Docetaxel In Castration-resistant Prostate Cancer Research Articles

The role of testicular nuclear receptor 4 in chemo-resistance of docetaxel in castration-resistant prostate cancer.

Docetaxel-based therapy is one of the first-line options for castration-resistant prostate cancer (CRPC). However, a large proportion of CRPC patients show different extents of docetaxel resistance. The current study aims to investigate the role of testicular nuclear receptor 4 (TR4) in docetaxel resistance in CRPC. TR4 expression level in prostate biopsy samples from CRPC patients treated with docetaxel was measured by immunohistochemistry (IHC). Alternation of TR4 expression in prostate cancer (PCa) cell line PC3 was applied to find out the influence of TR4 on half-maximal inhibitory concentration (IC50), cell viability and cell apoptosis. Patients who failed to achieve prostate-specific antigen (PSA) response (<50% PSA reduction from baseline) after docetaxel-based chemotherapy had a comparatively higher TR4 expression than those who achieved PSA response (⩾50% PSA reduction from baseline). Knocking down TR4 in PC3 cells led to a lower IC50 dose, poorer cell viability and more cell apoptosis when treated with docetaxel, whereas overexpression of TR4 in PC3 led to a higher IC50 dose, better cell viability and less cell apoptosis. TR4 enhances the chemo-resistance of docetaxel in CRPC. It may serve as a biomarker to determine the prognosis of docetaxel-based therapy and as a potential therapy target to combine with docetaxel to better suppress CRPC.

MP52-14 SYNERGISTIC EFFECTS OF COMBINATION OF DOCETAXEL AND SAHA ON AR SIGNALING IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-14 SYNERGISTIC EFFECTS OF COMBINATION OF DOCETAXEL AND SAHA ON AR SIGNALING IN PROSTATE CANCER Kyung-Sik Han, Taekmin Kwon, In Gab Jeong, Dalsan You, Bumjin Lim, Donghyun Lee, Chunwoo Lee, Sungwoo Hong, Ha-Gyeong Kim, Jung Jin Hwang, Jun Hyuk Hong, Myung-Soo Choo, Tai Young Ahn, and Choung-Soo Kim Kyung-Sik HanKyung-Sik Han More articles by this author , Taekmin KwonTaekmin Kwon More articles by this author , In Gab JeongIn Gab Jeong More articles by this author , Dalsan YouDalsan You More articles by this author , Bumjin LimBumjin Lim More articles by this author , Donghyun LeeDonghyun Lee More articles by this author , Chunwoo LeeChunwoo Lee More articles by this author , Sungwoo HongSungwoo Hong More articles by this author , Ha-Gyeong KimHa-Gyeong Kim More articles by this author , Jung Jin HwangJung Jin Hwang More articles by this author , Jun Hyuk HongJun Hyuk Hong More articles by this author , Myung-Soo ChooMyung-Soo Choo More articles by this author , Tai Young AhnTai Young Ahn More articles by this author , and Choung-Soo KimChoung-Soo Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1624AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Globally it is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, androgen is required for cell growth and progression of prostate cancer. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of hormone-refractory prostate cancer (HRPC) or castration-resistant prostate cancer (CRPC). Since the treatment for patient with CRPC is very limited, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. Therefore, we examined whether histone deacetylase inhibitor (HDACI) might enhance the effects of docetaxel in CRPCs. Methods Hormone-independent CWR22Rv1 cells harboring androgen receptor (AR) were treated with docetaxel and/or HDACI, suberoylanilide hydroxamic acid (SAHA). Cell viability was measured with CellTiter-Glo¢ç reagent. AR signaling was analyzed by immunocytochemistry and Western blot of total cell lysates and nuclear fractionated proteins. Results The growth inhibitory effect of sequential treatment with docetaxel and SAHA was synergistic in CWR22Rv1 cells. Combination treatment decreased the levels of androgen receptor (AR), prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently, compared with docetaxel or SAHA alone. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These synergistic effects of combination treatment were also observed in hormone-dependent LNCaP cells. Conclusions Docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing AR expression and translocation to nucleus, resulting in down regulation of AR signaling in hormone-independent CWR22Rv1 cells. These results suggest that combination treatment with docetaxel and SAHA can be a useful therapeutics for the treatment of CRPC patients. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e585 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Kyung-Sik Han More articles by this author Taekmin Kwon More articles by this author In Gab Jeong More articles by this author Dalsan You More articles by this author Bumjin Lim More articles by this author Donghyun Lee More articles by this author Chunwoo Lee More articles by this author Sungwoo Hong More articles by this author Ha-Gyeong Kim More articles by this author Jung Jin Hwang More articles by this author Jun Hyuk Hong More articles by this author Myung-Soo Choo More articles by this author Tai Young Ahn More articles by this author Choung-Soo Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Clinical outcome (CO) and predictive factors (PRE) evaluation of a cohort of castration resistant prostate cancer (CRPC) patients (pts) treated with abiraterone acetate (AA) in a named patient program (NPP): Preliminary results from a retrospective study.

