Meg Acet in Anorexia

Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Berenstein EG, Ortiz Z
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 3 http://www.thecochranelibrary.com
Megestrol acetate for treatment of anorexia-cachexia syndrome (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
TABLE OF CONTENTS ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 01. Patient condition and numbers recruited to each trial . . . . . . . . . . . . . . . . Table 02. EMBASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 03. Cochrane Pain, Palliative and Supportive Care Group Trials register . . . . . . . . . . . ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison 01. Megestrol acetate vs placebo (ITT) . . . . . . . . . . . . . . . . . . . . Comparison 02. Megestrol acetate vs other drugs (ITT) . . . . . . . . . . . . . . . . . . Comparison 03. Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.01. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 01 Appetite improvement . Analysis 01.02. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 02 Weight gain . . . . . Analysis 01.03. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 03 Weight gain . . . . . Analysis 01.04. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 04 Quality of life . . . . Analysis 01.05. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 05 Side effects . . . . . Analysis 02.01. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 01 Appetite improvement Analysis 02.02. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 02 Weight gain . . . . Analysis 02.03. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 03 Weight gain . . . . Analysis 02.04. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 04 Quality of life . . . Analysis 03.01. Comparison 03 Sensitivity analysis, Outcome 01 Appetite improvement, treatment duration Analysis 03.02. Comparison 03 Sensitivity analysis, Outcome 02 Weight gain, treatment duration . . . . Analysis 03.03. Comparison 03 Sensitivity analysis, Outcome 03 Weight gain, treatment duration . . . . Analysis 03.04. Comparison 03 Sensitivity analysis, Outcome 04 Appetite improvement, study quality . . Analysis 03.05. Comparison 03 Sensitivity analysis, Outcome 05 Weight gain, study quality . . . . . . Analysis 03.06. Comparison 03 Sensitivity analysis, Outcome 06 Weight gain, study quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 2 3 3 3 4 4 6 6 8 9 9 9 9 10 12 12 25 25 25 27 28 28 28 28 29 29 29 30 31 32 33 34 35 36 37 38 39 40 40 41 41 42 43
Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)

Berenstein EG, Ortiz Z
This record should be cited as: Berenstein EG, Ortiz Z. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD004310. DOI: 10.1002/14651858.CD004310.pub2. This version rst published online: 20 April 2005 in Issue 2, 2005. Date of most recent substantive amendment: 23 January 2005
ABSTRACT Background This is an updated version of a previously published review in The Cochrane Library (Issue 2, 2005) 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 USAs Federal 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 patients is under investigation. Objectives To evaluate the efcacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies. Search strategy Studies were sought through an extensive search of the 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 June 2006. Selection criteria Studies were included in the review if they assessed megestrol acetate compared to placebo or other drug treatments in randomized controlled trials of patients with a clinical diagnosis of anorexia-cachexia related to cancer, AIDS or another underlying pathology. Data collection and analysis Data extraction was conducted by two independent review authors, and methodological quality evaluated. Quantitative analyses were performed using appetite and quality of life as a dichotomous variable, and weight gain was analysed as continuous and dichotomous variables. Studies with more than 50% of patients lost to follow-up were excluded from the analysis. Main results Thirty trials were included in the original review, four new trials were identied for this update, but only two met the inclusion criteria (4123 + 703 patients). Twenty-two trials compared MA at different doses with placebo; ve compared different doses of MA versus other drugs; two compared MA with other drugs and placebo; and ve compared different doses of MA. For all patient conditions, metaanalysis showed a benet of MA compared with placebo, particularly with regard to appetite improvement and weight gain in cancer patients. Analysing quality of life, clinical and statistical heterogeneity was found and discussed. There was insufcient information to dene the optimal dose of MA. Authors conclusions This review demonstrates that MA improves appetite and weight gain in patients with cancer. No overall conclusion about Quality of Life (QoL) could be drawn due to heterogeneity. The small number of patients, methodological shortcomings and poor reporting have not allowed us to recommend megestrol acetate in AIDS patients or with other underlying pathologies. Since the last version of
Megestrol acetate for treatment of anorexia-cachexia syndrome (Review) Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 1
this review, none of the new relevant studies have provided additional information on this treatment, in contrast to other therapeutic approaches that should be considered.
PLAIN LANGUAGE SUMMARY Megestrol acetate improves appetite and weight gain in patients with anorexia cachexia syndrome related to cancer. Megestrol acetates mechanism of action is unknown. There are concerns regarding the possible recommendations for this drug; particularly in the improvement of quality of life in health care and in cancer patients. Quality of life is the cornerstone for delivery of good palliative medicine. The review found that megestrol acetate signicantly increased appetite and weight gain in cancer patients but there was not enough evidence to reach a conclusion about the effect on quality of life and the optimal dose. There was too little information on AIDS patients or those patients with other underlying pathologies. A low incidence of adverse effects was found.
BACKGROUND This review is an update of a previously published review in The Cochrane Library (Issue 2, 2005) on megestrol acetate for anorexia cachexia syndrome. Anorexia cachexia syndrome is a common clinical problem that substantially impacts upon the quality of life and survival of affected patients. It is characterized by loss of appetite, weight loss and tissue wasting, accompanied by a decrease in muscle mass and adipose tissue, impoverishing the quality of life, and often preceding the patients death (Nelson 1994; Splinter 1992). More than two-thirds of patients dying with advanced cancer suffer from anorexia cachexia syndrome (Argils 2001). Anorexia cachexia syndrome is also described in other pathologies such as Acquired Immune Deciency Syndrome (AIDS); anorexia nervosa; in degenerative illnesses of the central nervous system; and in terminally ill patients (Von Roenn 1996). Incidence is variable and difcult to determine but in general the syndrome may occur in 15% to 40% of patients with cancer, and in more than 80% of patients with advanced illness (Bruera 1992). Cachexia in cancer patients is thought to occur as a result of metabolic changes brought about by substances secreted by the tumour and the host (Alexander 1993). Substances have been identied that cause severe anorexia and weight loss. Tumour necrosis factor, synthesized by the hosts macrophages (important cells in the immune system), and inammatory cytokines (including interleukin 1 (I1) and 6 (I6)) are considered responsible for some of the clinical manifestations (Mantovani 1998). Early intervention and attention to nutritional status are essential in patients with anorexia cachexia syndrome. Pharmacological interventions for neoplastic cachexia include drugs that stimulate the appetite (megestrol acetate and dronabinol); cytokine inhibitors (such as cyproheptadine, thalidomide, pentoxifylline and an eicosapentaenoic acid (EPA)); and anabolic agents such as nandrolone decanoate, oxandrolone and corticosteroids (Balog 1998). EPA
seems to suppress well-characterized mediators of cancer associated wasting, including interleukin-6, an inammatory cytokine. It also acts over the proteolysis-inducing factor, another well-described mediator (Barber 1999; Wigmore 1997). Megestrol acetate is a synthetic progestogen agent. The biological mechanism of the anti-tumoral activity of megestrol acetate is not well understood but it probably acts on hormone-dependent tumoral cells. Inhibitory effects on growth in the cellular cycle are not phase-specic, but their activity seems to be maximized in phase G1 of cellular division (Tchekmedyian 1986). Megestrol acetate was rst synthesized in England in 1963. Developed as an oral contraceptive, the agent was rst tested in the treatment of breast cancer in 1967 and later on, for the treatment of endometrial cancer. Megestrol acetate is currently used to improve appetite and to increase weight in cancer-associated anorexia. From September 1993 megestrol acetate was approved by the Federal Drug Administration (FDA) in the USA for the treatment of anorexia, cachexia, or unexplained weight loss in patients with AIDS. In addition, there are recent reports of the drug being used to improve the quality of life of elderly patients with cachexia. A possible role in anorexia nervosa has also been proposed (Yeh 2000). Megestrol acetate is commonly available as a tablet of 80 mg or liquid form (40 mg of micronized megestrol acetate per mL). A great variability in doses is observed in the scientic literature, ranging from 100 mg to 1600 mg per day (Tchekmedyian 1992; Von Roenn 1994). The liquid form is usually dosed at 20 ml per day and the oral one is four tablets per day. The recommended duration of treatment is six weeks or more. Megestrol acetate is considered a relatively non toxic drug with a low incidence of adverse effects such as uid retention, venous thrombosis, diarrhea, rash, impotence, pruritus, increased blood sugar level, and headache (Loprinzi 1990a; Vadell 1998; Von Roenn 1994). Although the mechanism by which megestrol acetate increases appetite is unknown, most hypotheses point to action on cytokines,
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which inhibit the action of tumour necrosis factor on fatty tissue and its products. Currently, interest is focused especially on its effectiveness in the treatment of anorexia and cachexia in neoplastic and AIDS patients. Studies at the Mayo Clinic and The North Central Cancer Treatment Group Study have reported and reviewed multiple placebo-controlled, randomized, double blind, clinical trials of megestrol acetate and other drugs for the improvement of anorexia cachexia syndrome in all types of cancer (Jatoi 2004; Loprinzi 1990a).
measurements of the mid-arm circumference and triceps skin fold thickness by anthropometry, as a percentage of the differences in the total body muscle and fat mass; improvement in quality of life (QoL), by means of a validated instrument, or with scales of functional scores (e.g., Index of Karnofsky and performance status) that measure the well-being status of the patient. The QoL measures will depend on the instrument used, e.g., patient assessments using a Likerttype scale based on patients statements and self-report questionnaires; or the use of the Spitzer QL-Index of quality of life, completed by the clinician. Study withdrawals and dropouts were analyzed as:
OBJECTIVES 1) To evaluate the efcacy, effectiveness and safety of megestrol acetate in palliating anorexia-cachexia syndrome in sub-groups of patients with cancer, AIDS, and other underlying pathologies. 2) To determine the optimal dose regimen for megestrol acetate in palliating the anorexia-cachexia syndrome.
total number of dropouts and withdrawals, number of withdrawals due to lack of effectiveness of treatment, number of withdrawals due to adverse effects. Adverse effects: these were analyzed as the number of patients who suffer an event described as a side effect by the authors of each study.
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW Types of studies Randomized controlled trials (RCTs) which may be double blind, single blind or unblinded. Cross-over studies were included if they reported the results of the rst phase of the study. Both inpatient and outpatient study settings were included. Types of participants Trials of patients with a clinical diagnosis of anorexia-cachexia related to cancer, AIDS or another underlying pathology (independent of gender, age or race) were included. Types of intervention The review focuses on the following treatment comparisons: a) Megestrol acetate at any dose versus placebo; b) Megestrol acetate at any dose versus other active drug treatments (stimulants of appetite such as dronabinol; cytokine inhibitors such as cyproheptadine, EPA and anabolic agents such as nandrolone decanoate and corticosteroids); c) Megestrol acetate at different doses. Types of outcome measures The following outcome measures were assessed: appetite increase, expressed as a dichotomous variable (number of patients who experience appetite increase) or a continuous variable (caloric intake expressed as calories/day); weight gain, measured as a dichotomous variable (number of patients who gain weight) and as a continuous variable in kg/day at the end of the treatment compared with the baseline;
SEARCH METHODS FOR IDENTIFICATION OF STUDIES See: Cochrane Pain, Palliative and Supportive Care Group methods used in reviews. The following electronic databases were searched to identify relevant studies: MEDLINE from 1966 to October 2002, subsequent search June 2006 (see below); EMBASE from 1986 to 2002, subsequent search, week 28, 2006 (see additional Table 02); The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library Issue 1, 2002, subsequent search Issue 2, 2006. The Cochrane Pain, Palliative and Supportive Care Group Trials Register (June 2006) (see additional Table 03) For the identication of studies included or considered for this review, detailed search strategies were developed for each database searched. The general strategy for identifying RCTs in MEDLINE was combined with the following specic strategy designed to retrieve trials of megestrol acetate for cachexia. The Medline search strategy is as follows, the details of the other searches are included in the additional tables: (Acquired Immunodeciency Syndrome[All Fields] OR (acquired immunodeciency syndrome[MeSH Terms] OR AIDS [Text Word]))
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((neoplasms[MeSH Terms] OR Neoplasm [Text Word]) OR cancer [Text Word])) ((end of life[All Fields] OR (terminally ill [MeSH Terms] OR Terminally ill [Text Word])) OR (terminal care[MeSH Terms] OR Terminal care[Text Word])) (cachexia[MeSH Terms] OR cachexia [Text Word]) (megestrol acetate [MeSH Terms] OR megestrol acetate [Text Word]) Lists of references of the included studies were checked to identify further trials. Studies were not excluded on the basis of language or publication status (published, unpublished, in press, and in progress). Additional data from published trials were sought by contacting authors.
Data analysis Studies with more than 50% of patients lost to follow-up were not included in the analysis. We only analyzed crossover studies that included results from the rst treatment period in order to avoid carry-over effects. For dichotomous variables, treatment effects were computed as relative risk (RR) with 95% condence intervals (CI). For continuous variables measured weight gain differences in means and their 95% CI were calculated (weighted mean difference - (WMD)) and for quality of life (including different scales), differences in means and their 95% CI were calculated (standardised mean difference - (SMD)). Only validated scales with a normal distribution were included for the analysis. Validity of the scale was determined by the psychometric properties of the instrument described in the trial by the review authors. A random effect model was used in the analysis. Statistical heterogeneity between studies was analysed with a Chi-square test, using P < 0.1 as a cut-off value to represent the presence of signicant heterogeneity. When a high level of heterogeneity was detected, attempts were made to identify the sources of the heterogeneity, and subsequent meta-analysis were performed using a random effect model. Subgroup analysis Analysis of subgroups was undertaken according to the underlying pathology of the patients. Three subgroups of studies were dened: patients with AIDS; patients with cancer; patients with other underlying disease. Sensitivity analysis In order to explore the impact of specic factors on the metaanalysis results, sensitivity analyses was undertaken with: studies of high methodological quality (dened as studies with appropriate concealment of allocation, appropriate blinding, and analysis by intention-to-treat (ITT)); studies where patients received more than six weeks of treatment. The statistical analyses were carried out using the statistical package, RevMan Analyses 1.0.2, in RevMan 4.2.10.
METHODS OF THE REVIEW Study selection The results of the search strategy were independently screened by two review authors (EGB, ZO) and assessed for inclusion in the previous and updated review. Disagreement was resolved by discussion. Reasons for excluding trials were reported. Data extraction Data on patients, methods, interventions, outcomes and results were extracted by two review authors using a data extraction form (EGB, ZO) in the previous and updated review. Differences were resolved by consensus, and when necessary, in consultation with a third review author. Quality of studies The methodological quality of the studies was evaluated using a validated scale called the Oxford Quality Scale (Jadad 1996). This scale includes an evaluation of the randomisation, blinding and patient attrition. The scale produces a composite score ranging from one (low quality) to ve (high quality). The three item scale is applied as follows: is the study randomised ? If yes , then one point If described, is the randomisation appropriate? If yes add one point, if not deduct one; is the study double blind ? If yes, then one point. Is the double blind method appropriate ? If yes add one point, if not deduct one; are withdrawals and dropouts described? (i.e., the number and reason for drop-outs for each of the treatment groups). If yes, add one point. Allocation concealment was also evaluated as a parameter of quality of the design of the studies, and is reported in the Characteristics of included studies table.
DESCRIPTION OF STUDIES Searching electronic databases identied: 99 reports in MEDLINE (from 1966 to October 2002, the subsequent search identied 24 reports in MEDLINE (from 2002 to July 2006);
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164 reports in EMBASE (from 1986 to 2002), the subsequent search identied 24 in EMBASE (from 2002 to week 28, 2006); and 71 in The Cochrane Central Register of Controlled Trials (Central), (Issue 2, 2006), the subsequent search identied 59 reports (in Issue 1, 2002). Three abstracts retrieved from handsearching in CCRT (Central) were identied in this updated review. We attempted to contact the authors of these abstracts for further trials data but with no success. Excluded studies In this 2006 update we excluded one additional study (Yeh 2004) and one unpublished study (Macbeth 1994) taking the total of excluded studies to three. Included studies Further independent assessment by two review authors led to the selection of two new articles: one from Jatoi 2004 and the other from Ulutin 2002. Three abstracts were included (Gambardella 1998; Pardo 2003; Zeca 1995), but two had only a small amount of data, Gambardella 1998 had no data at all although it met the inclusion criteria, however, as there was no data available at present it was excluded from the analyses for now and should data become available at a later date, it will be included in a future update. Many of these citations were replicated across the three databases, and ve studies that appeared to meet the inclusion criteria were subsequently found to be follow-up reports or duplicate publications (see Characteristics of excluded studies table). A total of 34 reports (describing 35 trials) fully met the inclusion criteria for this update and provided data for analysis. The designs of the 34 trials were as follows: Megestrol acetate at different doses compared with placebo Twenty-two trials compared megestrol acetate at different doses with placebo (Beller 1997; Bruera 1990; Bruera 1998; De Conno 1998; Erkurt 2000; Eubanks 2002; Feliu 1992; Fietkau 1996; Loprinzi 1990b; Marchand 2000; McMillan 1994; McQuellon 2002; Oster 1994; Rowland 1996; Schmoll 1992; Tchekmedyian 1992; Vadell 1998; Von Roenn 1994; Weisberg 2002; Westman 1999; Yeh 2000; Zeca 1995). Megestrol acetate at different doses compared with other treatment drugs Five trials compared different doses of megestrol acetate with other drug treatments. Megestrol acetate was compared with dronabinol in two studies (Jatoi 2002; Timpone 1997); dexamethasone and uoximesterone in one study (Loprinzi 1999); nandrolone decanoate in one study (Batterham 2001) and eicosapentaenoic acid (EPA) in one study (Jatoi 2004). Megestrol acetate at different doses compared with other treatment drugs and placebo
Two studies compared megestrol acetate with other drugs and placebo (Lai 1994 (prednisolone); Chen 1997 (cisapride)). Megestrol acetate at different doses Five trials (compared different doses of megestrol acetate (Gebbia 1996; Heckmayr 1992; Loprinzi 1994; Pardo 2003; Ulutin 2002). The included studies were categorized according to the health care problem of the patient - see Table 01 for a summary. Patient characteristics A total of 4826 patients recruited were included in this update. The mean age of patients included in the treatment and control groups across all studies was 56 years. The proportion of males to females in the treatment groups was 1343/562, compared to 2038/833 in the control groups. Patients with any cancer Twenty-six trials (total number of patients 4148) (Beller 1997; Bruera 1990; Bruera 1998; Chen 1997; De Conno 1998; Erkurt 2000; Feliu 1992; Fietkau 1996; Gebbia 1996; Heckmayr 1992; Jatoi 2002; Jatoi 2004; Lai 1994; Loprinzi 1990b; Loprinzi 1994; Loprinzi 1999; McQuellon 2002; McMillan 1994;Pardo 2003; Rowland 1996; Schmoll 1992; Tchekmedyian 1992; Vadell 1998; Westman 1999; Ulutin 2002; Zeca 1995) assessed the effectiveness of megestrol acetate for anorexia-cachexia syndrome in cancer patients where the primary site was: lung cancer (1792 patients, 43%); gastrointestinal and pancreatic cancer (1045 patients, 25%); head and neck cancer (347 patients, 8%); gynecological cancer (74 patients, 2%); non-specied sites (890 patients, 21%). Patients with AIDS Four trials (total number of patients, 435) assessed the effectiveness of megestrol acetate for anorexia-cachexia syndrome in AIDS patients (Batterham 2001; Oster 1994; Timpone 1997; Von Roenn 1994) Patients with other underlying conditions Four trials (total number of patients, 243) assessed the effectiveness of megestrol acetate for anorexia-cachexia syndrome in patients with the following conditions: chronic obstructive pulmonary disease (COPD): one trial (Weisberg 2002) of 145 patients; cystic brosis: two trials (Marchand 2000 of 12 patients and Eubanks 2002 of 17 patients); elderly: one trial (Yeh 2000) of 69 patients. Dose Across the studies, the dose of megestrol acetate ranged from 100 mg per day to 1600 mg per day in at least one of the study arms.
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The doses of megestrol acetate assessed were as follows: 400 mg per day or less Seventeen trials: Batterham 2001(400 mg per day); Beller 1997 (160 mg per day); Chen 1997 (160 mg per day); De Conno 1998 (320 mg per day); Feliu 1992 (240 mg per day); Fietkau 1996 (160 mg per day); Gebbia 1996 (160 mg and 320 mg per day); Heckmayr 1992 (160 mg per day); Lai 1994 (160 mg per day); Loprinzi 1994 (160 mg per day); Pardo 2003 (320 mg per day); Timpone 1997 (250 mg per day); Ulutin 2002 (160 mg and 320 mg per day); Vadell 1998 (160 mg per day); Von Roenn 1994 (100 mg and 400 mg per day); Westman 1999 (320 mg per day); Zeca 1995 (320 mg per day). 480 mg per day Nine trials: Beller 1997; Bruera 1990; Bruera 1998; Erkurt 2000; Heckmayr 1992; Loprinzi 1994; McMillan 1994; Schmoll 1992; Vadell 1998 600 mg per day Two trials: Jatoi 2004; Pardo 2003 750 to 800 mg per day Eleven trials: Jatoi 2002; Timpone 1997; Loprinzi 1990b; Loprinzi 1994; Loprinzi 1999; McQuellon 2002; Oster 1994; Rowland 1996; Von Roenn 1994; Weisberg 2002; Yeh 2000 1280 mg per day One trial: Loprinzi 1994 1600 mg per day One trial: Tchekmedyian 1992 One trial in children with cystic brosis assessed megestrol acetate at a dose of 10 mg/kg per day (Marchand 2000) Study duration The study duration ranged from ten days to 24 weeks. One study ran for two years (Rowland 1996) and measured survival and response to chemotherapy as well as the effect of megestrol acetate on anorexia-cachexia syndrome. The median trial duration time was eight weeks. Five trials had a duration of more than 12 weeks, (see Characteristics of the included studies table). Assessment at seven days (Bruera 1990) Assessment at ten days (Bruera 1998) Final assessment at two weeks (Beller 1997; De Conno 1998; Zeca 1995) Assessment at three weeks (Lai 1994) Assessment at four weeks/one month (Chen 1997; Gebbia 1996; Heckmayr 1992; Jatoi 2002; Loprinzi 1990b; Loprinzi 1999; Pardo 2003)
Assessment at six weeks (Fietkau 1996; Tchekmedyian 1992) Assessment at eight weeks/two months (Chen 1997; Feliu 1992; Loprinzi 1994; Schmoll 1992; Weisberg 2002) Assessment at 12 weeks/three months (Batterham 2001; Erkurt 2000; Fietkau 1996; Jatoi 2004; Marchand 2000; McMillan 1994; McQuellon 2002; Oster 1994; Timpone 1997; Ulutin 2002; Vadell 1998; Von Roenn 1994; Westman 1999; Yeh 2000) Assessment at six months or more (Eubanks 2002; Rowland 1996)
METHODOLOGICAL QUALITY The methodological quality of the included studies was assessed using the Oxford Quality Scale (Jadad 1996). Each report was scored independently for quality by the review authors using the three-item scale described in the Methods section above who agreed a consensus score. The scores for methodological quality were generally high. Twenty one trials (62%) scored three or more out of a maximum of ve: Beller 1997; Bruera 1990; Bruera 1998; De Conno 1998; Eubanks 2002; Feliu 1992; Fietkau 1996; Jatoi 2002; Jatoi 2004; Loprinzi 1990b; Loprinzi 1994; Loprinzi 1999; Marchand 2000; McQuellon 2002; Oster 1994; Tchekmedyian 1992; Vadell 1998; Von Roenn 1994; Weisberg 2002; Westman 1999; Yeh 2000. Thirteen trials (38%) achieved a low score (two points or lower): Batterham 2001; Chen 1997; Erkurt 2000; Gebbia 1996; Heckmayr 1992; Lai 1994; McMillan 1994; Pardo 2003; Rowland 1996; Schmoll 1992; Timpone 1997; Ulutin 2002; Zeca 1995.
RESULTS Data from the included studies were meta-analysed in to three groups: megestrol acetate versus placebo, megestrol acetate versus other active drug treatments, megestrol acetate at different doses. they were further categorized into: patients with cancer, patients with AIDS, patients with other underlying pathologies. The two new complete studies and two abstracts could not be included in the analysis because of the drop-outs in Jatoi 2004, the comparison of two low doses of megestrol in Ulutin 2002,
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the comparison of one low dose of megestrol versus high dose in Pardo 2003 as explained below, and the lack of information in Gambardella 1998. Only Zeca 1995 was included in the analysis of appetite. To address the problem of patient attrition and loss to followup, both ITT and per protocol (PP) analyses were undertaken for each of the outcomes. Three trials were excluded from the analysis (Jatoi 2002; Jatoi 2004; Westman 1999) because more than 50% of patients were lost to follow-up. In addition, the cross-over trials conducted by Bruera et al (Bruera 1990; Bruera 1998) did not report the results from the rst treatment period and, because of the problem of carry-over effects, the data from these studies were not included. In some cases it was not possible to perform meta-analysis due to lack of information (Batterham 2001; Beller 1997; Chen 1997; De Conno 1998; Gebbia 1996; Oster 1994; Tchekmedyian 1992; Weisberg 2002; Westman 1999; Yeh 2000; ). Only three of ve intended outcome measures were analyzed: 1) appetite increase, expressed as a dichotomous variable (number of patients who experience appetite increase), 2) Weight gain, expressed both as a dichotomous and continuous variable in kg/day at the end of the treatment compared with the baseline, and 3) Improvement in quality of life (QoL) analysed as a dichotomous variable (number of patients who experienced improved QoL, measured in different and validated scales). Basically, quality of life was assessed by different scales and derived by different methods. No data were available for the analysis of mid-arm circumference, triceps skin fold thickness, appetite increase (caloric intake expressed as calories/day) and QoL expressed as a continuous variable. Megestrol acetate versus placebo The overall results have shown improvement in appetite for patients treated with megestrol acetate (RR = 2.76 (95% CI 1.65 to 4.61)) (Comparison 01 01). The only subcategory that could be analyzed was cancer patients (Loprinzi 1990b; Erkurt 2000; Feliu 1992; Lai 1994; Schmoll 1992; Zeca 1995). Both subcategories AIDS and other underlying pathologies could not be analyzed because there was only one trial included in each one. For cancer patients a statistically signicant benet was described in appetite improvement (RR 3.03, 95% CI 1.83 to 5.01) and weight gain as a continuous variable (WMD = 3.56 (95% CI 1.27 to 5.85)) (Comparison 01 02). The same direction and signicance of the results was seen with weight gain as a dichotomous variable (RR = 2.14 (95% CI 1.41 to 3.24)) (Comparison 01 03). Six trials (four on cancer sub-category and two on AIDS) were included for the comparison of the effect of megestrol acetate and placebo on health-related quality of life (HRQoL) and no significant results were seen. Clinical and statistical heterogeneity were
detected and explained by severity of illness, treatment duration and different scales (P < 0.0001) (Comparison 01 04). Three trials in the subcategory of patients with cancer have used the performance status and Karnofsky Index (KI), and one the Linear Analog Self Assessment, nine items (LAS). Studies included in the AIDS subcategory used KI and LAS. A random effect analysis was carried out and a P value < 0.1 was found. A single outlier study (Erkurt 2000) can make a very large contribution to the statistical heterogeneity, resulting in a conclusion that there is heterogeneity in both appetite and weight gain when the studies yield a credible conclusion. The pooled RR may be affected by Erkurts study, which had an enormous treatment effect. The pooled value in fact is dissimilar to individual values from all studies. Erkurt s quality study was low. The analysis and interpretation of data were difcult to understand and regarding QoL was excluded from the analysis due to the studies using an un-validated instrument for its measurement. Loprinzi 1990b, showed the largest pooled RR when we looked at the analysis of weight gain as a dichotomous variable. The authors reported that a percentage of patients gained at least 15 lb after they were given a high dose of MA. The data were obtained by two sources: patient-recorded home weights and institution weights. We have included the highest level of weight gain reported . This study was given ve points as a quality score. Megestrol acetate versus other drugs Five of seven identied studies comparing megestrol acetate with other drugs were pooled for the analysis. Three trials in cancer subcategory (Chen 1997; Lai 1994; Loprinzi 1999) and two in AIDS (Batterham 2001; Timpone 1997). Loprinzi et al have compared megestrol acetate to uoxymesterone and dexamethasone. To analyse this trial we divided the total number of patients included in the megestrol group by two. In other words, the number of megestrol patients in each comparison was taken to be 79 instead of 158. This method allowed us to perform the analysis. Jatoi 2002 and Jatoi 2004 were excluded due to the high rate of drop-outs. When we looked at the overall results, megestrol acetate did not show benets in terms of appetite improvement in comparison to other drugs (RR = 1.15 (95% CI 0.75 to 1.76)) (Comparison 02 01), and results were inconclusive for weight gain (RR = 1.29 (95% CI 0.94 to 1.96) (Comparison 02 03). Two studies (Lai 1994; Loprinzi 1999a) included in the analysis have measured HRQOL as an outcome using two different instruments. The rst one used the K I and Loprinzi used Spitzer QL index. No signicant results were found (RR = 1.08 (95% CI 0.80 to 1.45)) (Comparison 02 04). There was not enough data to compare megestrol acetate versus other drugs in HIV/AIDS and other underlying pathology patients. Different dose levels of megestrol acetate
7
In order to perform the meta-analysis, we dened 400 to 480 mg/d as the cut off value. This was the most frequently reported dose by authors. Then, we compared this dose to high doses (=>800 mg/d) and to low doses (<400 to 480 mg/d). In the rst group only two trials could be analysed (Loprinzi 1994; Schmoll 1992). In the second group two trials, out of four, were included in the analysis (Heckmayr 1992; Loprinzi 1994). We excluded the Gebbia 1996 and Ulutin 2002 studies from this analysis because they used only low doses and Pardo 2003 did not meet the criteria to include in the analysis. The results of the meta-analysis were not signicant. Study withdrawals and dropouts Only the studies who reported the total number of drop-outs and withdrawals in each arm were included. There were 224/1115 in the megestrol acetate group and 207/886 in the placebo group of all the analyzed categories. Only one study (Oster 1994) reported withdrawals due to lack of efcacy of treatment. A total of 29/1596 in the treated group and 24/1143 in the placebo group were withdrawals due to adverse effects in this update including the study of Ulutin 2002. The number of patients who suffer any side effect was analyzed and those studies that reported toxicity scores were also checked. The two abstracts included reported no side-effects. Drug safety, impotence in men, edema of the lower limbs, deep vein thrombosis and gastrointestinal intolerance were the most frequently reported adverse effects observed in the studies. None of the differences between treatment and placebo groups were found to be statistically signicant, except for the occurrence of edema, which occurred with greater frequency in patients receiving megestrol acetate (RR = 1.74 (95% CI 1.29 to 2.35)) (Comparison 01 05). Sensitivity analysis This 2006 update does not show any change to the sensitivity analysis from the previous review. The sensitivity analysis was undertaken with studies where cancer patients received more than six weeks of megestrol acetate versus placebo. Two outcomes were analyzed: appetite improvement and weight gain. We observed an overall benet in both outcomes of the treated group. Appetite improvement showed a RR = 3.21 (95% CI 1.54 to 6.70) (Comparison 03 01) and weight gain a RR = 1.86 (95% CI 1.31 to 2.63) (Comparison 03 02). Another subgroup analysis was performed considering methodological quality of the studies. The group with high Oxford Quality Scores (Quality Score of three, four or ve) showed a benet for the megestrol acetate in the outcome weight gain only, both as a dichotomous and continuos variable (RR = 1.66 (95% CI 1.13 to 2.44) (Comparison 03 06); WMD = 1.87 (95% CI 1.20 to 2.54) (Comparison 03 05). For the outcome of appetite improvement there were not enough studies with good Oxford Quality Scores. In the group of low methodological score, we observed an overall benet in the treatment group for the outcome appetite improve-
ment (RR = 3.63 (95% CI 2.06 to 6.39)) (Comparison 03 04) and weight gain (RR = 2.49 (95% CI 1.45 to 4.27)) (Comparison 03 06).
DISCUSSION This updated review does not provide any additional information on this treatment as the two new studies that were included did not provide data of any signicance Jatoi 2004; Ulutin 2002). Two systematic reviews have been undertaken recently. A systematic review by Maltoni 2001 assessed the efcacy of high dose progestins for the treatment of anorexia cachexia syndrome in patients with hormone-independent tumours. This review included 15 randomized clinical trials and more than 2000 patients. The authors concluded that high-dose progestins improve appetite and weight, but could not dene optimal dose, duration of treatment or the impact on quality of life. The review by Ruiz-Garca et al. (Ruiz-Garcia 2002) evaluated the efcacy of megestrol acetate versus placebo in patients with cancer and anorexia cachexia syndrome. Eight trials (719 patients) were included in the review and found that megestrol acetate was associated with a slight weight gain at doses of 240 mg per day or less. No statistically signicant effect was observed with higher doses. The aim of the present update was to assess the efcacy, effectiveness and safety of megestrol acetate for the management of anorexia-cachexia syndrome, a common clinical problem that substantially impacts upon the quality of life and survival of affected patients. Although the number of randomised trials retrieved was 71, only 34 of them were included for the analysis and 12 received a high quality score (quality scale score of four or ve). The total number of patients was 4826. However, we could not include more than 50% of the studies in the analysis. Data was available from only 19 studies. There was consistency between this review and results reported by the majority of other similar studies. This review conrms that Megestrol acetate is a good choice to increase appetite and weight gain in cancer patients compared to placebo. The improvement of the nutritional status by anthropometric changes could not be assessed due to lack of information. Although some authors have suggested that there may be a tendency towards greater efcacy with higher doses, this update showed that clinical effects of megestrol acetate appear not to be dose-related. When we analysed the improvement of QoL we found great heterogeneity between studies. Jatoi 2000 had described many methodological issues related to QoL measurement relevant to address in order to explain clinical heterogeneity: a) different types of instruments, b) extensive testing to assess global QoL,
8
c) difculty administering this testing led to inconclusive QoL ndings. On the other hand some patients cannot complete quality of life measures because they have cognitive impairments, communication decits, are in severe distress, or because the measures are too burdensome. The studies included in this update used ten types of instruments with different psychometric properties. Another factor which may explain the discordance between appetite improvement and the lack of benet on QoL, centers on the fact that multiple symptoms converge among advanced cancer patients. Donnelly et al (Donnelly 1995) evaluated symptom prevalence in 1000 such patients and found that although anorexia had a high prevalence, it was not an isolated symptom. Nausea, fatigue, dry mouth, pain, and a variety of other symptoms accompany anorexia. Sensitivity analysis showed that the poorest quality trials overestimated positive results. Finally, a more systematic approach to the measurement of HRQOL in these patients would be helpful in better understanding and analyzing treatment effects and the impact of megestrol acetate on patient QoL. Although we included studies which had up to 50% dropouts, we found a particularly high dropout rate probably due to advanced cancer. The population studied is very sick, so they tend to suffer substantial cancer anorexia/cachexia along with many co morbid problems linked to advanced cancer. The adverse event prole of megestrol acetate has shown edema to be the only one signicant difference between placebo and megestrol acetate, suggesting that megestrol acetate is a safe treatment option in these patients.
Many concerns are still to be resolved. HRQoL is an important goal in health care and cancer clinical trials and is the cornerstone for delivery of good palliative medicine. The increasing recognition of patient autonomy means that subjective measures will become more important and, in the current climate of evidencebased medicine, such measures must be valid and reliable. Implications for research This update has shown that there is still a need for high quality studies on the effectiveness of megestrol acetate in some of the outcomes we have reviewed, e.g. HRQOL. Even though the USAs Federal Drug Administration has approved megestrol acetate to be used in AIDS patients more research is needed.
POTENTIAL CONFLICT OF INTEREST The rst version of this review had evolved from an internal report on this topic for a pharmaceutical company that produces megestrol acetate. This review is independent of that report and has been prepared with the guidance of, and in line with, the requirements of the Pain, Palliative and Supportive Care review group. Aside from the above project, the review authors certify that they have no afliations with any organisation or entity with a direct nancial interest in the subject matter of the review.
ACKNOWLEDGEMENTS We would like to thank the Iberoamerican Cochrane Collaboration Centre for their support, particularly Marta Roque for her critical review and Gerard Urrutia for his comments. We are grateful to Dr CL Loprinzi and Paul Novotny from the Mayo Clinic; Professor E Bruera, Department of Palliative Care and Rehabilitation Medicine at Cross Cancer Institute, University of Alberta, Edmonton, and MD Anderson for supplying additional data for this review. We would also like to thank Marcelo Garca Diguez and Nicolas Garrigue from Argentina who have helped us with the search strategy and comments. We would like to thank Sylvia Bickley (Trials Search Co-ordinator, Cochrane Pain, Palliative Care & Supportive Care Group) for performing the bibliographic searches in the present version of this update.
AUTHORS CONCLUSIONS Implications for practice New trials located for this update have not provided additional information to the original conclusion. Megestrol acetate may be prescribed in patients with cancer to increase appetite and weight gain. At the moment, there is no evidence to recommend megestrol acetate to improve quality of life (QoL). This update has followed the Cochrane Collaboration Guidelines to perform an unbiased review. However, the results of a meta-analysis are inuenced by the quality of the primary studies included. Quality is difcult to dene. It could address the design, conduct and analysis of a trial, its clinical relevance, or the quality of reporting. Studies of low methodological quality can alter the interpretation of the benet of intervention. In this update 68% of the studies were assessed as moderate or low quality trials.
SOURCES OF SUPPORT External sources of support No sources of support supplied Internal sources of support Instituto de Investigaciones Epidemiolgicas. Academia Nacional de Medicina de Buenos Aires ARGENTINA
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REFERENCES
References to studies included in this review

