Hormone-refractory Prostate Cancer Patients Research Articles

Efficacy of 68Ga-PSMA PET/CT-derived whole-body volumetric parameters in predicting response to second-generation androgen receptor axis-targeted therapy, and the prognosis in metastatic hormone-refractory prostate cancer patients.

The present study investigates the role of 68Ga-PSMA PET/CT-derived whole-body metabolic and volumetric parameters in the prediction of treatment response and prognosis among metastatic hormone-refractory prostate cancer patients undergoing second-generation androgen receptor axis-targeted therapy (abiraterone or enzalutamide). This retrospective study included 44 metastatic hormone-refractory prostate cancer patients undergoing 68Ga-PSMA PET/CT, including 29 enzalutamide-treated and 15 abiraterone-treated patients. Of the 44 patients included in the study, 29 received enzalutamide and 15 received abiraterone. During treatment, the changes in PET parameters were correlated with the PSA (biochemical) response. More specifically, a positive correlation was noted between PSA response and percent change in TLP (ΔTLP) response, and there was concordance between the results (r = 0.652, k = 0.42, P < 0.001). Baseline PSA (P =0.05), high MTVw (P = 0.005), the increase in ΔPSA (P = 0.036), ΔTLP (P = 0.039) and percent change in MTV (ΔMTV) (P = 0.049) values were identified as factors associated with mortality risk.Multivariate analysis showed that PSA1 [odds ratio (OR): 1.005, 95% confidence interval (CI) 1.002-1.008, P = 0.004], ΔPSA (OR: 14.7, 95% CI 1.50-143.7, P = 0.02) and MTVw1 (OR: 11.4, 95% CI 1.11-116, 6, P = 0.04) were independent prognostic factors associated with mortality risk. A statistically significant concordance and correlation was noted between 68Ga-PSMA PET/CT-derived whole-body metabolic parameters (ΔTLP and ΔMTV) and ΔPSA. In addition, the baseline PSA, ΔPSA, ΔTLP, ΔMTV and TMTV were identified as predictive factors for mortality risk.

Efficacy and tolerability of current treatments for hormone-refractory prostate cancer patients with visceral metastases.

Aim: To assess the efficacy and tolerability of the first-line treatment options for hormone-refractory prostate cancer patients with visceral metastases. Materials & methods: The records of 191 patients diagnosed with hormone-refractory prostate cancer with visceral metastases were analyzed retrospectively. Results: Docetaxel was administered to 61.2% (n=117), abiraterone to 14.2% (n=27) and enzalutamide to 9.4% (n=18) as the first-line treatment. The median survival of the patients receiving docetaxel, abiraterone and enzalutamide as the first-line treatment during the hormone-refractory period was 15 (95% Cl: 12.9-17) months, 6 (95% Cl: 1.8-10.1) months and 11 (95% Cl: 0.9-23.1) months (p=0.038), respectively. Conclusion: The present study established a statistically significant difference in favor of docetaxel in terms of overall survival and progression-free survival.

Docetaxel-resistant prostate cancer cells become sensitive to gemcitabine due to the upregulation of ABCB1.

Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

Expression and correlation of microRNA-218 in prostate cancer tissues and serum

Objective To investigate and explore expression status of microRNA-218, and their correlation in serum and tissue samples of prostate cancer patients. Methods The serum and tissue samples of 72 patients in first diagnosised prostate cancer (PCa) and 80 benign prostate hyperplasia (BPH) patients were collected. Serum samples of 162 patients, including 86 patients with androgen-dependent prostate cancer (ADPC) and 76 patients with hormone-refractory prostate cancer (HRPC) were collected. The expression level of microRNA-218 in the tissue and serum samples were detected by specific SYBR Green quantitative real-time polymerase chain reaction (PCR). The correlation between the serum microRNAs and tissue microRNAs expressions tatus were analyzed, and their relationship with clinical characterization were also analyzed. Results The expression level of microRNA-218 in tissues and serum of patients with BPH was higher than that of patients with PCa (P<0.001). MicroRNA-218 level in PCa and BPH tissue were both correlated with that in the serum of PCa and BPH(rBPH=0.815, rPCa=0.423). The expression level of microRNAs in tissue and serum samples from PCa were negatively correlated to total prostate specific antigen (tPSA), clinical stages and pathological grade (P<0.05). Serum microRNA-218 expression was not significantly different between hormone-dependent PCa patients and newly diagnosed PCa patients, but was significantly lower than that of HRPC patients (P<0.05), and was positively correlated with tPSA (P<0.05). Conclusions The changes of microRNA-218 expression in serum of patients with BPH and prostate cancer can reflect the changes of microRNA-218 expression in tissues. Serum microRNA-218 is expected to be a potential biomarker for early diagnosis and progression of prostate cancer. Key words: MicroRNAs; Prostatic neoplasms; Neoplasms, hormone-dependent; Prostatic hyperplasia

Effects of shRNA Expression Vector-mediated Glutathione S-transferase P1 Gene Silencing on Prostate Cancer DU145 Cells

Objective: This study aims to explore the impact of silent GSTP1 gene on the proliferation activity, cell cycle and apoptotic rate of the androgen-independent prostate cancer cell strain DU145. Methods: Thirty subjects with benign prostatic hyperplasia (BPH) who had been subject to urinary surgical resection and pathological diagnosis, 30 subjects with radically cured prostate cancer (PCa), and another 30 subjects with hormone refractory prostate cancer (HRPC) were enrolled. The GSTP1 expression in the subjects was tested with the immunohistochemical S-P method, the GSTP1 expression in the blood serum of the patients with prostatic hyperplasia and prostate cancer was tested with Elisa, and the mRNA level of the GSTP1 gene after the DUl45 cells were transfected with shRNA was tested. Results: Four of the HRPC patients were complicated with bone metastasis, two with bladder invasion, and five with liver and lung metastasis. GSTP1 showed high expression in tissues with prostatic hyperplasia and hormone refractory prostate cancer and low expression in tissues with prostate cancer, and the differences were statistically significant (P 0.05). The GSTP1 mRNA content decreased significantly after shRNA554 intervention, with an IOD value of 67.1±8.7. The intervention effect was evidently lower than that of the carrier shRNA255 group (162.2±12.6) and the shRNA593 group (114.5±10.6) with statistically significant difference (P<0.01). Conclusion: The expression vector-mediated GSTP1-shRNA554 transfection can reduce the mRNA level of the GSTP1 gene of the androgen-independent prostate cancer DU145 cells and inhibit the proliferation activity of the in vitro cultivated DU145 cells.

MET expression during prostate cancer progression.

Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression.Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry (D1C2 C-terminal antibody). MET mRNA levels and MET DNA copy numbers were determined by in situ hybridization.None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression (p=0.025, χ2), in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC (p=0.37; χ2), with MET polysomy in 8/13 (61%) evaluable cases.In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.

Glucose-regulated protein 78 mediates the anticancer efficacy of shikonin in hormone-refractory prostate cancer cells.

Glucose-regulated protein 78 (GRP78) is a key modulator of prostate cancer progression and therapeutic resistance. Prostate cancer is a worldwide health problem, and therapeutic resistance is a critical obstacle for the treatment of hormone-refractory prostate cancer patients. Shikonin inhibits prostate cancer proliferation and metastasis. However, the role of GRP78 in the cytotoxic effect of shikonin in prostate cancer cells remains unclear. GRP78 expression was abolished using small interfering RNA (siRNA), and the anticancer effects of shikonin were assessed using MTT assays, the XCELLigence biosensor, flow cytometric cell cycle analysis, and Annexin V-PI apoptotic assays. PC-3 cells expressed more GRP78 than DU-145 cells, and the MTT assays revealed that DU-145 cells were more sensitive to shikonin than PC-3 cells. GRP78 knockdown (GRP78KD) PC-3 cells were more sensitive to shikonin treatment than scrambled siRNA control cells. Based on cell cycle analysis and AnnexinV-PI apoptotic assays, apoptosis dramatically increased in GRP78KD cells compared with the control PC-3 in response to shikonin. Finally, in response to shikonin treatment, Mcl-1 and Bcl-2 levels increased in the scrambled control cells treated with shikonin, whereas Bcl-2 decreased and Mcl-1 slightly increased in the GRP78KD PC-3 cells. The levels of Bax and Bad did not change in the scrambled control or GRP78KD cells after shikonin treatment. These results are consistent with the increased sensitivity to shikonin after knockdown of GRP78. GRP78 expression may determine the therapeutic efficacy of shikonin against prostate cancer cells.

Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer.

Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC-based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5×10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine.

A phase 1A/1B, two-stage study of a PSA/IL-2/GM-CSF vaccine for the treatment of PSA-recurrent prostate cancer in hormone-naive and hormone-independent patients.

TPS3131 Background: Prostate cancer vaccines demonstrate clinical benefit in hormone refractory metastatic prostate cancer patients. The broader application to earlier disease stages remains both c...

Impact of 18F-Choline PET/CT in Prostate Cancer Patients with Biochemical Recurrence: Influence of Androgen Deprivation Therapy and Correlation with PSA Kinetics

We evaluated the potential of (18)F-fluoromethyldimethyl-2-hydroxyethyl-ammonium (FCH) PET/CT in the detection of recurrent disease or distant metastases and correlated its diagnostic accuracy with prostate-specific antigen (PSA) levels in prostate cancer patients with biochemical evidence of recurrence. Furthermore, the influences of androgen deprivation therapy (ADT) and its duration on (18)F-FCH PET were assessed in this study. This prospective study included 250 prostate cancer patients with PSA relapse who underwent (18)F-FCH PET/CT. At the time of (18)F-FCH PET/CT imaging, the mean PSA level was 46.9 ± 314.7 ng/mL and 55.2% (138/250) of patients were receiving ADT. Overall, ADT was performed on 67.2% (168/250) of patients after initial treatment. Imaging was performed on an integrated PET/CT system. Acquisition started 1 min after intravenous injection of (18)F-FCH (4.07 MBq/kg of body weight) with dynamic PET images in the pelvic region during 8 min (1 min/frame) followed by a static semi-whole-body acquisition. The final diagnosis of positive PET lesions was based on histopathology or a consensus of clinical findings, additional imaging, or follow-up imaging modalities. (18)F-FCH PET/CT was able to correctly detect malignant lesions in 74% (185/250) of patients but was negative in 26% (65/250). In 28% of patients, only 1 lesion was detected (69/250); from these, 65.2% (45 patients) had a local recurrence, 18.8% (13 patients) a single lymph node, and 15.9% (11 patients) a solitary bone metastasis. The sensitivity of the (18)F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%-91%) than in patients without ADT (59.5%; confidence interval, 50%-69%). (18)F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively. Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001). Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings. (18)F-FCH PET/CT proved its potential as a noninvasive 1-stop diagnostic modality enabling us to correctly detect occult disease in 74% of patients and to differentiate localized from systemic disease. In patients with biochemical recurrence, it also guides to an optimal treatment approach after initial treatment. Trigger PSA and ADT are the 2 significant predictors of (18)F-FCH-positive PET lesions. ADT seems not to impair (18)F-FCH uptake in hormone-refractory prostate cancer patients.

Somatostatin and prostate cancer: role of somatostatin receptors in the control of tumor growth

The evidence that prostate cancer (PCa) expresses specific receptors for hormones and neuropeptides, including somatostatin (SRIF) receptors (SSRs) has driven the research towards the identification of new potential diagnostic/therapeutic paths besides the conventional treatment options. Although the first attempts has led to inconclusive results due to the heterogeneity of this tumor and to the complex mechanisms involved in the progression of PCa tumor growth, the potential role of SRIF and its synthetic analogues (SSAs) in the treatment of PCa represents an “open challenge” in the light of the new knowledge about SSR pathophysiology. Indeed, SRIF and SSAs can control tumor cell proliferation by two separate mechanisms: a direct mechanism through the activation of the five specific SSRs or an indirect mechanism through the inhibition of secretion of several growth factors and hormones responsible for tumor cell proliferation. Since new SSAs specific for each receptor subtype, as well as bi-specific compounds and panligands have been synthetized, the identification of alternative SSR targets on PCa cells and the consequent employment of these new specific molecules in the treatment of advanced PCa (alone or in combination with traditional treatment options), could improve the prognosis particularly of those patients not responding to (anti-) hormonal therapy (hormone-refractory PCa patients).