e16078 Background: AA provided a survival advantage compared to placebo, in pts who had received docetaxel for CRPC. Before the regulatory authority approval, AA was made available in Italy through a NPP supervised by the local ethic committees. The present retrospective study is aimed to assess PRE and CO in an unselected CRPC population which received AA by NPP. Methods: We retrospectively reviewed the clinical records of all pts treated with AA by NPP in our Institutions. For each pt we have recorded the pre and post-AA clinical history, the treatment details and outcomes. We have assessed the ability of a series of selected 22 clinical factors to predict AA response through a logistic regression analysis. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: To date we have collected a consecutive series of 136 pts from 13 Italian hospitals. The median age was 72 yrs (range 52-87). The median baseline PSA was 154 ng/ml (range 0.33-&gt;100.000); 80% and 16.7% of the pts showed bone and measurable lesions respectively. The median duration of AA treatment was 15 wks (range 1-73); 59 treatments are ongoing. Grade 3-4 toxicities were anemia (5 pts), nausea (1 pt), fatigue (4 pts), bone pain (3 pts), and hypokaliemia (1 pt). A PSA reduction &gt; 50% was observed in 37.5% of the pts. Having a performance status (PS) 0-1 [(exp(beta) 4.541; p= 0.018], a previous ormonotherapy lasting &gt;40 months [(exp(beta) 3.299; p= 0.020], baseline hemoglobin &gt;12 g/dl [(exp(beta) 2.595; p= 0.074], no visceral organ involvement [(exp(beta) 1.929; p= 0.097] resulted to be independently predictive of a PSA reduction &gt; 50%. The median PFS and OS were 5 mos and 14 mos, respectively; the 1-year PFS and OS rates were 25.7% and 53%, respectively. Conclusions: Our preliminary results have confirmed the efficacy of AA in second line CRPC outside clinical trials. Pts with good PS, with good hemoglobin levels, with long-lasting hormosensitivity, and without visceral organ involvement have higher probability to achieve a biochemical response to AA.

Reduced-dose docetaxel for castration-resistant prostate cancer has no inferior impact on overall survival in Japanese patients

In clinical practice, an adapted regimen with dose reduction is applied to castration-resistant prostate cancer (CRPC) treated with docetaxel because of its toxicity. However, there are few reports on the impact of dose reduction on survival. Fifty-seven patients with CRPC treated with first-line docetaxel in a single institution from 2005 to 2008 were evaluated retrospectively. The median follow-up period was 20.5 months. Twenty-eight patients (49 %) received a standard 60 mg/m(2) regimen (SR), and 29 patients (51 %) received an adapted regimen (AR) with dose reduction. There was no difference in their baseline characteristics. The prostate-specific antigen response rates were not significantly different between the SR and AR groups (50 vs. 62 %, p = 0.36). Progression-free survival (PFS) and overall survival (OS) were also not significantly different between the groups (PFS 5.3 vs. 7.3 months, p = 0.39; OS 26.4 vs. 27.1 months, p = 0.53, respectively). No significant difference in the incidence of grade 3 or 4 adverse events was noted between the groups (89 vs. 83 %, p = 0.70). In multivariate analysis, hemoglobin and alkaline phosphatase were significant predictive factors for OS (hazard ratios 2.81 and 2.39, p = 0.012 and 0.024, respectively). A reduced-dose regimen of docetaxel has no inferior impact on OS. Further studies on the optimal dose of docetaxel for Japanese patients are required.

