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1.  Intermittent tri-weekly docetaxel plus bicalutamide in patients with castration-resistant prostate cancer: a single-arm prospective study using a historical control for comparison 
Asian Journal of Andrology  2013;15(6):773-779.
Whether continuous docetaxel (DTX) chemotherapy offers an advantage over intermittent therapy for castration-resistant prostate cancer (CRPC) is unknown. In this study, we evaluated the efficacy, toxicity and quality of life (QoL) of intermittent tri-weekly DTX with bicalutamide in CRPC. Forty-two patients (group A) with CRPC were enrolled. The patients received intravenous DTX (75 mg m−2) once tri-weekly with oral bicalutamide (50 mg) once daily. Patients had a DTX holiday when the prostate-specific antigen (PSA) level declined ≥50%. DTX was restarted in patients with a PSA increase ≥25%. Sixty patients (group B) who had matching characteristics and had continuously received DTX without bicalutamide for 10–12 cycles were also enrolled. There were no statistically significant differences in progression-free survival (8 months vs. 9 months, P=0.866) or overall survival (19 months vs. 21 months, P=0.753) between groups A and B; however, the proportions of patients in group A with all grades of neutropenia (33% vs. 58%, P=0.013) and nausea/vomiting (11% vs. 29%, P=0.024) were significantly less compared to group B. A significant improvement in the global health and fatigue scores was recorded for group A post-chemotherapy compared to pre-chemotherapy (P<0.05). The fatigue, nausea/vomiting and appetite loss scores in group B were increased post-chemotherapy compared to pre-chemotherapy (P<0.05). In conclusion, intermittent tri-weekly DTX plus bicalutamide is well tolerated and has the potential to achieve comparable disease control with an improvement in QoL for patients with CRPC.
doi:10.1038/aja.2013.89
PMCID: PMC3854057  PMID: 23955552
androgen; chemotherapy; docetaxel; prostate cancer; safety
2.  External validation of risk classification in patients with docetaxel-treated castration-resistant prostate cancer 
BMC Urology  2014;14:31.
Background
Castration-resistant prostate cancer (CRPC) patients have poor prognoses, and docetaxel (DTX) is among the few treatment options. An accurate risk classification to identify CRPC patient groups for which DTX would be effective is urgently warranted. The Armstrong risk classification (ARC), which classifies CRPC patients into 3 groups, is superior; however, its usefulness remains unclear, and further external validation is required before clinical use. This study aimed to examine the clinical significance of the ARC through external validation in DTX-treated Japanese CRPC patients.
Methods
CRPC patients who received 2 or more DTX cycles were selected for this study. Patients were classified into good-, intermediate-, and poor-risk groups according to the ARC. Prostate-specific antigen (PSA) responses and overall survival (OS) were calculated and compared between the risk groups. A multivariate analysis was performed to clarify the relationship between the ARC and major patient characteristics.
Results
Seventy-eight CRPC patients met the inclusion criteria. Median PSA levels at DTX initiation was 20 ng/mL. Good-, intermediate-, and poor-risk groups comprised 51 (65%), 17 (22%), and 10 (13%) patients, respectively. PSA response rates ≥30% and ≥50% were 33%, 41%, and 30%, and 18%, 41%, and 20% in the good-, intermediate-, and poor-risk groups, respectivcixely, with no significant differences (p = 0.133 and 0.797, respectively). The median OS in the good-, intermediate-, and poor-risk groups were statistically significant (p < 0.001) at 30.1, 14.2, and 5.7 months, respectively. A multivariate analysis revealed that the ARC and PSA doubling time were independent prognostic factors.
Conclusions
Most of CRPC patients were classified into good-risk group according to the ARC and the ARC could predict prognosis in DTX-treated CRPC patients.
Trial registration
University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000011969.
doi:10.1186/1471-2490-14-31
PMCID: PMC3997751  PMID: 24742323
Castration-resistant prostate cancer; Docetaxel; Risk classification; Validation study
3.  A PHASE II STUDY OF ESTRAMUSTINE, DOCETAXEL, AND BEVACIZUMAB IN MEN WITH CASTRATE RESISTANT PROSTATE CANCER: RESULTS OF CANCER AND LEUKEMIA GROUP B (CALGB) 90006 
Cancer  2010;117(3):526-533.