Batterham 2001 {published data only} Batterham MJ, Garsia R. A comparison of megestrol acetate, nandrolone decanoate and dietary counselling for HIV associated weight loss. International Journal of Andology 2001;24(4):23240. Beller 1997 {published data only} Beller E, Tattersall M. Improved quality of life with megestrol acetate in patients with endocrine-insensitive advanced cancer: A randomised placebo-controlled trial. Annals of Oncology 1997;8:277 83. Bruera 1990 {published data only} Bruera E, Mc Millan K. A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status, and other symptoms in patients with advanced cancer. Cancer 1990;66:127982. Bruera 1998 {published data only} Bruera E, Scott E. Effectiveness of megestrol acetate in patients with advanced cancer: a randomized, double-blind, crossover study. Cancer Prevention & Control 1998;2(2):748. Chen 1997 {published data only} Chen Hui-Chun, Wan Leung S. Effect of megestrol acetate and prepulsid on nutritional improvement in patients with head and neck cancers undergoing radiotherapy. Radiotherapy and Oncology 1997; 43:759. De Conno 1998 {published data only} De Conno F, Martini C. Megestrol acetate for anorexia in patients with far-advanced cancer: a double-blind controlled clinical trial. European Journal of Cancer 1998;34:17059. Erkurt 2000 {published data only} Erkurt E, Erkisi M. Supportive treatment in weight-losing cancer patients due to the additive adverse effects of radiation treatment and/or chemotherapy. Journal of Experimental Clinical Cancer Research 2000; 19(4):4319. Eubanks 2002 {published data only} Eubanks V, Koppersmith N. Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic brosis. Journal of Pediatrics 2002;140(4):43944. Feliu 1992 {published data only} Feliu J, Gonzalez-Baron M. Usefulness of megestrol acetate in cancer cachexia and anorexia. A placebo controlled study. American Journal of Clinical Oncology 1992;15(5):43640. Fietkau 1996 {published data only} Fietkau R, Riepl M. Supportive treatment with megestrol acetate during radio (chemo) therapy. A randomised trial. Strahlenther Onkol 1996;172:1628. Fietkau R, Riepl M, Kettner H, Hinke A, Sauer R. Supportive use of megestrol acetate in patients with head and neck cancer during radio (chemo)therapy. European journal of cancer (Oxford, England: 1990) 1997;33(1):759.
Gambardella 1998 {published data only} Gambardella A, Pesce L, Bolognino P, Lombardi G, Barbieri M, Rinaldi C. Megestrol acetate prevents cachexia in elderly cancer patient. Annals of oncology 1998;9, Suppl 3:72. Gebbia 1996 {published data only} Gebbia V, Testa A. Prospective randomised trial of two dose levels of megestrol acetate in the management of anorexia-cachexia syndrome in patients with metastatic cancer. British Journal of Cancer 1996;73: 157680. Heckmayr 1992 {published data only} Heckmayr M, Gatzemeier U. Treatment of cancer weight loss in patients with advanced lung cancer. Oncology 1992;49(suppl 2):32 4. Jatoi 2002 {published data only} Jatoi A, Windschitl HE. Dronabinol versus megestrol acetate versus combination for cancer-associated anorexia: A North Central Cancer Tratment Group Study. Journal of Clinical Oncology 2002;20(2):567 73. Jatoi 2004 {published data only} Jatoi A, Rowland K, Loprinzi CL, et al.An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a north central cancer treatment group and National Cancer Institute of Canada Collaborative Effort. Journal of Clinical Oncology 2004;22:246976. Lai 1994 {published data only} Lai YL, Fang FM. Management of anorexic patients in radiotherapy: A prospective randomized comparison of megestrol and prednisolone. Journal of Pain and Symptom Management 1994;9:2658. Loprinzi 1990b {published data only} Loprinzi CL, Ellison NM. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. Journal of the National Cancer Institute 1990;82:112732. Loprinzi 1994 {published data only} Loprinzi CL, Bernath AM. Phase III evaluation of 4 doses of megestrol acetate for patients with cancer anorexia and/or cachexia. Oncology 1994;51:27. Loprinzi CL, Michalak Jc, Schaid DJ, et al.Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. Journal of clinical oncology: ofcial journal of the American Society of Clinical Oncology 1993;11(4):7627. Loprinzi 1999a {published data only} Loprinzi CL, Kugler JW. Randomized comparison of megestrol acetate versus dexamethasone versus uoxymesterone for the treatment of cancer anorexia/cachexia. Journal of Clinical Oncology 1999;17: 3299306. Loprinzi 1999b {published data only} Loprinzi CL, Kugler JW. Randomized comparison of megestrol acetate versus dexamethasone versus uoxymesterone for the treatment of cancer anorexia/cachexia. Journal of Clinical Oncology 1999;17: 3299306.
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Marchand 2000 {published data only} Marchand V, Baker SS. Randomized, double-blind, placebo-controlled pilot trial of megestrol acetate in malnourished children with cystic brosis. Journal of Pediatric Gastroenterology and Nutrition 2000;31:2649. McMillan 1994 {published data only} Mc Millan DC, Simpson JM. Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients. Clinical Nutrition 1994;13:859. McQuellon 2002 {published data only} Mc Quellon RP, Moose DB. Supportive use of megestrol acetate (MEGACE) with head/neck and lung cancer patients receiving radiation therapy. International Journal of Radiation Oncology Biology and Physics 2002;52:11805. Oster 1994 {published data only} Oster MH, Enders SR. Megestrol acetate in patients with AIDS and cachexia. Annals of Internal Medicine 1994;121:4008. Pardo 2003 {published data only} Pardo J, Mena AM, Montsech L. Megestrol acetate for anorexia in lung cancer patients undergoing radiation therapyA randomized trial comparing the efcacy of two different doses in 130 patients. Proceedings for the American Society for Clinical Oncology 2003;22 (abstr 3076):765. Rowland 1996 {published data only} Rowland KM, Loprinzi CL. Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/ placebo in extensive-stage small-cell lung cancer: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology 1996;14:135 41. Schmoll 1992 {published data only} Schmoll E. Risks and benets of various therapies for cancer anorexia. Oncology 1992;49:435. Schmoll E, Wilke H, Thole R, et al.Megestrol acetate in cancer cachexia. Seminars in oncology 1991;18(1 Suppl 2):324. Tchekmedyian 1992 {published data only} Tchekmedyian NS, Hickman M. Megestrol acetate in cancer anorexia and weight loss. Cancer 1992;69:126874. Timpone 1997 {published data only} Timpone JG, Wright DJ. The safety and pharmacokinetics of singleagent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Research and Human Retroviruses 1997;13:30515. Ulutin 2002 {published data only} Ulutin HC, Arpaci F, Pak Y. Megestrol acetate for cachexia and anorexia in advanced non-small cell lung cancer: a randomized study comparing two different doses. Tumori 2002;88:27780. Vadell 1998 {published data only} Vadell C, Segui MA. Anticachectic efcacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia. American Journal of Clinical Oncology 1998;21:34751. Von Roenn 1994 {published data only} Von Roenn JH, Armstrong D. Megestrol acetate in patients with AIDS-related cachexia. Annals of Internal Medicine 1994;121:3939.
Weisberg 2002 {published data only} Weisberg J, Wanger J. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest 2002;121(4): 10708. Westman 1999 {published data only} Westman G, Bergman B. Megestrol acetate in advanced, progressive, hormone-insensitive cancer. Effects on the quality of life: a placebocontrolled, randomised, multicentre trial. European Journal of Cancer 1999;35:58695. Yeh 2000 {published data only} Yeh SS, Wu SY. Improvement in quality of life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: Results of a double-blind, placebocontrolled study. Journal of the American Geriatric Society 2000;48 (5):48592. Zeca 1995 {published data only} Zeca E, Martini C, Venturino P, Tedeschi M, Ventafrida V, De Conno F. Efcacy of Megestrol Acetate on Anorexia in patients with advanced non hormone-related tumors: A double-blind placebo controlled clinical trial. European Journal of Cancer 1995;31 A:S261 S262.
References to studies excluded from this review