Combination of a polyamine-free oral nutritional supplement (ONS) with docetaxel in castrate-resistant prostate cancer (CRPC) patients (pts): A phase II trial.

e15131 Background: Polyamines (PA) are essential for cancer cell growth. Reducing exogenous PA (foods + gut flora) and blocking PA synthesis, reduces tumour growth and potentializes chemotherapy in rodent tumour models. We have developed a PA “free” ONS, which inhibits tumour growth by 40% in pre-clinical models and assessed its tolerance with docetaxel in CRPC pts. Methods: 30 pts, 71 ± 7 years, with metastatic CRPC, median PSA: 95 ng/ml, were assessed for tolerance, quality of life (QOL) (QLQ C-30 questionnaire), W.H.O. performance status (P.S.), pain scores and prostate specific antigen (PSA) response. 90% pts were painful. 75% pts had opiate or morphinic analgesics at day 0 (D0). Median pain score is 5 (0 to 10 scale). The PA free ONS was given as sole diet (6 cans a day) for 14 days then progressively reduced and given with low PA containing foods. Docetaxel administration started on day 21 for 6, 75 mg/m2 injections, every three weeks with prednisone. Nutrialys Medical Nutrition, France, provided the PA free ONS. Results: 27 pts were evaluated for the PA ONS free phase. 18 pts completed the trial at scheduled dates and docetaxel doses. 9 pts did not complete the trial: disease progression (n=4), initial thrombocytemia (n=2), 2 deaths and 1 GI intolerance PA free ONS stage: No specific toxicity. QOL (p=0,04), pain (p=0,03) and anorexia (p=0,01) are improved at day 14. 1 pt had a &gt; 50 % PSA decrease. PA free ONS + docetaxel stage: grade 1 or 2 nausea, vomiting or diarrhoea in &lt; 35 % pts, 12% grade 1 neuropathy, no onycholysis or skin toxicity. Body weight and biological parameters are preserved except for two grade 4 neutropenias. P.S., Q.O.L. and pain scores and anorexia are improved. 55% pts cut their analgesics by ≥ 30% WITH stable or improved pain score. 13 pts (70% pts who completed the trial) had an &gt; 50% PSA decrease with an 8 weeks median response time. Conclusions: A PA free ONS exclusive diet is well tolerated with significant QOL and pain improvements. The docetaxel PA free ONS combination tolerance is excellent with improved P.S., pain score and analgesic reduction. AE during chemotherapy are minimal. PSA responses are observed in a significant proportion of treated patients.

Prolonged treatment with three-weekly docetaxel plus daily prednisolone for metastatic castration-resistant prostate cancer: a multicenter, phase II, open-label, non-comparative, extension study in Japan

There are few reports of long-term treatment with docetaxel in castration-resistant prostate cancer (CRPC) because of the limit of a maximum of ten cycles of treatment in TAX327 showing a survival benefit. Therefore, this study, ARD6563, was conducted to evaluate the safety of more than ten cycles of docetaxel in metastatic CRPC. We enrolled patients who had received ten cycles of docetaxel in the preceding study, ARD6562. For ARD6563, patients received docetaxel every 3weeks, at the last dose (70, 60, or 50mg/m(2)) received for cycle 10 in ARD6562, with prednisolone 5mg orally twice daily. The safety analysis set comprised 15 patients (median age, 64years; performance status, 0 in 87%) out of 43 patients treated in ARD6562. The median initial dose of docetaxel was 60mg/m(2), and the median number of additional cycles administered was 8 (range, 1-42). The relative dose intensity was 78.0% for docetaxel and 98.0% for prednisolone. Dose reduction was needed in 3 cycles because of grade 3 infection, febrile neutropenia, and grade 2 neuropathy. Administration delay was necessitated in 6 cycles because of grade 1-2 nonhematological toxicities. The major grade 3-4 toxicities were myelosuppression. Five patients who had an observed partial response or stable disease in ARD6562 maintained their clinical response in ARD6563. The study treatment was discontinued in 10 patients because of disease progression and in 4 patients for serious toxicities. There were no treatment-related deaths. Long-term docetaxel with prednisolone is feasible in selected Japanese patients with CRPC.

