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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 Library2008, Issue 3
http://www.thecochranelibrary.com
1Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
T A B L E O F C O N T E N T S
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .
3SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .
4METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25Table 01. Patient condition and numbers recruited to each trial . . . . . . . . . . . . . . . . . . .
27Table 02. EMBASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28Table 03. Cochrane Pain, Palliative and Supportive Care Group Trials register . . . . . . . . . . . . . .
28ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28Comparison 01. Megestrol acetate vs placebo (ITT) . . . . . . . . . . . . . . . . . . . . . . .
28Comparison 02. Megestrol acetate vs other drugs (ITT) . . . . . . . . . . . . . . . . . . . . .
29Comparison 03. Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31Analysis 01.01. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 01 Appetite improvement . . . .
32Analysis 01.02. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 02 Weight gain . . . . . . . .
33Analysis 01.03. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 03 Weight gain . . . . . . . .
34Analysis 01.04. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 04 Quality of life . . . . . . .
35Analysis 01.05. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 05 Side effects . . . . . . . .
36Analysis 02.01. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 01 Appetite improvement . . .
37Analysis 02.02. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 02 Weight gain . . . . . . .
38Analysis 02.03. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 03 Weight gain . . . . . . .
39Analysis 02.04. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 04 Quality of life . . . . . .
40Analysis 03.01. Comparison 03 Sensitivity analysis, Outcome 01 Appetite improvement, treatment duration . . .
40Analysis 03.02. Comparison 03 Sensitivity analysis, Outcome 02 Weight gain, treatment duration . . . . . . .
41Analysis 03.03. Comparison 03 Sensitivity analysis, Outcome 03 Weight gain, treatment duration . . . . . . .
41Analysis 03.04. Comparison 03 Sensitivity analysis, Outcome 04 Appetite improvement, study quality . . . . .
42Analysis 03.05. Comparison 03 Sensitivity analysis, Outcome 05 Weight gain, study quality . . . . . . . . .
43Analysis 03.06. Comparison 03 Sensitivity analysis, Outcome 06 Weight gain, study quality . . . . . . . . .
iMegestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Megestrol acetate for treatment of anorexia-cachexiasyndrome (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 first published online: 20 April 2005 in Issue 2, 2005.
Date of most recent substantive amendment: 23 January 2005
A B S T R A C T
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 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 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 identified for this update, but only two met the inclusion criteria
(4123 + 703 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, meta-
analysis 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
1Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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 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 TheCochrane 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 suf-
fer from anorexia cachexia syndrome (Argilés 2001). Anorexia
cachexia syndrome is also described in other pathologies such as
Acquired Immune Deficiency Syndrome (AIDS); anorexia ner-
vosa; 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 tu-
mour and the host (Alexander 1993). Substances have been iden-
tified 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 in-
terleukin 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 in-
terventions for neoplastic cachexia include drugs that stimulate the
appetite (megestrol acetate and dronabinol); cytokine inhibitors
(such as cyproheptadine, thalidomide, pentoxifylline and an eicos-
apentaenoic acid (EPA)); and anabolic agents such as nandrolone
decanoate, oxandrolone and corticosteroids (Balog 1998). EPA
seems to suppress well-characterized mediators of cancer associ-
ated wasting, including interleukin-6, an inflammatory cytokine.
It also acts over the proteolysis-inducing factor, another well-de-
scribed 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 1963. De-
veloped as an oral contraceptive, the agent was first tested in the
treatment of breast cancer in 1967 and later on, for the treat-
ment 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 pa-
tients 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 pro-
posed (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, diar-
rhea, rash, impotence, pruritus, increased blood sugar level, and
headache (Loprinzi 1990a; Vadell 1998; Von Roenn 1994).
Although the mechanism by which megestrol acetate increases ap-
petite is unknown, most hypotheses point to action on cytokines,
2Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
which inhibit the action of tumour necrosis factor on fatty tis-
sue and its products. Currently, interest is focused especially on
its effectiveness in the treatment of anorexia and cachexia in neo-
plastic 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 improve-
ment 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.
C R I T E R I A F O R C O N S I D E R I N G
S T U D I E S F O R T H I S R E V I E W
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 re-
lated to cancer, AIDS or another underlying pathology (indepen-
dent 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 treat-
ments (stimulants of appetite such as dronabinol; cytokine in-
hibitors 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 differ-
ences 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-be-
ing status of the patient. The QoL measures will depend on
the instrument used, e.g., patient assessments using a Likert-
type scale based on patients’ statements and self-report ques-
tionnaires; 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.
S E A R C H M E T H O D S F O R
I D E N T I F I C A T I O N O F S T U D I E S
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 identification 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 specific 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 Immunodeficiency Syndrome“[All Fields] OR
(acquired immunodeficiency syndrome”[MeSH Terms] OR
AIDS [Text Word]))
3Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
• ((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.
