Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Metástasis cutáneas de adenocarcinoma de próstata / Cutaneous Metastases From Adenocarcinoma of the Prostate

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Intermittent, low-dose, antiandrogen monotherapy as an alternative therapeutic option for patients with positive surgical margins after radical prostatectomy.

The aim of the present study was to determine whether oncologic outcomes and adverse events associated with active on/off intermittent antiandrogen monotherapy (daily bicalutamide, 50 mg per day) are comparable with those of standard external beam radiation therapy (EBRT) or combined androgen blockade (CAB) therapy in prostate cancers with positive surgical margins after radical prostatectomy. Two hundred twenty-three patients with positive surgical margins post-radical prostatectomy who underwent active surveillance (AS, n = 32), EBRT without hormone therapy (n = 55), intermittent antiandrogen monotherapy without EBRT (IAAM, n = 50), or CAB without EBRT (n = 86), between 2007 and 2014, were reviewed retrospectively. Pathologic outcomes, biochemical recurrence rates, radiological disease progression, and adverse events were collected from medical records. Biochemical recurrence rates, biochemical recurrence-free survival rates, and radiological recurrence were not different between the groups (P = 0.225, 0.896, and 0.284, respectively). Adverse event rates and severities were lower for IAAM compared with EBRT or CAB (both P < 0.05), but were comparable to those for AS (P = 0.591 and 0.990, respectively). Grade ≥3 adverse events were not reported in the IAAM or AS groups. Erectile dysfunction and loss of libido rates were lower in the IAAM group compared with the EBRT and CAB groups (P = 0.032). Gastrointestinal complications were more frequently reported in the EBRT group (P = 0.008). Active on/off IAAM treatment might be an appropriate treatment option for patients with positive surgical margins after radical prostatectomy. Furthermore, regarding oncologic outcomes, IAAM was comparable to standard EBRT but had a milder adverse event profile.

[Clinical efficacy of integrated traditional Chinese and Western medicine for castration-resistant prostate cancer].

OBJECTIVE: To investigate the clinical effects of integrated traditional Chinese and Western medicine in the treatment of castration-resistant prostate cancer (CRPC). METHODS: A total of 54 CRPC patients were randomly divided into a control and a trial group, all treated by endocrine therapy (oral Bicalutamide at 50 mg per d plus subcutaneous injection of Goserelin at 3.6 mg once every 4 wk) and chemotherapy (intravenous injection of Docetaxel at 75 mg/m2 once every 3 wk plus oral Prednisone at 5 mg bid), while the latter group by Fuyang Huayu Prescription (a Traditional Chinese Medicine ï¼»TCMï¼½ prescription for tonifying yang and dispersing blood stasis) in addition, for a course of 24 weeks. Comparisons were made between the two groups of patients in the level of serum prostate-specific antigen (PSA), Karnofsky physical condition scores, function assessment of cancer therapy-prostate (FACT-P) scores, and TCM symptoms scores before and after 12 or 24 weeks of treatment. RESULTS: Compared with the baseline, the serum PSA level was significantly decreased after 12 weeks of treatment both in the control (ï¼»25.9 ± 39.3ï¼½ vs ï¼»20.0 ± 21.1ï¼½ µg/L, P <0.05) and in the trial group (ï¼»22.1 ± 33.9ï¼½ vs ï¼»17.9 ± 19.1ï¼½ µg/L, P <0.05), with no statistically significant differences between the two groups (P >0.05). At 24 weeks, however, the PSA levels in the control and trial groups were slightly increased to (23.1 ± 28.4) and (19.6 ± 23.5) µg/L, respectively, with no statistically significant differences in between (P >0.05). Karnofsky, FACT-P and TCM symptoms scores were all markedly improved in the trial group after 12 weeks of treatment (P <0.05) and remained stable at 24 weeks, but not in the control group either at 12 or at 24 weeks (P >0.05). CONCLUSIONS: TCM Fuyang Huayu Prescription combined with endocrine therapy and chemotherapy is effective for CRPC.

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial.

BACKGROUND: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING: Spanish National Health Investigation Fund, AstraZeneca.

Clinical research of Tashinone IIA combined with endocrine therapy in treating advanced-stage prostate cancer.

To observe the clinical effect of tashinone IIA combined with endocrine therapy in treating advanced-stage prostate cancer. 96 cases of advanced-stage prostate cancer were divided into observation group (44 cases received treatment) and control group (46 cases received treatment). Control group was given leuprolide acetate 3.75 mg hypodermic injection per month, combined with bicalutamide 50 mg per os per day for a 6-month treatment course. Observation group was given tashinone IIA injection 60 mg intravenously per day. They were treated for 2 weeks and paused for 2 weeks as one treatment course for six courses in total. After treating for 6 months, the general therapeutic effect, prostate-specific antigen (PSA), free prostate-specific antigen (f-PSA), hemoglobin (Hb), the quality of life questionnaire Core 30 (QLQ-C30), traditional Chinese medicine symptom information score, international prostate symptom score (I-PSS), and adverse effect rate were observed. The effective rate of observation group and control group was 52.3 and 28.3 %, respectively (P < 0.05). PSA, f-PSA, and Hb in two groups had no statistical difference before treatment. PSA and f-PSA in both groups obviously decreased compared to those before treatment, and they were lower in observation group than in control group (P < 0.01). Hb in observation group was higher than before treatment, whereas Hb in control group was lower than before treatment (P < 0.01). Life quality, motive score, the traditional Chinese medicine symptom score, and I-PSS in observation group were significantly better those that in control group after treatment (P < 0.01). Laboratory tests such as hemogram, and liver and kidney function had no obvious change, and adverse effect rate had no statistical difference. Routine endocrine treatment combined with tashinone IIA can enhance the clinical effects on treating advanced-stage prostate cancer and improve the clinical symptom score.

Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft.

BACKGROUND: The mechanisms underlying antiandrogen withdrawal syndrome (AWS) and alternative antiandrogen therapy (AAT) effectiveness were assumed to be mutations in the androgen receptor (AR), which resulted in an altered response to antiandrogens. The aim of the present study was to test this assumption using the novel prostate cancer xenograft model KUCaP-1 harboring the W741C mutant AR (Yoshida et al., Cancer Res 2005; 65(21): 9611-9616). METHODS: Mice bearing xenograft tumors were castrated, and the long-term sequential changes in tumor volume were observed. To determine whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn. The effect of flutamide (FLT) on the W741C mutant AR was examined with transactivation assays in vitro and with the oral administration of FLT to non-castrated mice harboring KUCaP-1 in vivo. The AAT efficacy against KUCaP-1 was evaluated by changing BCL with FLT. RESULTS: KUCaP-1 regressed significantly after castration and did not re-grow. KUCaP-1 treated with BCL continued to grow even after castration and started regressing 2 months after BCL withdrawal, replicating clinically recognized AWS. The antagonistic effect of FLT against the W741C mutant AR was revealed in vitro and in vivo. AAT with FLT suppressed tumor growth after BCL withdrawal. CONCLUSIONS: KUCaP-1 was an entirely androgen-dependent xenograft and mimicked the clinical phenomena of AWS and AAT caused by the agonistic and antagonistic activity of BCL and FLT, respectively. KUCaP-1 could be an in vivo model for screening novel antiandrogens for the treatment of BCL resistant prostate cancer harboring the W741C mutation in the AR.

Inhibition of androgen receptor transcriptional activity as a novel mechanism of action of arsenic.

Environmental sodium arsenite is a toxin that is associated with male infertility due to decreased and abnormal sperm production. Arsenic trioxide (ATO), another inorganic trivalent semimetal, is an effective therapy for acute promyelocytic leukemia, and there is investigation of its possible efficacy in prostate cancer. However, the mechanism of arsenic action in male urogenital tract tissues is not clear. Because the androgen receptor (AR) plays an important role in spermatogenesis and prostate cancer, we explored the possibility that trivalent arsenic regulates AR function. We found that arsenic inhibited AR transcriptional activity in prostate cancer and Sertoli cells using reporter gene assays testing several androgen response element-containing regions and by assessing native target gene expression. Arsenic inhibition of AR activity was not due to down-regulation of AR protein levels, decreased hormone binding to AR, disruption of AR nuclear translocation, or interference with AR-DNA binding in vitro. However, chromatin immunoprecipitation studies revealed that arsenic inhibited AR recruitment to an AR target gene enhancer in vivo. Consistent with a deficiency in AR-chromatin binding, arsenic disrupted AR amino and carboxyl termini interaction. Furthermore, ATO caused a significant decrease in prostate cancer cell proliferation that was more pronounced in cells expressing AR compared with cells depleted of AR. In addition, inhibition of AR activity by ATO and by the AR antagonist, bicalutamide, was additive. Thus, arsenic-induced male infertility may be due to inhibition of AR activity. Further, because AR is an important target in prostate cancer therapy, arsenic may serve as an effective therapeutic option.

Dramatic prostate-specific antigen response with activated hemicellulose compound in metastatic castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an incurable disease with limited treatment options. Herbal supplements are unconventional treatments for a variety of diseases. Active hemicellulose compound (AHCC) is a Japanese supplement discovered by hybridizing several mushrooms used in traditional healing for the purpose of maintaining 'super immunity'. We report on a 66-year-old gentleman with CRPC with an excellent serologic response to AHCC. This case hypothesizes that AHCC may have potential activity against CRPC.

Does small-cell phenotype predict the natural history of prostate cancer? A case study in disease behavior.

BACKGROUND: A 52-year-old man presented to his urologist with hematuria and symptoms of frequency and incomplete voiding. The patient received antibiotics without symptom resolution. His prostate-specific antigen (PSA) level was 6.6 ng/ml and digital rectal examination revealed a normal-sized firm prostate gland. Biopsy obtained by transurethral resection revealed poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. Pure small-cell cancer or poorly differentiated prostate cancer may secrete little or no PSA. One should be alerted to this phenotype in a patient with large volume disease on biopsy or examination and a low PSA or PSA not in proportion to tumor burden. INVESTIGATIONS: Digital rectal examination, laboratory tests, cystoscopy, prostatic chips obtained from transurethral resection, prostate biopsy, bone scan, CT scan of the chest, abdomen and pelvis. DIAGNOSIS: Poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. MANAGEMENT: Transurethral resection, androgen blockade with a gonadotropin-releasing hormone analog and antiandrogen flutamide, oral bicalutamide, docetaxel and oral estramustine. Total pelvic exenteration with ileal conduit urinary diversion and permanent end-colostomy formation, percutaneous nephrostomy placement, cisplatin combined with etoposide.

Inhaled ICI 204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma.

Three inhalation formulations of ICI 204,219 were compared for antagonism of antigen-induced bronchoconstriction in 16 subjects with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each subject received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204,219 until the forced expiratory volume in 1 s (FEV1) decreased by 20 percent or the maximum allergen concentration (100 micrograms/ml) was reached. The majority of subjects tolerated 100 micrograms/ml of allergen without a 20 percent decrease in FEV1. Inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.