Combination of a polyamine-free oral nutritional supplement (ONS) with docetaxel in castrate-resistant prostate cancer (CRPC) patients (pts): A phase II trial.

67 Background: Polyamines (PA) are essential for cancer cell growth. Reducing exogenous PA (foods + gut flora) and blocking PA synthesis, reduces tumour growth and potentializes chemotherapy in rodent tumour models. We have developed a PA “free” ONS, which inhibits tumour growth by 40% in pre-clinical models and assessed its tolerance with docetaxel in CRPC pts. Methods: 30 pts, 71 ± 7 years, with metastatic CRPC, median PSA: 95 ng/ml, were assessed for tolerance, quality of life (QLQ C-30 questionnaire), W.H.O. performance status (P.S.), pain scores and prostate specific antigen (PSA) response. 90% pts were painful. 75% pts had opiate or morphinic analgesics at day 0 (D0). Median pain score is 5 (0 to 10 scale). The PA free ONS was given as sole diet (6 cans a day) for 14 days then progressively reduced and given with low PA containing foods. Docetaxel administration started on day 21 for 6, 75 mg/m2 injections, every three weeks with prednisone. Nutrialys Medical Nutrition, France, provided the PA free ONS. Results: 27 pts were evaluated for the PA ONS free phase. 18 pts completed the trial at scheduled dates and docetaxel doses. 9 pts did not complete the trial: disease progression (n=4), initial thrombocytemia (n=2), 2 deaths and 1 GI intolerance PA free ONS stage: No specific toxicity was recorded. Quality of life (p=0,03), pain (p=0,03) and anorexia (p=0,01) are improved at day 14. 1 pt had a &gt; 50 % PSA decrease. PA free ONS + docetaxel stage: grade 1 or 2 nausea, vomiting or diarrhoea are observed in less than 35 % pts with no onycholysis or neuropathy. Body weight and biological parameters are preserved except for two grade 4 neutropenias. P.S., pain scores and anorexia are improved. 50% pts reduced their analgesic consumption by 50%. 13 pts (46 % of the whole population, 70% pts who completed the trial) had an &gt; 50% PSA decrease. Conclusions: The PA free ONS is well tolerated during the neo-adjuvant phase with quality of life and pain improvements. The docetaxel PA free ONS combination tolerance is excellent with improved P.S., pain score and analgesic consumption. AE during chemotherapy are minimal. PSA responses are observed in a significant proportion of treated patients.

Docetaxel-Induced Fatal Interstitial Pneumonitis in a Patient with Castration-Resistant Prostate Cancer

A 69-year-old man with castration-resistant prostate cancer (CRPC) received docetaxel and a corticosteroid. After the third cycle of docetaxel administration, he presented with dyspnea, cough, sputum, and fever of 39.2℃. The chest X-ray and chest computed tomography (CT) revealed a diffuse reticulonodular shadow in both lungs, which suggested interstitial pneumonitis. Initially, we used empiric broad-spectrum antibiotics and high-dose corticosteroids. However, his condition progressively became worse and he was transferred to the intensive care unit, intubated, and placed on mechanical ventilation. He died 4 days after hospital admission. Here we report this case of fatal interstitial pneumonitis after treatment with docetaxel for CRPC. We briefly consider docetaxel-induced pneumonitis to make physicians aware of the possibility of pulmonary toxicity so that appropriate treatment can be begun as soon as possible.