Background
The use of docetaxel prolongs survival for patients with castrate resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the anti-tumor effect of docetaxel and estramustine in patients with CRPC.
Patients and Methods
This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg three times per day on days 1-5 of every cycle, with 70 mg/m2 of docetaxel and bevacizumab at 15 mg/kg on day 2, every three weeks. PSA values were monitored every cycle and imaging was performed every 3 cycles. The primary endpoint was progression free survival (PFS) with safety, prostate specific antigen decline, measurable disease response, and overall survival secondary objectives.
Results
Seventy-nine patients were enrolled; 77 received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%) The median time of PFS was 8.0 months with an overall median survival of 24 months. Neutropenia without fever (69%), fatigue (25%), thrombosis\emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment due to disease progression, 35/77 for physician or patient decision and 15 patients secondary to toxicity.
Conclusion
The combination of docetaxel, estramustine and bevacizumab was tolerable but complicated by toxicity. Although progression free survival did not meet the desired endpoint, encouraging anti-tumor activity and overall survival was observed. Further phase III evaluation of the role of bevacizumab in CRPC is ongoing.
doi:10.1002/cncr.25421
PMCID: PMC3010428  PMID: 20862750
Docetaxel; Bevacizumab; castrate resistant prostate cancer
4.  Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer 
Cell Death & Disease  2014;5(5):e1210-.
There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen-sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti-proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53±0.001 to 57±1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10–20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti-tumoral epitope/NT3. Although NT3–DTX-5 mg/kg combination was inefficient, NT3–DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3–CTX combinations were advantageous. Inversely, PEDF–DTX-5 mg/kg and PEDF–CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF–DTX-5 mg/kg, PEDF–CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin-1 as possible mechanism and marker, respectively. As well, both PEDF–CTX-10 mg/kg and PEDF–DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF–DTX-5 mg/kg compared with other treatments, suggesting that PEDF–DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC.
doi:10.1038/cddis.2014.180
PMCID: PMC4047872  PMID: 24810046
prostate cancer; pigment epithelium-derived factor; low-dose chemotherapy; docetaxel; cyclophosphamide
5.  Prostate-specific antigen response rate of sequential chemotherapy in castration-resistant prostate cancer: the results of real life practice 
Prostate International  2013;1(3):125-132.
Purpose:
Prostate-specific antigen (PSA) response rate (>50% PSA decline in pretreatment PSA following chemotherapy) carries a significant survival advantage in castration-resistant prostate cancer (CRPC). We compared PSA response rates in first-, second- and third-line chemotherapy after failure of previous chemotherapy according to chemotherapeutic agents.
Methods:
We retrospectively evaluated the oncological outcomes and PSA response rates of 384 patients with CRPC, who were treated with chemotherapy and had histologically proven adenocarcinoma of the prostate with failure after androgen ablation therapy between 1991 and 2012, at Asan Medical Center.
Results:
In 384 eligible patients, the median age was 67.5 years. The median pretreatment PSA and initial Gleason scores at baseline were 92.4 ng/mL (range, 2.0 to 6,370 ng/mL) and 9 (range, 6 to 10), respectively. The time from first diagnosis of prostate cancer to CRPC was 23 months (range, 1 to 164 months). As first-line chemotherapy, 245 patients (63.8%) received estramustine, 91 (23.7%) received docetaxel, and 39 (10.2%) received mitoxantrone. The PSA response rates were 39.6%, 51.6%, and 46.2%, respectively. Of 169 patients with second-line chemotherapy, estramustine was 15 (8.9%), docetaxel was 84 (49.7%), and mitoxantrone was 52 (30.8%). PSA response rates were 57.1%, 52%, and 28.0%, respectively. Of 81 patients with third-line chemotherapy, estramustine was 18 (22.2%), docetaxel was 16 (19.8%), and mitoxantrone was 28 (34.6%). The PSA response rates were 41.2%, 53.8%, and 11.1%, respectively. Declines in serum PSA levels of at least 50% occurred more frequently after treatment with docetaxel than with other chemo-agents regardless of second-and third-line chemotherapy. Even in third-line chemothrapy, docetaxel maintained the PSA response rate, whereas the PSA response rate of other agents, including mitoxantrone, decreased in patients in whom prior therapy failed.
Conclusions:
Docetacel was the most effective chemotherapeutic agent in second- and third-line trials of chemotherapy in Korean CRPC patients. Although docetaxel is not used as first-line chemotherapy, and new agents are not available for therapy in CRPC patients, we can consider docetaxel a second- or third-line chemotherapy in CRPC.
doi:10.12954/PI.13024
PMCID: PMC3814118  PMID: 24223414
Castration refractory prostate cancer; Chemotherapy; Prostate-specific antigen
6.  Subverting ER-Stress towards Apoptosis by Nelfinavir and Curcumin Coexposure Augments Docetaxel Efficacy in Castration Resistant Prostate Cancer Cells 
PLoS ONE  2014;9(8):e103109.
Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3–9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX’s (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections indicated decreased Ki-67 staining and increased TUNEL intensity in mice exposed to the 3-drug combination. Therefore, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.
doi:10.1371/journal.pone.0103109
PMCID: PMC4133210  PMID: 25121735
7.  Comparison of Ketoconazole and Estramustine for Treating Patients with Castration-Resistant Prostate Cancer 
Korean Journal of Urology  2011;52(11):746-751.
Purpose
We investigated the efficacy of ketoconazole and estramustine before chemotherapy for treating patients with progressive castration-resistant prostate cancer (CRPC) after anti-androgen withdrawal syndrome.
Materials and Methods
Eighty-four patients who were diagnosed with CRPC and were treated between 2005 and 2009 were included. Thirty-nine patients were treated with 600 mg of ketoconazole and 10 mg of prednisolone per day (group I), and 45 patients were treated with 560 mg of estramustine per day (group II). The prostate-specific antigen (PSA) response, progression-free survival, and side effects were compared.
Results
The median age of the patients, PSA level, and follow-up period were 72 years, 48.5 ng/ml, and 4 months (range, 1 to 29 months), respectively. The overall PSA response rate was 35.7%, and the PSA response rates were 33.3% for group I and 37.8% for group II (p=0.672). The median progression-free survival times were 8 months (95% confidence interval [CI] 5.9-10.1) overall, 5 months (95% CI 1.6-8.3) in group I, and 8 months (95% CI 5.9-10.0) in group II (p=0.282). The most common complications in groups I and II were nausea and vomiting (51.3%) and anemia (77.8%), respectively. Nausea and vomiting and hepatotoxicity were observed more often in group I, and gynecomastia, neutropenia, and anemia were observed more often in group II. The toxicities of each adverse effect were ≤grade 2.
Conclusions
With a resultant PSA decline and mild adverse effects, both ketoconazole and estramustine are worth consideration as treatment options for progressive CRPC patients after primary hormonal therapy.
doi:10.4111/kju.2011.52.11.746
PMCID: PMC3242987  PMID: 22195263
Estramustine; Ketoconazole; Prostatic neoplasms
8.  Risk Factors for Metastatic Castration-Resistant Prostate Cancer (CRPC) Predict Long-Term Treatment with Docetaxel 
PLoS ONE  2012;7(10):e48186.
Purpose
For patients with metastatic castration-resistant prostatic cancer (mCRPC), docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS) in Japanese patients with mCRPC.
Patients and Methods
Fifty-two patients with mCRPC were administered 55 mg/m2 docetaxel and 8 mg dexamethasone, every 3 or 4 weeks, simultaneously with hormonal therapy and daily oral dexamethasone. They were divided into two groups, short-term (9 or fewer cycles) and long-term (10 or more cycles). Four risk factors including the presence of anemia, bone metastases, significant pain and visceral metastases were utilized for the risk group classification.
Results
Fourteen patients (27%) had an elevation of PSA in spite of docetaxel treatment, while 23 patients (44%) had a decline in PSA level, including 9 patients (17%) whose PSA level declined by ≥50%. The median duration of OS after the initiation of this therapy was 11.2 months in the short-term group and 28.5 months in the long-term group. The good risk group showed a significant difference in OS compared with the intermediate and poor risk groups (P<0.001). The median number of cycles of treatment was 14, 4 and 3 for each risk group, respectively (p<0.01).
Conclusions
The present study indicated that ≥10 cycles of this docetaxel therapy can significantly prolong survival in Japanese men with CRPC. This risk group classification for men with mCRPC at the initiation of this chemotherapy is useful.
doi:10.1371/journal.pone.0048186
PMCID: PMC3484044  PMID: 23118948
9.  Efficacy of carboplatin–taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials 
Annals of Oncology  2009;21(2):312-318.
Background: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane–estramustine–carboplatin (TEC) chemotherapy may be greatest.
Patients and methods: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as ≥50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram.
Results: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival.
Conclusions: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.
doi:10.1093/annonc/mdp308
PMCID: PMC2852201  PMID: 19633053
carboplatin; estramustine; prostate cancer; taxanes
10.  Epirubicin combined with estramustine phosphate in hormone-resistant prostate cancer: a phase II study. 
British Journal of Cancer  1997;76(1):93-99.
Twenty-four assessable patients with hormone-resistant prostate cancer (HRPC) were to receive daily doses of oral estramustine phosphate (EMP), 10 mg kg(-1), and intravenous epirubicin (EPR) infusions, 100 mg m(-2), every third week up to a cumulative dose of 500 mg m(-2). Biochemical response [> or = 50% reduction in pretreatment serum prostate-specific antigen (PSA) after three cycles of > or = 3 weeks' duration] was demonstrated in 13 of 24 patients included (54%). No objective response (WHO criteria) was observed, although seven of nine evaluable patients achieved a > or = 50% serum PSA reduction. Subjective improvement (pain score, performance status) occurred in 7 of 24 patients, whereas nine patients progressed subjectively. There was no correlation between subjective and biochemical response. Biochemical progression (> or = 50% increase of nadir PSA) occurred after a median of 12 weeks. All but two patients were alive after a median follow-up time of 8.7 months for surviving patients (range 3.3-13.2). Eight patients experienced grade 3/4 leucopenia, with no indication of cumulative myelosuppression. Cardiovascular toxicity was experienced by four patients. Two patients developed angioedema twice, in one patient requiring hospitalization at the intensive ward. Based on this limited series, the combination of EPR and EMP in patients with HRPC is tolerable and appears to be effective in terms of significant PSA reduction. The results warrant further investigations of the two drugs and, in particular, of the clinical significance of > or = 50% PSA decrease in patients with HRPC.
PMCID: PMC2223802  PMID: 9218739
11.  Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer 
Journal of Clinical Oncology  2010;28(12):2070-2076.
Purpose
We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients.
Patients and Methods
Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of ≥ 50%. Secondary end points included time to progression, overall survival, and safety.
Results
In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of ≥ 50%, and 88% achieved a PSA decline of ≥ 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia.
Conclusion
The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.
doi:10.1200/JCO.2009.25.4524
PMCID: PMC2860408  PMID: 20308663
12.  Clinical predictor of survival following docetaxel-based chemotherapy 
Oncology Letters  2014;8(4):1788-1792.
Prostate cancer (PCa) is the most common type of cancer in males in the USA and the incidence is increasing. For castration-resistant PCa (CRPC), previous studies have identified docetaxel-based chemotherapy as the first-line therapy. In the present study, the efficacy of docetaxel-based chemotherapy was investigated in a population of patients with CRPC. This study included 26 individuals (mean age, 73 years) with CRPC who were patients between July 2007 and October 2012 at the Kaohsiung Medical University Hospital (Kaohsiung, Taiwan). The regimen consisted of intravenous docetaxel (70 mg/m2) once every four weeks plus oral prednisolone (5 mg) twice daily for five days. Prostate-specific antigen (PSA) response (defined as a PSA decrease of >50% over four weeks), time to PSA progression, PCa-specific survival and overall survival (OS) were evaluated. For these 26 patients, the mean PSA level prior to chemotherapy treatment was 335.58 ng/ml. During follow-up, the average number of cycles of chemotherapy was approximately seven and 15 patients (58%) achieved a PSA response. PSA response was found to significantly correlate with OS and PCa-specific survival (P=0.014 and P=0.028, respectively). The mean value of the PSA nadir level was 89.97 ng/ml and time to PSA nadir was five months. The most common adverse event was leucopenia, which affected 88% of the patients. The results indicated that the length of time to PSA nadir and the occurrence of leucopenia may impact the PSA response. The docetaxel-based chemotherapy was a feasible and effective treatment regimen in patients with CRPC. However, the occurrence of adverse events, particularly the high incidence of leucopenia, may be cause for concern.
doi:10.3892/ol.2014.2349
PMCID: PMC4156217  PMID: 25202411
castration-resistant prostate cancer; docetaxel
13.  Circulating Endothelial Progenitor Cells in Castration Resistant Prostate Cancer: A Randomized, Controlled, Biomarker Study 
PLoS ONE  2014;9(4):e95310.
Background
Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients.
Patients and methods
Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy.
Results
A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6–3.6 months, 95% CI) and 6.2 months (4.9–7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable.
Conclusion
In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS.
Trial Registery
clinicaltrialsregister.eu EudraCT 2007-003705-27
doi:10.1371/journal.pone.0095310
PMCID: PMC3995874  PMID: 24755958
14.  Predictive Factors for Premature Discontinuation of Docetaxel-Based Systemic Chemotherapy in Men With Castration-Resistant Prostate Cancer 
Korean Journal of Urology  2013;54(3):157-162.
Purpose
The objective was to determine predictive factors for premature discontinuation of docetaxel-based systemic chemotherapy in men with castration-resistant prostate cancer (CRPC).
Materials and Methods
We retrospectively reviewed the medical records of men who were treated with docetaxel-based systemic chemotherapy for CRPC in a single institution between May 2005 and April 2010. After being screened, 30 patients fit the eligibility criteria for inclusion in this study. Group 1 included 12 patients who were treated with five or fewer cycles of docetaxel chemotherapy for CRPC, and group 2 included 18 patients who were treated with six or more cycles of docetaxel chemotherapy for CRPC. The treatment consisted of 5 mg prednisolone twice daily and 75 mg/m2 docetaxel once every 3 weeks.
Results
The median age was 72 years, and the median Eastern Cooperative Oncology Group (ECOG) performance status was 0. The median baseline prostate-specific antigen (PSA) level was 33.8 ng/mL. The median cycle of docetaxel-based chemotherapy was 5.8. Of 30 patients, 13 patients (48.2%) had a decline in PSA of >50% from baseline; 3 of 22 patients (13.6%) with measurable disease had achieved partial response on imaging. No differences in age, ECOG performance status, hemoglobin, serum creatinine, or PSA response were observed between the two groups. Body mass index was significantly lower (p=0.034) in group 1 (21.8 kg/m2) than in group 2 (23.6 kg/m2). Group 1 included more patients with prior systemic chemotherapy (p=0.039), and group 1 had a shorter overall survival rate (p=0.039).
Conclusions
Premature discontinuation of docetaxel-based systemic chemotherapy is associated with lower body mass index and prior systemic chemotherapy. Premature discontinuation of docetaxel-based chemotherapy is associated with a shorter overall survival rate.
doi:10.4111/kju.2013.54.3.157
PMCID: PMC3604567  PMID: 23526149
Induction chemotherapy; Prostatic neoplasms; Treatment outcome
15.  Synergistic Antitumor Activities of Docetaxel and Octreotide Associated with Apoptotic-Upregulation in Castration-Resistant Prostate Cancer 
PLoS ONE  2014;9(3):e91817.
Androgen deprivation therapy has become the fist-line treatment of metastatic prostate cancer; however, progression to castrate resistance disease occurs in the majority of patients. Thus, there is an urgent need for improvements in therapy for castration-resistant prostate cancer. The aims of the present study were to determine the efficacy somatostatin analogue octreotide (OCT) combined with a low dose of docetaxel (DTX) using castration resistant prostate cancer cells and to investigate the involved molecular mechanisms in vitro. The anti-proliferative and synergism potential effects were determined by MTT assay. Induction of apoptosis was analyzed employing annexing V and propidium iodide staining and flow cytometry. VEGFA, CASP9, CASP3 and ABCB1 gene expression was evaluated by RT-PCR and Q-RT-PCR analysis. OCT in combination with DTX treatments on DU145 cell migration was also evaluated. Investigation revealed that combined administration of DTX and OCT had significant, synergistically greater cytotoxicity than DTX or OCT treatment alone. The combination of the two drugs caused a more marked increase in apoptosis and resulted in greater suppression of invasive potential than either individual agent. There was obvious increase in caspase 3 expression in the OCT alone and two-drug combined treatment groups, however, VEGFA expression was markedly suppressed in them. These results support the conclusion that somatostatin analogues combined with docetaxel may enhance the chemotherapy efficacies through multiple mechanisms in castration-resistant PCa cell line. This work provides a preclinical rationale for the therapeutic strategies to improve the treatment in castrate resistance disease.
doi:10.1371/journal.pone.0091817
PMCID: PMC3954761  PMID: 24632829
16.  Cabazitaxel (Jevtana) 
Pharmacy and Therapeutics  2012;37(8):440-448.
Cabazitaxel (Jevtana) for metastatic castration-resistant prostate cancer
Objective:
This article presents current clinical evidence supporting the use of cabazitaxel (Jevtana) in men with metastatic castration-resistant prostate cancer (mCRPC).
Data Sources:
We conducted a literature search using abstracts from MEDLINE and PubMed (from January 1966 to December 2011) and the American Society of Clinical Oncology (from January 2000 to December 2011). The search included clinical studies and abstracts in the English language that described the pharmacology, pharmacokinetics, clinical activity, and safety of cabazitaxel in mCRPC.
Results:
Cabazitaxel, a semisynthetic microtubule inhibitor that induces cell death by microtubule stabilization, was approved in combination with prednisone for the treatment of mCRPC in patients who had been treated with a docetaxel-(Taxotere)-containing regimen. The approval of this taxane derivative was based primarily on the results of a randomized, open-label trial in patients with mCRPC who were treated with either cabazitaxel 25 mg/m2 or mitoxantrone (Novantrone) 12 mg/m2 intravenously every 3 weeks, both in combination with prednisone 10 mg/day. The median survival period was 15.1 months with cabazitaxel and 12.7 months with mitoxantrone. Neither group experienced complete responses. Cabazitaxel has also shown activity in breast cancer and other malignancies. In clinical trials, common grade 3 or grade 4 adverse reactions were myelosuppression, febrile neutropenia, diarrhea, fatigue, and asthenia. Other adverse effects included abdominal pain, back pain, arthralgia, and peripheral neuropathy.
Conclusion:
Cabazitaxel appeared to be an effective second-line agent in patients with mCRPC refractory to a docetaxel-containing regimen. Studies comparing cabazitaxel with existing first-line regimens for mCRPC are under way. Until the results of these head-to-head trials are published, it remains uncertain whether cabazitaxel is more effective or more tolerable than the currently available first-line regimens.
PMCID: PMC3474423  PMID: 23091336
cabazitaxel; castration-resistant prostate cancer; docetaxel resistance; XRP6258
17.  HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer 
Investigational new drugs  2013;32(2):235-242.
Summary
Background
Given the immunogenicity of NYESO-1 peptides in prostate cancer, a phase I clinical trial was designed to evaluate HLA class-I and class-II restricted NYESO-1 peptides in metastatic castration-resistant prostate cancer (mCRPC).
Methods
Patients with progressive mCRPC, Zubrod Performance Status ≤2, PSA ≥10 ng/ml who had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 received a peptide presented by an HLA class I haplotype (HLA-A2), Group 2 with a peptide presented by HLA class II haplotype (DR4, DP4), and Group 3 with peptides presented by both Class I and II haplotypes. Androgen-deprivation was continued. Owing to a myocardial infarction, the protocol was amended to omit the use of GMCSF.
Results
Fourteen patients were evaluable for toxicities and 9 received all 6 doses and were evaluable for efficacy. One death from myocardial infarction following GM-CSF occurred in a patient with generalized myalgias. After omitting GM-CSF, no grade >2 toxicities were observed. Among 9 patients evaluable for efficacy, the median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. NY-ESO-1 specific T-cell response observed by ELISPOT appeared more frequent in docetaxel-naïve patients (4 of 4) than docetaxel-pretreated patients (2 of 5).
Conclusion
In men with mCRPC, individualized HLA class-I and/or class-II restricted NY-ESO-1 peptides were tolerable, appeared to slow PSA doubling time and yielded antigen-specific T-cell responses more often in chemonaïve patients.
doi:10.1007/s10637-013-9960-9
PMCID: PMC4100683  PMID: 23609828
NY-ESO-1; Castration-resistant prostate cancer; Peptide; Immunotherapy; HLA-restricted; Cancer vaccines
18.  Effective oral combination metronomic chemotherapy with low toxicity for the management of castration-resistant prostate cancer 
Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26–99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.
doi:10.3892/etm.2011.272
PMCID: PMC3440841  PMID: 22977543
prostate cancer; castration-resistant; hormone-refractory; metronomic; chemotherapy; angiogenesis
19.  Repetitively Dosed Docetaxel and 153Samarium-EDTMP as an Anti-Tumor Strategy for Metastatic Castration-Resistant Prostate Cancer 
Cancer  2013;119(17):3186-3194.
Background
Beta-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation while docetaxel prolongs life in metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize anti-tumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established.
Methods
Patients with progressive mCRPC and ≥3 bone lesions received 153Sm-EDTMP 1.0 mCi/kg every 9 weeks and docetaxel 75mg/m2 every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic progression.
Results
Of 30 patients treated, 50% were taxane-naïve, 36.7% taxane-refractory, and 13.3% previously exposed to taxanes but not considered refractory. Patients received on average 2.5 cycles: 6.5 doses of docetaxel and 2.5 doses of 153Sm-EDTMP. Twelve (40%) demonstrated decline in prostate-specific antigen of ≥50%. Median progression-free survival (biochemical or radiographic) was 7.0 months and overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts above 100 K/mm3 after a median of 3 cycles to allow for additional treatment, with four experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity.
Discussion
153Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis. Thrombocytopenia limited therapy for some patients; preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, an appealing strategy given the anticipated availability of alpha emitters that can prolong survival.
doi:10.1002/cncr.28103
PMCID: PMC3775970  PMID: 23765638
prostate cancer; 153Sm-EDTMP; docetaxel; chemotherapy; radiopharmaceutical
20.  Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study 
British Journal of Cancer  2007;97(9):1206-1210.
The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m−2 of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1–3, 8–10, 15–17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1–9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44–72) and median duration of PSA response was 8.0 months (95% CI: 6.9–9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.
doi:10.1038/sj.bjc.6604030
PMCID: PMC2360463  PMID: 17955053
COX-2 inhibitor; docetaxel; estramustine; celecoxib; prostate cancer; androgen-independent
21.  The role of cabazitaxel in the treatment of metastatic castration-resistant prostate cancer 
For decades, cytotoxic therapy was considered ineffective for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Earlier therapies such as estramustine and mitoxantrone received regulatory approval based upon improvement in palliative endpoints. In 2004, docetaxel became the first treatment to demonstrate a significant survival benefit in patients with mCRPC based on two randomized phase III studies, TAX327 and SWOG 99-16. Cabazitaxel, a third-generation taxane, was chosen for clinical development based on its decreased affinity for the drug efflux pump, p-glycoprotein, which is a frequent cause of drug resistance in docetaxel-resistant preclinical models. In 2010, cabazitaxel was approved by the US Food and Drug Administration as the first therapy to show a survival benefit for the treatment of patients with docetaxel-refractory mCRPC. This review summarizes the existing literature on the use of cabazitaxel, focusing on its efficacy and safety in combination with prednisone in the treatment of mCRPC, as well as its role in an era of new therapeutic options.
doi:10.1177/1756287214528557
PMCID: PMC4003844  PMID: 24883107
cabazitaxel; castration resistant; docetaxel; efficacy; prostate cancer; safety; taxane
22.  A Multicenter, Randomized Clinical Trial Comparing the Three-Weekly Docetaxel Regimen plus Prednisone versus Mitoxantone plus Prednisone for Chinese Patients with Metastatic Castration Refractory Prostate Cancer 
PLoS ONE  2015;10(1):e0117002.
Purpose
To explore the feasibility and efficacy of docetaxel plus prednisone for Chinese population with metastatic castration refractory prostate cancer (mCRPC).
