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1.
Efficacy and safety of pharmacological cachexia interventions: systematic review and network meta-analysis.
Saeteaw, M, Sanguanboonyaphong, P, Yoodee, J, Craft, K, Sawangjit, R, Ngamphaiboon, N, Shantavasinkul, PC, Subongkot, S, Chaiyakunapruk, N
BMJ supportive & palliative care. 2021;(1):75-85
Abstract
AIMS: Randomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia. METHODS PubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI. RESULTS 80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo. CONCLUSIONS Our findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.
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The effects of megestrol acetate on nutrition, inflammation and quality of life in elderly haemodialysis patients.
Zheng, Z, Chen, J, He, D, Xu, Y, Chen, L, Zhang, T
International urology and nephrology. 2019;(9):1631-1638
Abstract
PURPOSE Malnutrition, inflammation and poor quality of life are prevalent among elderly haemodialysis patients. Megestrol acetate (MA) is a synthetic progestin that is widely used to increase appetite and weight in various clinical settings. MA has been indicated to be effective in improving quality of life in patients with cancers. The aim of the present study was to evaluate the efficacy and safety of MA in treating malnourished elderly haemodialysis patients. METHODS A randomized controlled study involving 46 hypoalbuminemia haemodialysis patients aged 70 years or older was conducted. The patients in MA-treated group (n = 23) took 160 mg of MA daily, while those in control group (n = 23) were enrolled without any intervention. Anthropometric parameters and laboratory results, including height, dry weight, body mass index, and modified subjective global assessment score as well as serum albumin, triglyceride, total cholesterol, hsCRP, IL-1b and IL-6 concentrations were measured in all patients before and after the intervention. Health-related quality of life was also evaluated using the KDQOL-SF 1.3. RESULTS In the MA-treated group, a total of 18 patients finished the therapy over a 3-month period. Appetite was reported as improved by 15 patients, and a statistically significant increase was observed in dry weight (53.36 ± 6.15 vs. 54.24 ± 6.32, P < 0.01) and serum albumin concentration (29.05 ± 3.91 vs. 37.67 ± 4.88, P < 0.01) in the MA-treated group compared to those of the control group. The quality of life in both the physical domain (46.73 ± 18.17 vs. 63.37 ± 22.35, P < 0.01) and the mental domain (50.28 ± 20.36 vs. 68.02 ± 25.48, P < 0.01) was also improved in the same group. There was no significant change in the inflammatory marker concentrations after the intervention. No serious or unexpected adverse events were observed except that one patient who withdrew due to excessive fluid gain between haemodialysis sessions. CONCLUSION Our data suggest that MA can be effective in improving nutritional status and quality of life by increasing appetite in elderly haemodialysis patients with acceptable side effects; however, MA might not ameliorate inflammation.
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3.
Appetite stimulants for people with cystic fibrosis.
Chinuck, R, Dewar, J, Baldwin, DR, Hendron, E
The Cochrane database of systematic reviews. 2014;(7):CD008190
Abstract
BACKGROUND Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index and nutritional status. However, these may have adverse effects on clinical status. OBJECTIVES The aim of this review is to systematically search for and evaluate evidence on the beneficial effects of appetite stimulants in the management of CF-related anorexia and synthesize reports of any side-effects. SEARCH METHODS Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, CINAHL, handsearching reference lists and contacting local and international experts.Last search of online databases: 01 April 2014.Last search of the Cystic Fibrosis Trials Register: 08 April 2014. SELECTION CRITERIA Randomised and quasi-randomised controlled trials of appetite stimulants, compared to placebo or no treatment for at least one month in adults and children with cystic fibrosis. DATA COLLECTION AND ANALYSIS Authors independently extracted data and assessed the risk of bias within eligible trials. Meta-analyses were performed. MAIN RESULTS Three trials (total of 47 recruited patients) comparing appetite stimulants (cyproheptadine hydrochloride and megesterol acetate) to placebo were included; the numbers of adults or children within each trial were not always reported. The risk of bias of the included trials was graded as moderate.A meta-analysis of all three trials showed appetite stimulants produced a larger increase in weight z score at three months compared to placebo, mean difference 0.61 (95% confidence interval 0.29 to 0.93) (P < 0.001) (n = 40) with no evidence of a difference in effect between two different appetite stimulants. One of these trials also reported a significant weight increase with megesterol acetate compared to placebo at six months (n = 17). The three trials reported no significant differences in forced expiratory volume at one second (per cent predicted) between the appetite stimulant groups and placebo at follow up, with durations ranging from two to nine months. A meta-analysis of two trials showed a significantly higher proportion of patients reporting increased appetite, odds ratio 45.25 (95% confidence interval 3.57 to 573.33) (P = 0.003) (n = 23), but the frequency of reported side effects was undetermined. AUTHORS' CONCLUSIONS In the short term (six months) in adults and children, appetite stimulants improved only two of the outcomes in this review - weight (or weight z score) and appetite; and side effects were insufficiently reported to determine the full extent of their impact. Whilst the data may suggest the potential use of appetite stimulants in treating anorexia in adults and children with cystic fibrosis, this is based upon moderate quality data from a small number of trials and so this therapy cannot be conclusively recommended based upon the findings in the review. Clinicians need to be aware of the potential adverse effects of appetite stimulants and actively monitor any patients prescribed these medications accordingly.Research is needed to determine meaningful surrogate measures for appetite and define what constitutes quality weight gain. Future trials of appetite stimulants should use a validated measure of symptoms including a disease-specific instrument for measuring poor appetite. This review highlights the need for multicentred, adequately powered and well-designed trials to evaluate agents to safely increase appetite in people with cystic fibrosis and to establish the optimal mode of treatment.
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A randomized, double-blind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy.
Cuvelier, GD, Baker, TJ, Peddie, EF, Casey, LM, Lambert, PJ, Distefano, DS, Wardle, MG, Mychajlunow, BA, Romanick, MA, Dix, DB, et al
Pediatric blood & cancer. 2014;(4):672-9
Abstract
BACKGROUND Megestrol acetate (MA) is an appetite stimulant with efficacy in promoting weight gain in adults with cancer-associated anorexia-cachexia. Studies documenting MA efficacy in children, however, are limited. We present the first randomized, double-blind, placebo-controlled clinical trial of MA versus placebo in children with cancer and weight loss. METHODS Subjects <18 years of age with weight loss (minimum 5% from highest previous weight; or %ideal body weight <90%) due to cancer and/or cancer therapy were randomized to either MA (7.5 mg/kg/day) or placebo for a planned study duration of 90 days. Primary outcome was the difference between groups in mean percent weight change from beginning to end of the study period. Secondary outcomes included effects on anthropometrics, body composition, need for tube feeding or parenteral nutrition, and toxicities. RESULTS Twenty-six patients were randomly assigned (13 MA, 13 placebo). The MA group experienced a mean weight gain of +19.7% compared to a mean weight loss of -1.2% in the placebo group, for a difference of +20.9% (95%CI: +11.3% to +30.5%, P = 0.003) in favor of MA over placebo. MA subjects experienced significant increases in weight for age z-scores, body mass index z-scores, and mid upper arm circumference compared to placebo. DXA scanning suggested disproportionate increases in fat accrual. Adrenal suppression was the main toxicity of MA. CONCLUSION In children with high-risk malignancies, MA resulted in significant increases in mean percent weight change compared to placebo. Further studies of MA should be pursued to better delineate the effect on nutritional status.
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Comparison of three different treatment modalities in the management of cancer cachexia.
Kanat, O, Cubukcu, E, Avci, N, Budak, F, Ercan, I, Canhoroz, M, Olmez, F
Tumori. 2013;(2):229-33
Abstract
AIMS AND BACKGROUND The optimal treatment of cancer cachexia remains unknown. In this study, we compared the efficacy of three different treatment modalities in the management of cancer cachexia. METHODS Sixty-two assessable cachectic cancer patients were randomized to one of the following three arms: 1) megesterol acetate (MA) plus meloxicam (n = 23); 2) MA plus meloxicam plus oral eicosapentaenoic acid (EPA)-enriched nutritional supplement (n = 21); or 3) meloxicam plus oral EPA-enriched nutritional supplement (n = 18). Treatment duration was 3 months. RESULTS The treatment arms were well balanced at baseline. The primary efficacy (body weight and lean body mass) and secondary efficacy (body mass index, quality of life, and serum levels of IL-6 and TNF-α) parameters improved after treatment in all three arms. There were no statistically significant differences between treatment groups in the mean percentage changes in all efficacy parameters from baseline to end of study. CONCLUSIONS MA plus meloxicam or EPA supplement plus meloxicam may be effective treatment options in the management of cancer cachexia. The combined use of these agents does not provide further advantages.