C11-Acetate and F-18 FDG PET for Men With Prostate Cancer Bone Metastases

This study tested the feasibility of C11-acetate (acetate) positron emission tomography (PET) imaging to assess response to therapy in men with bone metastatic prostate cancer and compared results for disease detection and response evaluation with F-18 fluorodeoxyglucose (FDG) PET. Men with ≥3 prostate cancer bone metastases identified by Tc-99m methylene diphosphonate (MDP) bone scintigraphy and/or computed tomography were enrolled in a prospective study of serial acetate and FDG PET imaging. Patients were imaged before and 6 to 12 weeks after initial androgen deprivation therapy for new metastatic prostate cancer or first-line chemotherapy with docetaxel for castration-resistant prostate cancer. Qualitative assessment and changes in the tumor:normal uptake ratio were used to assess response by both acetate and FDG PET. In addition, the detection of bone metastases pretherapy was compared for acetate and FDG PET. A total of 8 patients with documented bone metastases were imaged, of which 6 were imaged both pre- and post-therapy. Acetate PET detected bone metastases in all 8 patients, whereas FDG PET detected lesions in 6 of the 7 imaged patients. Acetate PET generally detected more metastases with a higher tumor:normal uptake ratio. Qualitative and quantitative assessments of post-treatment response correlated with composite clinical designations of response, stable disease, or progression in 6 of 6 and 5 of 6 by acetate and 4 of 5 and 3 of 5 by FDG PET, respectively. In this pilot study, results indicate that acetate PET holds promise for response assessment of prostate cancer bone metastases and is complementary to FDG PET in bone metastasis detection.

Correlation of elevated alkaline phosphatase (ALP) and survival in metastatic castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy: Results of SWSW Uro-oncology Group study from three U.K. centers.

206 Background: Treatment with docetaxel in CRPC based on the results of the TAX 327 study has been recommended by NICE guidance in UK. Paucity of UK data on any significant difference in median survival of CRPC patients receiving chemotherapy with normal or elevated ALP is a possible contributory factor to the delayed consideration of chemotherapy in CRPC. We therefore analysed differences in survival in metastatic CRPC patients with normal or elevated ALP treated with docetaxel chemotherapy in 3 cancer centres in UK with a contemporary referral population. Methods: Survival data were collected on consecutive cases of metastatic CRPC treated with at least 1 cycle of docetaxel chemotherapy in these 3 centres. Variables analysed included: presence or absence of pain, PSADT, Gleason score, Haemoglobin, Alkaline phosphatase and number of previous lines of hormone therapy. Results: Median overall survival in 170 eligible patients was 18.1 months (15.3-20.7) with median follow-up of 30.1 months. 84 cases had normal ALP and 86 cases had elevated ALP at time of commencing docetaxel chemotherapy. Median survival was 14.1 months (95% CI= 11.1-17.1) in the elevated ALP group and 22.2 months (95% CI= 17.5- 26.9) in the normal ALP group. The difference between group medians was significant (p&lt;0.001). In multivariate analysis, elevated ALP was a significant prognostic factor for outcome after docetaxel chemotherapy in metastatic CRPC. Conclusions: Regular monitoring of ALP along with PSA monitoring can be a relatively simple way of ensuring that patients with metastatic CRPC are referred for chemotherapy appropriately. To our knowledge this is the first UK data on the impact of ALP level on survival in this group of patients after docetaxel chemotherapy. It is important that decision regarding chemotherapy is based on the parameters of disease progression and regular ALP monitoring may be a relatively simple and practical way of ensuring the right timescales for referral for chemotherapy in metastatic CRPC. [Table: see text]

Phase II study of docetaxel re‐treatment in docetaxel‐pretreated castration‐resistant prostate cancer

To determine the activity and tolerability of docetaxel re-treatment after first-line therapy with docetaxel in castration-resistant prostate cancer (CRPC). Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re-treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as > 50% prostate-specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression-free survival (PFS) and overall survival (OS). Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1-2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months. Docetaxel re-treatment preserves anti-tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

BackgroundThe selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen.MethodsCYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test.ResultsPatients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome.ConclusionsCYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment.

Metronomic epirubicin plus ketoconazole after docetaxel in castration-resistant prostate cancer.

