=15 ng/mL, or clinical >or=T2b disease, or biopsy Gleason score [GS] >or=8) and no evidence of metastatic disease received 6 doses of intravenous docetaxel (40 mg/m(2)) administered weekly for 6 weeks followed by radical prostatectomy (RP). The Wilcoxon signed-rank test was used to compare pretreatment and posttreatment markers. RESULTS: Twenty-eight patients completed chemotherapy and underwent RP at the Cleveland Clinic; none achieved a pathologic complete response. Pretreatment diagnostic prostate biopsies (PBx) were reviewed in all patients, and unstained sections of formalin-fixed tissue were available from 11 patients. The median patient age was 62 years (range, 49-72 years), and the median iPSA was 6.8 ng/mL (range, 2.5-24 ng/mL). At a median follow-up of 49.5 months (range, 23-72 months), 12 patients (43%) remained clinically and biochemically free of disease with no additional therapy, and 16 patients (57%) had biochemical failure. The pretreatment GS was 6 in 2 patients (7%), 7 in 10 patients (36%), 8 in 11 patients (39%) and 9 in 5 patients (18%). Two patients (7.1%) had organ-confined disease, and 23 patients (82.1%) had extraprostatic extension. Four patients (14.3%) had positive lymph nodes, and 11 patients (39.3%) had seminal vesicle involvement. Immunohistochemical (IHC) staining for a panel of markers involved in various cellular functions (alpha-methylacyl-coenzyme A racemase [AMACR], beta-tubulin I, beta-tubulin III, cyclin D1, p27, p21, Ki-67, p53, Bcl-2, and an apoptosis detection kit [ApopTag]) was performed on a tissue microarray that contained the posttreatment (RP) tissue specimens and on the PBx specimens, if available. When the IHC staining patterns were compared between PBx and RP specimens using the Wilcoxon signed-rank test, only p53 expression (P = .017) and Bcl-2 expression (P = .014) were found to be increased significantly after neoadjuvant docetaxel treatment. However, after performing the Bonferroni adjustment, these differences were no longer significant (P > .005). Ki-67, ApopTag, beta-tubulin I, and beta-tubulin III expression levels also were increased after treatment; however, the differences were not found to be statistically significant. The expression levels of AMACR, p27, p21, and cyclin D1 were comparable in pretreatment and posttreatment specimens. CONCLUSIONS: The current results indicated that, although it will require longer follow-up studies and larger numbers of patients to ascertain the value of neoadjuvant treatment, the negative findings of the current study may explain the lack of clinical response in patients who received neoadjuvant docetaxel for PCa. Although the results were subject to interpretation limits based on the study size, the increased expression of p53 and Bcl-2 that was detected after treatment using the Wilcoxon signed-rank test suggested that the apoptotic pathway may be an important target for this drug, and further investigation is warranted.