M E T H O D S O F T H E R E V I E W
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 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.
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 meta-
analysis 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 4.2.10.
D E S C R I P T I O N O F S T U D I E S
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);
4Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
• 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 (Cen-
tral), (Issue 2, 2006), the subsequent search identified 59 re-
ports (in Issue 1, 2002).
Three abstracts retrieved from handsearching in CCRT (Central)
were identified 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 five studies that appeared to meet the inclusion criteria were
subsequently found to be follow-up reports or duplicate publica-
tions (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 treat-
ment drugs
Five trials compared different doses of megestrol acetate with other
drug treatments. Megestrol acetate was compared with dronabi-
nol 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 treat-
ment 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 effective-
ness 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 pa-
tients (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.
5Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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 fibrosis assessed megestrol ac-
etate 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 re-
sponse 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)
M E T H O D O L O G I C A L Q U A L I T Y
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 five:
Beller 1997; Bruera 1990; Bruera 1998; De Conno 1998; Eu-
banks 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; Heck-
mayr 1992; Lai 1994; McMillan 1994; Pardo 2003; Rowland
1996; Schmoll 1992; Timpone 1997; Ulutin 2002; Zeca 1995.
R E S U L T S
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,
6Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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 follow-
up, 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) 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 dichoto-
mous variable (number of patients who experienced improved
QoL, measured in different and validated scales). Basically, qual-
ity 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 ex-
pressed as calories/day) and QoL expressed as a continuous vari-
able.
Megestrol acetate versus placebo
The overall results have shown improvement in appetite for pa-
tients 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 be-
cause 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 signif-
icant 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 tri-
als in the subcategory of patients with cancer have used the per-
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 conclu-
sion 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 com-
pared megestrol acetate to fluoxymesterone and dexamethasone.
To analyse this trial we divided the total number of patients in-
cluded in the megestrol group by two. In other words, the num-
ber 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 in-
struments. 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 pa-
tients.
Different dose levels of megestrol acetate
7Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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) re-
ported 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 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 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 method-
ological quality of the studies. The group with high Oxford Qual-
ity 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 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
benefit 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).
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 system-
atic review by Maltoni 2001 assessed the efficacy of high dose
progestins for the treatment of anorexia cachexia syndrome in pa-
tients 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 etal. (Ruiz-Garcia 2002) evaluated the efficacy of megestrol acetate
versus placebo in patients with cancer and anorexia cachexia syn-
drome. 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, effec-
tiveness and safety of megestrol acetate for the management of
anorexia-cachexia syndrome, a common clinical problem that sub-
stantially 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 to-
tal 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 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 ten-
dency 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 ad-
dress in order to explain clinical heterogeneity:
a) different types of instruments,
b) extensive testing to assess global QoL,
8Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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, communica-
tion 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 ap-
petite improvement and the lack of benefit on QoL, centers on
the fact that multiple symptoms converge among advanced can-
cer 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 accom-
pany anorexia.
Sensitivity analysis showed that the poorest quality trials over-
estimated positive results.
Finally, a more systematic approach to the measurement of
HRQOL in these patients would be helpful in better understand-
ing 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 mege-
strol 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
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 recogni-
tion of patient autonomy means that subjective measures will be-
come more important and, in the current climate of evidence-
based 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.
P O T E N T I A L C O N F L I C T O F
I N T E R E S T
The first version of this review had evolved from an internal report
on this topic for a pharmaceutical company that produces mege-
strol acetate. This review is independent of that report and has
been prepared with the guidance of, and in line with, the require-
ments of the Pain, Palliative and Supportive Care review group.
Aside from the above project, the review authors certify that they
have no affiliations with any organisation or entity with a direct
financial interest in the subject matter of the review.
A C K N O W L E D G E M E N T S
We would like to thank the Iberoamerican Cochrane Collabora-
tion Centre for their support, particularly Marta Roque for her
critical review and Gerard Urrutia for his comments. We are grate-
ful to Dr CL Loprinzi and Paul Novotny from the Mayo Clinic;
Professor E Bruera, Department of Palliative Care and Rehabili-
tation 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 Bick-
ley (Trials Search Co-ordinator, Cochrane Pain, Palliative Care &
Supportive Care Group) for performing the bibliographic searches
in the present version of this update.
S O U R C E S O F S U P P O R T
External sources of support
• No sources of support supplied
Internal sources of support
• Instituto de Investigaciones Epidemiológicas. Academia Na-
cional de Medicina de Buenos Aires ARGENTINA
9Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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, nan-
drolone decanoate and dietary counselling for HIV associated weight
loss. International Journal of Andology 2001;24(4):232–40.
Beller 1997 {published data only}
Beller E, Tattersall M. Improved quality of life with megestrol ac-
etate in patients with endocrine-insensitive advanced cancer: A ran-
domised 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;66:1279–82.
Bruera 1998 {published data only}
Bruera E, Scott E. Effectiveness of megestrol acetate in patients with
advanced cancer: a randomized, double-blind, crossover study. Can-
cer Prevention & Control 1998;2(2):74–8.
Chen 1997 {published data only}
Chen Hui-Chun, Wan Leung S. Effect of megestrol acetate and pre-
pulsid 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;34:1705–9.
Erkurt 2000 {published data only}
Erkurt E, Erkisi M. Supportive treatment in weight-losing cancer pa-
tients due to the additive adverse effects of radiation treatment and/or
chemotherapy. Journal of Experimental Clinical Cancer Research 2000;
19(4):431–9.
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):439–44.
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):436–40.
Fietkau 1996 {published data only}∗Fietkau R, Riepl M. Supportive treatment with megestrol acetate
during radio (chemo) therapy. A randomised trial. Strahlenther Onkol
1996;172:162–8.
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.
Gambardella 1998 {published data only}
Gambardella A, Pesce L, Bolognino P, Lombardi G, Barbieri M, Ri-
naldi 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:
1576–80.
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;22:2469–76.
Lai 1994 {published data only}
Lai YL, Fang FM. Management of anorexic patients in radiother-
apy: A prospective randomized comparison of megestrol and pred-
nisolone. Journal of Pain and Symptom Management 1994;9:265–8.
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;82:1127–32.
Loprinzi 1994 {published data only}∗Loprinzi CL, Bernath AM. Phase III evaluation of 4 doses of mege-
strol acetate for patients with cancer anorexia and/or cachexia. On-
cology 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):762–7.
Loprinzi 1999a {published data only}∗Loprinzi CL, Kugler JW. Randomized comparison of megestrol ac-
etate versus dexamethasone versus fluoxymesterone for the treatment
of cancer anorexia/cachexia. Journal of Clinical Oncology 1999;17:
3299–306.
Loprinzi 1999b {published data only}
Loprinzi CL, Kugler JW. Randomized comparison of megestrol ac-
etate versus dexamethasone versus fluoxymesterone for the treatment
of cancer anorexia/cachexia. Journal of Clinical Oncology 1999;17:
3299–306.
10Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Marchand 2000 {published data only}
Marchand V, Baker SS. Randomized, double-blind, placebo-con-
trolled pilot trial of megestrol acetate in malnourished children with
cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition
2000;31:264–9.
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;13:85–9.
McQuellon 2002 {published data only}
Mc Quellon RP, Moose DB. Supportive use of megestrol acetate
(MEGACE) with head/neck and lung cancer patients receiving ra-
diation therapy. International Journal of Radiation Oncology Biology
and Physics 2002;52:1180–5.
Oster 1994 {published data only}
Oster MH, Enders SR. Megestrol acetate in patients with AIDS and
cachexia. Annals of Internal Medicine 1994;121:400–8.
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.
Rowland 1996 {published data only}
Rowland KM, Loprinzi CL. Randomized double-blind placebo-con-
trolled 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 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):32–4.
Tchekmedyian 1992 {published data only}
Tchekmedyian NS, Hickman M. Megestrol acetate in cancer
anorexia and weight loss. Cancer 1992;69:1268–74.
Timpone 1997 {published data only}
Timpone JG, Wright DJ. The safety and pharmacokinetics of single-
agent and combination therapy with megestrol acetate and dronabi-
nol for the treatment of HIV wasting syndrome. AIDS Research and
Human Retroviruses 1997;13:305–15.
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;88:277–80.
Vadell 1998 {published data only}
Vadell C, Segui MA. Anticachectic efficacy of megestrol acetate at dif-
ferent doses and versus placebo in patients with neoplastic cachexia.
American Journal of Clinical Oncology 1998;21:347–51.
Von Roenn 1994 {published data only}
Von Roenn JH, Armstrong D. Megestrol acetate in patients with
AIDS-related cachexia. Annals of Internal Medicine 1994;121:393–9.
Weisberg 2002 {published data only}
Weisberg J, Wanger J. Megestrol acetate stimulates weight gain
and ventilation in underweight COPD patients. Chest 2002;121(4):
1070–8.
Westman 1999 {published data only}
Westman G, Bergman B. Megestrol acetate in advanced, progressive,
hormone-insensitive cancer. Effects on the quality of life: a placebo-
controlled, randomised, multicentre trial. European Journal of Cancer
1999;35:586–95.
Yeh 2000 {published data only}
Yeh SS, Wu SY. Improvement in quality of life measures and stim-
ulation of weight gain after treatment with megestrol acetate oral
suspension in geriatric cachexia: Results of a double-blind, placebo-
controlled study. Journal of the American Geriatric Society 2000;48
(5):485–92.