Macbeth 1994 Macbeth FR, Gregor A, Cottier B. A randomised study of megestrol acetate (MA) and prednisolone (P) for anorexia and weight loss in patients with lung cancer. McMillan 1999 Mc Millan DC, Wigmore SJ. A prospective randomised study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. British Journal of Cancer 1999;79:495500. Yeh 2004 Yeh S, Hafner A, Chang C, et al.Risk Factors Relating Blood Markers of Inammation and Nutritional Status to Survival in Cachectic Geriatric Patients in a Randomized Clinical Trial. Journal of the American Geriatrics Society 2004;52:170812.
Additional references
Alexander 1993 Alexander HR, Norton JA. Pathophisiology of cancer cachexia. In: DoyleD, HanksGWC, MacDonaldN editor(s). Textbook of palliative medicine. 3rd Edition. Oxford: Oxford University Press, 1998. Argils 2001 Argils JM, Meijsing SH, Pallares-Trujillo J. Cancer cachexia. A therapeutic approach. Medical Research Review (US) 2001;21:83101. Balog 1998 Balog DL, Epstein ME, Amidio-Groton MI. HIV wasting syndrome: Treatment update. Annals of Pharmacotherapy 1998;32(4):44658. Barber 1999 Barber MD, Ross JA, Voss AC, et al.The effect of an oral nutritional supplement enriched with sh oil on weight-loss in patients with pancreatic cancer. British Journal of Cancer 1999;81:806. Bruera 1992 Bruera E. Clinical management of anorexia and cachexia in patients with advanced cancer. Oncology 1992;49(2):3542.
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Donnelly 1995 Donnelly S, Walsh D. The symptoms of advanced cancer: Identication of clinical and research priorities by assessment of prevalence and severity. Journal of Palliative Care 1995;22:2732. Jadad 1996 Jadad A, Moore RA, Carrol D, et al.Assessing the quality of reports on randomized clinical trials: Is blinding necessary?. Controlled Clinical Trials 1996;170:112. Jatoi 2000 Jatoi A, Kumar S. On appetite and its loss. Journal of Clinical Oncology 2000;18:29302. Loprinzi 1990a Loprinzi C, Ellison NM, Goldberg RM, et al.Alleviation of cancer anorexia and cachexia: Studies of the Mayo Clinic and the North Central Cancer Treatment Group. Seminars in oncology 1990;17(6 suppl 9):812. Loprinzi 1999 Loprinzi CL, Kugler JW, Sloan JA. Randomized comparison of Megestrol Acetate versus dexamethasone versus uoxymesterone for the treatment of cancer anorexia/cachexia. Journal of Clinical Oncology 1999;17:3299306. Maltoni 2001 Maltoni M, Nanni O, Scarpi E, et al.High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: A systematic review of randomised clinical trials. Annals of Oncology 2001;12(3):289 300. Mantovani 1998 Mantovani G, Maccio A, Lai P, et al.Cytokyne activity in cancerrelated anorexia/cachexia: role of megestrol acetate and medroxypro-
gesterone acetate. Seminars in oncology 1998 (US);25(2 suppl 16): 4552. Nelson 1994 Nelson KA, Walsh D, Sheehan FA, et al.The cancer anorexia-cachexia syndrome. Journal of Clinical Oncology 1994;12:21325. Ruiz-Garcia 2002 Ruiz-Garcia V, Juan O, Perez Hoyos S, et al.Megestrol acetate: a systematic review usefulness about the weight gain in neoplastic patients with cancer. Medicina Clinica (Barcelona) 2002;119(5):16670. Splinter 1992 Splinter TA. Cachexia and cancer: a clinician s view. Annals of Oncology 1992;3(3):257. Tchekmedyian 1986 Tchekmedyian NS, Tait N, Aisner J. High dose megestrol acetate in the treatment of postmenopausal women with advanced breast cancer. Seminars in oncology 1986;13(4):205. Von Roenn 1996 Von Roenn JH, Knopf K. Anorexia/cachexia in patients with HIV: lessons for the oncologist. Oncology 1996;10(7):104956. Wigmore 1997 Wigmore SJ, Fearon KCH, Maingay JP, et al.Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6. Clinical Science 1997;92:21521.
Indicates the major publication for the study
TABLES
Characteristics of included studies

Study Methods Participants Batterham 2001 Randomised controlled In a tertiary referral hospital, Sydney 15 HIV pts a) 4 M mean age 46 yrs b) 6 M mean age 44 yrs c) 5 M mean age 42 yrs, ve completed and then randomized three to nandrolone and two to megestrol a) MA 400 mg/d orally b) nandrolone decanoate 100 mg/fortnight IM injection c) diet counseling duration 12 weeks Weight Appetite VAS ten points score 0 = poor appetite 10 = good appetite
12
Interventions
Outcomes
Characteristics of included studies (Continued )

Dietary intake % Notes Allocation concealment Study Methods 12 weeks of treatment QS = 2 B Unclear Beller 1997 Double blind, randomised controlled multicentre (15), stratied by institution and whether receiving any anti tumor treatment 240 cancer pts a) 81 pts = 53M + 28F (nine pts = 50 yrs, 49 pts = 51 to 70 yrs, 23pts = > 71 yrs) b) 80 pts = 52M + 28F (seven pts = lower than 50 yrs, 52 pts = 51 to 70 yrs, 21 pts = >70 yrs) c) 79 pts = 54M + 25F (12 pts = 50 yrs, 51 pts = 51 to 70 yrs, 16 pts = >70 yrs) Interventions a) MA 480 mg/d orally b) MA 160 mg/d c) placebo QoL ve linear analogue self assessment scales (LASA) asked patients about ve factors: physical well being, mood, pain, nausea and vomiting, and appetite. and a LASA uniscale of overall QoL and the Spitzer QL - Index, completed by the clinician - Appetite (LASA score) Nutritional status - weight - triceps skinfold - mid-arm circumference Two weeks of treatment QS = 4 A Adequate Bruera 1990 Double blind, cross over randomised controlled 40 advanced cancer pts 31 included pts = 25M + 6F a) MA 480 mg/d b) placebo Appetite, subjective energy level, well being depression, and pain were assessed with VAS (0 to 100 mm) Nutritional status, weight, triceps skin fold, arm and calf circumference. Caloric intake, in calories Seven days rst phase QS = 3 B Unclear Bruera 1998 Cross over
13
Participants
Outcomes
Notes Allocation concealment Study Methods Participants Interventions Outcomes
Notes Allocation concealment Study Methods

double blind randomised controlled 84 advanced cancer pts 47M + 37F mean age 62 yrs a) MA 480 mg/d b) placebo Appetite (VAS) weight triceps skinfold QoL Functional Living Index Cancer (FLIC) Ten days of treatment QS = 4 B Unclear Chen 1997 Randomised controlled 129 cancer pts a) 48 pts = 36M + 12F mean age 50 yrs b) 41 pts = 30M + 11F mean age 52 yrs c) 40 pts = 30M + 10F mean age 51 yrs a) MA 160 mg/d b) cisapride 10 mg/d c) placebo Weight Appetite score zero to ve Four and eight weeks of treatment during a full course of radiotherapy QS = 2 B Unclear De Conno 1998 Double blind randomised controlled 42 cancer pts a) 21 pts = 15M + 6F mean age 63 yrs b) 21 pts = 16M + 5F mean age 58 yrs a) MA 320 mg/d b) placebo Appetite Score zero to ten Weight QoL Therapy Impact Questionnaire (TIQ) 14 days of treatment QS = 3
14
Participants
Interventions Outcomes
Notes Allocation concealment Study Methods Participants
Interventions
Outcomes Notes
Allocation concealment Study Methods Participants
Notes

Allocation concealment Study Methods Participants B Unclear Erkurt 2000 Randomised controlled 115 cancer pts a) 58 pts = 38M + 12F mean age 51 yrs b) 57 pts = 45M + 5F mean age 57 yrs a) MA 480 mg/d b) placebo Weight Appetite score zero to ve QoL Eastern Cooperative Oncology Group Performance status (ECOG PS) Three months of treatment 46 pts during RT, and four at the end of RT of MA group QS = 2 B Unclear Eubanks 2002 Double blind randomised controlled 17 cystic brosis pts a) ten pts = 5M + 4F range age six to 18 yrs. 1F 35 yrs b) 7pts = 3F + 4M range age six to 15 yrs a) MA 10 mg/kg per day b) placebo Weight Triceps skinfold Mid arm circumference Six months of treatment QS = 4 A Adequate Feliu 1992 Double blind randomised controlled 150 cancer pts a) 76 pts = 58M + 8F mean age 57 yrs b) 74 pts = 55M + 7F mean age 58 yrs a) MA 240 mg/d b) placebo Weight Appetite VAS score QoL performance status KI Two months of treatment QS = 4
15
Notes
Allocation concealment Study Methods Participants
Notes

Allocation concealment Study Methods Participants B Unclear Fietkau 1996 Double blind randomised controlled 64 cancer pts 61 pts = a) 31pts = 25M + 6F mean age 52 yrs b) 30 pts = 24M + 6F mean age 48 yrs a) MA 160 mg/d b) placebo Nutritional status weight QoL index according to Padilla Index Six weeks of treatment during and up six weeks following radiotherapy Pts were stratied according oral feeding versus gastrostomy QS = 3 Allocation concealment Study Methods Participants Interventions Outcomes Notes Allocation concealment Study Methods Participants B Unclear Gambardella 1998 NO DATA AVAILABLE NO DATA AVAILABLE NO DATA AVAILABLE NO DATA AVAILABLE NO DATA AVAILABLE D Not used Gebbia 1996 Randomised controlled 122 cancer pts a) 62 pts = 46M + 16F mean age 63 yrs b) 60 pts = 42M + 18F mean age 65 yrs a) MA 160 mg/d b) MA 320 mg/d Appetite, Symptom Distress Scale (SDS) Weight Performance Status 30 days of treatment QS = 2 B Unclear Heckmayr 1992 Randomised controlled 66 cancer
16
Interventions Outcomes Notes

a) 33 pts = 24M + 9F mean age 65 yrs b) 33 pts = 27M + 6F mean age 68 yrs Interventions Outcomes Notes Allocation concealment Study Methods Participants a) MA 160 mg/d b) MA 480 mg/d Appetite (subjective ten point scale) Weight Four weeks of treatment QS = 1 B Unclear Jatoi 2002 Double blind randomised controlled multicentre (20) 469 cancer pts a) 159 pts = 103M + 56F mean age 65 yrs b)152 pts = 100M + 52F mean age 67 yrs c) 158 pts = 104M + 54F mean age 67 yrs a) MA 800 mg/d liquid suspension +2 capsules placebo b) Dronabinol capsules 2.5 mg orally x 2 + liquid placebo c) MA suspension 800 mg/d + Dronabinol capsules 2.5 mg x 2 Appetite (validated questionnaires) Weight QoL Functional Assessment of Anorexia/Cachexia Therapy (FAACT) instrument uniscale and thirteen item Duration more than four weeks of treatment QS = 3 B Unclear Jatoi 2004 Double blind randomised controlled multicentre (26) 421 cancer pts a) 140 pts = 97M + 43F mean age 65 yrs b) 141 pts = 104M + 37F mean age 66 yrs c) 140 pts = 92M + 48F mean age 66 yrs a) MA 600 mg/d liquid suspension + isocaloric, isonitrogenous placebo cans b) EPA supplement, two cans/d + placebo liquid suspension c) EPA supplement two cans/d plus MA liquid suspension 600 mg/d orally in combination Weight Appetite (NCCTG questionnaire and FAACT) QoL (single-item Uniscale) Duration more than three months QS = 4 B Unclear
17
Interventions
Outcomes
Interventions
Outcomes
Notes Allocation concealment

Study Methods Participants Lai 1994 Randomised controlled 52 Cancer pts a) 18 pts = 2M + 16F mean age 64 yrs b) 17 pts = 17F mean age 60 yrs c) 17 pts = 2M + 15F mean age 57 yrs a) MA 160 mg/d b) Prednisolone 30 mg/d c) placebo x 3 Weight Appetite, self report QoL performance status KI Duration 21 days QS = 2 B Unclear Loprinzi 1990b Double blind randomised controlled 133 Cancer pts a) 67 pts = 44M + 23F mean age 69 yrs b) 66 pts = 44M + 22F mean age 67 yrs a) MA 800 mg/d b) placebo Weight Appetite One month of treatment QS = 5 A Adequate Loprinzi 1994 Randomised controlled 342 cancer pts a) 88 pts = 56M + 32F mean age 67 yrs b) 86 pts = 54M + 32F mean age 67 yrs c) 85 pts = 55M + 30F mean age 67 yrs d) 83 pts = 54M + 29F mean age 66 yrs a) MA 160 mg/d b) MA 480 mg/d c) MA 800 mg/d d) MA 1280 mg/d Weight Appetite Median 66 days of treatment
18
Interventions
Outcomes
Interventions Outcomes Notes Allocation concealment Study Methods Participants
Interventions
Outcomes Notes

QS = 3 Allocation concealment Study Methods Participants A Adequate Loprinzi 1999a Randomised controlled multicentre 475 cancer pts a) 79 pts = 55M + 30F mean age 66 yrs b) 159 pts = 99M + 60F mean age 66 yrs a) MA 800 mg/d b) dexamethasone 3 mg/d Appetite Weight QoL (uniscale) One month of treatment QS = 3 A Adequate Loprinzi 1999b Randomised controlled multicentre 475 cancer pts a) 79 pts = 54M + 29F mean age 66 yrs b) 158 pts = 100M + 58F mean age 67 yrs a) MA 800 mg/d b) uoxymesterone 20 mg/d Appetite Weight QoL (uniscale) One month of treatment QS = 3 A Adequate Marchand 2000 Double blind cross over controlled randomised 12 cystic brosis children pts a) six pts b) six pts mean age seven, four yrs, 9F + 3M a) MA 10 mg/ kg/d x 2 b) placebo Appetite Weight Triceps skinfold
19
Notes Allocation concealment Study Methods
Participants

Notes Allocation concealment Study Methods Participants Mid arm circumference 12 weeks of treatment QS = 3 B Unclear McMillan 1994 Randomised controlled 38 cancer pts a) 20 pts mean age 73 yrs b) 18 pts mean age 70 yrs a) MA 480 mg/d b) placebo Weight 12 weeks of treatment QS = 2 B Unclear McQuellon 2002 Double blind randomised controlled 57 cancer pts a) 28 pts = 20M + 8F, mean age 60 yrs b) 28 pts = 16M + 12F mean age 65 yrs (one excluded due to positive ndings in bone scan) a) MA 800 mg/ d suspension b) placebo suspension 20 ml Weight QoL FACT 12 weeks of treatment QS = 3 A Adequate Oster 1994 Double blind randomised controlled multicenter (13) 100 HIV pts a) 52 pts = 50M + 2F mean age 40 yrs b) 48 pts = 47M + 1F mean age 40 yrs a) MA 800 mg/d suspension b) placebo, suspension Appetite Weight Triceps skinfold Mid arm circunference Performance status KI 12 weeks of treatment
20
Notes

QS = 5 Allocation concealment Study Methods Participants A Adequate Pardo 2003 Randomized controlled 130 cancer patients a) 64 pts = 58M + 6F mean age 66.8 yrs b) 66 pts = 62 M + 4F mean age 65.3 yrs a) MA 320mg/day b) MA 600mg/day Appetite 30 days of treatment QS = 1 B Unclear Rowland 1996 Double blind randomised controlled 243 cancer pts a) 122 pts = 56M + 44F b) 121 pts = 64M + 36F a) MA 800 mg/d b) placebo Appetite questionnaire QoL VAS uniscale Mean duration four months and up to two years QS = 2 B Unclear Schmoll 1992 Randomised controlled 91 cancer pts a) 29 pts = 18M + 11F mean age 60 yrs b) 28pts = 16M + 12F mean age 58 yrs c) 34 pts = 25M + 9F mean age 60 yrs a) MA 960 mg/d b) placebo c) MA 480 mg/d Appetite Weight a) median duration eight weeks of treatment b) median duration six weeks c) median duration seven weeks QS = 2 B Unclear
21
Interventions
Outcomes Notes
Allocation concealment

Study Methods Participants Tchekmedyian 1992 Double blind randomised controlled 89 cancer pts a) 49 pts = 28M + 9F mean age 63 yrs b) 40 pts = 18M + 12F mean age 64 yrs a) MA 1600 mg/d, ten tablets a day, in divided doses b) placebo ten tablets Appetite, categoric scale of ve levels QoL LAS, 29 items Weight Triceps skinfold Mid arm circunference Six weeks of treatment QS = 4 A Adequate Timpone 1997 Randomised controlled multicenter (9) 50 HIV pts a) 12 pts = 10M + 2F mean age 46 yrs b) 12 pts = 10M + 2F mean age 39 yrs c) 13 pts = 12M + 1F mean age 38 yrs d) 13 pts = 12M + 1F mean age 40 yrs a) MA 750 mg/d, tablets x 1 b) Dronabinol 5 mg/d, tablets x 2 c) a) + b) d) MA 250 mg/d + Dronabinol 5 mg/d, two tablets Weight QoL KI 12 weeks of treatment QS = 2 B Unclear Ulutin 2002 Randomised controlled study 119 cancer pts a) 59 pts = 48M + 11F mean age 56 (range 38 to 72) b) 60 pts = 47M + 13F mean age 58 (range 40 to 74) a) MA 160 mg/d orally b) MA 320 mg/d orally in two divided doses 12 hrs apart Weight Appetite (Symptom Distress Scale)
22
Interventions
Outcomes Notes Allocation concealment Study Methods Participants

QoL (ten point scale) based on patient statements Notes Allocation concealment Study Methods Participants Three month duration treatment QS = 2 B Unclear Vadell 1998 Double blind randomised controlled multicenter (nine) 150 cancer pts a) 49 pts = 38M + 11F mean age 66 yrs b) 51 pts = 42M + 9F mean age 63 yrs c) 50 pts = 31M + 19F mean age 65 yrs a) MA 480 mg/d, three tablets b) placebo, three tablets c) MA 160 mg/d, one tablet + placebo two tablets Weight Mid arm circumference Triceps skinfold QoL KI 12 weeks of treatment QS = 3 B Unclear Von Roenn 1994 Double blind randomised controlled multicenter 270 HIV pts a) 75 pts = 75M mean age 38 yrs b) 75 pts = 75M mean age 39 yrs c) 82 pts = 81M + 1F mean age 39 yrs d) 38 pts = 38M mean age 38 yrs a) MA 800 mg/d, suspension b) MA 400 mg/d, suspension c) MA 100 mg/ d, suspension d) placebo, suspension Weight Appetite Mid arm circumference Triceps skinfold QoL, by Linear Analog Self Assessment questionnaire 12 weeks of treatment QS = 4 A Adequate Weisberg 2002 Double blind randomised controlled multicenter (18) 145 COPD pts a) 72 pts = 46M + 26F
23
Interventions
Outcomes
Interventions
Outcomes

mean age 68 yrs b) 73 pts = 45M + 28F mean age 66 yrs Interventions Outcomes a) MA 800 mg/d, suspension b) placebo, suspension Weight Triceps skinfold Mid arm circumference Appetite Eight weeks of treatment QS = 4 B Unclear Westman 1999 Double blind randomised controlled multicenter (15) 255 cancer pts a) 128 pts = 77M + 51F mean age 71 yrs b) 127 pts = 64M + 63F mean age 69 yrs a) MA 320 mg/d, tablets b) placebo, tablets Weight QoL EORTC QLQ-C30 Appetite 12 weeks of treatment QS = 5 A Adequate Yeh 2000 Double blind randomised controlled 69 geriatric pts a) 36 pts = 35M + 1F mean age 76 yrs b) 33 pts = 31M + 2F mean age 76 yrs a) MA 800 mg/d, suspension b) placebo, suspension Weight Appetite QoL VAS nine items 12 weeks of treatment QS = 5 A Adequate Zeca 1995 Double blind randomized controlled 33 cancer pts a) 16 pts (no data available of age and sex)
24
b) 17 pts b) 17 pts Interventions Outcomes a) 320 mg/day, tablets b) placebo Appetite measured in a categoric numeric Scale Weight Performance status (Karnofsky) A) phase A 14 days of treatment B) phase B, open of 76 days of treatment QS = 2 B Unclear
Notes
Allocation concealment
Pts = patients = females (F) + males (M) VAS = Visual Analog Self reported scale *** = CHRONIC OBSTRUCCION PULMONARY DISEASE (COPD) KI = Karnofsky Index yrs = Years M = male F = female MA - Megesterol acetate QS = Quality Score (Oxford Quality Scale)
Characteristics of excluded studies

Study Macbeth 1994 McMillan 1999 Yeh 2004 Reason for exclusion This study was unpublished and closed early due to the numbers of withdrawals (> 50% of death in the megestrol arm) This study was excluded because the two arms of the treated patients were receiving megestrol acetate This study involved the same participants as Yeah 2000, in which they measured different outcomes
ADDITIONAL TABLES
Table 01. Patient condition and numbers recruited to each trial

Study Bruera 1990 Loprinzi 1990 Feliu 1992 Heckmayr 1992 Schmoll 1992 Tchekmedyan 1992 27 23 4 Lung cancer 15 42 75 66 91 35 Gastroint & pancreas 14 53 36 9 Head & neck cancer Gynecological cancer Other cancer 11 38 30 AIDS COPD Cystic brosis Elderly
25
Table 01. Patient condition and numbers recruited to each trial (Continued )
Lung cancer Gastroint & pancreas 8 130 111 26 Head & neck cancer Gynecological cancer 44 Other cancer 0 101 12 100 270 64 50 243 48 106 18 129 50 37 21 75 191 74 42 20 10 35 170 126 5 4 42 22 3 6 5 8 24 5 27 114 29 26 12 69 15 17 208 33 139 23
26
Study Lai 1994 Loprinzi 1994 McMillan 1994 Oster 1994 Von Roenn 1994 Fietkau 1996 Gebbia 1996 Rowland 1996 Beller 1997 Chen 1997 Timpone 1997 Bruera 1998 De Conno 1998 Vadell 1998 Loprinzi 1999 Westman 1999 Erkurt 2000 Marchand 2000 Yeh 2000 Batterham 2001 Eubanks 2002 Jatoi 2002 Mc Quellon
AIDS
COPD
Cystic brosis
Elderly
22
40
10
68
122
Table 01. Patient condition and numbers recruited to each trial (Continued )
Lung cancer Gastroint & pancreas Head & neck cancer Gynecological cancer Other cancer Cystic brosis
Study 2002 Weisberg 2002 Ulutin HC 2002 Pardo 2003 Jatoi 2004 Zeca 1995 Total
AIDS
COPD
Elderly
145 119 130 166 141 114 33 1792 1045 347 74 890 435 145 29 69
Table 02. EMBASE

No 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Search term Acquired Immunodeciency Syndrome/ acquired immunodeciency syndrome.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] AIDS.ab,ti. exp Neoplasm/ (neoplasm$ or cancer$ or tumor$ or tumour$ or carcinoma$ or malignan$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] Terminally Ill patient/ Terminal Care/ ((terminal adj6 ill$) or (terminal$ adj6 care)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (end adj6 life).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] or/1-9 anorexia-cachexia syndrome.mp. Anorexia/ Cachexia/ Weight Reduction/ (anorexi$ or cachexi$ or cachectic or (weight adj4 loss) or wasting).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] emaciat$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
27
Table 02. EMBASE

No 17. 18. 19. 20. Search term or/11-16 Megestrol Acetate/
(Continued )
megace$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (megestrol adj acetate).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] or/18-20 10 and 17 and 21 22 (88) limit 23 to yr=2002 - 2006 (24)
21. 22. 23. 24.
Table 03. Cochrane Pain, Palliative and Supportive Care Group Trials register
Search strategy (Acquired Immunodeciency Syndrome[All Fields] OR (acquired immunodeciency syndrome[MeSH Terms] OR AIDS [Text Word])) ((neoplasms[MeSH Terms] OR Neoplasm [Text Word]) OR cancer [Text Word])) ((end of life[All Fields] OR (terminally ill [MeSH Terms] OR Terminally ill [Text Word])) OR (terminal care[MeSH Terms] OR Terminal care[Text Word])) (cachexia[MeSH Terms] OR cachexia [Text Word]) (megestrol acetate [MeSH Terms] OR megestrol acetate [Text Word])
ANALYSES
Comparison 01. Megestrol acetate vs placebo (ITT)

No. of studies 10 10 10 6 11 No. of participants 885 843 1246 952 1767
Outcome title 01 Appetite improvement 02 Weight gain 03 Weight gain 04 Quality of life 05 Side effects
Statistical method Relative Risk (Random) 95% CI Weighted Mean Difference (Random) 95% CI Relative Risk (Random) 95% CI Relative Risk (Random) 95% CI Relative Risk (Random) 95% CI
Effect size 2.76 [1.65, 4.61] 2.78 [1.61, 3.95] 1.95 [1.44, 2.62] 1.52 [0.87, 2.66] 1.74 [1.29, 2.35]
Comparison 02. Megestrol acetate vs other drugs (ITT)

No. of studies 3 5 4 3 No. of participants 514 598 524 514
Outcome title 01 Appetite improvement 02 Weight gain 03 Weight gain 04 Quality of life
Statistical method Relative Risk (Random) 95% CI Weighted Mean Difference (Random) 95% CI Relative Risk (Random) 95% CI Relative Risk (Random) 95% CI
Effect size 1.15 [0.75, 1.76] 3.82 [0.06, 7.57] 1.29 [0.94, 1.76] 1.08 [0.80, 1.45]
28
Comparison 03. Sensitivity analysis

Outcome title 01 Appetite improvement, treatment duration 02 Weight gain, treatment duration 03 Weight gain, treatment duration 04 Appetite improvement, study quality 05 Weight gain, study quality 06 Weight gain, study quality No. of studies 4 6 4 6 6 7 No. of participants 489 856 393 561 499 895 Statistical method Relative Risk (Random) 95% CI Relative Risk (Random) 95% CI Effect size 3.21 [1.54, 6.70] 1.86 [1.31, 2.63]
Weighted Mean Difference (Random) 95% CI 4.54 [0.43, 8.66] Relative Risk (Random) 95% CI 3.03 [1.83, 5.01]
Weighted Mean Difference (Random) 95% CI 3.53 [1.43, 5.62] Relative Risk (Random) 95% CI 1.83 [1.35, 2.50]
INDEX TERMS Medical Subject Headings (MeSH) Acquired Immunodeciency Syndrome [complications]; Anorexia [ drug therapy; etiology]; Appetite Stimulants [ therapeutic use]; Cachexia [ drug therapy; etiology]; Megestrol Acetate [ therapeutic use]; Neoplasms [complications]; Randomized Controlled Trials as Topic; Syndrome MeSH check words Humans
COVER SHEET Title Authors Contribution of author(s) Megestrol acetate for treatment of anorexia-cachexia syndrome Berenstein EG, Ortiz Z ZO put forward the idea of reviewing megestrol acetate. GB performed the search and located trials with MGD. GB and ZO applied the inclusion/exclusion criteria, extracted the data, appraised the quality of the trials. Data entry into RevMan was carried out by GB. Both review authors wrote the review. 2003/3 2005/2 20 August 2007 23 January 2005 For the update for Issue 3, 2007 the following changes were made: Four new studies and three abstracts were identied, two of these studies were full text and were included in this updated review (Ulutin 2002; Jatoi 2004). These trials added 540 additional participants to the review. Two of these studies were excluded (Macbeth 1994; Yeh 2004). There has been no change to the previous conclusions of the review. Information not supplied by author
29
Issue protocol rst published Review rst published Date of most recent amendment Date of most recent SUBSTANTIVE amendment Whats New
Date new studies sought but none found
Date new studies found but not yet included/excluded Date new studies found and included/excluded Date authors conclusions section amended Contact address
Information not supplied by author 01 June 2006 Information not supplied by author Dr Graciela Berenstein Medical Doctor Epidemiology Department Alejandro Posadas National Hospital Paraguay 1835, 3 Buenos Aires 1121 ARGENTINA E-mail: gracielaberenstein@bertel.com.ar Tel: +54 11 4811 4908 Fax: +54 11 4931 2558 10.1002/14651858.CD004310.pub2 CD004310 Cochrane Pain, Palliative and Supportive Care Group HM-SYMPT GRAPHS AND OTHER TABLES
DOI Cochrane Library number Editorial group Editorial group code
30
Analysis 01.01.
Review:
Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 01 Appetite improvement
Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT) Outcome: 01 Appetite improvement Study Megestrol acetate n/N 01 Cancer Batterham 2001 Erkurt 2000 Feliu 1992 Gebbia 1996 Lai 1994 Loprinzi 1990b Schmoll 1992 Zeca 1995 0/1 55/58 30/76 0/1 11/20 24/67 37/63 13/16 0/1 7/57 8/74 0/1 4/19 16/66 6/28 5/17 0.0 13.7 13.5 0.0 11.2 15.3 13.3 12.9 Not estimable 7.72 [ 3.85, 15.49 ] 3.65 [ 1.79, 7.44 ] Not estimable 2.61 [ 1.00, 6.80 ] 1.48 [ 0.87, 2.52 ] 2.74 [ 1.31, 5.74 ] 2.76 [ 1.28, 5.99 ] placebo n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
302
263
79.9
3.03 [ 1.83, 5.01 ]
Total events: 170 (Megestrol acetate), 46 (placebo) Test for heterogeneity chi-square=14.78 df=5 p=0.01 I =66.2% Test for overall effect z=4.30 02 AIDS Von Roenn 1994 181/270 19/38 17.0 1.34 [ 0.97, 1.86 ] p=0.00002
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect z=1.75 03 Other underlying pathology Marchand 2000 p=0.08
270
38
17.0
1.34 [ 0.97, 1.86 ]
Total events: 181 (Megestrol acetate), 19 (placebo)
6/6
0/6
3.0
13.00 [ 0.89, 189.39 ]
Subtotal (95% CI)

Total events: 6 (Megestrol acetate), 0 (placebo) Test for heterogeneity: not applicable Test for overall effect z=1.88 p=0.06
3.0
13.00 [ 0.89, 189.39 ]
Total (95% CI)
578
307
100.0
2.76 [ 1.65, 4.61 ]
Total events: 357 (Megestrol acetate), 65 (placebo) Test for heterogeneity chi-square=30.29 df=7 p=<0.0001 I =76.9% Test for overall effect z=3.89 p=0.0001
0.1 0.2
0.5
10
Favours placebo
Favours MA
31
Analysis 01.02.
Review:
Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 02 Weight gain
Comparison: 01 Megestrol acetate vs placebo (ITT) Outcome: 02 Weight gain Study Megestrol acetate N 01 Cancer Chen 1997 De Conno 1998 Erkurt 2000 Fietkau 1996 Loprinzi 1990b McQuellon 2002 48 -1.71 (4.56) 21 1.06 (1.95) 58 5.00 (6.00) 32 -0.80 (3.60) 67 1.36 (4.99) 28 -1.22 (6.25) 40 -3.99 (5.52) 21 -0.34 (1.01) 57 -5.90 (7.00) 32 -3.20 (3.20) 66 -0.22 (3.01) 29 -4.80 (4.80) 8.8 11.6 8.3 10.0 10.7 7.1 2.28 [ 0.14, 4.42 ] 1.40 [ 0.46, 2.34 ] 10.90 [ 8.52, 13.28 ] 2.40 [ 0.73, 4.07 ] 1.58 [ 0.18, 2.98 ] 3.58 [ 0.68, 6.48 ] Mean(SD) Placebo N Mean(SD) Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random) 95% CI (%) 95% CI
Subtotal (95% CI)

Test for overall effect z=3.05 02 AIDS Von Roenn 1994
254
p=0.002
245
56.5
3.56 [ 1.27, 5.85 ]
Test for heterogeneity chi-square=55.13 df=5 p=<0.0001 I =90.9%
75 3.54 (4.29)
38 -0.72 (2.87)
10.8
4.26 [ 2.93, 5.59 ]
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect z=6.27 03 Other underlying pathology Eubanks 2002 Weisberg 2002 Yeh 2000
75
p<0.00001
38
10.8
4.26 [ 2.93, 5.59 ]
10 5.30 (3.60) 72 1.20 (1.40) 36 1.05 (1.00)
7 1.50 (1.60) 73 0.60 (1.10) 33 0.91 (0.68)
7.9 12.4 12.4
3.80 [ 1.27, 6.33 ] 0.60 [ 0.19, 1.01 ] 0.14 [ -0.26, 0.54 ]
Subtotal (95% CI)

Test for overall effect z=1.62 p=0.1
118
113
32.7
0.65 [ -0.14, 1.44 ]
Test for heterogeneity chi-square=9.48 df=2 p=0.009 I =78.9%
Total (95% CI)

Test for overall effect z=4.66
447
p<0.00001
396
100.0
2.78 [ 1.61, 3.95 ]
-10
-5
10
Favours Placebo
Favours M A
32
Analysis 01.03.
Review:
Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 03 Weight gain
Comparison: 01 Megestrol acetate vs placebo (ITT) Outcome: 03 Weight gain Study Megestrol acetate n/N 01 Cancer Feliu 1992 Lai 1994 Loprinzi 1990b Rowland 1996 Schmoll 1992 Tchekmedyian 1992 Vadell 1998 21/76 6/20 11/67 26/122 17/63 27/49 38/99 5/74 3/19 1/66 8/121 4/28 16/40 13/51 7.7 4.9 2.0 10.3 6.9 17.4 15.2 4.09 [ 1.63, 10.27 ] 1.90 [ 0.55, 6.54 ] 10.84 [ 1.44, 81.58 ] 3.22 [ 1.52, 6.83 ] 1.89 [ 0.70, 5.10 ] 1.38 [ 0.87, 2.17 ] 1.51 [ 0.89, 2.56 ] placebo n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
496
399
64.5
2.14 [ 1.41, 3.24 ]
Total events: 146 (Megestrol acetate), 50 (placebo) Test for heterogeneity chi-square=10.98 df=6 p=0.09 I =45.3% Test for overall effect z=3.59 02 AIDS Von Roenn 1994 127/232 8/38 12.8 2.60 [ 1.39, 4.87 ] p=0.0003
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect z=2.99 03 Other underlying pathology Marchand 2000 Yeh 2000 p=0.003
232
38
12.8
2.60 [ 1.39, 4.87 ]
Total events: 127 (Megestrol acetate), 8 (placebo)
6/6 9/36
4/6 7/33
14.3 8.5
1.50 [ 0.85, 2.64 ] 1.18 [ 0.50, 2.81 ]
Subtotal (95% CI)
42
39
22.7
1.40 [ 0.87, 2.24 ]
Total events: 15 (Megestrol acetate), 11 (placebo) Test for heterogeneity chi-square=0.31 df=1 p=0.58 I =0.0% Test for overall effect z=1.38 p=0.2
Total (95% CI)
770
476
100.0
1.95 [ 1.44, 2.62 ]
0.1 0.2
0.5
10
Favours Placebo
Favours M A
33
Analysis 01.04.
Review:
Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 04 Quality of life
Comparison: 01 Megestrol acetate vs placebo (ITT) Outcome: 04 Quality of life Study Megestrol acetate n/N 01 Cancer Feliu 1992 Lai 1994 Rowland 1996 Vadell 1998 26/76 7/20 87/122 18/99 10/74 3/19 91/121 7/51 18.4 11.6 24.2 16.3 2.53 [ 1.31, 4.88 ] 2.22 [ 0.67, 7.34 ] 0.95 [ 0.81, 1.10 ] 1.32 [ 0.59, 2.96 ] placebo n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
317
265
70.5
1.52 [ 0.79, 2.91 ]
Total events: 138 (Megestrol acetate), 111 (placebo) Test for heterogeneity chi-square=13.18 df=3 p=0.004 I =77.2% Test for overall effect z=1.26 02 AIDS Oster 1994 Von Roenn 1994 5/52 91/232 6/48 6/38 12.4 17.1 0.77 [ 0.25, 2.36 ] 2.48 [ 1.17, 5.27 ] p=0.2
Subtotal (95% CI)
284
86
29.5
1.49 [ 0.47, 4.69 ]
Total events: 96 (Megestrol acetate), 12 (placebo) Test for heterogeneity chi-square=2.94 df=1 p=0.09 I =66.0% Test for overall effect z=0.68 03 Other underlying pathology p=0.5
Subtotal (95% CI)

Total events: 0 (Megestrol acetate), 0 (placebo) Test for heterogeneity: not applicable Test for overall effect: not applicable
0.0
Not estimable
Total (95% CI)
601
351
100.0
1.52 [ 0.87, 2.66 ]
0.1 0.2
0.5
10
Favours placebo
Favours M A
34
Analysis 01.05.
Review:
Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 05 Side effects
Comparison: 01 Megestrol acetate vs placebo (ITT) Outcome: 05 Side effects Study Megestrol acetate n/N 01 Edema Beller 1997 Bruera 1998 Chen 1997 Feliu 1992 Loprinzi 1990b Rowland 1996 Schmoll 1992 Tchekmedyian 1992 Vadell 1998 Von Roenn 1994 Weisberg 2002 4/161 1/84 1/48 7/76 18/67 44/122 2/63 8/49 2/99 14/232 11/72 0/79 0/84 0/40 3/74 8/66 24/121 0/28 6/40 0/51 4/38 4/73 1.1 0.9 0.9 5.2 15.6 49.1 1.0 9.6 1.0 8.1 7.5 4.44 [ 0.24, 81.54 ] 3.00 [ 0.12, 72.61 ] 2.51 [ 0.11, 59.98 ] 2.27 [ 0.61, 8.45 ] 2.22 [ 1.04, 4.74 ] 1.82 [ 1.18, 2.79 ] 2.27 [ 0.11, 45.71 ] 1.09 [ 0.41, 2.88 ] 2.60 [ 0.13, 53.16 ] 0.57 [ 0.20, 1.65 ] 2.79 [ 0.93, 8.35 ] Placebo n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Total (95% CI)
1073
694
100.0
1.74 [ 1.29, 2.35 ]
Total events: 112 (Megestrol acetate), 49 (Placebo) Test for heterogeneity chi-square=7.13 df=10 p=0.71 I =0.0% Test for overall effect z=3.60 p=0.0003
0.1 0.2
0.5
10
Favours M A
Favours Placebo
35
Analysis 02.01.
Review:
Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 01 Appetite improvement
Comparison: 02 Megestrol acetate vs other drugs (ITT) Outcome: 01 Appetite improvement Study Megestrol acetate n/N 01 Cancer Lai 1994 Loprinzi 1999a Loprinzi 1999b 11/20 26/79 26/79 6/19 64/159 39/158 20.3 41.5 38.2 1.74 [ 0.81, 3.77 ] 0.82 [ 0.57, 1.18 ] 1.33 [ 0.88, 2.02 ] Other drugs n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
178
336
100.0
1.15 [ 0.75, 1.76 ]
Total events: 63 (Megestrol acetate), 109 (Other drugs) Test for heterogeneity chi-square=4.66 df=2 p=0.10 I =57.1% Test for overall effect z=0.64 02 AIDS p=0.5
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect: not applicable 03 Other underlying pathology
0.0
Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect: not applicable
0.0
Not estimable
Total (95% CI)
178
336
100.0
1.15 [ 0.75, 1.76 ]
Total events: 63 (Megestrol acetate), 109 (Other drugs) Test for heterogeneity chi-square=4.66 df=2 p=0.10 I =57.1% Test for overall effect z=0.64 p=0.5
0.1 0.2
0.5
10
Favours other drugs
Favours treatment
36
Analysis 02.02.
Review:
Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 02 Weight gain
Comparison: 02 Megestrol acetate vs other drugs (ITT) Outcome: 02 Weight gain Study Megestrol acetate N 01 Cancer Chen 1997 Loprinzi 1999a Loprinzi 1999b 48 -1.71 (4.56) 79 2.50 (4.45) 79 2.50 (4.45) 41 -5.41 (3.19) 159 2.01 (3.24) 158 1.77 (2.58) 20.6 21.0 21.1 3.70 [ 2.08, 5.32 ] 0.49 [ -0.61, 1.59 ] 0.73 [ -0.33, 1.79 ] Mean(SD) Other drugs N Mean(SD) Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random) 95% CI (%) 95% CI
Subtotal (95% CI)

Test for overall effect z=1.76 02 AIDS Batterham 2001 Timpone 1997
206
p=0.08
358
62.7
1.53 [ -0.18, 3.25 ]
4 10.20 (4.51) 12 6.50 (1.10)
6 4.01 (1.68) 12 -2.00 (1.30)
16.2 21.1
6.19 [ 1.57, 10.81 ] 8.50 [ 7.54, 9.46 ]
Subtotal (95% CI)

Test for overall effect z=17.46 03 Other underlying pathology
16
p<0.00001
18
37.3
8.40 [ 7.46, 9.35 ]
Subtotal (95% CI)