e15146 Background: This single institution study compared epirubicin/ketoconazole/hydrocortisone (ME-K) as second-line chemotherapy after docetaxel in castration-resistant prostate cancer (CRPC). This combination was already in use prior to the advent of taxanes in CRPC (Sella A et al JCO 1994 Apr; 12 (4): 683-8) (Rangel C et al Urology 1992 Jun, 39 (6): 577-82). Methods: Men with CRPC treated at Sint-Maria Regional Hospital with ME-K as second-line chemotherapy after docetaxel, were retrospectively identified. Patients on ME-K received epirubicin 20 mg/m2on day 1, ketoconazole 3 x 200mg daily and hydrocortisone 20+10mg 3 weeks out of 4 (+ zoledronic acid if bone metastases). PSA response and time to PSA progression, as defined in Bubley, JCO 1999; 17: 3461-3467, were used to assess efficacy of chemotherapy. Clinical progression was defined as death or progression of symptoms requiring change of treatment regardless PSA levels. Results: 12 patients were treated with ME-K after docetaxel. Median age at start of second-line chemotherapy was 68y. Decline of PSA level of >50% was observed in 6 men (50%) receiving ME-K after docetaxel Partial response according to RECIST in 2 patients (lymph node, pleural). Besides alopecia, there were no significant side effects. Median time to clinical or PSA progression was 4 months in both groups (8 months in PSA responders and 2 months in non-responders in E-weekly-K group). Median overall survival was 14.5 months in patients treated with second-line E-weekly-K. Patient progression during first-line chemotherapy with docetaxel had a high chance of responding to n E-weekly-K as second-line chemotherapy and also had a subsequent longer TTP than under docetaxel. Conclusions: Metronomic, weekly low dose epirubicin and ketoconazole combination is an active second-line chemotherapy regimens in men with CRPC after docetaxel failure. This effect is most pronounced in patients progressing, whilst under docetaxel. Two patients with visceral metastases had a near complete response. The efficacy and toxicity of ME-K after docetaxel should be evaluated in larger prospective trials. No significant financial relationships to disclose.

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-κB (NF-κB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-κB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (P<0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (P<0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

Oxaliplatin and docetaxel in castration-resistant prostate cancer (CRPC) patients treated with up to two prior chemotherapeutic regimens: Updated results of a phase II trial

5148 Background: Docetaxel has a survival benefit in CRPC. Oral and IV platinum derivatives have activity in CRPC. We hypothesized that a novel combination of docetaxel and oxaliplatin may be beneficial in treating CRPC. Methods: A single arm phase II trial in patients with metastatic CRPC who were treated with docetaxel (60 mg/m2) and oxaliplatin (110 mg/m2) administered intravenously every 21 days for up to 6 cycles. The primary endpoint was response rate defined as a > 50% reduction in PSA levels, sustained for > 4 weeks. Secondary objectives were progression free survival (PFS), overall survival (OS), and toxicity (tolerance/safety). Results: 34 patients were accrued between June 2005 and August 2007. The median age was 66 years (49–84), with 24% over the age of 75. Prior therapies included androgen deprivation (100%); palliative radiation therapy (65%); and chemotherapy (44%), with 38% having received prior docetaxel. 68% of patients received all 6 cycles, with 80% of the maximum dose intensities of docetaxel and oxaliplatin being delivered. Median follow-up time was 15.75 months (range, 1.4–30.6 months). Median PSA at baseline was 370 ng/ml (range 1.5-3,559.4). 32 of the 34 patients were evaluable for response. Response rates are summarized in the table below. Four of 11 (36%) evaluable for response using RECIST had a partial response. Significant grade 3/4 hematologic adverse events (AE) were neutropenia (35%) and thrombocytopenia (6%). Grade 3/4 non-hematologic side effects were nausea (12%), dehydration (12%), diarrhea (9%), edema (6%), mucositis (6%) and infection (3%). Grade 2 or less neuropathy occurred in 71%. Conclusions: The combination of docetaxel and oxaliplatin has promising activity in CRPC. Toxicities were mostly hematologic and easily manageable. Randomized phase III trials with this novel regimen are warranted given the high PSA response rates, long progression free survival and overall survival. Prior chemotherapy Chemo-naïve Overall PSA decline >50% 9 of 14 (64%) (95% CI, 35%, 87%) 13 of 18 (72%) (95% CI, 46%, 90%) 22 of 32 (69%) (95% CI, 52%, 85%) PFS (median) 5.8 mo (95% CI, 3.5–6.4) 7.7 mo (95% CI, 4.9–10.4) 6.3 mo (95% CI, 4.9–7.7) OS (median) 14.9 mo (95% CI, 11.9–22.1) 24.7 mo (95% CI, 18–NA) 20.1 mo (95% CI, 15.1–NA) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis