- The role of androgen deprivation therapy plus radiation therapy in patients with non-metastatic prostate cancer. [JOURNAL ARTICLE]
- Expert Rev Anticancer Ther 2016 Jul 27.
Androgen deprivation therapy (ADT) has a long and illustrious history in the treatment for prostate cancer and continues to be a mainstay treatment for locally advanced and high-risk patients. Because the survival for even high-risk prostate patients is lengthy, details of treatment such as duration and timing must be considered carefully and weighed against the various side effects.In the following article, we discuss the evolution of ADT from its initial applications in metastatic prostate cancer to its more recent incorporation into front line treatment in conjunction with radiation therapy (RT) for intermediate and high risk disease. We emphasize the results of phase III trials, which have defined the role of ADT in combination with RT in this patient population. We emphasize not only the potential benefits of ADT with RT, but also the potential risks, and underscore the need to consider both in order to maximize the therapeutic ration for each patient. Studies were identified via a search of PubMed as well as the bibliographies of articles discussed herein. Expert commentary: Even with advanced radiation techniques and dose escalation, adjuvant ADT continues to confer an overall survival benefit in intermediate and high-risk patients, although some evidence suggest that duration of treatment may be shortened, particularly for the high-risk group. The coming years will shed further information on this complicated topic with maturing of results from several ongoing trials.
- ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells. [JOURNAL ARTICLE]
- Biochem Biophys Res Commun 2016 Jul 23.
Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function.
- Do androgen deprivation and the biologically equivalent dose matter in low-dose-rate brachytherapy for intermediate-risk prostate cancer? [JOURNAL ARTICLE]
- Cancer Med 2016 Jul 25.
The objective of this study was to investigate the impact of the biologically equivalent dose (BED) on treatment outcomes after iodine-125 low-dose-rate brachytherapy (LDR-BT) with or without supplemental external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for intermediate-risk prostate cancer (PCa). We retrospectively evaluated 292 Japanese patients. The impact of the BED and ADT on treatment outcomes was investigated. Cox proportional hazard models were used for univariate and multivariate analysis with biological progression-free survival (bPFS) and clinical progression-free survival (cPFS) as the primary outcome measures. The median follow-up was 66 months. The bPFS and cPFS rates at 5-/7-years were 91.6/87.7% and 95.9/94.0%, respectively. When stratified by BED levels, the bPFS rates at 5-/7-years were 92.1/89.3% for <178.0 Gy2, and 91.2/86.0% for ≥178.0 Gy2 , respectively (P > 0.05). Based on ADT duration, the bPFS rates at 5-/7-years were 89.8/83.5%, 89.7/89.7%, and 97.5/97.5% for none, 1-3 months, and 4-12 months, respectively (P = 0.03). For the univariate analysis, the use of ADT and its duration were significant predictors for bPFS, whereas BED was not significant. A multivariate analysis did not indicate the use of ADT itself was significant, however, when covariates were accounted for by the duration of ADT, the longer use of ADT was found to significantly improve bPFS. Although cPFS was associated neither with the BED levels nor ADT duration (P > 0.05), ADT duration had a trend of improving cPFS (P = 0.053). The higher levels of BED did not significantly impact bPFS for intermediate-risk PCa after LDR-BT with or without supplemental EBRT and ADT. The longer duration of ADT could provide an additional benefit in the context of high-dose irradiation generated by LDR-BT.
- Clinical Outcomes for Patients with Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis. [JOURNAL ARTICLE]
- Eur Urol 2016 Jul 21.
The long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons.To compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP.Retrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy.Kaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS).The median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts.Radiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP.While some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival.
- Occurrence, risk factors and outcome of adenovirus infection in adult recipients of allogeneic hematopoietic stem cell transplantation. [JOURNAL ARTICLE]
- J Clin Virol 2016 Jul 10.:33-40.
