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In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.

In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is one of the most common cancers among males and the second factor resulting to death due to cancer among them.(1) The median age of its diagnosis is 65 years. The initial treatment includes androgen ablation or orchiectomy.(2, 3) In case of patient’s hormone refractory, chemotherapy would be substituted. The objective of this study is the consideration of intermittent chemotherapy’s role in patients’ survival and their quality of life.Materials & Methods: Since (1384,07,07), 25 patients with Hormone Refractory Prostate Cancer that referred to Taleghani & Imam Reza hospital were enrolled in this study, and Taxotere, Mitoxantrone and Navalbine were prescribed along with Estramustin 140 mg/m2 and Prednisolone 10 mg/BD for 4 days respectively(4, 5, 6) and the quality of life (QoL), toxicity and overall survival were evaluated. The most toxicity included grade 2 and 3 neuropathy and neutropenia that was compliant for patients. The overall survival was 22months.Conclusion: Intermittent chemotherapy in elderly patients with hormone refractory prostate cancer provides compliant toxicity and improvement of QoL and overall survival.

Objectives To determine the risk of failure during drug development in castration-resistant prostate cancer ( CRPC) and to identify factors that could improve outcomes., Methods We investigated CRPC by analysing compounds in phase I to phase III clinical trials between 1998 and April 2011., Drug development failures were classified as medical or commercial and were compared with industry expectations., Compounds were excluded from analysis if their phase I occurred before 1998, if they targeted patients that were did not have hormone-refractory prostate cancer, or if they did not assess outcomes such as overall survival, time to disease progression, or prostate-specific antigen levels., Results Thorough searches of clinicaltrial.gov and other databases yielded 77 compounds that met the inclusion criteria., The cumulative pass rate for first-line compounds in CRPC was 3% and was far below aggregate industry expectations., In total, there were nearly equivalent numbers of commercial and medical failures., Biological products were found to have had greater relative success than small-molecule drugs and biotechnology firms had been slightly more successful than pharmaceutical firms in this disease indication., Phase III failures were high, despite equally high failures during phase II., Conclusions Currently, one in 33 compounds that enters clinical testing will be awarded US Food and Drug Administration approval. This appears to be the highest risk indication investigated to date, based on clinical trial studies alone, with an average cost of $1.411bn to bring a new drug to market when adjusted for risk., Development of radical therapeutics such as immunotherapies may also be warranted instead of classic antineoplastic therapeutics., Given the high clinical trial risk, efforts may have to shift to biomarker and surrogate endpoints to manage future clinical trial risk in prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is one of the most common cancers among males and the second factor resulting to death due to cancer among them.(1) The median age of its diagnosis is 65 years. The initial treatment includes androgen ablation or orchiectomy.(2, 3) In case of patient’s hormone refractory, chemotherapy would be substituted. The objective of this study is the consideration of intermittent chemotherapy’s role in patients’ survival and their quality of life. Materials & Methods: Since (1384,07,07), 25 patients with Hormone Refractory Prostate Cancer that referred to Taleghani & Imam Reza hospital were enrolled in this study, and Taxotere, Mitoxantrone and Navalbine were prescribed along with Estramustin 140 mg/m2 and Prednisolone 10 mg/BD for 4 days respectively(4, 5, 6) and the quality of life (QoL), toxicity and overall survival were evaluated. The most toxicity included grade 2 and 3 neuropathy and neutropenia that was compliant for patients. The overall survival was 22months. Conclusion: Intermittent chemotherapy in elderly patients with hormone refractory prostate cancer provides compliant toxicity and improvement of QoL and overall survival.