Patients and methods
A total of 228 patients recruited from 15 centers were randomized to receive 10 cycles of D3P arm (docetaxel: 75 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily) or M3P arm (mitoxantrone: 12 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily). Primary end point was overall survival, and secondary end points were events progression-free survival (PFS), response rate, response duration. Quality of life (QoL) was also assessed in both treatment groups.
Results
The median overall survival was 21.88 months in D3P arm and 13.67 months in M3P arm (P = 0.0011, hazard ratio = 0.63, 95% confidence interval, 0.46–0.86). Subgroup analysis was consistent with the results of overall analysis. Events progression-free survival (pain, PSA, tumor and disease) were significantly improved in D3P arm compared with M3P arm. PSA response rate was 35.11% for patients treated by D3P arm and 19.39% for M3P arm (P = 0.0155). Pain response rate was higher in D3P arm (61.11%, P = 0.0011) than in M3P (23.08%) arm. No statistical differences were found between D3P arm and M3P arm for QoL, tumor response rate and response duration of PSA and pain. The tolerability and overall safety of D3P arm were generally comparable to that of M3P arm.
Conclusions
Compared with M3P arm, D3P arm significantly prolonged overall survival for the Chinese patients with mCRPC and improved the response rate for PSA and pain.
Trial Registration
clinicaltrials.gov NCT00436839
doi:10.1371/journal.pone.0117002
PMCID: PMC4307981  PMID: 25625938
23.  Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles 
British Journal of Cancer  2006;94(11):1592-1598.
Caspase-cleaved proteins are released from disintegrated apoptotic cells and can be detected in the circulation. We here addressed whether caspase-cleaved cytokeratin 18 (CK18-Asp396) can be used as a serum biomarker for assessment of the clinical efficiency of chemotherapy in hormone-refractory prostate cancer (HRPC). A total of 82 patients with HRPC were evaluated during 751 treatment cycles, either with estramustine (EMP)/vinorelbine or with EMP/docetaxel. The levels of CK18-Asp396 and of total CK18 were measured in patient serum before and during therapy by ELISA. Docetaxel induced significant increases in serum CK18-Asp396 (P<0.0001) and total CK18 (P<0.0002), suggesting induction of apoptosis. Similarly, vinorelbine induced increases in both CK18-Asp396 and CK18 (P<0.001 and 0.011). In contrast, EMP induced increases in total serum CK18 (P<0.0001), but not in CK18-Asp396 (P=0.13). The amplitudes of docetaxel-induced increases were associated with baseline prostate-specific antigen (PSA) and CK18 serum levels in these patients, consistent with tumoral origin of caspase-cleaved fragments. Docetaxel induced significant increases in CK18-Asp396 during second-, third- and fourth-line therapy and induced increased levels of CK18-Asp396 during treatment cycles 1–8. In contrast, vinorelbine induced significant increases only during cycles 1–3. In a subgroup of 32 patients that received EMP/vinorelbine in second line followed by EMP/docetaxel in third line, docetaxel induced stronger increases than vinorelbine (P=0.008). These results show that the CK18-Asp396 serum marker can be used to assess tumour apoptosis in vivo and suggest that the clinical efficiency of docetaxel in HRPC is due to induction of apoptosis during multiple treatment cycles.
doi:10.1038/sj.bjc.6603129
PMCID: PMC2361322  PMID: 16685278
prostate cancer; treatment; apoptosis; biomarker; M30-ELISA
24.  Efficacy, Pharmacokinetics, and Biodistribution of Thermosensitive Chitosan/β-Glycerophosphate Hydrogel Loaded with Docetaxel 
AAPS PharmSciTech  2014;15(2):417-424.
Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.
doi:10.1208/s12249-014-0077-z
PMCID: PMC3969486  PMID: 24442774
antitumor efficacy; biodistribution; chitosan/β-glycerophosphate; docetaxel; pharmacokinetics
25.  A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899 
Background
To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC).
Methods
70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC).
Results
The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03).
Conclusions
Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.
Trial Registration
Clinical Trials Registration number: CDR0000067865
doi:10.1186/1479-5876-8-20
PMCID: PMC2837641  PMID: 20178647

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