Adenovirus (ADV) infections can have a high mortality in immunocompromised patients and are difficult to treat.We retrospectively analyzed occurrence and risk factors of ADV infection in 399 adults with hematological disorders undergoing hematopoietic stem cell transplantation (allo-HSCT), focusing on alternative donor transplantation (ADT) and disseminated disease.ADV infection occurred in 42 patients (10.5%). Disease was localized in 18 and disseminated in 6 patients. ADV infection was observed in 15% after ADT, performed in 29% of all recipients, and was less frequent (6%) in T-cell-replete (TCR) haploidentical transplantation using post-transplantation cyclophosphamide (PTCY) than in other ADT protocols. Lower age, the use of alternative donor grafts and acute graft-versus-host disease (GvHD)≥grade II were risk factors for ADV infection. After failure of standard antiviral treatment, three patients with disseminated ADV disease received one dose of ADV-specific T cells, resulting in virological response in 2/3 patients, clearance of ADV viremia in 2/2 patients, and survival of 1/3 patients; both patients with pneumonia died.ADV infection was of moderate occurrence in our adult recipients of allo-HSCT despite a high proportion of potential high-risk patients receiving ADT. TCR strategies using PTCY might limit ADV complications in haploidentical transplantation. Despite feasible adoptive therapy strategies, outcome of disseminated disease remains dismal.
- Pathologic, Oncologic and Functional Outcomes of a Prospective Registry of Salvage High Intensity Focused Ultrasound Ablation for Radio-Recurrent Prostate. [JOURNAL ARTICLE]
- J Urol 2016 Jul 12.
and Objective: The objective of this Prospective Registry was to prospectively assess the oncologic, functional and safety outcomes of salvage HIFU in radio-recurrent prostate cancer (rrPCa).Eighty one men were prospectively recruited and evaluated at regular scheduled study visits to 6 months post-HIFU and thereafter as per standard of care. Transrectal ultrasound guided biopsy (TRUS Bx) was performed at 6 months. Primary endpoint was absence or histologic persistence of disease at 6 months Bx. Secondary endpoints included QoL, biochemical recurrence-free survival (BRFS), overall survival (OS), cancer specific survival (CSS) and progression to androgen deprivation therapy (ADT). Survival analysis was carried out according to Kaplan-Meier's method and multivariate analysis was performed using the log-rank (Mantel-Cox) test.The mean pre-HIFU PSA was 4.06 ± 2.88 ng/mL. At 6 months, 63 men underwent Bx, of which 22 (35%) were found to have residual disease. With a mean follow-up of 53.5 ±31.6 months, the median BRFS was 63 months. The 5-year OS and CSS were 88% and 94.4% respectively. Nadir PSA of <0.5ng/mL was a significant predictor (p=0.014, 95% CI 1.22-5.87) of BRFS. IPSS scores significantly increased (p<0.001) while IIEF-5 scores decreased and the SF-36 score did not change significantly. The rate of rectal fistulization and severe incontinence was 3.7% each. A total of 223 complications were recorded in the 180-days after HIFU (Clavien-Dindo grades 1=195, grade II= 20, grade III= 7, grade IVa=1).Salvage HIFU appears to be a viable treatment option for rr-PCa, with acceptable morbidity.
- [Docetaxel for metastatic prostate cancer: early is better]. [English Abstract, Journal Article]
- Ned Tijdschr Geneeskd 2016; 160(0):D215.
Androgen deprivation therapy (ADT) has been used to treat patients with metastatic prostate cancer for many years. Docetaxel chemotherapy administered to patients with metastatic castrate-resistant prostate cancer has been standard since 2004 with a modest survival benefit. Recent data from two randomised studies (CHAARTED and STAMPEDE) demonstrate that combining ADT with docetaxel in men with hormone-naïve metastatic prostate cancer resulted in an impressive overall survival benefit of more than a year as compared with ADT alone. In a meta-analysis, the consistency of these data was confirmed. On the basis of these data, addition of six 3-weekly courses of docetaxel to ADT should be considered as standard treatment in chemo-fit patients with hormone-naïve metastatic prostate cancer.
- Prevalence of Cardiovascular Disease and Osteoporosis during Androgen Deprivation Therapy Prescription Discordant to EAU Guidelines: Results From a Multi-Center Cross-Sectional Analysis From the CHOsIng Treatment for Prostate canCEr (CHOICE) Study. [JOURNAL ARTICLE]
- Urology 2016 Jul 8.