Castration-resistant prostate cancer is the second most common cause of cancer death and results in a median survival of less than 2 years. In prostate cancer, fusions between TMPRSS2 and ERG are common. The ERG rearrangement prevalence in local recurrent castration-resistant prostate cancer compared to distant metastatic prostate cancer is unknown. We investigated the frequency of ERG rearrangement in local recurrent castration-resistant prostate cancer compared to distant metastatic prostate cancer, and assessed for associations between androgen receptor ( AR) amplification and ERG rearrangement status. Samples from 134 patients diagnosed with prostate cancer (84 local recurrent castration resistant prostate cancer, 55 distant metastatic prostate cancer) were assessed for their ERG rearrangement and AR amplification status by fluorescence in situ hybridization. Statistical analysis was performed using the χ test. We found that the ERG rearrangement occurs at a significantly lower frequency in distant metastatic prostate cancer (25 %) than in local recurrent castration-resistant prostate cancer (45 %). The AR amplification frequencies were 45 and 35 % in local recurrent castration-resistant prostate cancer and distant metastatic prostate cancer, respectively. The ERG rearrangement occurred at a lower frequency in distant metastatic prostate cancer compared to local recurrent castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Small cell carcinomas of the genitourinary system represent a rare entity, accounting for less than 1% of organ tumors. We aimed to review literature regarding the disease entity, organs involved, associated pathology, and treatment strategies. Medline was reviewed for all publications in English, plus within the Turkish Journal of Urology for published articles both in English and Turkish. The search criteria included "bladder", "prostate", "ureter", "urethra", "testis", "epididymes", and "penis" in combination with "small cell carcinoma" or "neuroendocrinal differentiation". Totally 60 articles were found to be of high impact; studying every organ within the genitourinary system separately. Studies in the literature showed that small cell carcinoma of the genitourinary tract is rare, and mostly associated with other pathologies. Thus, if not considered, it can be easily missed and can adversely affect the prognosis. Platinum based chemotherapy for an average duration of 8 months, together with surgical resection, represents a relative promise for treatment of such pathology. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether circulating tumor cells with tumor-related methylated DNA can be used to predict survival in patients with hormone-refractory prostate cancer. Methods: Blood samples from 76 patients with hormone-refractory prostate cancer were analyzed. Circulating tumor cells were enumerated with the CellSearch System in whole blood. This system was developed using an epithelial cell adhesion molecule antibody-based immunomagnetic capture and automated staining methodology. Hypermethylation at adenomatosis polyposis coli, glutathione-S-transferase-π, prostaglandin-endoperoxide synthase 2, multidrug resistance 1 and Ras association domain family 1 isoform A was analyzed using a sensitive SYBR green methylation-specific polymerase chain reaction. Patient charts were retrospectively examined. Results: Median overall survival time was 19.3 months (range 11–48). Of the 76 patients, 47 (62%) had five or more circulating tumor cells, with a median overall survival of 12.0 months compared with 26.0 months for patients with fewer than five circulating tumor cells ( P < 0.001). Circulating tumor cells were detected in 36 of 39 (92%) patients with tumor-related methylated DNA but only 11 of 37 (30%) patients without methylated DNA ( P < 0.001). Thirty-nine (51%) patients had one or more methylated marker. Their median overall survival time was 12.0 months compared with 48.0 months or more for patients without methylated DNA ( P < 0.001). Prostate-specific antigen-doubling time, circulating tumor cells and methylated DNA were independent predictors of overall survival time. Conclusions: Hormone refractory prostate cancer patients with circulating tumor cells and/or tumor-related methylated DNA show a significantly poorer outcome than those without these blood markers. [ABSTRACT FROM AUTHOR]

Introduction: The percentage of positive prostate biopsy cores (%PBC) has been shown to be a prognostic factor in localized prostate cancer. We hypothesized that it would predict time to hormonal independence and survival in prostate cancer patients treated with androgen deprivation therapy (ADT). Patients and Methods: We used clinical data from 403 men treated with ADT between 1980 and 1999 and focused on a subgroup of 220 patients treated with GnRH analogue. %PBC was defined as the number of positive biopsy cores multiplied by 100 and divided by the total number of biopsy cores. Results: Median %PBC was 83.3% (16.7–100%). Mean follow-up was 57.4 months. Survival at 5 years in men with 83.3% PBC or less was 62.3, 89.1 and 82.6% for recurrence-free, specific and overall survival, respectively, significantly better than that of men with a %PBC of more than 83.3% (32.2, 74.7 and 67.7%, respectively; p < 0.004). Among the factors available in the pretreatment setting, namely age, clinical stage, PSA, Gleason score, bone scan and %PBC, the latter was independently associated with survival in multivariate analysis. Conclusions: %PBC may improve the ability to predict time to hormonal resistance and survival in patients treated with ADT for prostate cancer. This finding warrants further investigation. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hormone-refractory prostate cancer (HRPC) patients are a very heterogeneous group of patients. Management is guided by a number of patient-related factors such as previous treatment, site of disease (prostatespecific antigen only/bone only/visceral or lymph node involvement), pace of disease, performance status, comorbidities and patient choice. Treatment choices include secondary hormonal manipulations, palliative radiotherapy, first- and second-line chemotherapy, clinical trials of new agents, radioisotopes and quality supportive care. [ABSTRACT FROM AUTHOR]

With docetaxel as effective chemotherapy for hormone refractory prostate cancer (HRPC), the number of new treatment combinations for HRPC is expanding demanding a fast-track screening system. This review elaborates on the use of xenograft models to select the most promising combination therapies for entering into phase II clinical trials. [ABSTRACT FROM AUTHOR]

Development of effective agents for treatment of hormone-refractory prostate cancer (HRPC) has become a national medical priority. d-Allose is a monosaccharide (C-3 epimer of glucose) distributed rarely in nature; because of its scarcity and cost, the biological effect has hardly been studied. In the present study, we demonstrated the inhibitory action of d-allose on proliferation of human HRPC cell lines, DU145 and PC-3 in a dose- and time-dependent manner, while human normal prostate epithelial (NPE) cell line, PrEC showed no remarkable effect. In vitro treatment of d-allose resulted in the alteration of Bcl-2/Bax ratio in favor of apoptosis (programmed cell death, PCD) in both the HRPC cell lines, which was associated with the lowering of mitochondrial transmembrane potential (Δψm) and the release of cytochrome C (cyt C), the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), and the elevation of calcium concentration in cytosol ([Ca2+]c). d-Allose also induced G1 phase arrest of the cell cycle in DU145 cell line. This study for the first time suggested the antiproliferative effect of d-allose through induction of PCD in HRPC cell lines, which could be due to the modulation of mitochondria mediated intrinsic apoptotic pathway. [ABSTRACT FROM AUTHOR]

The molecular mechanisms for hormone-resistant prostate cancer progression still remain elusive, mainly due to the limited availability of corresponding tissue. As transurethral resection (TUR) is a common palliative therapy for patients with hormone refractory prostate cancer (HRPC) who have subvesical obstruction, we aimed to demonstrate that TUR samples can be used to identify significantly affected biological pathways during the switch to HRPC using oligonucleotide microarray analysis. Among the most significantly deregulated pathways in HRPC, we observed an induction of oxidative phosphorylation and a repression of cytoskeletal components.Prostate Cancer and Prostatic Diseases (2008) 11, 166–172; doi:10.1038/sj.pcan.4501001; published online 24 July 2007 [ABSTRACT FROM AUTHOR]

Despite advances in the treatment of hormone-refractory prostate cancer (HRPC) with docetaxel chemotherapy as evidenced by the TAX 327 and SWOG 99-16 trials, therapeutic options remain limited in patients with cancer that progresses while they are receiving hormone manipulation and chemotherapy. Targeted therapies against receptor tyrosine kinases of the ErbB family have shown some promise in the treatment of HRPC; however, patient characteristics defining susceptibility to ErbB-targeted therapies remain unknown in HRPC and limits their efficacy in the clinic. Targeted inhibition of downstream pathways, namely mammalian target of rapamycin (mTOR) may prove to be important in the treatment of HRPC because of the prevalence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss, and it has been shown preclinically that mTOR inhibition reverses the phenotype of PTEN loss. Further investigation is necessary for the targeted inhibition of receptor tyrosine kinases and mTOR in HRPC. However, these classes of drugs may prove efficacious as tumoricidal agents or as chemo- and radiosensitizers. [ABSTRACT FROM AUTHOR]

The results of two phase III trials demonstrating a significant prolongation of survival with docetaxel-based chemotherapy has fueled interest in expanding therapeutic development in prostate cancer. This coupled with improved understanding of the mechanisms responsible for prostate cancer development and progression has lead to discovery of several biologic targets that can be exploited using novel therapeutics in what has been referred to as the era of “targeted therapy.” Several of these therapies have shown promise either as single agents or in combination with proven chemotherapeutic agents. This review focuses upon some of the more promising targeted therapies under investigation for the treatment of hormone refractory prostate cancer and highlights some of challenges faced in therapeutic development. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Combining antineoplastic agents is the key to improving the treatment options for men with hormone refractory prostate cancer (HRPC). The current study investigated the combination of docetaxel, vinorelbine, and zoledronic acid as a first-line treatment for HRPC. Methods: Patients were treated repeatedly with docetaxel (25mg/mq) and vinorelbine (10mg/mq) intravenously for three consecutive weeks followed by a 1-wk rest until disease progression or side effects. Zoledronic acid was administered every 4 wk. Changes in prostate-specific antigen (PSA) levels and objective responses were evaluated after two and three cycles, respectively. Toxicity and pain evaluation, based on pain intensity reduction and analgesic drug reduction, were assessed every cycle. Results: Forty men with HRPC (median age: 65 yr) were treated. Among 38 evaluable patients, complete and major PSA responses were observed in seven (18%) and 12 (32%), respectively; a partial objective response was observed in six of 15 (40%) patients with measurable disease. Neutropenia (25%) was the most important grade 3 haematologic toxicity observed. Only three patients (7.5%) reported grade 4 neutropenia. Nineteen patients (47.5%) achieved a reduction of pain intensity and analgesic drug use after two cycles. Median progression-free survival was 7 mo (95% CI: 2–10 mo), with a median overall survival of 17 mo (95% CI: 6–22 mo). Conclusions: The combination of docetaxel, vinorelbine, and zoledronic acid is associated with improvement in biochemical, objective, and pain responses and is well tolerated as a first-line treatment for HRPC. [Copyright &y& Elsevier]

Despite recent progress in the treatment of hormone refractory prostate cancer—with a survival advantage seen with docetaxel chemotherapy—there remains a need for further improvements in this important patient group. Novel targeted agents have promise both as single agents, and in combination with chemotherapy. However, further work is needed to identify therapeutic targets and to develop active agents with a view to introducing them into standard clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Background: Responses to monotherapy corticosteroid or thalidomide have been described in prostate cancer, in chemotherapy naïve subjects. Methods: A total of 39 men with hormone refractory, metastatic prostate cancer who had progression during or after at least 1 conventional cytotoxic drug were treated on a single-arm Phase II trial with dexamethasone, 0.75 mg twice a day plus thalidomide, 100–400 mg/day. Results: Best-observed responses included >50% prostate-specific antigen (PSA) reduction with no radiologic progression: 10 of 39 (26%; 95% confidence interval 13% to 42%). An additional 14 of 39 had decreased PSA but then with radiologic or other progression by 12 weeks. Median progression-free survival was 84 days. Toxicity appeared treatable; there were 5 nonfatal thromboses. There was 1 subject who had complete PSA and radiologic response; 4 responders tolerated treatment without progression for more than 1 year. Conclusions: PSA responses were frequent. Mostly, these were not durable, but some lasted more than a year. Further investigation on determinants of response durability for these or related compounds should be considered. The response rate of the present data does not support Phase III testing of this regimen for this population. [Copyright &y& Elsevier]

We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5–20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Adecatumumab (also known as MT201) is a human recombinant IgG1 monoclonal antibody binding with low affinity to epithelial cell adhesion molecule (EpCAM). To explore safety, pharmacokinetics and pharmacodynamics of adecatumumab, a phase I trial in patients with hormone refractory prostate cancer (HRPC) was performed. Methods: Twenty patients were treated with two adecatumumab infusions on days 0 and 14 in cohorts with doses of ten up to 262mg/m2. Results: Adecatumumab was well tolerated at all doses tested, and no maximum tolerated dose reached. Most adverse events were mild or moderate with pyrexia and nausea being most frequent. The highest dose of adecatumumab induced shortly after infusion robust and transient increases of TNF-alpha serum levels. At all doses, significant transient declines of peripheral natural killer cells were observed shortly after antibody infusions. Adecatumumab had a serum half-life of 15 days, and immune responses to the antibody were not detected. Conclusions: A benign safety profile, long serum half-life and low immunogenicity do warrant further exploration of adecatumumab for treatment of EpCAM-expressing neoplasia. [Copyright &y& Elsevier]

Abstract: Introduction: In its advanced stages, hormone refractory prostate cancer (HRPC) is an incurable condition which consists of a spectrum of disease. This requires an integrated multidisciplinary approach by an uro-oncologic team supported by radiologists, skeletal surgeons and palliative care. Aim of this review was to critically evaluate the current and potential approaches to patients affected by HRPC. Materials and Methods: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1981 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. Results: Most men with hormone refractory prostate cancer will die of their disease in the absence of intercurrent illness, and the various conditions arising as a consequence of local and distal cancer progression commonly lead to a spectrum of morbidity requiring treatment. Recent data regarding docetaxel-based chemotherapy have shown small but significant improvements in survival and improvement in quality of life in men receiving treatment. However, this therapy may not be suitable for all patients. New agents used alone or in combination with docetaxel currently are under trial in an attempt to provide much needed improvements in outcome. Bone-targeted treatments, particularly late-generation bisphosphonates, have added to the range of options, reducing the incidence of skeletal complications in some men. Further work is needed to target their use more effectively, to explore their efficacy in combination with existing proven therapies and to develop new approaches to treat bone metastases. Complications arising as a consequence of upper and lower tract dysfunction, haematologic, neurologic and psychologic disorders are common. These complications often are amenable to effective treatment, but interventions may engender difficult clinical and ethical decisions. Conclusions: Although HRPC is incurable, it is not untreatable, and that the clinical management embraces not just chemotherapy, but many interventional and supportive therapies. A holistic and supportive approach to patient care is vital for optimal management, and is best provided by a coordinated, multidisciplinary team including urologists and oncologists. [Copyright &y& Elsevier]

Sipuleucel-T (Provenge; APC8015; Dendreon Corp, WA, USA) is a novel immunotherapeutic cellular product, which includes autologous dendritic cells pulsed ex vivo with a recombinant fusion protein (PA2024) consisting of granulocyte macrophage colony-stimulating factor and prostatic acid phosphatase. Two Phase II trials in men with androgen-dependent biochemically relapsed prostate cancer have demonstrated a decrease in prostate-specific antigen and prolongation in prostate-specific antigen doubling time. In men with hormone-refractory prostate cancer, clinical trials have demonstrated both biological activity and clinical response to sipuleucel-T. Data from two Phase III trials in men with asymptomatic, metastatic hormone-refractory prostate cancer demonstrated an improved median overall survival in men who received sipuleucel-T compared with placebo. Clinical trials are ongoing or are being developed to evaluate sipuleucel-T in various prostate cancer disease states and in combination with other treatment modalities. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis inhibition with bevacizumab and other agents of this class are showing significant activity in a variety of cancers. In prostate cancer, the single agent activity has been low, but the addition of these agents to chemotherapy may be the area in which they provide their greatest clinical benefit. An ongoing study conducted by the Cancer and Leukemia Group B will test this approach in men with metastatic hormone refractory prostate cancer. Future studies may test the efficacy of anti-angiogenic strategies in earlier stage disease as well as in combination with other approaches. This review will highlight the clinical experience to date with angiogenesis inhibitors in prostate cancer and the ongoing studies. [Copyright &y& Elsevier]

Summary: Effective therapeutic options have not existed for prostate cancer progressing after androgen deprivation therapy until very recently. Secondary hormonal manipulations offer marginal benefits. Docetaxel based chemotherapy has been demonstrated to extend survival and change the natural history of the disease in two large randomized trials. These studies have provided the impetus to combine docetaxel with novel biologic agents to further consolidate the gains in long-term outcome. With the arrival of exciting agents including vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, anti-angiogenic drugs and small molecule receptor tyrosine kinase inhibitors, the future treatment of prostate cancer appears promising. [Copyright &y& Elsevier]

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Objective: To compare the efficacy of diethylstilboestrol (DES) with bicalutamide in the treatment of hormone refractory prostate cancer in relation to its effect on prostate-specific antigen (PSA) and survival. Methods: Patients on LHRH analogues for prostate carcinoma with evidence of biochemical or clinical progression were randomized into one of the treatment arms (n = 58). The first group (group A, n = 26) received 1 mg of DES with 75 mg of aspirin per day in addition to the primary hormonal treatment. The second group (group B, n = 32) received bicalutamide at a dose of 50 mg/day in addition to the primary treatment. Patients were followed up every 3 months with their PSA being checked and were also monitored for any clinical progression and adverse effects as a result of treatment. Any adverse event occurring after patients were started on treatment was attributed to the drug and patients were clinically assessed at each visit. Failure of treatment was defined as a 50% or greater increase in PSA after commencing treatment. Once randomized, all patients were followed up for survival regardless of failure of second-line hormonal manipulation. Results: The mean age of the patients was 76.7 years (60–88, SD 7.4) in group A and 76 years (67–86, SD 6.9) in group B. Twelve patients in each group had metastatic disease. The median follow-up periods for both groups were 24 months (range 6–48 in group A, range 3–54 in group B). 65% of the patients in group A (17/26) and 43.5% (14/32) in group B had a fall in their PSA levels (p = 0.08, Fisher’s exact test) with 23% (6/26) and 31% (10/32) having a >50% response respectively (p = 0.34, Fisher’s exact test). Mean PSA nadir in those who responded were 20.6 ng/ml (range 1.6–59.4) and 7.41 ng/ml (range 0.1–42.6) in groups A and B respectively. The median duration of response was 9 months (3–18 months) for group A and 12 months (3–18 months) for group B. Seven patients in group A and 6 in group B experienced adverse events. Three of the 7 in the group A experienced cardiovascular related adverse effects (1 congestive cardiac failure, 1 pulmonary embolism and 1 stroke). At the end of the study period, 14 (54%) of group A patients were alive and 12 (46%) were dead. In group B, 15 (47%) were alive, 16 (50%) were dead and 1 (3%) lost to follow-up. At the completion of the study, 3 patients in each group were still on treatment. Conclusion: Low-dose DES and 50 mg of bicalutamide per day are equally effective in hormone refractory prostate carcinoma with respect to biochemical response, although DES has more severe adverse effects. This is a small sample and larger multicentre trials are needed to give us a definite conclusion. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m2 on day 1 and vinorelbine 15 mg/m2 on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2-6 and 9-13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by > 50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: The anti-cancer agent docetaxel is approved for the treatment of patients with locally advanced or metastatic breast cancer, non-small cell lung cancer (NSCLC) and for the treatment of androgen-independent prostate cancer. At the recommended dose of 60–100mg/m2 given every 3 weeks, severe neutropenia is the dose-limiting toxicity and a major concern especially when treating patients at high-risk from myelotoxic complications. A less toxic schedule, involving weekly docetaxel administration was developed for patients with poor performance status, multiple comorbidities, poor haematological reserves or those who were heavily pre-treated, elderly or patients for whom palliation is the focus of treatment. Recent randomised trials allow a comparison of efficacy and toxicity between weekly and 3-weekly treatments. Efficacy appears to be similar for the two schedules regardless of the disease while weekly docetaxel is significantly less myelotoxic. However, this benefit comes at the cost of cumulative increases in hyperlacrimation, skin- and nail-toxicity and negatively affects quality of life. Currently, 3-weekly docetaxel remains the standard schedule for treatment, whereas the weekly schedule offers a possibility of treatment individualisation for those patients where the risk of myelosuppression is considered unacceptable. [Copyright &y& Elsevier]

Abstract: The detection of prostate-specific antigen (PSA) mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in the bloodstream of prostate cancer patients has been hypothesized as a prognostic marker, however little data are available concerning the association between this molecular marker and other laboratory values of potential importance. In this study, in patients with hormone-refractory prostate cancer (HRPC), relationships were determined between PSA RT-PCR positivity, survival, and various relevant markers including serum PSA, LDH, albumin, alkaline phosphatase and hemoglobin. A total of 19/30 HRPC patients were positive for PSA by RT-PCR. Positivity was significantly linked to serum PSA (P = 0.004) and serum alkaline phosphatase (P = 0.026) but not to the other laboratory variables. Median survival time for RT-PCR-positive patients was 9 months, compared to 19 months for RT-PCR-negative patients (P = 0.035). Median survival time for patients with a hemoglobin ≥11 g/dL was 12 months, compared to 9 months for patients with &#60;11 g/dL (P = 0.005). Dichotomized (≥ or &#60; median) serum PSA, LDH, alkaline phosphatase, and albumin were not significantly associated with survival in univariate analyses. In multivariate analysis, only dichotomized hemoglobin (&#60;11g/dL vs. ≥11g/dL) remained statistically significant (P = 0.019), indicating that RT-PCR had no independent association with survival after controlling for hemoglobin status in this study. [Copyright &y& Elsevier]

Patients with metastatic hormone refractory prostate cancer (HRPC) have limited treatment options and new therapies are needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets including Bcl-2, an important pro-survival regulator of apoptotic cell death. Bcl-2 is overexpressed in a variety of human malignancies including prostate cancer where it has also been associated with androgen independent progression and treatment resistance. Oblimersen is a phosphorothioate antisense oligonucleotide complimentary to the Bcl-2 mRNA and a potent inhibitor of Bcl-2 expression which in pre-clinical testing can significantly enhance the therapeutic effect of chemotherapy, hormone and radiation therapy. Clinical trials evaluating oblimersen in combination with chemotherapy in a variety of cancers have shown good tolerability and promising response rates. Randomized trials are required to determine if oblimersen can enhance the effectiveness of docetaxel in patients with HRPC. [ABSTRACT FROM AUTHOR]