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

Transcription

1 Megestrol acetate for treatment of anorexia-cachexia syndrome (Review) Berenstein G, Ortiz Z This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2005, Issue 2

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES i

3 [Intervention Review] Megestrol acetate for treatment of anorexia-cachexia syndrome Graciela Berenstein 2, Zulma Ortiz 1 1 Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina. 2 (Deceased) Epidemiology Department, Hospital Nacional Dr Alejandro Posadas, Buenos Aires, Argentina Contact address: Zulma Ortiz, Epidemiological Research Center, National Academy of Medicine, Conde H, Pacheco de Melo 3081, Buenos Aires, Federal Capital, 1425, Argentina. zortiz@arnet.com.ar. zuortiz2001@yahoo.com.ar. Editorial group: Cochrane Pain, Palliative and Supportive Care Group. Publication status and date: Edited (no change to conclusions), published in Issue 7, Review content assessed as up-to-date: 19 August Citation: Berenstein G, Ortiz Z. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T 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 USA s 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 efficacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies. Search methods 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 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. 1

4 Main results Thirty trials were included in the original review, four new trials were identified for this update, but only two met the inclusion criteria ( patients). Twenty-two trials compared MA at different doses with placebo; five compared different doses of MA versus other drugs; two compared MA with other drugs and placebo; and five compared different doses of MA. For all patient conditions, metaanalysis showed a benefit 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 insufficient information to define 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 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. P L A I N L A N G U A G E S U M M A R Y Megestrol acetate for the treatment of anorexia-cachexia syndrome Megestrol acetate improves appetite and weight gain in patients with anorexia cachexia syndrome related to cancer.megestrol acetate s 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 significantly 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. B A C K G R O U N D 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 patient s death (Nelson 1994; Splinter 1992). More than two-thirds of patients dying with advanced cancer suffer from anorexia cachexia syndrome (Argilés 2001). Anorexia cachexia syndrome is also described in other pathologies such as Acquired Immune Deficiency Syndrome (AIDS); anorexia nervosa; in degenerative illnesses of the central nervous system; and in terminally ill patients (Von Roenn 1996). Incidence is variable and difficult 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 identified that cause severe anorexia and weight loss. Tumour necrosis factor, synthesized by the host s macrophages (important cells in the immune system), and inflammatory 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 2

5 seems to suppress well-characterized mediators of cancer associated wasting, including interleukin-6, an inflammatory 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-specific, but their activity seems to be maximized in phase G1 of cellular division (Tchekmedyian 1986). Megestrol acetate was first synthesized in England in Developed as an oral contraceptive, the agent was first 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 scientific 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 fluid retention, venous thrombosis, diarrhoea, 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, 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). O B J E C T I V E S 1) To evaluate the efficacy, 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. M E T H O D S 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 first 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 interventions 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 (calorific 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; 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 3

6 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: 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. Search methods for identification of studies Electronic searches The following electronic databases were searched to identify relevant studies: MEDLINE from 1966 to October 2002, subsequent search June 2006 (see Appendix 1); EMBASE from 1986 to 2002, subsequent search, week 28, 2006 (see Appendix 2); The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library Issue 1, 2002, subsequent search Issue 2, The Cochrane Pain, Palliative and Supportive Care Group Trials Register (June 2006) (see Appendix 3) The general strategy for identifying RCTs in MEDLINE was combined with a strategy designed to retrieve trials of megestrol acetate for cachexia. For the identification of studies included or considered for this review, detailed search strategies were developed for each database searched. Searching other resources 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 collection and analysis 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 five (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. 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 first treatment period in order to avoid carry-over effects. For dichotomous variables, treatment effects were computed as relative risk (RR) with 95% confidence 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 4

7 P < 0.1 as a cut-off value to represent the presence of significant 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. 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. Subgroup analysis Analysis of subgroups was undertaken according to the underlying pathology of the patients. Three subgroups of studies were defined: patients with AIDS; patients with cancer; patients with other underlying disease. Sensitivity analysis In order to explore the impact of specific factors on the metaanalysis results, sensitivity analyses was undertaken with: studies of high methodological quality (defined 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 R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. Searching electronic databases identified: 99 reports in MEDLINE (from 1966 to October 2002, the subsequent search identified 24 reports in MEDLINE (from 2002 to July 2006); 164 reports in EMBASE (from 1986 to 2002), the subsequent search identified 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 identified 59 reports (in Issue 1, 2002). Three abstracts retrieved from handsearching in CCRT (CEN- TRAL) were identified in this updated review. We attempted to contact the authors of these abstracts for further trials data but with no success. 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 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 five 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 fluoximesterone 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)). 5

8 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 1 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-specified 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 fibrosis: 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. 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 mg per day Two trials: Jatoi 2004; Pardo 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 mg per day One trial: Loprinzi mg per day One trial: Tchekmedyian 1992 One trial in children with cystic fibrosis 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 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) 6

9 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) in included studies 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 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 five: 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 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 Effects of interventions 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, the comparison of one low dose of megestrol versus high dose in Pardo 2003 as explained below, and the lack of information in Gambardella 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 first 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 five intended outcome measures were analyzed: 1) appetite increase, expressed as a dichotomous variable (number of patients who experience appetite increase), 2) 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 (calorific 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 significant benefit 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 significance 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 < ) (Comparison 01 04). Three trials in the subcategory of patients with cancer have used the per- 7

10 formance 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 Erkurt s 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 difficult 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 five points as a quality score. Megestrol acetate versus other drugs Five of seven identified 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 fluoxymesterone 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 benefits 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 first one used the K I and Loprinzi used Spitzer QL index. No significant 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 In order to perform the meta-analysis, we defined 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 first 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 significant. 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 efficacy 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 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 sideeffects. 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 significant, 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 benefit 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 five) showed a benefit for the megestrol acetate in the outcome weight gain only, both as a dichotomous and continuous 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 8

11 Scores. In the group of low methodological score, we observed an overall benefit in the treatment group for the outcome appetite improvement (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). D I S C U S S I O N 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 significance Jatoi 2004; Ulutin 2002). Two systematic reviews have been undertaken recently. A systematic review by Maltoni 2001 assessed the efficacy 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 define optimal dose, duration of treatment or the impact on quality of life. The review by Ruiz-García et al. (Ruiz-Garcia 2002) evaluated the efficacy 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 significant effect was observed with higher doses. The aim of the present update was to assess the efficacy, 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 five). The total number of patients was 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 confirms 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 efficacy 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, c) difficulty administering this testing led to inconclusive QoL findings. On the other hand some patients cannot complete quality of life measures because they have cognitive impairments, communication deficits, 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 benefit 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 profile of megestrol acetate has shown edema to be the only one significant difference between placebo and megestrol acetate, suggesting that megestrol acetate is a safe treatment option in these patients. A U T H O R S C O N C L U S I O N S 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 9

12 the Cochrane Collaboration Guidelines to perform an unbiased review. However, the results of a meta-analysis are influenced by the quality of the primary studies included. Quality is difficult to define. 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 benefit of intervention. In this update 68% of the studies were assessed as moderate or low quality trials. 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 USA s Federal Drug Administration has approved megestrol acetate to be used in AIDS patients more research is needed. A C K N O W L E D G E M E N T S 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 García Diéguez 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. R E F E R E N C E S 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): 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: 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: 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): 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;43:75 9. 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: Erkurt 2000 {published data only} Erkurt E, Erkisi M. Supportive treatment in weightlosing cancer patients due to the additive adverse effects of radiation treatment and/or chemotherapy. Journal of Experimental Clinical Cancer Research 2000;19(4): 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 fibrosis. Journal of Pediatrics 2002;140 (4): 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): 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: 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):75 9. [: CN ] 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. [: CN ] 10

13 Gebbia 1996 {published data only} Gebbia V, Testa A. Prospective randomised trial of two dose levels of megestrol acetate in the management of anorexiacachexia syndrome in patients with metastatic cancer. British Journal of Cancer 1996;73: 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): 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: 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: 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: 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;51:2 7. 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: official journal of the American Society of Clinical Oncology 1993;11(4): [: CN ] Loprinzi 1999a {published data only} Loprinzi CL, Kugler JW. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/ cachexia. Journal of Clinical Oncology 1999;17: Loprinzi 1999b {published data only} Loprinzi CL, Kugler JW. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/ cachexia. Journal of Clinical Oncology 1999;17: Marchand 2000 {published data only} Marchand V, Baker SS. Randomized, double-blind, placebo-controlled pilot trial of megestrol acetate in malnourished children with cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 2000;31: 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: 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: Oster 1994 {published data only} Oster MH, Enders SR. Megestrol acetate in patients with AIDS and cachexia. Annals of Internal Medicine 1994;121: 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 efficacy of two different doses in 130 patients. Proceedings for the American Society for Clinical Oncology 2003;22 (abstr 3076):765. [: CN ] 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: Schmoll 1992 {published data only} Schmoll E. Risks and benefits of various therapies for cancer anorexia. Oncology 1992;49:43 5. Schmoll E, Wilke H, Thole R, et al.megestrol acetate in cancer cachexia. Seminars in oncology 1991;18(1 Suppl 2): [: CN ] Tchekmedyian 1992 {published data only} Tchekmedyian NS, Hickman M. Megestrol acetate in cancer anorexia and weight loss. Cancer 1992;69: Timpone 1997 {published data only} Timpone JG, Wright DJ. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Research and Human Retroviruses 1997;13: 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: Vadell 1998 {published data only} Vadell C, Segui MA. Anticachectic efficacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia. American Journal of Clinical Oncology 1998;21: 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: