Article

Sarcopenia and change in body composition following maximal androgen suppression with abiraterone in men with castration-resistant prostate cancer

Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK.
British Journal of Cancer (Impact Factor: 4.82). 06/2013; 109(2). DOI: 10.1038/bjc.2013.340
Source: PubMed

ABSTRACT Background:
Standard medical castration reduces muscle mass. We sought to characterize body composition changes in men undergoing maximal androgen suppression with and without exogenous gluocorticoids.

Methods:
Cross-sectional areas of total fat, visceral fat and muscle were measured on serial CT scans in a post-hoc analysis of patients treated in Phase I/II trials with abiraterone followed by abiraterone and dexamethasone 0.5 mg daily. Linear mixed regression models were used to account for variations in time-on-treatment and baseline body mass index (BMI).

Results:
Fifty-five patients received a median of 7.5 months abiraterone followed by 5.4 months abiraterone and dexamethasone. Muscle loss was observed on single-agent abiraterone (maximal in patients with baseline BMI >30, −4.3%), but no further loss was observed after addition of dexamethasone. Loss of visceral fat was also observed on single-agent abiraterone, (baseline BMI >30 patients −19.6%). In contrast, addition of dexamethasone led to an increase in central visceral and total fat and BMI in all the patients.

Interpretation:
Maximal androgen suppression was associated with loss of muscle and visceral fat. Addition of low dose dexamethasone resulted in significant increases in visceral and total fat. These changes could have important quality-of-life implications for men treated with abiraterone.

Download full-text

Full-text

Available from: Deborah Mukherji, May 11, 2014
0 Followers
 · 
100 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic syndrome (MS) has not yet been studied in castration-resistant prostate cancer (CRPC) men treated with novel hormonal therapies. The study aims to assess the impact of MS on outcome from time starting abiraterone. We retrospectively evaluated a consecutive series of metastatic CRPC patients treated with abiraterone after docetaxel failure. MS, as defined by modified Adult Treatment Panel (ATP) III criteria, was assessed at the time of initiation of abiraterone, during treatment and follow-up. Sixty-seven of 178 patients evaluated (37.6%) met MS criteria at baseline, before abiraterone initiation, whereas for 11 (9.9%) without MS before treatment with abiraterone this occurred during treatment. Median PFS was equal to 4.7 months for patients with MS versus 9 months for those without MS. Patients with MS had an increased risk of 71% of progression or death for all causes than patients without MS (HR = 1.7, 95% CI [1.2-2.4], P = 0.03). Median OS was 14.7 months and 22.3 months in patients with and without MS, respectively. After adjusting for covariates, MS resulted not significantly associated to OS (HR = 1.42, 95% CI [0.91-2.22], P = 0.073). The presence of MS is a significant risk factor for shorter PFS in CRPC patients treated with abiraterone, even if it does not show a significant impact on OS. A prospective evaluation is warranted. Prostate 9999: XX-XX, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    The Prostate 05/2015; DOI:10.1002/pros.23014 · 3.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients with advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated the initial body mass index (BMIi), percent weight loss after 1 month of chemotherapy (ΔW 1m), percent weight loss after last administration of chemotherapy (ΔW end), and average weight loss per month during chemotherapy (ΔW/m). We correlated these data with overall survival (OS) by receiver-operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. The probabilities of longer OS had stronger correlations with ΔW/m and ΔW 1m than with ΔW end or BMIi. A significant positive correlation between ΔW 1m and ΔW/m (r (2) = 0.591, p < 0.001) was observed. Median OS of patients with ΔW 1m more than 3 % was significantly shorter than in patients with less weight loss (OS: 9.7 vs. 16.3 months, p < 0.001). Subgroup analysis revealed that ΔW 1m accompanied poor survival irrespective of other clinical characteristics. Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
    Asian Journal of Andrology 04/2014; 16(3). DOI:10.4103/1008-682X.129133 · 2.53 Impact Factor