[Corrigendum] Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

OBJECTIVES/GOALS: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. METHODS/STUDY POPULATION: Sixty-four participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants’ whole blood. An ADT/RT-induced fatigue mouse model was developed with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using Western blot analysis of Glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). RESULTS/ANTICIPATED RESULTS: Fatigue in the ADT group was exacerbated during RT compared to the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated a synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model, and its mechanism may be related to bioenergetics in the CNS.

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Effect of Salvage Radiotherapy and Endocrine Therapy on Patients with Biochemical Recurrence After Prostate Cancer Operation— a Meta‑Analysis

American Journal of Men s Health ◽

10.1177/15579883211024881 ◽

2021 ◽

Vol 15 (3) ◽

pp. 155798832110248

Author(s):

Yong Yuan ◽

Qiang Zhang ◽

Chaofan Xie ◽

Tao Wu

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

Endocrine Therapy ◽

Androgen Deprivation Therapy ◽

Biochemical Recurrence ◽

Meta Analysis ◽

Combined Treatment ◽

Androgen Deprivation ◽

Salvage Radiotherapy ◽

End Point

Context: Several studies reported the application of androgen deprivation therapy and radiotherapy in patients with biochemical recurrence after prostate cancer operation. Objective: To perform a systematic review and meta-analysis evaluating of endocrine therapy and radiotherapy in patients with biochemical recurrence after prostate cancer surgery. The primary end point was biochemical progression-free survival (bPFS). Secondary end point was overall survival (OS). Methods: A systematic review of PubMed/Medline, Embase, and Cochrane databases to identify relevant studies published in English up to March 2020. Twelve studies were selected for inclusion. Results: There were 11 studies included in the present study. Including two randomized controlled trials and nine cohort studies. The meta-analysis shows a significant bPFS benefit from androgen deprivation therapy and radiotherapy in patients with biochemical recurrence after prostate cancer operation. (hazard ratio [HR]: 0.57; 95% confidence interval CI, 0.52–0.63; p < .001). For patients with GS < 7 and low-risk patients, combined treatment can have a benefit for BPFs (HR: 0.53; 95% CI, 0.37–0.76; HR: 0.58; 95% CI, 0.36–0.93). Androgen deprivation therapy and radiotherapy in patients with biochemical recurrence was associated with a slightly OS improvement (HR: 0.73; 95% CI, 0.57–0.93; p = 0.01). Conclusions: Compared with salvage radiotherapy alone, This meta-analysis shows a significant bPFS benefit from endocrine therapy combined with salvage radiotherapy in patients with biochemical recurrence after prostate cancer operation. And benefit more for high-risk groups. However, there was no significant benefit in group GS ≥ 8. It shows a slightly OS benefit from endocrine therapy combined with salvage radiotherapy in patients with biochemical recurrence.

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The effects of androgen deprivation therapy and radiation therapy on cancer-related fatigue.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.31_suppl.10 ◽

2019 ◽

Vol 37 (31_suppl) ◽

pp. 10-10

Author(s):

Leorey Saligan

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Wheel Running ◽

Androgen Deprivation ◽

Common Symptom ◽

Cancer Related Fatigue ◽

Running Activity ◽

Fatigue Development ◽

Wheel Running Activity ◽

Significant Difference

10 Background: Fatigue is a common symptom characterized by incapacitating tiredness. Androgen deprivation therapy (ADT) in combination with radiotherapy (RT) is one of the standard treatments for prostate cancer. Fatigue often worsens during RT with concomitant ADT and it persists long after treatment completion. The purpose of this study is to examine the effects of combined ADT and RT on fatigue in prostate cancer men and in a fatigue mouse model. Methods: 64 participants were recruited and followed at baseline, midpoint, completion, and 1 year post-RT. Two cohorts of men: +ADT cotinued after RT (n=27), +ADT during RT only (n=20), and -ADT (n=17). Fatigue was measured using FACT-F. Male C57BI/6 mice (n=55) were randomly placed into 2 groups: +ADT and –ADT (control). Mice were further subdivided into +RT and –RT (sham) groups. Voluntary Wheel Running Activity (VWRA) data from all mice were recorded for 6 days post-irradiation and the total average of all 6 days was used for analysis. Results: Fatigue (n=64) worsened during RT ( p=.02 at midpoint, p=.04 at completion). ADT significantly affected fatigue development over time (F3,42 = 3.80, p=.02) with the most significant difference occurring at midpoint ( p<.001) and completion of RT ( p<0.001). VWRA significantly decreased in mice that received the combination of ADT and irradiation, compared to those that received only ADT + sham radiation ( p=.001) and no ADT + sham radiation ( p=.004). Transcription factor A, mitochondrial (TFAM) in brain cortical samples was significantly reduced in irradiated mice compared to control mice ( p=.014). Glucose transported type 4 (GLUT4) in brain cortices was significantly reduced in irradiated mice compared to non-irradiated mice ( p=.0057). GLUT4 was also significantly reduced in irradiated mice receiving ADT compared to control mice receiving sham RT ( p=.043). Conclusions: There is a significant combined effect of ADT and RT on fatigue in both humans and mice. Mitochondrial function/neuronal bioenergetic markers were altered in the cortices of irradiated mice that received concomitant ADT. These findings suggest that fatigue experienced by subjects who receive ADT + RT could be attributable to impaired cortical energy production.

