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Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison.

ABSTRACT: Men receiving androgen-deprivation therapy (ADT) for prostate cancer may be at risk for cognitive impairment; however, evidence is mixed in the existing literature. Our study examined the impact of ADT on impaired cognitive performance and explored potential demographic and genetic predictors of impaired performance.Patients with prostate cancer were assessed before or within 21 days of starting ADT (n = 58) and 6 and 12 months later. Age- and education-matched patients with prostate cancer treated with prostatectomy only (n = 84) and men without prostate cancer (n = 88) were assessed at similar intervals. Participants provided baseline blood samples for genotyping. Mean-level cognitive performance was compared using mixed models; cognitive impairment was compared using generalized estimating equations.ADT recipients demonstrated higher rates of impaired cognitive performance over time relative to all controls (P = .01). Groups did not differ at baseline (P > .05); however, ADT recipients were more likely to demonstrate impaired performance within 6 and 12 months (P for both comparisons < .05). Baseline age, cognitive reserve, depressive symptoms, fatigue, and hot flash interference did not moderate the impact of ADT on impaired cognitive performance (P for all comparisons ? .09). In exploratory genetic analyses, GNB3 single-nucleotide polymorphism rs1047776 was associated with increased rates of impaired performance over time in the ADT group (P < .001).Men treated with ADT were more likely to demonstrate impaired cognitive performance within 6 months after starting ADT relative to matched controls and to continue to do so within 12 months after starting ADT. If confirmed, findings may have implications for patient education regarding the risks and benefits of ADT.

SUBMITTER: Gonzalez BD

PROVIDER: S-EPMC4461804 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison.

Gonzalez Brian D BD Jim Heather S L HS Booth-Jones Margaret M Small Brent J BJ Sutton Steven K SK Lin Hui-Yi HY Park Jong Y JY Spiess Philippe E PE Fishman Mayer N MN Jacobsen Paul B PB

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20150511 18

<h4>Purpose</h4>Men receiving androgen-deprivation therapy (ADT) for prostate cancer may be at risk for cognitive impairment; however, evidence is mixed in the existing literature. Our study examined the impact of ADT on impaired cognitive performance and explored potential demographic and genetic predictors of impaired performance.<h4>Patients and methods</h4>Patients with prostate cancer were assessed before or within 21 days of starting ADT (n = 58) and 6 and 12 months later. Age- and educati ...[more]

PMID: 25964245

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Project description:BackgroundPrevious evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.MethodsRADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.FindingsBetween Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.InterpretationCompared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.FundingCancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Project description:BackgroundPrevious evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.MethodsRADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.FindingsBetween Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths.InterpretationMetastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population.FundingCancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Project description:PurposeMany men receiving androgen deprivation therapy for prostate cancer experience hot flashes. This study aimed to describe the course of hot flash interference with time in androgen deprivation therapy recipients relative to matched prostate cancer and cancer-free controls from before the start of androgen deprivation therapy to 12 months later. We also examined demographic, clinical and genetic predictors of the impact of androgen deprivation therapy on hot flash interference.Materials and methodsThree groups were examined, including 60 patients with prostate cancer recruited before or within 21 days of starting androgen deprivation therapy, 83 age and education matched patients with prostate cancer treated with prostatectomy only, and 86 age and education matched men with no history of cancer. Participants provided blood samples and completed the Hot Flash Related Daily Interference Scale at baseline as well as 6 and 12 months later.ResultsAndrogen deprivation therapy recipients reported increasing hot flash interference with time relative to controls (p <0.001). Group differences were evident at 6 and 12 months (all p <0.001) with androgen deprivation therapy recipients reporting greater hot flash interference than controls. Several genetic polymorphisms were found to predict greater increases in hot flash interference (all p <0.01), including polymorphisms on genes associated with vasoconstriction, immune function, neurotransmission and circadian rhythms. Androgen deprivation therapy recipients who were younger and had a lower body mass index at baseline also showed greater increases in hot flash interference with time (all p ≤0.01).ConclusionsThis study, which is to our knowledge the first to prospectively examine hot flash interference in androgen deprivation therapy recipients, reveals that those with certain genetic polymorphisms, younger age and lower body mass index had greater increases in hot flash interference with time relative to controls.

Dataset Information

Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison.

Publications

Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison.

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