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- Bench-to-bedside development of agonists and antagonists of luteinizing hormone-releasing hormone for treatment of advanced prostate cancer. [REVIEW]
- Urol Oncol 2014 Dec 12.
Androgen deprivation therapy (ADT) has been the standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for 3 decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.The application of agonists of LHRH has improved and modernized the treatment of advanced PCa; millions of patients have benefited from therapy with LHRH agonists as a preferred alternative to surgical castration, as the psychological effects and perpetuity of orchiectomy are undesirable for most men. Despite their efficacy, agonists of LHRH have several shortcomings, including initial surge in testosterone, producing exacerbation of clinical symptoms, and microsurges in testosterone that might occur after each administration. A new, alternate approach to ADT is emerging with the improvements in antagonists of LHRH. This class of LHRH analogues produces a direct and immediate blockade of pituitary LHRH receptors and leads to a more rapid suppression of testosterone without an initial surge or subsequent microsurges. Degarelix, a third-generation LHRH antagonist, is the only antagonist with a low histamine-releasing activity that is currently on the market for clinical use in advanced PCa with improved testosterone suppression, better control of follicle-stimulating hormone and prostate-specific antigen, and which offers a prolonged delay to progression and more favorable effects on serum alkaline phosphatase.Although LHRH agonists are still the mainstay for treatment of advanced PCa, antagonists of LHRH offer an alternative as a pharmacological approach.
- The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. [JOURNAL ARTICLE]
- Oncogene 2014 Dec 15.
Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain-containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long-term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1α in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC.Oncogene advance online publication, 15 December 2014; doi:10.1038/onc.2014.401.
- Testosterone Replacement Therapy in Men with Prostate Cancer: A Time-Varying Analysis. [JOURNAL ARTICLE]
- J Sex Med 2014 Dec 11.
The use of testosterone replacement therapy (TRT) in men with prostate cancer is controversial given concerns of androgen-related cancer progression. Although emerging evidence suggests that TRT may be safe in this setting, no study has investigated dose-related effects.We used time-varying analysis to determine whether increasing TRT exposure is associated with worse outcomes.Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1991 to 2007. Subjects treated with TRT were stratified by duration of treatment. Weighted propensity score methods were used to adjust for differences between groups. A Cox proportional hazards model was constructed to assess the effect of injectable TRT exposure on outcomes.Overall mortality (OM), prostate cancer-specific mortality (PCSM), and use of salvage androgen deprivation therapy (ADT).Men treated with TRT, regardless of duration, did not experience higher OM or PCSM (all hazard ratio [HR] < 1.0, all P ≤ 0.002). We found no difference in use of salvage ADT in the ≤30-day and 31-60 day groups compared with no-TRT (HR 1.23 and 1.05, P = 0.06 and 0.81, respectively), whereas it was lower for men on long-term TRT (HR 0.70, P = 0.04).TRT following prostate cancer diagnosis and treatment does not increase mortality or the use of salvage ADT. Using time-varying analysis, we demonstrate that longer duration of TRT is not associated with adverse mortality or greater need for ADT. Kaplan AL, Lenis AT, Shah A, Rajfer J, and Hu JC. Testosterone replacement therapy in men with prostate cancer: A time-varying analysis. J Sex Med **;**:**-**.
- The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer. [JOURNAL ARTICLE]
- Pract Radiat Oncol 2014 Dec 6.
Sexual function is an important concern in men receiving intensity modulated radiation therapy (IMRT) for prostate cancer. Our aim was to study the impact of IMRT and androgen deprivation therapy (ADT) on sexual function over time and to report the effectiveness of sexual medications or aids.A total of 179 men, median age 69, received definitive IMRT for prostate cancer and completed 2 surveys (Expanded Prostate Cancer Index Composite-26 and a sexual medicines/devices survey) for at least 2 time points. Surveys were prospectively collected at baseline (before all therapy), and 2, 6, 12, 18, and 24 months after IMRT. Median dose was 76 Gy to the prostate. ADT was administered to 59% of patients (median duration 5 months, initiated 2 months before IMRT). Global scores were generated for the Expanded Prostate Cancer Index Composite-26 questions. Longitudinal analysis was performed by constructing a generalized estimation equations model, and clinical variables were tested for association with global scores.Overall, there was a significant decline in global sexual score through 2 years. Men receiving ADT had a lower sexual score at 2 and 6 months, but this difference disappeared at 24 months. Analysis of individual sexual symptoms showed no significant difference at 24 months except that men on ADT were less likely to be sexually active (P = .02); this difference was not observed for men receiving short-term ADT only. Longitudinal analysis revealed that duration of ADT was the only factor associated with global sexual score. Phosphodiesterase inhibitors were attempted by roughly half of all men, with 66% experiencing benefit, whereas other aids were attempted by roughly 5% of men.Although ADT adversely affected short-term sexual function, there was no significant difference in global score and most sexual symptoms by 24 months. These data are useful for anticipatory guidance regarding expectations after IMRT.
- A Comprehensive Review of Contemporary Role of Local Treatment of the Primary Tumor and/or the Metastases in Metastatic Prostate Cancer. [REVIEW]
- Biomed Res Int 2014.:501213.
To provide an overview of the currently available literature regarding local control of primary tumor and oligometastases in metastatic prostate cancer and salvage lymph node dissection of clinical lymph node relapse after curative treatment of prostate cancer. Evidence Acquisition. A systematic literature search was conducted in 2014 to identify abstracts, original articles, review articles, research articles, and editorials relevant to the local control in metastatic prostate cancer. Evidence Synthesis. Local control of primary tumor in metastatic prostate cancer remains experimental with low level of evidence. The concept is supported by a growing body of genetic and molecular research as well as analogy with other cancers. There is only one retrospective observational population based study showing prolonged survival. To eradicate oligometastases, several options exist with excellent local control rates. Stereotactic body radiotherapy is safe, well tolerated, and efficacious treatment for lymph node and bone lesions. Both biochemical and clinical progression are slowed down with a median time to initiate ADT of 2 years. Salvage lymph node dissection is feasible in patients with clinical lymph node relapse after local curable treatment. Conclusion. Despite encouraging oncologic midterm results, a complete cure remains elusive in metastatic prostate cancer patients. Further advances in imaging are crucial in order to rapidly evolve beyond the proof of concept.
- Effect of dutasteride in men receiving intermittent androgen ablation therapy: The AVIAS trial. [JOURNAL ARTICLE]
- Can Urol Assoc J 2014 11; 8(11-12):E789-E794.
We studied the effect of dutasteride on the length of the off-treatment period in prostate cancer patients on intermittent androgen deprivation (IAD) therapy.We conducted a randomized, placebo-controlled Phase II trial in men with localized prostate cancer and a rising prostate-specific antigen (PSA) level post-primary treatment. Patients were randomized to dutasteride (0.5 mg/day) or placebo. All patients received androgen deprivation therapy (ADT), which was stopped at month 9 if the PSA level was <1.0 ng/mL. ADT was resumed when PSA increased to ≥5.0 ng/mL. End points included time off treatment, PSA nadir after 9 months of ADT, serum testosterone and dihydrotestosterone levels, and time to castrate-resistant prostate cancer (rising PSA while testosterone levels remain <50 ng/mL).There were 87 evaluable patients: 49 dutasteride, 38 placebo. In total, 80 patients completed one treatment cycle: 45 dutasteride, 35 placebo. The median time off treatment for patients reaching ≥5 ng/mL was 18.6 and 16.7 months for dutasteride and placebo, respectively (p = 0.7600). The median PSA nadir at 9 months was 0.1 and 0.075 ng/mL, respectively (p = 0.4486). There were no cases of androgen-independent prostate cancer. Our study limitations include its short duration with only one treatment cycle evaluated.This small-scale Phase II randomized controlled trial showed no benefit to the addition of dutasteride to an IAD regimen.
- Quantifying Observational Evidence for Risk of Fatal and Nonfatal Cardiovascular Disease Following Androgen Deprivation Therapy for Prostate Cancer: A Meta-analysis. [REVIEW]
- Eur Urol 2014 Dec 4.
Whether androgen deprivation therapy (ADT) for men with prostate cancer (PCa) increases the risk of cardiovascular disease (CVD) remains controversial. Pooled analyses using data from randomised controlled trials suggest no increased risk of fatal CVD following ADT, but no pooled analyses exist for observational studies.To perform a meta-analysis using observational data on ADT and risk of CVD events in men with PCa.PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on associations between types of ADT and nonfatal and fatal CVD outcomes using information from observational studies. Random effects meta-analyses were conducted to estimate relative risks (RRs) and 95% confidence intervals (CIs).A total of eight observational studies were identified studying at least one type of ADT and a nonfatal or fatal CVD outcome. The RR for risk of any type of nonfatal CVD was 1.38 (95% CI, 1.29-1.48) for men with PCa on gonadotropin-releasing hormone (GnRH) agonists, compared with men not treated with ADT. When analysing nonfatal ischemic heart disease only, the RR was 1.39 (95% CI, 1.26-1.54). The associations between GnRH agonists and nonfatal or fatal myocardial infarction or stroke were even stronger: RR: 1.57 (95% CI, 1.26-1.94) and RR: 1.51 (95% CI, 1.24-1.84), respectively. The results for other types of ADT in relation to the risk of any nonfatal CVD were RR: 1.44 (95% CI, 1.28-1.62) for orchiectomy and RR: 1.21 (95% CI, 1.07-1.367) for antiandrogens.Observational data show a consistent positive association between ADT and the risk of CVD. This finding supports the need for future randomised trials of PCa patients that include older patients and men with multiple comorbidities to better reflect the general population.We investigated all the available data from observational studies on hormonal treatment for prostate cancer and its possible cardiovascular adverse effects. We found consistent evidence that this treatment may increase the risk of cardiovascular disease.
- A switch from CD44+ cell to EMT cell drives the metastasis of prostate cancer. [JOURNAL ARTICLE]
- Oncotarget 2014 Nov 25.
Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.
- Is There a Correlation Between Androgens and Sexual Desire in Women? [JOURNAL ARTICLE]
- J Sex Med 2014 Dec 5.
For women, the correlation between circulating androgens and sexual desire is inconclusive. Substitution with androgens at physiological levels improves sexual function in women who experience decreased sexual desire and androgen deficiency from surgical menopause, pituitary disease, and age-related decline in androgen production in the ovaries. Measuring bioactive testosterone is difficult and new methods have been proposed, including measuring the primary androgen metabolite androsterone glucuronide (ADT-G).The aim of this study was to investigate a possible correlation between serum levels of androgens and sexual desire in women and whether the level of ADT-G is better correlated than the level of circulating androgens with sexual desire.This was a cross-sectional study including 560 healthy women aged 19-65 years divided into three age groups. Correlations were considered to be statistically significant at P < 0.05.Sexual desire was determined as the total score of the sexual desire domain of the Female Sexual Function Index. Total testosterone (TT), calculated free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEAS), and ADT-G were analyzed using mass spectrometry.Sexual desire correlated overall with FT and androstenedione in the total cohort of women. In a subgroup of women aged 25-44 years with no use of systemic hormonal contraception, sexual desire correlated with TT, FT, androstenedione, and DHEAS. In women aged 45-65 years, androstenedione correlated with sexual desire. No correlations between ADT-G and sexual desire were identified.In the present study, FT and androstenedione were statistically significantly correlated with sexual desire in the total cohort of women. ADT-G did not correlate more strongly than circulating androgens with sexual desire and is therefore not superior to measuring circulating androgens by mass spectrometry. Wåhlin-Jacobsen S, Pedersen AT, Kristensen E, Laessøe NC, Lundqvist M, Cohen AS, Hougaard DM, and Giraldi A. Is there a correlation between androgens and sexual desire in women? J Sex Med **;**:**-**.
- Survival outcomes of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy in relation to prostate-specific antigen nadir level. [JOURNAL ARTICLE]
- Asia Pac J Clin Oncol 2014 Dec 3.
To evaluate the progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy (ADT) in relation to prostate-specific antigen (PSA) nadir level.All Chinese prostate cancer patients with bone metastases who were treated with primary ADT from 2000 to 2009 were included. Patients' and disease characteristics were recorded. Patients were categorized into two PSA nadir groups (≤1.0 and >1.0 ng/mL). Associations of PSA nadir with PFS, CSS and OS were analyzed with Kaplan-Meier and Cox regression analyses. The survival outcomes of the two PSA nadir groups were presented.Four hundred nineteen patients were included in the study. PSA nadir appeared to be a good predictor for PFS (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.35-2.56, P < 0.001), CSS (HR 1.60, 95% CI 0.98-2.64, P = 0.063) and OS (HR 1.77, 95% CI 1.20-2.41, P < 0.001) upon multivariate Cox regression analyses. In the PSA nadir groups of ≤1.0 and >1.0 ng/mL, the median PFS were 15 and 10 months, and the 1-year PFS rates were 64% and 40%, respectively; the median CSS were 42 and 27 months, and the 5-year OS rates were 53% and 28%, respectively; and the median OS were 41 and 24 months, and the 5-year OS rates were 45% and 19%, respectively.Higher PSA nadir was associated with shorter PFS, CSS and OS in Chinese metastatic prostate cancer patients following primary ADT. The survival outcomes may serve as references in deciding the best treatment strategy in Chinese prostate cancer patients.