Zeca 1995 {published data only}
Zeca E, Martini C, Venturino P, Tedeschi M, Ventafrida V, De Conno
F. Efficacy of Megestrol Acetate on Anorexia in patients with ad-
vanced non hormone-related tumors: A double-blind placebo con-
trolled 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;79:495–500.
Yeh 2004∗Yeh S, Hafner A, Chang C, et al.Risk Factors Relating Blood Mark-
ers of Inflammation and Nutritional Status to Survival in Cachec-
tic Geriatric Patients in a Randomized Clinical Trial. Journal of the
American Geriatrics Society 2004;52:1708–12.
Additional references
Alexander 1993
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∗Indicates the major publication for the study
T A B L E S
Characteristics of included studies
Study Batterham 2001
Methods Randomised controlled
In a tertiary referral hospital, Sydney
Participants 15 HIV pts
a) 4 M mean age 46 yrs
b) 6 M mean age 44 yrs
c) 5 M mean age 42 yrs, five completed and then randomized three to nandrolone and two to megestrol
Interventions a) MA 400 mg/d orally
b) nandrolone decanoate 100 mg/fortnight IM injection
c) diet counseling
duration 12 weeks
Outcomes Weight
Appetite VAS ten points score
0 = poor appetite
10 = good appetite
12Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Dietary intake %
Notes 12 weeks of treatment
QS = 2
Allocation concealment B – Unclear
Study Beller 1997
Methods Double blind,
randomised controlled
multicentre (15), stratified by institution and whether receiving any anti tumor treatment
Participants 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
Outcomes QoL five linear analogue self assessment scales (LASA) asked patients about five 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
Notes Two weeks of treatment
QS = 4
Allocation concealment A – Adequate
Study Bruera 1990
Methods Double blind, cross over randomised controlled
Participants 40 advanced cancer pts
31 included pts = 25M + 6F
Interventions a) MA 480 mg/d
b) placebo
Outcomes 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
Notes Seven days first phase
QS = 3
Allocation concealment B – Unclear
Study Bruera 1998
Methods Cross over
13Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
double blind
randomised
controlled
Participants 84 advanced cancer pts
47M + 37F
mean age 62 yrs
Interventions a) MA 480 mg/d
b) placebo
Outcomes Appetite (VAS)
weight
triceps skinfold
QoL Functional Living Index Cancer (FLIC)
Notes Ten days of treatment
QS = 4
Allocation concealment B – Unclear
Study Chen 1997
Methods Randomised controlled
Participants 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
Interventions a) MA 160 mg/d
b) cisapride 10 mg/d
c) placebo
Outcomes Weight
Appetite score zero to five
Notes Four and eight weeks of treatment
during a full course of radiotherapy
QS = 2
Allocation concealment B – Unclear
Study De Conno 1998
Methods Double blind
randomised controlled
Participants 42 cancer pts
a) 21 pts = 15M + 6F mean age 63 yrs
b) 21 pts = 16M + 5F mean age 58 yrs
Interventions a) MA 320 mg/d
b) placebo
Outcomes Appetite
Score zero to ten
Weight
QoL Therapy Impact Questionnaire (TIQ)
Notes 14 days of treatment
QS = 3
14Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Allocation concealment B – Unclear
Study Erkurt 2000
Methods Randomised controlled
Participants 115 cancer pts
a) 58 pts = 38M + 12F mean age 51 yrs
b) 57 pts = 45M + 5F
mean age 57 yrs
Interventions a) MA 480 mg/d
b) placebo
Outcomes Weight
Appetite score zero to five
QoL Eastern Cooperative Oncology Group Performance status (ECOG PS)
Notes Three months of treatment
46 pts during RT, and four at the end of RT of MA group
QS = 2
Allocation concealment B – Unclear
Study Eubanks 2002
Methods Double blind randomised controlled
Participants 17 cystic fibrosis 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
Interventions a) MA 10 mg/kg per day
b) placebo
Outcomes Weight
Triceps skinfold
Mid arm circumference
Notes Six months of treatment
QS = 4
Allocation concealment A – Adequate
Study Feliu 1992
Methods Double blind
randomised controlled
Participants 150 cancer pts
a) 76 pts = 58M + 8F mean age 57 yrs
b) 74 pts = 55M + 7F
mean age 58 yrs
Interventions a) MA 240 mg/d
b) placebo
Outcomes Weight
Appetite VAS score
QoL performance status KI
