leuprolide and Prostatic-Neoplasms--Castration-Resistant

A growing number of treatment options exist to treat metastatic castrate-resistant prostate cancer (mCRPC), and with these newer options, many questions about optimising treatment remain unanswered. One recommendation that may potentially be overlooked by practitioners is that androgen deprivation therapy (ADT) should be maintained when CRPC develops and when treatment with any of the newer agents is initiated.. However, to emphasise this recommendation, it is valuable to interrogate the evidence for maintaining ADT in different clinical situations.. This statement, reflecting the views of the authors, provides a discussion of this evidence and the rationale behind the recommendation that ADT should be continued in CRPC.

Topics: Androstenes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Taxoids; Tissue Extracts

Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.. Men with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.. Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%; P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.. During the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.

Topics: Aged; Aged, 80 and over; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Testosterone; Time Factors; Treatment Outcome

When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and

Topics: Humans; Leuprolide; Liquid Crystals; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Aged; Androgen Receptor Antagonists; Humans; Leuprolide; Male; Prostatic Neoplasms, Castration-Resistant; Pyrazoles

Cancer is a well-recognized cause of fever, which is related to cytokines produced by malignant cells. Prostate cancer presenting with fever and other inflammatory markers as a paraneoplastic syndrome rarely occurs.. We describe the case of high fever and lower-urinary tract symptoms that progressed 1 month prior to presentation. A 78-year-old man had been diagnosed with prostate cancer 8 months ago. He received androgen deprivation therapy with leuprolide acetate 22.5 mg for every 3 months. Castration-resistant prostate cancer was diagnosed due to elevated prostate specific antigen (1639 ng/mL) and cancer fever.. The patient received docetaxel-based systemic chemotherapy 50 mg/mm2 biweekly. Naproxen 500 mg was administered twice a day.. After one cycle of systemic chemotherapy, the patient had no major side effects, no more fever was observed, and the systemic condition improved.. Differentiating cancer-related fever from infection-related fever is important for appropriate patient management. In this case, fever appeared as the first symptom of castration-resistant prostate cancer and was managed by naproxen and resolved with systemic chemotherapy.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Leuprolide; Male; Naproxen; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

Topics: Adenocarcinoma; Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Gonadotropin-Releasing Hormone; Goserelin; Humans; Kallikreins; Leuprolide; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Testosterone; Tosyl Compounds

Topics: Alternative Splicing; Androgens; Animals; Cell Count; Cell Line, Tumor; Cell Survival; Gonadotropin-Releasing Hormone; Leuprolide; Male; Mice, SCID; Oligopeptides; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Receptors, LHRH; Xenograft Model Antitumor Assays

ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors.. AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model.. We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression.. ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672-82. ©2016 AACR.

Topics: Androgens; Androstenes; Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Leuprolide; Male; Mice; Mice, SCID; Phosphatidylinositol 3-Kinases; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptor, ErbB-2; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays

To report the outcome and course of disease in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel followed by abiraterone acetate in a single center.. In this retrospective observational study, we reviewed the course of disease of all applicable patients with mCRPC treated with docetaxel followed by abiraterone at our center. We analyzed progression-free survival (PFS) of docetaxel and abiraterone treatments. We further searched for predictive factors for the duration of treatment response.. Median PFS between initiation of androgen deprivation therapy and the diagnosis of mCRPC was 32 months. Median PFS on docetaxel treatment was 9 months. Median PFS on abiraterone treatment was 11 months. Patients with higher Gleason scores (GS) (8-10) at initial diagnosis had a significantly longer median PFS on docetaxel as compared to patients with GS 6-7, p = 0.01. We demonstrate a significant correlation between the PFS on docetaxel and PFS on abiraterone in the post-docetaxel setting (Kendall tau r = 0.32, p = 0.019) as well as a significant negative correlation between the PSA nadir under abiraterone treatment and the time to progression under abiraterone (Kendall tau r = -0.43, p = 0.007).. High Gleason score appears to be predictive of duration of response to docetaxel. Interestingly, progression-free survival with abiraterone appears to be correlated with the duration of response with docetaxel, whereas PSA decline and low nadir appear to be predictive of response to abiraterone.

Topics: Aged; Androgen Antagonists; Androstenes; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Buserelin; Cohort Studies; Disease-Free Survival; Docetaxel; Flutamide; Humans; Leuprolide; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Tosyl Compounds; Treatment Outcome; Triptorelin Pamoate

The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.. AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.. The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.. These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; DNA Helicases; DNA-Binding Proteins; Drug Resistance, Neoplasm; Dutasteride; Humans; Ketoconazole; Leuprolide; Male; Middle Aged; Mutation; Progesterone; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Receptors, Androgen; Steroid 17-alpha-Hydroxylase