0.0
Not estimable
Total (95% CI)

222
p=0.05
376
100.0
3.82 [ 0.06, 7.57 ]
-10
-5
10
Favours other drugs
Favours M A
37
Analysis 02.03.
Review:
Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 03 Weight gain
Comparison: 02 Megestrol acetate vs other drugs (ITT) Outcome: 03 Weight gain Study Megestrol acetate n/N 01 Cancer Lai 1994 Loprinzi 1999a Loprinzi 1999b 6/20 6/79 5/79 4/19 8/159 5/158 8.1 9.3 6.6 1.43 [ 0.48, 4.27 ] 1.51 [ 0.54, 4.20 ] 2.00 [ 0.60, 6.71 ] Other drugs n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
178
336
24.0
1.60 [ 0.85, 3.03 ]
Total events: 17 (Megestrol acetate), 17 (Other drugs) Test for heterogeneity chi-square=0.19 df=2 p=0.91 I =0.0% Test for overall effect z=1.45 02 AIDS Batterham 2001 4/4 5/6 76.0 1.20 [ 0.84, 1.72 ] p=0.1
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect z=1.00 03 Other underlying pathology p=0.3
76.0
1.20 [ 0.84, 1.72 ]
Subtotal (95% CI)

0.0
Not estimable
Total (95% CI)
182
342
100.0
1.29 [ 0.94, 1.76 ]
0.1 0.2
0.5
10
Favours other drugs
Favours M A
38
Analysis 02.04.
Review:
Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 04 Quality of life
Comparison: 02 Megestrol acetate vs other drugs (ITT) Outcome: 04 Quality of life Study Megestrol acetate n/N 01 Cancer Lai 1994 Loprinzi 1999a Loprinzi 1999b 7/20 22/79 21/79 5/19 45/159 37/158 9.8 48.1 42.1 1.33 [ 0.51, 3.48 ] 0.98 [ 0.64, 1.52 ] 1.14 [ 0.71, 1.80 ] Other drugs n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
178
336
100.0
1.08 [ 0.80, 1.45 ]
Total events: 50 (Megestrol acetate), 87 (Other drugs) Test for heterogeneity chi-square=0.40 df=2 p=0.82 I =0.0% Test for overall effect z=0.48 02 AIDS p=0.6
Subtotal (95% CI)

Test for heterogeneity: not applicable Test for overall effect: not applicable 03 Other underlying pathology
0.0
Not estimable
Subtotal (95% CI)

0.0
Not estimable
Total (95% CI)
178
336
100.0
1.08 [ 0.80, 1.45 ]
0.1 0.2
0.5
10
Favours other drugs
Favours M A
39
Analysis 03.01.
Review:
Comparison 03 Sensitivity analysis, Outcome 01 Appetite improvement, treatment duration
Comparison: 03 Sensitivity analysis Outcome: 01 Appetite improvement, treatment duration Study Megestrol acetate n/N 01 treatment duration more than 6 weeks Erkurt 2000 Feliu 1992 Loprinzi 1990b Schmoll 1992 55/58 30/76 24/67 37/63 7/57 8/74 16/66 6/28 24.6 24.4 27.1 23.9 7.72 [ 3.85, 15.49 ] 3.65 [ 1.79, 7.44 ] 1.48 [ 0.87, 2.52 ] 2.74 [ 1.31, 5.74 ] placebo n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Total (95% CI)
264
225
100.0
3.21 [ 1.54, 6.70 ]
0.1 0.2
0.5
10
Favours placebo
Favours MA
Analysis 03.02.
Review:
Comparison 03 Sensitivity analysis, Outcome 02 Weight gain, treatment duration
Comparison: 03 Sensitivity analysis Outcome: 02 Weight gain, treatment duration Study Treatment n/N 01 Treatment duration more than 6 weeks Feliu 1992 Loprinzi 1990b Rowland 1996 Schmoll 1992 Tchekmedyian 1992 Vadell 1998 21/76 16/67 26/122 17/63 27/49 38/99 5/74 11/66 8/121 4/28 16/40 13/51 10.9 16.5 14.7 9.7 25.9 22.3 4.09 [ 1.63, 10.27 ] 1.43 [ 0.72, 2.85 ] 3.22 [ 1.52, 6.83 ] 1.89 [ 0.70, 5.10 ] 1.38 [ 0.87, 2.17 ] 1.51 [ 0.89, 2.56 ] Control n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Total (95% CI)
476
380
100.0
1.86 [ 1.31, 2.63 ]
Total events: 145 (Treatment), 57 (Control) Test for heterogeneity chi-square=7.89 df=5 p=0.16 I =36.6% Test for overall effect z=3.50 p=0.0005
0.1 0.2
0.5
10
Favours treatment
Favours control
40
Analysis 03.03.
Review:
Comparison 03 Sensitivity analysis, Outcome 03 Weight gain, treatment duration
Comparison: 03 Sensitivity analysis Outcome: 03 Weight gain, treatment duration Study Treatment N Mean(SD) Control N Mean(SD) Weighted Mean Difference (Random) 95% CI Weight (%) Weighted Mean Difference (Random) 95% CI
01 Treatment duration more than 6 weeks Chen 1997 Erkurt 2000 Loprinzi 1990b McQuellon 2002 48 58 67 28 -1.71 (4.56) 5.00 (6.00) 1.36 (4.99) -1.22 (6.25) 40 57 66 29 -3.99 (5.52) -5.90 (7.00) -0.22 (3.01) -4.80 (4.80) 25.2 24.8 26.2 23.8 2.28 [ 0.14, 4.42 ] 10.90 [ 8.52, 13.28 ] 1.58 [ 0.18, 2.98 ] 3.58 [ 0.68, 6.48 ]
Total (95% CI)
201
p=0.03
192
100.0
4.54 [ 0.43, 8.66 ]
Test for heterogeneity chi-square=45.47 df=3 p=<0.0001 I =93.4% Test for overall effect z=2.16
-10
-5
10
Favours Placebo
Favours MA
Analysis 03.04.
Review:
Comparison 03 Sensitivity analysis, Outcome 04 Appetite improvement, study quality
Comparison: 03 Sensitivity analysis Outcome: 04 Appetite improvement, study quality Study Megestrol acetate n/N 01 Study quality (Jadad score 3, 4 or 5) Feliu 1992 Loprinzi 1990b 30/76 24/67 8/74 16/66 17.0 19.9 3.65 [ 1.79, 7.44 ] 1.48 [ 0.87, 2.52 ] Control n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
143
140
36.9
2.25 [ 0.92, 5.52 ]
Total events: 54 (Megestrol acetate), 24 (Control) Test for heterogeneity chi-square=4.09 df=1 p=0.04 I =75.6% Test for overall effect z=1.77 p=0.08
02 Study quality (Jadad score 2 or low) Erkurt 2000 Lai 1994 Schmoll 1992 Zeca 1995 55/58 11/20 37/63 13/16 7/57 4/19 6/28 5/17 17.2 13.3 16.5 16.0 7.72 [ 3.85, 15.49 ] 2.61 [ 1.00, 6.80 ] 2.74 [ 1.31, 5.74 ] 2.76 [ 1.28, 5.99 ]
Subtotal (95% CI)
157
121
63.1
3.63 [ 2.06, 6.39 ]
Total events: 116 (Megestrol acetate), 22 (Control)
0.1 0.2
0.5
10
Favours Control
Favours MA
(Continued . . . )
41
(. . .
Study Megestrol acetate n/N Test for heterogeneity chi-square=6.25 df=3 p=0.10 I =52.0% Test for overall effect z=4.47 p<0.00001 Control n/N Relative Risk (Random) 95% CI Weight (%)
Continued)
Relative Risk (Random) 95% CI
Total (95% CI)
300
261
100.0
3.03 [ 1.83, 5.01 ]
Total events: 170 (Megestrol acetate), 46 (Control) Test for heterogeneity chi-square=14.78 df=5 p=0.01 I =66.2% Test for overall effect z=4.30 p=0.00002
0.1 0.2
0.5
10
Favours Control
Favours MA
Analysis 03.05.
Review: Comparison: 03 Sensitivity analysis
Comparison 03 Sensitivity analysis, Outcome 05 Weight gain, study quality
Outcome: 05 Weight gain, study quality Study Megestrol acetate N 01 Study quality (Jadad score 3,4 or 5) De Conno 1998 Fietkau 1996 Loprinzi 1990b McQuellon 2002 21 1.06 (1.95) 32 -0.80 (0.20) 67 1.36 (4.99) 28 -1.22 (6.25) 21 -0.34 (1.01) 32 -3.20 (3.20) 66 -0.22 (3.01) 29 -4.80 (4.80) 18.5 18.3 17.7 14.1 1.40 [ 0.46, 2.34 ] 2.40 [ 1.29, 3.51 ] 1.58 [ 0.18, 2.98 ] 3.58 [ 0.68, 6.48 ] Mean(SD) Control N Mean(SD) Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random) 95% CI (%) 95% CI
Subtotal (95% CI)

148
p<0.00001
148
68.6
1.87 [ 1.20, 2.54 ]
02 Study quality (Jadad score o or low) Chen 1997 Erkurt 2000 48 -1.71 (4.56) 58 5.00 (6.00) 40 -3.99 (5.52) 57 -5.90 (7.00) 16.0 15.4 2.28 [ 0.14, 4.42 ] 10.90 [ 8.52, 13.28 ]
Subtotal (95% CI)

Test for overall effect z=1.53 p=0.1
106
97
31.4
6.57 [ -1.87, 15.02 ]
Total (95% CI)

254
p=0.001
245
100.0
3.53 [ 1.43, 5.62 ]
-10
-5
10
Favours control
Favours MA
42
Analysis 03.06.
Review: Comparison: 03 Sensitivity analysis
Comparison 03 Sensitivity analysis, Outcome 06 Weight gain, study quality
Outcome: 06 Weight gain, study quality Study Treatment n/N 01 Study quality (Jadad score 3,4 or 5) Feliu 1992 Loprinzi 1990b Tchekmedyian 1992 Vadell 1998 21/76 16/67 27/49 38/99 5/74 11/66 16/40 13/51 9.5 15.2 26.2 21.8 4.09 [ 1.63, 10.27 ] 1.43 [ 0.72, 2.85 ] 1.38 [ 0.87, 2.17 ] 1.51 [ 0.89, 2.56 ] Control n/N Relative Risk (Random) 95% CI Weight (%) Relative Risk (Random) 95% CI
Subtotal (95% CI)
291
231
72.7
1.66 [ 1.13, 2.44 ]
02 Study quality (Jadad score 2 or low) Lai 1994 Rowland 1996 Schmoll 1992 6/20 26/122 17/63 3/19 8/121 4/28 5.7 13.3 8.4 1.90 [ 0.55, 6.54 ] 3.22 [ 1.52, 6.83 ] 1.89 [ 0.70, 5.10 ]
Subtotal (95% CI)
205
168
27.3
2.49 [ 1.45, 4.27 ]
Total (95% CI)
496
399
100.0
1.83 [ 1.35, 2.50 ]
0.1 0.2
0.5
10
Favours treatment
Favours control
43

Meg Acet in Anorexia

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Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)

Berenstein EG, Ortiz Z

Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)

References to studies included in this review

References to studies excluded from this review

Indicates the major publication for the study

Characteristics of included studies

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants Interventions Outcomes

Notes Allocation concealment Study Methods

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Allocation concealment Study Methods Participants

Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Interventions Outcomes Notes

Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Notes Allocation concealment

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Interventions Outcomes Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Notes Allocation concealment Study Methods

Characteristics of included studies (Continued )

Interventions Outcomes Notes Allocation concealment Study Methods Participants

Interventions Outcomes Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Interventions Outcomes Notes Allocation concealment Study Methods Participants

Interventions Outcomes Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Outcomes Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Notes Allocation concealment Study Methods Participants

Characteristics of included studies (Continued )

Notes Allocation concealment Study Methods Participants

Notes Allocation concealment Study Methods Participants

Notes Allocation concealment Study Methods Participants

Characteristics of excluded studies

Table 01. Patient condition and numbers recruited to each trial

Table 02. EMBASE

Table 02. EMBASE

21. 22. 23. 24.

Comparison 01. Megestrol acetate vs placebo (ITT)

Comparison 02. Megestrol acetate vs other drugs (ITT)

Comparison 03. Sensitivity analysis

Date new studies sought but none found

DOI Cochrane Library number Editorial group Editorial group code

Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 01 Appetite improvement

Megestrol acetate for treatment of anorexia-cachexia syndrome

Subtotal (95% CI)

3.03 [ 1.83, 5.01 ]

Subtotal (95% CI)

1.34 [ 0.97, 1.86 ]

Total events: 181 (Megestrol acetate), 19 (placebo)

13.00 [ 0.89, 189.39 ]

Subtotal (95% CI)