To analyze the prevalence of cardiovascular disease and osteoporosis in patients treated with androgen deprivation therapy (ADT) for prostate cancer (PCa) but not adherent to European association of urology (EAU) guidelines.The CHOsIng treatment for prostate canCEr (CHOICE) study was an Italian multicenter cross-sectional study conducted from December 2010 to January 2012. A total of 1386 patients treated with ADT for PCa (first prescription or renewal of ADT) were selected. According to EAU guidelines, the cohort was categorized in discordant ADT (Group A) and concordant ADT (Group B). The prevalence of cardiovascular disease and osteoporosis after ADT were recorded.The final cohort included 1075 patients. According to EAU guidelines adherence, 285 (26.51%) and 790 (73.49%) were considered discordant and concordant respectively. The proportion of men with CCI > 2 at baseline was statistically similar in Group A (81.8%) compared to Group B (80.8%) (p=0.96). The number of complications reported at enrolment was as following: cardiovascular in 351 (32.7%) subjects, endocrine in 166 (15.4%), sexual in 498 (46.3%), osteoporosis in 181 (16.8%) and gynecomastia in 274 (25.5%). At the multivariate logistic regression analysis adjusted for confounding factors, discordant ADT was associated with greater risk of cardiovascular complications (OR: 2.07; p<0.01) and osteoporosis (OR: 1.75; p=0.04).About one third of patients with PCa received inappropriate ADT and showed a greater risk cardiovascular disease and osteoporosis. These results could be useful for setting better policy strategies in order to limit the inappropriateness of ADT prescription.
- Survival Outcomes of Concurrent Treatment with Docetaxel and Androgen Deprivation Therapy in Metastatic Castration-Resistant Prostate Cancer. [Journal Article]
- Yonsei Med J 2016 Sep; 57(5):1070-8.
Docetaxel-based chemotherapy (DTX) improves overall survival (OS) of men with metastatic castration-resistant prostate cancer (mCRPC). Considering the potential existence of androgen receptors that remain active at this stage, we aimed to assess the impact of the combined use of androgen deprivation therapy (ADT) with DTX for mCRPC.We performed a single-institutional retrospective analysis of patients with mCRPC who received either DTX alone (DTX group, n=21) or concurrent DTX and ADT (DTX+ADT group, n=26) between August 2006 and February 2014. All patients received DTX doses of 75 mg/m² every three weeks for at least three cycles. In the DTX+ADT group, all patients used luteinizing hormone releasing hormone agonist continuously as a concurrent ADT.The median follow-up period was 24.0 months (interquartile range 12.0-37.0) for the entire cohort. The median radiographic progression-free survival (rPFS) was 9.0 months and 6.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.036). On multivariable Cox regression analysis, concurrent administration of ADT was the only significant predictor of rPFS [hazard ratio (HR)=0.525, 95% confidence intervals (CI) 0.284-0.970, p=0.040]. The median OS was 42.0 and 38.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.796). On multivariable analysis, hemoglobin level at the time of DTX initiation was associated with OS (HR=0.532, 95% CI 0.381-0.744, p<0.001).In chemotherapy-naive patients with mCRPC, the combined use of ADT with DTX improved rPFS. Our result suggests that the concurrent administration of ADT and DTX is superior to DTX alone.
- Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial. [Journal Article]
- Med Oncol 2016 Aug; 33(8):89.
After curative local therapy, biochemical recurrence is a mode of relapse among patient with prostate cancer (PC). Deferring androgen deprivation therapy (ADT) or offering non-hormonal therapies may be an appropriate option for these non-symptomatic patients with no proven metastases. Metronomic cyclophosphamide (MC) has shown activity in metastatic PC setting and was chosen to be assessed in biochemical relapse. This prospective single-arm open-label phase II study was conducted to evaluate MC regimen in patients with biochemical recurrent PC. MC was planned to be administered orally at a daily dose of 50 mg for 6 months. Primary endpoint was PSA response. Thirty-eight patients were included and treated. Median follow-up was 45.5 months (range 17-100). Among them, 14 patients (37 %) achieved PSA stabilisation and 22 patients (58 %) experienced PSA progression. Response rate was 5 % with one complete response (2.6 %), and 1 partial response with PSA decrease >50 % (2.6 %). The median time until androgen deprivation therapy initiation was around 15 months. The treatment was well tolerated. Neither grade 3-4 toxicity nor serious adverse events were observed. This first prospective clinical trial with MC therapy in patients with non-metastatic biochemical recurrence of PC displayed modest efficacy when measured with PSA response rate, without significant toxicity. It might offer a new safe and non-expensive option to delay initiation of ADT. These results would need to be confirmed with larger prospective randomised trials.