Progression of bone metastases in patients with prostate cancer - automated detection of new lesions and calculation of bone scan index

BackgroundThe objective of this study was firstly to develop and evaluate an automated method for the detection of new lesions and changes in bone scan index (BSI) in serial bone scans and secondly to evaluate the prognostic value of the method in a group of patients receiving chemotherapy.MethodsThe automated method for detection of new lesions was evaluated in a group of 266 patients using the classifications by three experienced bone scan readers as a gold standard. The prognostic value of the method was assessed in a group of 31 metastatic hormone-refractory prostate cancer patients who were receiving docetaxel. Cox proportional hazards were used to investigate the association between percentage change in BSI, number of new lesions and overall survival. Kaplan-Meier estimates of the survival function were used to indicate a significant difference between patients with an increase/decrease in BSI or those with two or more new lesions or less than two new lesions.ResultsThe automated method detected progression defined as two or more new lesions with a sensitivity of 93% and a specificity of 87%. In the treatment group, both BSI changes and the number of new metastases were significantly associated with survival. Two-year survival for patients with increasing and decreasing BSI from baseline to follow-up scans were 18% and 57% (p = 0.03), respectively. Two-year survival for patients fulfilling and not fulfilling the criterion of two or more new lesions was 35% and 38% (n.s.), respectively.ConclusionsAn automated method can be used to calculate the number of new lesions and changes in BSI in serial bone scans. These imaging biomarkers contained prognostic information in a small group of patients with prostate cancer receiving chemotherapy.

Abstract 351: 2-Methoxyestradiol targets RON kinase and FLIP to inhibit epithelial-mesenchymal transition in prostate cancer

Abstract Prostate Cancer (PCA) is the second leading cause of cancer-related deaths among men in the United States. Despite significant progress in our understanding of prostate biology, early detection and treatment, the five-year survival for hormone refractory metastatic prostate cancer (HRPCA) patients is less than 30%. Current therapies targeting PCA are not effective against the metastatic stage. 2-Methoxyestradiol (2-ME2) is a metabolic product of 17-β-estradiol and is found in trace amounts in the body; it has shown anti-tumorigenic properties in multiple cancer models. Previous studies from our lab have shown that 2-ME2 can induce apoptosis in PCA cells by blocking cell cycle progression, and also inhibits PCA growth and progression in TRAMP mice. However, the precise mechanism of action of 2-ME2 has not yet been elucidated. In order to classify the mechanism behind PCA inhibition by 2-ME2, we tested its effectiveness on an array containing genes associated with epithelial-mesenchymal transition (EMT). We identified Recepteur d'Origine Nantais (RON) as one of the most significantly downregulated genes in response to 2-ME2 treatment. RON has been shown to promote cell invasiveness, migration, survivability, and proliferation in many cancers such as breast, colon, lung, and pancreatic. However, very little is known about RON's signaling mechanism in PCA. We've found RON to be highly increased in advanced stage PCA cell lines. RON knockdown shows a concomitant decrease in the expression of FLICE-like inhibitory protein (FLIP). FLIP is an anti-apoptotic protein which prevents death receptor-induced apoptotic signaling. FLIP has been found to promote EMT as well as androgen-independent PCA growth. Stimulation with the RON ligand HGF yielded elevated expression of RON and FLIP in PCA cell lines while treatment with 2-ME2 caused downregulation. Immunoprecipitation experiments showed RON to be associated with the androgen-induced proliferation inhibitor (APRIN) in PCA cells. Our data suggest that RON/FLIP crosstalk plays a role in prostate cancer. Therefore, targeting RON/FLIP signaling could have potential therapeutic benefit for metastatic PCA. Supported by NIH CA 135451 (APK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 351. doi:1538-7445.AM2012-351

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Background:BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.Methods:This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.Results:Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.Conclusion:Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.

Surgical castration in hormone-refractory metastatic prostate cancer patients can be an alternative for medical castration.

Background. Most patients with metastatic prostate cancer are endocrinologically treated with LHRH agonist, but finally castration-refractory and hormone-refractory cancers occur. Serum testosterone levels get low to “the castration level” by LHRH agonists but may not get low enough against castration-refractory prostate cancer. Methods. As case series, twelve patients suffering from hormone-refractory prostate cancer continuously on LHRH agonist underwent surgical castration. Additionally, one hundred and thirty-nine prostate cancer patients on LHRH agonist or surgical castration were tested for serum total testosterone levels. Results. Surgical castration caused decrease in serum PSA in one out of 12 hormone-refractory prostate cancer patients with PSA reduction rate 74%. Serum total testosterone levels were below the sensitivity threshold (0.05 ng/mL) in 40 of 89 (44.9%) medically castrated patients and 33 of 50 (66.0%) surgically castrated patients (P = .20). Conclusion. Even hormone-refractory prostate cancer patients are candidates for surgical castration because of endocrinological, oncological, and economical reasons.