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Muscle wasting in hemodialysis patients: new therapeutic strategies for resolving an old problem.
Chen, CT, Lin, SH, Chen, JS, Hsu, YJ
TheScientificWorldJournal. 2013;:643954
Abstract
Muscle wasting has long been recognized as a major clinical problem in hemodialysis (HD) patients. In addition to its impact on quality of life, muscle wasting has been proven to be associated with increased mortality rates. Identification of the molecular mechanisms underlying muscle wasting in HD patients provides opportunities to resolve this clinical problem. Several signaling pathways and humeral factors have been reported to be involved in the pathogenic mechanisms of muscle wasting in HD patients, including ubiquitin-proteasome system, caspase-3, insulin/insulin-like growth factor-1 (IGF-1) signaling, endogenous glucocorticoids, metabolic acidosis, inflammation, and sex hormones. Targeting the aforementioned crucial signaling and molecules to suppress protein degradation and augment muscle strength has been extensively investigated in HD patients. In addition to exercise training, administration of megestrol acetate has been proven to be effective in improving anorexia and muscle wasting in HD patients. Correction of metabolic acidosis through sodium bicarbonate supplements can decrease muscle protein degradation and hormone therapy with nandrolone decanoate has been reported to increase muscle mass. Although thiazolidinedione has been shown to improve insulin sensitivity, its role in the treatment of muscle wasting remains unclear. This review paper focuses on the molecular pathways and potential new therapeutic approaches to muscle wasting in HD patients.
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Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome.
Madeddu, C, Dessì, M, Panzone, F, Serpe, R, Antoni, G, Cau, MC, Montaldo, L, Mela, Q, Mura, M, Astara, G, et al
Clinical nutrition (Edinburgh, Scotland). 2012;(2):176-82
Abstract
BACKGROUND & AIMS A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. METHODS Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. RESULTS The results did not show a significant difference between tre atment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. CONCLUSIONS The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.
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Influence of megestrol acetate on nutrition, inflammation and quality of life in dialysis patients.
Gołębiewska, JE, Lichodziejewska-Niemierko, M, Aleksandrowicz-Wrona, E, Majkowicz, M, Lysiak-Szydłowska, W, Rutkowski, B
International urology and nephrology. 2012;(4):1211-22
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Abstract
AIM: Malnutrition is a common clinical problem in dialysis patients. The objective of this study was to evaluate the efficacy and safety of megestrol acetate in malnourished dialysis patients. Thirty-two hypoalbuminemic dialysis patients took 160 mg of megestrol acetate daily for up to 6 months. METHODS We measured height, dry weight, BMI, modified Subjective Global Assessment (SGA) score, and serum albumin, triglycerides, total cholesterol, hsCRP, IL-1β and IL-6 concentrations. We used validated questionnaires to evaluate selected dimensions of the quality of life. RESULTS Only 12 patients completed the study. All patients reported improved appetite, and there were concurrent statistically significant increases in weight, BMI, SGA and albumin concentration (P < 0.05). For the 12 patients who completed 6 months of treatment the increase in these parameters was from 63.26 ± 13.04 to 65.58 ± 12.53 kg, from 23.5 ± 3.8 to 24.66 ± 4.23 kg/m(2), from 5.16 ± 0.94 to 6.16 ± 0.72 points, and from 36.45 ± 1.82 to 40.33 ± 2.71 g/l, respectively. However, there were no significant changes in the levels of inflammatory markers and in quality of life. Side effects included overhydration, excessive weight gain and hyperglycaemia. CONCLUSION Megestrol acetate may be effective in reversing poor appetite in carefully selected maintenance dialysis patients, but it might not reduce inflammation or improve the quality of life. Because of the potential side effects, close monitoring is essential.
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Report of a pilot, double-blind, placebo-controlled study of megestrol acetate in elderly dialysis patients with cachexia.
Yeh, SS, Marandi, M, Thode, HC, Levine, DM, Parker, T, Dixon, T, Schuster, MW
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2010;(1):52-62
Abstract
OBJECTIVE We examined the effects of megestrol acetate versus placebo and progressive resistance physical exercise on weight, lean muscle mass, quality of life, ability to exercise, proinflammatory cytokines, and anti-inflammatory cytokines, and their correlations with one another. DESIGN We organized a prospective 20-week, randomized, double-blind, placebo-controlled pilot trial of hemodialysis patients. SETTING This study took place at the Outpatient Unit of the Northport Veteran Affairs Medical Center. SUBJECTS We studied nine male hemodialysis patients who had two or more of the following: albumin level <4.0 g/dL, total cholesterol <150 mg/dL, protein catabolic rate <0.8 g/kg/day, and predialysis serum urea nitrogen <60 mg/dL. Their ages were 50 to 83 years. Two were diabetic, and seven were nondiabetic. INTERVENTIONS Interventions included megestrol acetate (MA) or placebo 800 mg oral daily for 20 weeks, along with weight resistance physical therapy with weights twice a week before dialysis. Patients were followed prospectively for an additional 4 weeks. MAIN OUTCOME MEASUREMENTS Weight, body composition, activities of daily living, ability to exercise, and plasma cytokine levels were measured. RESULTS At 24 weeks, the MA group had a statistically significant weight gain (11.1-pound increase vs. 1.5-pound decrease for the placebo group, P = .018), body fat gain (6.2-pound increase vs. a 0.4-pound decrease for the placebo group, P = .044) and fat-free mass gain (5-pound increase vs. a 1.2-pound decrease in the placebo group). The MA group also had a greater tendency toward increased appetite and sense of well-being. The MA group showed a greater improvement in ability to exercise (mean change in rate of perceived exertion (RPE), 4.7) vs. the placebo group (mean change in RPE vs. 0.5, P = .02). Elevated cytokine levels were evident at baseline in both groups. In all patients, increases in weight, fat-free mass, sense of well-being, appetite, and ability to exercise were negatively correlated with tumor necrosis factor receptor subunit p75 (P < .05). There was a trend toward all of these parameters to be negatively correlated with tumor necrosis factor receptor subunit p55, although only sense of well-being was statistically significant (P < .05). CONCLUSION In a pilot trial in dialysis patients, MA showed significant benefits in improving weight and ability to exercise. Cytokine changes were correlated with weight gains and increases in fat-free mass.
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Effect of megestrol acetate on serum albumin level in malnourished dialysis patients.
Monfared, A, Heidarzadeh, A, Ghaffari, M, Akbarpour, M
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2009;(2):167-71
Abstract
OBJECTIVE Malnutrition is a common problem in dialysis patients, and may affect up to one third of patients. It is associated with high mortality and morbidity. Although a number of studies were performed to determine effective treatment, there is no proven medication for this condition. This study aimed to evaluate the effect of megestrol acetate (MA) on serum albumin levels in malnourished dialysis patients. DESIGN This was a randomized, controlled clinical trial. SETTING The setting, a dialysis center at Razi Hospital, Rasht, Iran, provides services to dialysis patients. PATIENTS Twenty-two malnourished dialysis patients with persistent hypoalbuminemia (albumin, <3.5 g/dL for 2 months) participated, and were randomly assigned to either an experimental group or a control group. INTERVENTION The experimental group was treated with MA, 40 mg twice daily, over 2 months, and was compared with the control group. The collected data were analyzed using SPSS (version 10; Chicago, IL). RESULTS After 2 months, the mean (+/-SD) serum albumin level in the experimental group rose from 3.31 +/- 0.31 g/dL to 4.41 +/- 0.31 g/dL, but in the control group, it declined, from 3.35 +/- 0.21 to 3.02 +/- 0.48 g/dL. The difference between the two groups was significant (P = .002). CONCLUSION At a dose of 40 mg twice a day, MA safely increased serum albumin in malnourished dialysis patients.