Dataset Information

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.

ABSTRACT: BACKGROUND:For specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well-described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk-benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review. METHODS:A 14-member panel comprised of urologic and medical oncologists were chosen for an expert review panel, to provide guidance on a more judicious use of ADT in advanced PC patients. Panel members were chosen based upon their academic and community experience and expertise in the management of PC patients. Four academic members of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, and were tasked with addressing the role of ADT in specific PC settings. RESULTS:This article describes the practical recommendations of an expert panel for the use of ADT throughout the PC disease continuum, as well as an algorithm summarizing the key recommendations. The target for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. CONCLUSION:The panel has provided recommendations for monitoring PC patients while on ADT, recognizing that PC patients will progress despite testosterone suppression and, therefore, early identification of conversion from castrate-sensitive to castration resistance is critical. Also, the requirement to both identify and mitigate side effects of ADT as well as the importance of quality of life maintenance are essential to the optimization of patient care, especially as more combinatorial therapeutic strategies with ADT continue to emerge.

SUBMITTER: Shore ND

PROVIDER: S-EPMC7154535 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.

Shore Neal D ND Antonarakis Emmanuel S ES Antonarakis Emmanuel S ES Cookson Michael S MS Crawford E David ED Morgans Alicia K AK Albala David M DM Hafron Jason J Harris Richard G RG Saltzstein Daniel D Brown Gordon A GA Henderson Jonathan J Lowentritt Benjamin B Spier Jeffrey M JM Concepcion Raoul R

The Prostate 20200304 6

<h4>Background</h4>For specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well-described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk-benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review.<h4>Methods</ ...[more]

PMID: 32130741

Similar Datasets

Project description:ContextAndrogen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.ObjectiveReview the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.Evidence acquisitionA comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.Evidence synthesisData from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.ConclusionsAlthough ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio.

Project description:BackgroundAndrogen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.ObjectiveTo undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.Design, setting, and participantsRNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.Outcome measurements and statistical analysisWe searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.Results and limitationsWe identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.ConclusionsRNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.

Project description:BackgroundWhether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.MethodsPatients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633.ResultsBetween 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).InterpretationThe benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer.FundingCanadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.

Dataset Information

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.

Publications

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets