The effect of androgen deprivation therapy on body composition in men with prostate cancer systematic review and meta analysis

The use of androgen deprivation therapy (ADT) in the treatment of prostate cancer is associated with changes in body composition including increased fat and decreased lean mass. Limited information exists regarding the rate and extent of these changes. This systematic review was conducted to determine the effects of ADT on body composition in prostate cancer patients.

A randomised controlled trial to evaluate the efficacy of a 6-month dietary and physical activity intervention for patients receiving androgen deprivation therapy for prostate cancer

PURPOSE: Treatment of prostate cancer with androgen deprivation therapy (ADT) is associated with an increased fat mass, decreased lean mass, increased fatigue and a reduction in quality of life (QoL). The aim of this study was to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer patients receiving ADT, to help minimise these side effects.

METHODS: Patients (n = 94) were recruited to this study if they were planned to receive ADT for prostate cancer for at least 6 months. Men randomised to the intervention arm received a dietary and exercise intervention, commensurate with UK healthy eating and physical activity recommendations. The primary outcome of interest was body composition; secondary outcomes included fatigue, QoL, functional capacity, stress and dietary change.

RESULTS: The intervention group had a significant (p < 0.001) reduction in weight, body mass index and percentage fat mass compared to the control group at 6 months; the between-group differences were -3.3 kg (95 % confidence interval (95 % CI) -4.5, -2.1), -1.1 kg/m(2) (95 % CI -1.5, -0.7) and -2.1 % (95 % CI -2.8, -1.4), respectively, after adjustment for baseline values. The intervention resulted in improvements in functional capacity (p < 0.001) and dietary intakes but did not significantly impact fatigue, QoL or stress scores at endpoint.

CONCLUSIONS: A 6-month diet and physical activity intervention can minimise the adverse body composition changes associated with ADT.

IMPLICATIONS FOR CANCER SURVIVORS: This study shows that a pragmatic lifestyle intervention is feasible and can have a positive impact on health behaviours and other key outcomes in men with prostate cancer receiving ADT.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours; informed scheduling of the bioreductive drug AQ4N improves treatment response

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment hypoxia is known to drive malignant progression. This study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold chambers (DSF) were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide and vehicle-only treated tumours were re-established in vitro and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2mg/kg/day) decreased tumour oxygenation by 45% within 24h, reaching a nadir of 0.09% oxygen (0.67±0.06 mmHg) by day 7; this persisted until day 14 when it increased up to day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at days 7 and 14 with revascularization occurring by day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50mg/kg; single dose) caused greater tumour growth delay than bicalutamide alone. This study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit.

Evaluation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy

Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)–like interleukin 1ß-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)–promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)–targeted therapy.

Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.

Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7–mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.

Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822–33.

Quality of life in men receiving radiotherapy and neo-adjuvant androgen deprivation for prostate cancer:Results from a prospective longitudinal study

Aim. To report a study measuring the quality of life and side effects in men receiving radiotherapy and hormone ablation for prostate cancer up to 1year after treatment. Background. Prostate cancer incidence is increasing with the result that more men are living longer with the disease and the side effects of treatment. It is important to know the effects this has on their quality of life. Design. Survey. Method. Between September 2006-September 2007, all men who were about to undergo radical conformal radiotherapy ± neo-adjuvant androgen deprivation for localized prostate cancer were invited to participate in the study; 149 men were recruited. They completed the European Organization on Research and Treatment of Cancer quality of life questionnaire C-30 and Prostate Cancer module PR25 at four time-points. Results. At 4-6weeks after radiotherapy, participants experienced the biggest relative decline in global quality of life, social, physical, and role functioning and an increase in treatment side effects. At 6months postradiotherapy the majority of men experienced an improvement in their side effects. However, a minority of men were experiencing severe side effects of radiotherapy at 1year post-treatment. Single men and men who had a low quality of life prior to radiotherapy, reported a lower quality of life at 1year after treatment in comparison to married men. Conclusion. Men with prostate cancer suffer limitations due to the symptoms they experience and disruption to their quality of life. It is essential that nurses develop and deliver follow-up care which is flexible and appropriate to the individual needs of these men. © 2012 Blackwell Publishing Ltd.

A longitudinal study of coping strategies in men receiving radiotherapy and neo-adjuvant androgen deprivation for prostate cancer: a quantitative and qualitative study.

Aim: This paper reports a study on how men cope with the side-effects of radiotherapy and neo-adjuvant androgen deprivation for prostate cancer up to 1 year after treatment.

Background: With early detection and improved treatments, prostate cancer survivors are living longer with the disease and the side-effects of treatment. How they cope affects their long-term physical and mental health.

Design: A prospective, longitudinal, exploratory design using both qualitative and quantitative methods was used in this study.

Method: Between September 2006–September 2007 149 men who were about to undergo radical radiotherapy ± androgen deprivation for localized prostate cancer in Northern Ireland were recruited to the study. They completed the Brief Cope scale at four time-points.

Results: Acceptance, positive reframing, emotional support, planning and, just getting on with it, were the most common ways of coping. Fewer men used coping strategies less at 6 months and 1 year after radiotherapy in comparison to pre-treatment and 4–6 weeks after radiotherapy. Interviews with these men demonstrated that men adapted to a new norm, with the support of their wives/partners and did not readily seek professional help. A minority of men used alcohol, behavioural disengagement and self blame as ways of coping.

Conclusion: Men used a variety of ways of coping to help them deal with radiotherapy and neo-adjuvant androgen deprivation for up to 12 months after radiotherapy. Interventions need to be developed to take account of the specific needs of partners of men with prostate cancer and single men who have prostate cancer.

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).

PATIENT SUMMARY: This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.

Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability

Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl Lewis(X) (SLe(X)), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy.

Stereotactic radiosurgery as a therapeutic strategy for intracranial metastatic prostate carcinoma.

Intracranial metastatic prostate carcinoma is rare. We sought to determine the clinical outcomes after Gamma Knife® stereotactic radiosurgery (GKSRS) for patients with intracranial prostate carcinoma metastases. We studied data from 10 patients who underwent radiosurgery for 15 intracranial metastases (9 dural-based and 6 parenchymal). Six patients had radiosurgery for solitary tumors and four had multiple tumors. The primary pathology was adenocarcinoma (eight patients) and small cell carcinoma (two patients). All patients received multimodality management for their primary tumor (including resection, radiation therapy, androgen deprivation therapy) and eight patients had evidence of systemic disease at time of radiosurgery. The mean tumor volume was 7.7 cm3 (range 1.1-17.2 cm3) and a median margin dose of 16 Gy was administered. Two patients had progressive intracranial disease in spite of fractionated partial brain radiation therapy (PBRT) prior to SRS. A local tumor control rate of 85% was achieved (including patients receiving boost, upfront and salvage SRS). New remote brain metastases developed in three patients (33%) and one patient had repeat SRS for tumor recurrence. The median survival after radiosurgery was 13 months and the 1-year survival rate was 60%. SRS was a well tolerated and effective therapy either alone or as a boost to fractionated radiation therapy in the management of patients with intracranial prostate carcinoma metastases. © 2009 Springer Science+Business Media, LLC.

Long-term health-related quality of life of prostate cancer survivors varies by primary treatment. Results from the PiCTure (Prostate Cancer Treatment, your experience) study

PURPOSE: Men are living longer with prostate cancer. In a two-country study, we investigated the health-related quality of life (HRQoL) of prostate cancer survivors up to 18 years post-diagnosis.

METHODS: Postal questionnaires were administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors 2-18 years post-diagnosis, identified through population-based cancer registries in Ireland. HRQoL was measured using QLQ-C30 and QLQ-PR25. HRQoL, functional and symptom scores were compared by primary treatment(s) using multiple linear regression.

RESULTS: Fifty-four percent responded (n = 3348). After controlling for socio-demographic and clinical factors, global HRQoL varied significantly by primary treatment (p < 0.001); compared to radical prostatectomy (RP), survivors who received androgen deprivation therapy alone (ADT; p < 0.001) or external beam radiotherapy (EBRT) without concurrent ADT (p = 0.001) had significantly lower global HRQoL. The global HRQoL of men who received brachytherapy (p = 0.157), EBRT with concurrent ADT (p = 0.940) or active surveillance/watchful waiting (p = 0.388) was not significantly different from men treated with RP. There were statistically and clinically significant differences in general (fatigue, pain, dyspnoea, appetite loss, constipation, diarrhoea, financial difficulties) and disease-specific symptoms (sexual, urinary, bowel, ADT) by primary treatment. Fatigue and insomnia scores were high for survivors in all treatment groups.

CONCLUSIONS: Prostate cancer survivors' long-term HRQoL varied with primary treatment.

IMPLICATIONS OF CANCER SURVIVORS: Population-based information regarding statistically and clinically significant treatment effects on long-term global HRQoL, symptom burden and functionality should be provided during treatment decision-making. Screening for symptoms and utilising interventions during long-term follow-up may improve survivors' HRQoL.

Failure to Achieve PSA Level ≤I ng/ml Following Neo-Adjuvant LHRHa Therapy Predicts for a Lower Biochemical Control Rate and Overall Survival in Localized Prostate Cancer Treated with Radiotherapy

PURPOSE: To investigate whether failure to suppress the prostate-specific antigen (PSA) level to /=2 months of neoadjuvant luteinizing hormone-releasing hormone agonist therapy in patients scheduled to undergo external beam radiotherapy for localized prostate carcinoma is associated with reduced biochemical failure-free survival. METHODS AND MATERIALS: A retrospective case note review of consecutive patients with intermediate- or high-risk localized prostate cancer treated between January 2001 and December 2002 with neoadjuvant hormonal deprivation therapy, followed by concurrent hormonal therapy and radiotherapy was performed. Patient data were divided for analysis according to whether the PSA level in Week 1 of radiotherapy was 1 ng/mL in 52. At a median follow-up of 49 months, the 4-year actuarial biochemical failure-free survival rate was 84% vs. 60% (p = 0.0016) in favor of the patients with a PSA level after neoadjuvant hormonal deprivation therapy of 1 ng/mL at the beginning of external beam radiotherapy after >/=2 months of neoadjuvant luteinizing hormone-releasing hormone agonist therapy have a significantly greater rate of biochemical failure and lower survival rate compared with those with a PSA level of

Hypoxia in prostate cancer:a powerful shield against tumour destruction?

Tumour hypoxia is progressively emerging as a common feature of prostate tumours associated with poor prognosis. While the molecular basis of disease progression is increasingly well documented, the potential role of hypoxia in these processes remains poorly evaluated. By dissecting the impact of hypoxia-inducible factor 1 alpha on molecular responses, this review provides evidence for a powerful protecting role of oxygen deprivation against oxidative stress injury, androgen deprivation, chemotherapeutic and radiation cytotoxicity. We propose hypoxia as a potent tumour-induced shield against destruction and suggest its targeting may need to be routinely addressed in the management of prostate cancer.