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The Cochrane Database of Systematic... Mar 2013This is an updated version of a previously published review in The Cochrane Library (2005, Issue 2) on 'Megestrol acetate for the treatment of anorexia-cachexia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of a previously published review in The Cochrane Library (2005, Issue 2) on 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. Megestrol acetate (MA) is currently used to improve appetite and to increase weight in cancer-associated anorexia. In 1993, MA was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia or unexplained weight loss in patients with AIDS. The mechanism by which MA increases appetite is unknown and its effectiveness for anorexia and cachexia in neoplastic and AIDS (acquired immunodeficiency syndrome) patients is under investigation.
OBJECTIVES
To evaluate the efficacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies.
SEARCH METHODS
We sought studies through an extensive search of electronic databases, journals, reference lists, contact with investigators and other search strategies outlined in the methods. The most recent search for this update was carried out in May 2012.
SELECTION CRITERIA
Studies were included in the review if they assessed MA compared to placebo or other drug treatments in randomised controlled trials of patients with a clinical diagnosis of anorexia-cachexia syndrome related to cancer, AIDS or any other underlying pathology.
DATA COLLECTION AND ANALYSIS
Two independent review authors conducted data extraction and evaluated methodological quality. We performed quantitative analyses using appetite and quality of life as a dichotomous variable, and analysed weight gain as continuous and dichotomous variables.
MAIN RESULTS
We included 35 trials in this update, the same number but not the same trials as in the previous version of the review. The trials comprised 3963 patients for effectiveness and 3180 for safety. Sixteen trials compared MA at different doses with placebo, seven trials compared different doses of MA with other drug treatments and 10 trials compared different doses of MA. Meta-analysis showed a benefit of MA compared with placebo, particularly with regard to appetite improvement and weight gain in cancer, AIDS and other underlying conditions, and lack of benefit in the same patients when MA was compared to other drugs. There was insufficient information to define the optimal dose of MA, but higher doses were more related to weight improvement than lower doses. Quality of life improvement in patients was seen only when comparing MA versus placebo but not other drugs in both subcategories: cancer and AIDS. Oedema, thromboembolic phenomena and deaths were more frequent in the patients treated with MA. More than 40 side effects were studied.
AUTHORS' CONCLUSIONS
This review shows that MA improves appetite and is associated with slight weight gain in cancer, AIDS and in patients with other underlying pathology. Despite the fact that these patients are receiving palliative care they should be informed of the risks involved in taking MA.
Topics: Acquired Immunodeficiency Syndrome; Anorexia; Appetite Stimulants; Cachexia; Humans; Megestrol Acetate; Neoplasms; Randomized Controlled Trials as Topic; Syndrome
PubMed: 23543530
DOI: 10.1002/14651858.CD004310.pub3 -
Cancers Apr 2022Endometrial cancer (EC) rarely develops in young women. Most cases are associated with known risk factors: BMI > 30, history of Polycystic Ovary Syndrome (PCOs), and... (Review)
Review
Endometrial cancer (EC) rarely develops in young women. Most cases are associated with known risk factors: BMI > 30, history of Polycystic Ovary Syndrome (PCOs), and race differentiation. The molecular EC classification based on The Cancer Genome Atlas Research Network divides these heterogeneous cancers into four types: Polymerase Epsilon Mutation (POLE), Microsatellite Instability (MSI), Copy Number Low (CNL), and Copy Number High (CNH). This division was introduced to allow for early assessment of neoplastic changes and clinical management, including targeted therapies. The basic technique for imaging endometrium changes is transvaginal sonography. Hysteroscopy is the standard for obtaining endometrial material for histological evaluation. The MRI result permits assessment of the extent of EC cancer infiltration. In young women who want to preserve fertility, apart from surgery, conservative management is often implemented after strict selection based on clinical and pathological data. This pharmacological treatment involves the administration of progestogens MPA (medroxyprogesterone acetate) and MA (megestrol acetate). The use of metformin may increase the effectiveness of such treatment. An alternative option is to apply progestogens locally—via the levonorgestrel-releasing intrauterine device. In addition to pharmacological treatment, hysteroscopic resection may be used—part of the uterine muscle adjacent to the pathologically changed endometrium may also undergo resection. An alternative is the administration of estrogen receptor modulators (e.g., SERMs) or aromatase inhibitors, or GnRH agonists.
PubMed: 35454829
DOI: 10.3390/cancers14081922 -
The Cochrane Database of Systematic... Oct 2017Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain.
OBJECTIVES
To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar, OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and cross-over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health-related quality of life, and adverse effects during treatment.
MAIN RESULTS
We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision.We performed a meta-analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low-quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low-quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low-quality evidence). We found no data for recurrence of endometrial hyperplasia or health-related quality of life. Both studies (n = 59) provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others.Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low-quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low-quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low-quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37, one RCT, n = 16, very low-quality evidence). Investigators provided no data on abnormal uterine bleeding or health-related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea.
AUTHORS' CONCLUSIONS
At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy - specifically, megestrol acetate - versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long-term outcome data are needed to address this clinical question.
Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Disease Progression; Endometrial Hyperplasia; Female; Humans; Hysterectomy; Megestrol Acetate; Metformin; Middle Aged; Precancerous Conditions; Randomized Controlled Trials as Topic; Recurrence; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 29077194
DOI: 10.1002/14651858.CD012214.pub2 -
World Journal of Gastrointestinal... Apr 2015It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal... (Review)
Review
It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.
PubMed: 25897346
DOI: 10.4251/wjgo.v7.i4.17 -
Acta Crystallographica. Section E,... Apr 2012The title compound, C(24)H(34)O(4), is a precursor of Megestrol acetate. Ring A has a half-chair conformation [Q = 0.446 (3) Å, θ = 54.6 (4)° and ϕ =...
The title compound, C(24)H(34)O(4), is a precursor of Megestrol acetate. Ring A has a half-chair conformation [Q = 0.446 (3) Å, θ = 54.6 (4)° and ϕ = 9.5 (4)°]. Ring D adopts a 13β-envelope conformation [Q = 0.463 (2) Å and ϕ = 188.2 (3)°].
PubMed: 22590046
DOI: 10.1107/S1600536812008665 -
Xenobiotica; the Fate of Foreign... Oct 20181. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for...
1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 μM (HLM K for metabolite 1; M1) and 28 μM (HLM K for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 μM MA. 3. At 28 μM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.
Topics: Cell Line, Tumor; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Glucuronides; Humans; Ketoconazole; Kinetics; Megestrol Acetate; Metabolome; Microsomes, Liver; Oxidation-Reduction; Prostate-Specific Antigen; Proton Magnetic Resonance Spectroscopy; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Substrate Specificity; Troleandomycin
PubMed: 29050522
DOI: 10.1080/00498254.2017.1386335 -
Journal of Clinical Medicine Jun 2022Cancer-related anorexia/cachexia is known to be associated with worsened quality of life and survival; however, limited treatment options exist. Although megestrol... (Review)
Review
Cancer-related anorexia/cachexia is known to be associated with worsened quality of life and survival; however, limited treatment options exist. Although megestrol acetate (MA) is often used off-label to stimulate appetite and improve anorexia/cachexia in patients with advanced cancers, the benefits are controversial. The present meta-analysis aimed to better elucidate the clinical benefits of MA in patients with cancer-related anorexia/cachexia. A systematic search of PubMed, EMBASE, OVID Medline, Clinicaltrials.gov, and Google Scholar databases found 23 clinical trials examining the use of MA in cancer-related anorexia. The available randomized, controlled trials were appraised using Version 2 of the Cochrane risk-of-bias tool (RoB 2) and they had moderate-to-high risk of bias. A total of eight studies provided sufficient data on weight change for meta-analysis. The studies were divided into high-dose treatment (>320 mg/day) and low-dose treatment (≤320 mg/day). The overall pooled mean change in weight among cancer patients treated with MA, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ2 = 9.35, I2 = 96%). Patients who received high-dose MA tended to have weight loss rather than weight gain. There were insufficient studies to perform a meta-analysis for the change in tricep skinfold, midarm circumference, or quality of life measures. MA was generally well-tolerated, except for a clear thromboembolic risk, especially with higher doses. On balance, MA did not appear to be effective in providing the symptomatic improvement of anorexia/cachexia in patients with advanced cancer.
PubMed: 35807039
DOI: 10.3390/jcm11133756 -
International Journal of Nanomedicine 2006The aim is to review major clinical trials that have used megestrol acetate (MA) in the treatment of cachexia across several disease states. A review of general usage... (Review)
Review
The aim is to review major clinical trials that have used megestrol acetate (MA) in the treatment of cachexia across several disease states. A review of general usage and potential side-effects are discussed. A theory that the newly approved nanocrystal formation of MA can better deliver this potent medication for treatment will also be reviewed.
Topics: Anorexia; Cachexia; Clinical Trials as Topic; Drug Carriers; Humans; Megestrol Acetate; Nanoparticles
PubMed: 17722275
DOI: 10.2147/nano.2006.1.4.411 -
Bulletin Du Cancer Oct 1999Aromatase inhibitors used in breast cancer, are drugs that inhibit the transformation of androstenedione and testosterone, respectively in estradiol and estrone. Two... (Review)
Review
Aromatase inhibitors used in breast cancer, are drugs that inhibit the transformation of androstenedione and testosterone, respectively in estradiol and estrone. Two classes have been described: steroidal inhibitors which act competitively and irreversibly and non steroidal inhibitors which block the P 450 cytochrome. The first one is aminoglutethimide which has an adrenal effect on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a aminoglutethimide analogue. The response rates obtained with formestane is not different. The clinical development has been stopped due to a lack of specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful and more specific. Letrozole and vorozole are at least as efficient and better tolerated than aminoglutéthimide. Anastrozole, letrozole and vorozole are at least as efficient as megestrol acetate and better tolerated in advanced breast cancer patients receiving a second line hormone therapy.
Topics: Aminoglutethimide; Anastrozole; Androstadienes; Androstenedione; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Estrogen Antagonists; Estrone; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 10572233
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Jan 2017Weight loss is distressing to cancer patients and caregivers. Anorexia/cachexia syndrome is characterized by lipolysis and the loss of lean body mass, and is not... (Review)
Review
Weight loss is distressing to cancer patients and caregivers. Anorexia/cachexia syndrome is characterized by lipolysis and the loss of lean body mass, and is not reversible by increasing caloric intake. The pathophysiology of cancer cachexia is complex and includes symptoms that impact caloric intake, as well as chronic inflammation, hypermetabolism, and hormonal alterations. Cancer patients require routine screening for cachexia and, ideally, interventions should be initiated in the early stages of weight loss. No guidelines exist for the treatment of cancer cachexia. Appetite stimulants, such as megestrol acetate and glucocorticoids, have been shown to increase appetite and weight; however, single pharmaceutical interventions alone for cachexia do not result in meaningful functional outcomes. In the future, clinicians should consider multimodality treatment that is personalized for each patient. These interventions would include nutritional counseling, assessing and treating symptoms that have an impact on caloric intake, and a rational combination of pharmacologic approaches directed at underlying pathophysiology. Use of an appetite stimulant could be considered for patients who exhibit decreased appetite. Treatment with an anti-inflammatory agent should be considered for patients with elevated C-reactive protein, and hormonal alterations resulting from anti-cachexia therapy should be thoughtfully addressed.
Topics: Appetite Stimulants; Cachexia; Energy Intake; Humans; Neoplasms; Nutritional Support; Practice Guidelines as Topic
PubMed: 28090619
DOI: No ID Found