1014 poster EFFICACY OF KETOCONAZOLE AND DIETHYLSTILBESTROL IN HORMONE REFRACTORY PROSTATE CANCER

Purpose: Diethylstilbestrol (DES), a synthetic ethynyl estrogen, and intermediate dose ketoconazole (IDK) and hydrocortisone, a combination of antimycotic and corticosteroid, are often used as salvage therapy after several hormone manipulations. We investigated their efficacy in patients with hormone refractory prostate cancer (HRPC). Materials: A retrospective review of medical records of 32 HRPC pts receiving IDK and 19 pts receiving DES from Jan 2005 to Dec 2009. Results: Prior to IDK, patients received four lines of hormonal therapy. The median baseline serum PSA level was 75.8 ng/ml (range 1.75-563.3). A PSA response (defined by ≥ 50% decline in baseline PSA) or any PSA decline were observed in 5 (17.9%) and 11 (39.3%) pts, respectively.For the entire study group, the median time to progression (TTP) was 2.25 months (interquartile range (IQR) 2.0-5.75 mths), and the median survival was 11 months (IQR 5-21 mths). In PSA responders, TTP was significantly longer (7 mths) than in PSA non-responders (2.0 mths) (p=0.014). TTP was also significantly longer (6 mths) in patients with any PSA decline than in the group without decline (2.0 mths)(p 50% decline were observed in 11 (68.7%) and 6 (37.5%) pts, respectively. The median TTP was 7.25 months (IQR 4.0-9.25 mths) and the median overall survival was 12 months (IQR 7.4-17.5 mths). Using the >50% response criteria, the median TTP for responders was 8.25 mths compared to 4.5 mths for non-responders (p=0.093). DES toxicity was reported in only one patient. Conclusions: Diethylstilbestrol and ketoconazole are a valuable option for HRPC patients. DES can induce prolonged responses and is well tolerated. Early identified PSA responders to IDK will benefit from this therapy. A substantial proportion of patients discontinue therapy due to intolerable side effects. Long responses are more likely to occur in men initiating IDK or DES early in the course of their disease.

1015 poster EVALUATION OF ROTATIONAL IMRT FOR THE TREATMENT OF PROSTATE CANCER PATIENTS WITH PROSTHETIC HIP

Purpose: Diethylstilbestrol (DES), a synthetic ethynyl estrogen, and intermediate dose ketoconazole (IDK) and hydrocortisone, a combination of antimycotic and corticosteroid, are often used as salvage therapy after several hormone manipulations. We investigated their efficacy in patients with hormone refractory prostate cancer (HRPC). Materials: A retrospective review of medical records of 32 HRPC pts receiving IDK and 19 pts receiving DES from Jan 2005 to Dec 2009. Results: Prior to IDK, patients received four lines of hormonal therapy. The median baseline serum PSA level was 75.8 ng/ml (range 1.75-563.3). A PSA response (defined by ≥ 50% decline in baseline PSA) or any PSA decline were observed in 5 (17.9%) and 11 (39.3%) pts, respectively.For the entire study group, the median time to progression (TTP) was 2.25 months (interquartile range (IQR) 2.0-5.75 mths), and the median survival was 11 months (IQR 5-21 mths). In PSA responders, TTP was significantly longer (7 mths) than in PSA non-responders (2.0 mths) (p=0.014). TTP was also significantly longer (6 mths) in patients with any PSA decline than in the group without decline (2.0 mths)(p 50% decline were observed in 11 (68.7%) and 6 (37.5%) pts, respectively. The median TTP was 7.25 months (IQR 4.0-9.25 mths) and the median overall survival was 12 months (IQR 7.4-17.5 mths). Using the >50% response criteria, the median TTP for responders was 8.25 mths compared to 4.5 mths for non-responders (p=0.093). DES toxicity was reported in only one patient. Conclusions: Diethylstilbestrol and ketoconazole are a valuable option for HRPC patients. DES can induce prolonged responses and is well tolerated. Early identified PSA responders to IDK will benefit from this therapy. A substantial proportion of patients discontinue therapy due to intolerable side effects. Long responses are more likely to occur in men initiating IDK or DES early in the course of their disease.

Abstract 851: Interactions among transcription factors as a potential mechanism for inhibiting castrate-resistant prostate cancer (CRPCa) in transgenic adenocarcinoma of mouse prostate (TRAMP) through regulation of FLIP

Abstract Androgens are critical regulators of prostate differentiation and function as well as prostate cancer growth and survival. Prostate tumors initially regress in response to androgen-ablation therapy. However, most cancers eventually relapse with an androgen-depletion-independent phenotype that is often more aggressive than the original androgen-dependent tumor. Studies from our laboratory demonstrated that intervention with 2-ME2[2-methoxyestradiol] prevents early stage prostate cancer development and causes regression of established prostate tumors in the transgenic adenocarcinoma of mouse prostate model. Although 2-ME2 was found to be safe, well tolerated, reduce or stabilize PSA levels when given to hormone refractory prostate cancer patients who had failed other treatments including hormone therapy, it was found to be less bioavailable. Accordingly second generation 2-ME2 was developed using nanocrystal colloidal dispersion technology and has increased its bioavailability by 5-10 fold (EntreMed, Inc, Rockville, MD). In the current study we tested the ability of this newly formulated 2-ME2 on the development and progression of castrate-resistant prostate cancer in TRAMP mice. 10-12 week old TRAMP mice were castrated and fed water containing different amounts of 2-ME2 for 6 weeks. Efficacy was evaluated by magnetic resonance imaging, determining the prostate seminal vesicle complex volume and histological analysis of prostate tumor or tissue. Our results also show that 2-ME2 inhibited development of CRPCa in these mice. Further molecular analysis using cell lines demonstrated 2-ME2 treatment significantly inhibited DHT-stimulated cell proliferation in androgen-responsive LNCaP cells (p&amp;lt;0.001). Further DHT-induced FLIP, PSA and AR transcriptional activity (as measured by promoter activities) were also reduced by 2-ME2 (p&amp;lt;0.001). Transient expression assays coupled with gel-shift and ChIP assays show binding of multiple transcription factors including Sp1, Sp3, NFκB and AR to the FLIP promoter. 2-ME2 treatment reduced such binding to the FLIP promoter as evidenced by ChIP. 2-ME2 treatment also modulated the interactions among these transcription factors as evidenced by Re-ChIP assays. Interestingly transcription factor CREB but not Sp1 seems to play a predominant role in androgen regulation of FLIP expression. Our findings suggest that 2-ME2 affects androgen induced survival of prostate cancer cells through regulation of FLIP involving potential interactions between multiple transcription factors. Supported by ACS RSG-04-169 and NIH CA 135451 (APK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 851. doi:10.1158/1538-7445.AM2011-851

Cost effectiveness of zoledronic acid in the management of skeletal metastases in hormone-refractory prostate cancer patients in France, Germany, Portugal, and the Netherlands

Objective:Zoledronic acid (ZOL) reduces the risk of skeletal related events (SREs) in hormone-refractory prostate cancer (HRPC) patients with bone metastases. This study assessed the cost effectiveness of ZOL for SRE management in French, German, Portuguese, and Dutch HRPC patients.Methods:This analysis was based on the results of a randomized phase III clinical trial wherein HRPC patients received up to 15 months of ZOL (n = 214) or placebo (n = 208). Clinical inputs were obtained from the trial. Costs were estimated using hospital tariffs, published, and internet sources. Quality adjusted life-years (QALYs) gained were estimated from a separate analysis of EQ-5D scores reported in the trial. Uncertainty surrounding outcomes was addressed via univariate sensitivity analyses.Results:ZOL patients experienced an estimated 0.759 fewer SREs and gained an estimated 0.03566 QALYs versus placebo patients. ZOL was associated with reduced SRE-related costs [net costs] (−€2396 [€1284] in France, −€2606 [€841] in Germany, −€3326 [€309] in Portugal and −€3617 [€87] in the Netherlands). Costs per QALY ranged from €2430 (Netherlands) to €36,007 (France).Conclusions:This analysis is subject to the limitations of most cost-effectiveness analyses: it combines data from multiple sources. Nevertheless, the results strongly suggest that ZOL is cost effective versus placebo in French, German, Portuguese, and Dutch HRPC patients.