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Effects of Exercise on Cancer-related Fatigue and Quality of Life in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Meta-analysis of Randomized Clinical Trials

Chinese Medical Sciences Journal ◽

10.24920/j1001-9242.2007.002 ◽

2017 ◽

Vol 32 (1) ◽

pp. 13-21 ◽

Cited By ~ 6

Author(s):

Bo Yang ◽

Jiansheng Wang ◽

Jiansheng Wang

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Clinical Trials ◽

Cancer Patients ◽

Androgen Deprivation Therapy ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Androgen Deprivation ◽

Cancer Related Fatigue

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Steroid Hormone Biosynthesis Metabolism Is Associated With Fatigue Related to Androgen Deprivation Therapy for Prostate Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.642307 ◽

2021 ◽

Vol 9 ◽

Author(s):

Li Rebekah Feng ◽

Jennifer J. Barb ◽

Hannah Allen ◽

Jeniece Regan ◽

Leorey Saligan

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

Androgen Deprivation Therapy ◽

Steroid Hormone ◽

Androgen Deprivation ◽

Partial Least Square ◽

Steroid Hormone Biosynthesis ◽

Cancer Related Fatigue ◽

Fatigue Severity ◽

Hormone Biosynthesis

BackgroundAndrogen deprivation therapy (ADT) is a cornerstone treatment for prostate cancer. Despite the clinical benefits, ADT is associated with multiple adverse effects including fatigue. The goal of the study was to examine metabolomic changes to better understand cancer-related fatigue specific to ADT treatment.MethodsA total of 160 plasma samples collected from participants with (+ADT, n = 58) or without neoadjuvant ADT (−ADT, n = 102) prior to radiation therapy for treatment of non-metastatic localized prostate cancer were included in the study. Fatigue and sleep-related impairment were measured using the Patient Reported Outcomes Measurement Information System. Plasma metabolites were identified and measured using untargeted ultrahigh-performance liquid chromatography/mass spectrometry metabolomics analyses. Partial least square discriminant analysis was used to identify discriminant metabolite features, and the diagnostic performance of selected classifiers was quantified using AUROC curve analysis. Pathway enrichment analysis was performed using metabolite sets enrichment analyses.FindingsSteroid hormone biosynthesis pathways, including androstenedione metabolism as well as androgen and estrogen metabolism, were overrepresented by metabolites that significantly discriminated samples in the +ADT from the −ADT group. Additional overrepresented metabolic pathways included amino acid metabolism, glutathione metabolism, and carnitine synthesis. Of the metabolites that were significantly different between the groups, steroid hormone biosynthesis metabolites were most significantly correlated with fatigue severity. Sleep-related impairment was strongly correlated with fatigue severity and inversely correlated with ADT-induced reduction in androsterone sulfate.ConclusionsPatients with non-metastatic prostate cancer receiving neoadjuvant ADT prior to radiation therapy reported relatively more severe fatigue. Increased fatigue in this population may be attributable to sleep-related impairment associated with alterations in steroid hormone biosynthesis. Findings in this study provide a basis for further research of changes in sleep patterns and their role in this specific subcategory of cancer-related fatigue caused by the treatment.

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Mediterranean-style dietary pattern improves cancer-related fatigue and quality of life in men with prostate cancer treated with androgen deprivation therapy: A pilot randomised control trial

Clinical Nutrition ◽

10.1016/j.clnu.2020.05.016 ◽

2021 ◽

Vol 40 (1) ◽

pp. 245-254 ◽

Cited By ~ 1

Author(s):

Brenton J. Baguley ◽

Tina L. Skinner ◽

David G. Jenkins ◽

Olivia R.L. Wright

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Dietary Pattern ◽

Androgen Deprivation ◽

Randomised Control Trial ◽

Cancer Related Fatigue

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Real World Evaluation of Upfront Docetaxel in Metastatic Castrate Sensitive Prostate Cancer

10.21203/rs.3.rs-209518/v1 ◽

2021 ◽

Author(s):

Jenny Isaksson ◽

Henrik Green ◽

Dimitrios Papantoniou ◽

Linn Pettersson ◽

Mats Andén ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Real World ◽

Treatment Strategy ◽

Statistical Significance ◽

Combined Treatment ◽

Dose Intensity ◽

Androgen Deprivation ◽

Phase Iii ◽

Study Cohort

Abstract Background: Recent randomised phase III trials demonstrate survival benefit for the addition of upfront docetaxel to androgen deprivation therapy (ADT) in metastatic castrate sensitive prostate cancer (mCSPC). Following its implementation in routine care, this combined treatment strategy needs further evaluation in a real world setting.Methods: A multicentre retrospective cohort study in the South East Health care region of Sweden was conducted. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. Primary endpoint was progression free survival (PFS) at 12 months and secondary endpoints were PFS at 24 months, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalisations. Exploratory analyses on potentially prognostic parameters were performed.Results: 94 patients were eligible and formed the study cohort. PFS at 12 and 24 months were 75% (95% CI 66-84) and 58% (46-70). OS at 12 and 24 months were 93% (87-99) and 86% (76-96). 91% (n=86) initiated docetaxel according to the standard protocol of 75 mg/m2 every 3 weeks (6 cycles), whereas 9% (n=8) received a modified protocol of 50 mg/m2 every 2 weeks (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate cox regression analyses revealed that baseline PSA >180 vs <180 and presence vs absence of distant metastases were negative prognostic factors (HR 2.86, 95% CI 1.39-5.87, p =0.0041 and 3.36, 95% CI 1.03-10.96, p=0.045). Following multivariate analysis, the statistical significance remained for PSA (2.51, CI 1.21-5.19, p =0.013) but not for metastatic status (2.60, 95% CI 0.78-8.65, p=0.12). Febrile neutropenia was recorded in 21% (n=20) and 26% (n=24) had at least one episode of unplanned hospitalisation under and up to 30 days after the treatment course. Conclusions: The outcome and safety profile of upfront docetaxel in addition to androgen deprivation therapy in metastatic castrate sensitive prostate cancer appear similar in real world and randomised controlled populations. Further implementation of this treatment strategy is encouraged.

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Multimodal therapy for cancer related fatigue in patients with prostate cancer receiving radiotherapy and androgen deprivation therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10114 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10114-10114

Author(s):

Sriram Yennu ◽

Karen Basen-Engquist ◽

Valerie Klairisa Reed ◽

Cindy L. Carmack ◽

Andrew Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Multimodal Therapy ◽

Behavioral Therapy ◽

Androgen Deprivation ◽

Effect Estimate ◽

Double Blind ◽

Cancer Related Fatigue ◽

Chronic Illness Therapy ◽

Significant Difference

10114 Background: There are limited studies to evaluate treatments that target causative mechanisms of Cancer-related-fatigue (CRF) using validated tools in a defined population. The objective is to determine the feasibility, and the preliminary estimates of the effects of various combinations of standardized exercise, cognitive behavioral therapy (CBT), and methylphenidate (multimodal therapy, or MMT) on CRF as measured by AUC of Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) subscale scores in Pts with prostate cancer receiving radiotherapy with androgen deprivation therapy. Methods: Prostate cancer Pts with CRF scheduled to receive radiotherapy with androgen deprivation therapy were eligible. Using a double blind (patient, investigators) randomized factorial study design, eligible Pts were randomized into 1 of the 8 arms, which included all possible combinations of the interventions (exercise, CBT, and methylphenidate) and/or their corresponding placebo treatments for a duration of 8 weeks. Results: 62/69 (89%) randomized Pts were evaluable. There were no differences in the demographics and baseline fatigue between groups. The adherence rates for pills, exercise and CBT were 96.5%, 67%, and 90% respectively. The study was feasible and there was no significant difference in adverse events by groups. Table 1 shows the comparison of AUC by treatment. For Pts receiving drug compared to placebo, the median FACIT-F AUC was 2328 vs 2095. The drug effect (estimate, 95% CI) in Pts who received Exercise was 596 (68.3, 1125); CBT was 354 (-121, 830); combined Exercise and CBT was -187 (-802,427); and control Exercise, control CBT was 294 (-192,781). Conclusions: Methylphenidate containing combinations were superior to no drug combinations. Methylphenidate + Exercise provided the best signal and should proceed to large randomized control trials. Clinical trial information: NCT01410942. [Table: see text]

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