Notes Two months of treatment
QS = 4
15Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Allocation concealment B – Unclear
Study Fietkau 1996
Methods Double blind
randomised controlled
Participants 64 cancer pts
61 pts =
a) 31pts = 25M + 6F mean age 52 yrs
b) 30 pts = 24M + 6F
mean age 48 yrs
Interventions a) MA 160 mg/d
b) placebo
Outcomes Nutritional status weight
QoL index according to Padilla Index
Notes Six weeks of treatment during and up six weeks following radiotherapy
Pts were stratified according oral feeding versus gastrostomy
QS = 3
Allocation concealment B – Unclear
Study Gambardella 1998
Methods NO DATA AVAILABLE
Participants NO DATA AVAILABLE
Interventions NO DATA AVAILABLE
Outcomes NO DATA AVAILABLE
Notes NO DATA AVAILABLE
Allocation concealment D – Not used
Study Gebbia 1996
Methods Randomised controlled
Participants 122 cancer pts
a) 62 pts = 46M + 16F
mean age 63 yrs
b) 60 pts = 42M + 18F
mean age 65 yrs
Interventions a) MA 160 mg/d
b) MA 320 mg/d
Outcomes Appetite, Symptom Distress Scale (SDS)
Weight
Performance Status
Notes 30 days of treatment
QS = 2
Allocation concealment B – Unclear
Study Heckmayr 1992
Methods Randomised controlled
Participants 66 cancer
16Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
a) 33 pts = 24M + 9F
mean age 65 yrs
b) 33 pts = 27M + 6F mean age 68 yrs
Interventions a) MA 160 mg/d
b) MA 480 mg/d
Outcomes Appetite (subjective ten point scale)
Weight
Notes Four weeks of treatment
QS = 1
Allocation concealment B – Unclear
Study Jatoi 2002
Methods Double blind
randomised controlled multicentre (20)
Participants 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
Interventions 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
Outcomes Appetite (validated questionnaires)
Weight
QoL Functional Assessment of Anorexia/Cachexia Therapy (FAACT) instrument uniscale and thirteen item
Notes Duration more than four weeks of treatment
QS = 3
Allocation concealment B – Unclear
Study Jatoi 2004
Methods Double blind randomised controlled multicentre (26)
Participants 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
Interventions 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
Outcomes Weight
Appetite (NCCTG questionnaire and FAACT)
QoL (single-item Uniscale)
Notes Duration more than three months
QS = 4
Allocation concealment B – Unclear
17Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Study Lai 1994
Methods Randomised controlled
Participants 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
Interventions a) MA 160 mg/d
b) Prednisolone 30 mg/d
c) placebo x 3
Outcomes Weight
Appetite, self report
QoL performance status KI
Notes Duration 21 days
QS = 2
Allocation concealment B – Unclear
Study Loprinzi 1990b
Methods Double blind
randomised controlled
Participants 133 Cancer pts
a) 67 pts = 44M + 23F mean age 69 yrs
b) 66 pts = 44M + 22F
mean age 67 yrs
Interventions a) MA 800 mg/d
b) placebo
Outcomes Weight
Appetite
Notes One month of treatment
QS = 5
Allocation concealment A – Adequate
Study Loprinzi 1994
Methods Randomised controlled
Participants 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
Interventions a) MA 160 mg/d
b) MA 480 mg/d
c) MA 800 mg/d
d) MA 1280 mg/d
Outcomes Weight
Appetite
Notes Median 66 days of treatment
18Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
QS = 3
Allocation concealment A – Adequate
Study Loprinzi 1999a
Methods Randomised controlled multicentre
Participants 475 cancer pts
a) 79 pts = 55M + 30F
mean age 66 yrs
b) 159 pts = 99M + 60F mean age 66 yrs
Interventions a) MA 800 mg/d
b) dexamethasone 3 mg/d
Outcomes Appetite
Weight
QoL (uniscale)
Notes One month of treatment
QS = 3
Allocation concealment A – Adequate
Study Loprinzi 1999b
Methods Randomised controlled multicentre
Participants 475 cancer pts
a) 79 pts = 54M + 29F
mean age 66 yrs
b) 158 pts = 100M + 58F mean age 67 yrs
Interventions a) MA 800 mg/d
b) fluoxymesterone 20 mg/d
Outcomes Appetite
Weight
QoL (uniscale)
Notes One month of treatment
QS = 3
Allocation concealment A – Adequate
Study Marchand 2000
Methods Double blind
cross over
controlled
randomised
Participants 12 cystic fibrosis children pts
a) six pts
b) six pts
mean age seven, four yrs, 9F + 3M
Interventions a) MA 10 mg/ kg/d x 2
b) placebo
Outcomes Appetite
Weight
Triceps skinfold
19Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Mid arm circumference
Notes 12 weeks of treatment
QS = 3
Allocation concealment B – Unclear
Study McMillan 1994
Methods Randomised controlled
Participants 38 cancer pts
a) 20 pts
mean age 73 yrs
b) 18 pts
mean age 70 yrs
Interventions a) MA 480 mg/d
b) placebo
Outcomes Weight
Notes 12 weeks of treatment
QS = 2
Allocation concealment B – Unclear
Study McQuellon 2002
Methods Double blind randomised controlled
Participants 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 findings in bone scan)
Interventions a) MA 800 mg/ d suspension
b) placebo suspension 20 ml
Outcomes Weight
QoL FACT
Notes 12 weeks of treatment
QS = 3
Allocation concealment A – Adequate
Study Oster 1994
Methods Double blind
randomised controlled multicenter (13)
Participants 100 HIV pts
a) 52 pts = 50M + 2F mean age 40 yrs
b) 48 pts = 47M + 1F mean age 40 yrs
Interventions a) MA 800 mg/d suspension
b) placebo, suspension
Outcomes Appetite
Weight
Triceps skinfold
Mid arm circunference
Performance status KI
Notes 12 weeks of treatment
20Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
QS = 5
Allocation concealment A – Adequate
Study Pardo 2003
Methods Randomized controlled
Participants 130 cancer patients
a) 64 pts = 58M + 6F mean age 66.8 yrs
b) 66 pts = 62 M + 4F mean age 65.3 yrs
Interventions a) MA 320mg/day
b) MA 600mg/day
Outcomes Appetite
Notes 30 days of treatment
QS = 1
Allocation concealment B – Unclear
Study Rowland 1996
Methods Double blind randomised controlled
Participants 243 cancer pts
a) 122 pts = 56M + 44F
b) 121 pts = 64M + 36F
Interventions a) MA 800 mg/d
b) placebo
Outcomes Appetite questionnaire
QoL VAS uniscale
Notes Mean duration four months and up to two years
QS = 2
Allocation concealment B – Unclear
Study Schmoll 1992
Methods Randomised controlled
Participants 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
Interventions a) MA 960 mg/d
b) placebo
c) MA 480 mg/d
Outcomes Appetite
Weight
Notes a) median duration eight weeks of treatment
b) median duration six weeks
c) median duration seven weeks
QS = 2
Allocation concealment B – Unclear
21Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
Study Tchekmedyian 1992
Methods Double blind
randomised controlled
Participants 89 cancer pts
a) 49 pts = 28M + 9F
mean age 63 yrs
b) 40 pts = 18M + 12F
mean age 64 yrs
Interventions a) MA 1600 mg/d, ten tablets a day, in divided doses
b) placebo ten tablets
Outcomes Appetite, categoric scale of five levels
QoL LAS, 29 items
Weight
Triceps skinfold
Mid arm circunference
Notes Six weeks of treatment
QS = 4
Allocation concealment A – Adequate
Study Timpone 1997
Methods Randomised controlled multicenter (9)
Participants 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
Interventions 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
Outcomes Weight
QoL KI
Notes 12 weeks of treatment
QS = 2
Allocation concealment B – Unclear
Study Ulutin 2002
Methods Randomised controlled study
Participants 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)
Interventions a) MA 160 mg/d orally
b) MA 320 mg/d orally in two divided doses 12 hrs apart
Outcomes Weight
Appetite (Symptom Distress Scale)
22Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
QoL (ten point scale) based on patient statements
Notes Three month duration treatment
QS = 2
Allocation concealment B – Unclear
Study Vadell 1998
Methods Double blind randomised controlled multicenter (nine)
Participants 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
Interventions a) MA 480 mg/d, three tablets
b) placebo, three tablets
c) MA 160 mg/d, one tablet + placebo two tablets
Outcomes Weight
Mid arm circumference
Triceps skinfold
QoL KI
Notes 12 weeks of treatment
QS = 3
Allocation concealment B – Unclear
Study Von Roenn 1994
Methods Double blind randomised controlled multicenter
Participants 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
Interventions a) MA 800 mg/d, suspension
b) MA 400 mg/d, suspension
c) MA 100 mg/ d, suspension
d) placebo, suspension
Outcomes Weight
Appetite
Mid arm circumference
Triceps skinfold
QoL, by Linear Analog Self Assessment questionnaire
Notes 12 weeks of treatment
QS = 4
Allocation concealment A – Adequate
Study Weisberg 2002
Methods Double blind randomised controlled multicenter (18)
Participants 145 COPD pts
a) 72 pts = 46M + 26F
23Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Characteristics of included studies (Continued )
mean age 68 yrs
b) 73 pts = 45M + 28F mean age 66 yrs
Interventions a) MA 800 mg/d, suspension
b) placebo, suspension
Outcomes Weight
Triceps skinfold
Mid arm circumference
Appetite
Notes Eight weeks of treatment
QS = 4
Allocation concealment B – Unclear
Study Westman 1999
Methods Double blind randomised controlled multicenter (15)
Participants 255 cancer pts
a) 128 pts = 77M + 51F mean age 71 yrs
b) 127 pts = 64M + 63F
mean age 69 yrs
Interventions a) MA 320 mg/d, tablets
b) placebo, tablets
Outcomes Weight
QoL EORTC QLQ-C30
Appetite
Notes 12 weeks of treatment
QS = 5
Allocation concealment A – Adequate
Study Yeh 2000
Methods Double blind randomised controlled
Participants 69 geriatric pts
a) 36 pts = 35M + 1F mean age 76 yrs
b) 33 pts = 31M + 2F mean age 76 yrs
Interventions a) MA 800 mg/d, suspension
b) placebo, suspension
Outcomes Weight
Appetite
QoL VAS nine items
Notes 12 weeks of treatment
QS = 5
Allocation concealment A – Adequate
Study Zeca 1995
Methods Double blind
randomized controlled
Participants 33 cancer pts
a) 16 pts (no data available of age and sex)
24Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
b) 17 pts
b) 17 pts
Interventions a) 320 mg/day, tablets
b) placebo
Outcomes Appetite measured in a categoric numeric Scale
Weight
Performance status (Karnofsky)
Notes A) phase A 14 days of treatment
B) phase B, open of 76 days of treatment
QS = 2
Allocation concealment B – Unclear
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 Reason for exclusion
Macbeth 1994 This study was unpublished and closed early due to the numbers of withdrawals (> 50% of death in the megestrol
arm)
McMillan 1999 This study was excluded because the two arms of the treated patients were receiving megestrol acetate
Yeh 2004 This study involved the same participants as Yeah 2000, in which they measured different outcomes
A D D I T I O N A L T A B L E S
Table 01. Patient condition and numbers recruited to each trial
Study
Lung
cancer
Gastroint
& pancreas
Head &
neck cancer
Gynecolog-
ical cancer
Other
cancer AIDS COPD
Cystic
fibrosis Elderly
Bruera 1990 15 14 11
Loprinzi
1990
42 53 38
Feliu 1992 75 36 9 30
Heckmayr
1992
66
Schmoll
1992
91
Tchekme-
dyan 1992
27 23 4 35
25Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 01. Patient condition and numbers recruited to each trial (Continued )
Study
Lung
cancer
Gastroint
& pancreas
Head &
neck cancer
Gynecolog-
ical cancer
Other
cancer AIDS COPD
Cystic
fibrosis Elderly
Lai 1994 8 44 0
Loprinzi
1994
130 111 101
McMillan
1994
26 12
Oster 1994 100
Von Roenn
1994
270
Fietkau
1996
64
Gebbia
1996
50 22 40 10
Rowland
1996
243
Beller 1997 48 106 18 68
Chen 1997 129
Timpone
1997
50
Bruera 1998 37 20 3 24
De Conno
1998
21 10 6 5
Vadell 1998 75 35 5 8 27
Loprinzi
1999
191 170 114
Westman
1999
74 126 4 22 29
Erkurt 2000 42 5 42 26
Marchand
2000
12
Yeh 2000 69
Batterham
2001
15
Eubanks
2002
17
Jatoi 2002 208 139 122
Mc Quellon 33 23
26Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 01. Patient condition and numbers recruited to each trial (Continued )
Study
Lung
cancer
Gastroint
& pancreas
Head &
neck cancer
Gynecolog-
ical cancer
Other
cancer AIDS COPD
Cystic
fibrosis Elderly
2002
Weisberg
2002
145
Ulutin HC
2002
119
Pardo 2003 130
Jatoi 2004 166 141 114
Zeca 1995 33
Total 1792 1045 347 74 890 435 145 29 69
Table 02. EMBASE
No Search term
1. Acquired Immunodeficiency Syndrome/
2. acquired immunodeficiency syndrome.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title,
device manufacturer, drug manufacturer name]
3. AIDS.ab,ti.
4. exp Neoplasm/
5. (neoplasm$ or cancer$ or tumor$ or tumour$ or carcinoma$ or malignan$).mp. [mp=title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]
6. Terminally Ill patient/
7. Terminal Care/
8. ((terminal adj6 ill$) or (terminal$ adj6 care)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original
title, device manufacturer, drug manufacturer name]
9. (end adj6 life).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,
drug manufacturer name]
10. or/1-9
11. anorexia-cachexia syndrome.mp.
12. Anorexia/
13. Cachexia/
14. Weight Reduction/
15. (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]
16. emaciat$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
27Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Table 02. EMBASE (Continued )
No Search term
17. or/11-16
18. Megestrol Acetate/
19. megace$.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
20. (megestrol adj acetate).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]
21. or/18-20
22. 10 and 17 and 21
23. 22 (88)
24. limit 23 to yr=“2002 - 2006” (24)
Table 03. Cochrane Pain, Palliative and Supportive Care Group Trials register
Search strategy
(Acquired Immunodeficiency Syndrome“[All Fields] OR (acquired immunodeficiency 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])
A N A L Y S E S
Comparison 01. Megestrol acetate vs placebo (ITT)
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Appetite improvement 10 885 Relative Risk (Random) 95% CI 2.76 [1.65, 4.61]
02 Weight gain 10 843 Weighted Mean Difference (Random) 95% CI 2.78 [1.61, 3.95]
03 Weight gain 10 1246 Relative Risk (Random) 95% CI 1.95 [1.44, 2.62]
04 Quality of life 6 952 Relative Risk (Random) 95% CI 1.52 [0.87, 2.66]
05 Side effects 11 1767 Relative Risk (Random) 95% CI 1.74 [1.29, 2.35]
Comparison 02. Megestrol acetate vs other drugs (ITT)
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Appetite improvement 3 514 Relative Risk (Random) 95% CI 1.15 [0.75, 1.76]
02 Weight gain 5 598 Weighted Mean Difference (Random) 95% CI 3.82 [0.06, 7.57]
03 Weight gain 4 524 Relative Risk (Random) 95% CI 1.29 [0.94, 1.76]
04 Quality of life 3 514 Relative Risk (Random) 95% CI 1.08 [0.80, 1.45]
28Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Comparison 03. Sensitivity analysis
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Appetite improvement,
treatment duration
4 489 Relative Risk (Random) 95% CI 3.21 [1.54, 6.70]
02 Weight gain, treatment
duration
6 856 Relative Risk (Random) 95% CI 1.86 [1.31, 2.63]
03 Weight gain, treatment
duration
4 393 Weighted Mean Difference (Random) 95% CI 4.54 [0.43, 8.66]
04 Appetite improvement, study
quality
6 561 Relative Risk (Random) 95% CI 3.03 [1.83, 5.01]
05 Weight gain, study quality 6 499 Weighted Mean Difference (Random) 95% CI 3.53 [1.43, 5.62]
06 Weight gain, study quality 7 895 Relative Risk (Random) 95% CI 1.83 [1.35, 2.50]
I N D E X T E R M S
Medical Subject Headings (MeSH)
Acquired Immunodeficiency 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
C O V E R S H E E T
Title Megestrol acetate for treatment of anorexia-cachexia syndrome
Authors Berenstein EG, Ortiz Z
Contribution of author(s) 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.
Issue protocol first published 2003/3
Review first published 2005/2
Date of most recent amendment 20 August 2007
Date of most recent
SUBSTANTIVE amendment
23 January 2005
What’s New For the update for Issue 3, 2007 the following changes were made:
Four new studies and three abstracts were identified, 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.
Date new studies sought but
none found
Information not supplied by author
29Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Date new studies found but not
yet included/excluded
Information not supplied by author
Date new studies found and
included/excluded
01 June 2006
Date authors’ conclusions
section amended
Information not supplied by author
Contact address Dr Graciela Berenstein
Medical Doctor
Epidemiology Department
Alejandro Posadas National Hospital
Paraguay 1835, 3
Buenos Aires
1121
ARGENTINA
E-mail: [email protected]
Tel: +54 11 4811 4908
Fax: +54 11 4931 2558
DOI 10.1002/14651858.CD004310.pub2
Cochrane Library number CD004310
Editorial group Cochrane Pain, Palliative and Supportive Care Group
Editorial group code HM-SYMPT
G R A P H S A N D O T H E R T A B L E S
30Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 01.01. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 01 Appetite improvement
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT)
Outcome: 01 Appetite improvement
Study Megestrol acetate placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Batterham 2001 0/1 0/1 0.0 Not estimable
Erkurt 2000 55/58 7/57 13.7 7.72 [ 3.85, 15.49 ]
Feliu 1992 30/76 8/74 13.5 3.65 [ 1.79, 7.44 ]
Gebbia 1996 0/1 0/1 0.0 Not estimable
Lai 1994 11/20 4/19 11.2 2.61 [ 1.00, 6.80 ]
Loprinzi 1990b 24/67 16/66 15.3 1.48 [ 0.87, 2.52 ]
Schmoll 1992 37/63 6/28 13.3 2.74 [ 1.31, 5.74 ]
Zeca 1995 13/16 5/17 12.9 2.76 [ 1.28, 5.99 ]
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 I² =66.2%
Test for overall effect z=4.30 p=0.00002
02 AIDS
Von Roenn 1994 181/270 19/38 17.0 1.34 [ 0.97, 1.86 ]
Subtotal (95% CI) 270 38 17.0 1.34 [ 0.97, 1.86 ]
Total events: 181 (Megestrol acetate), 19 (placebo)
Test for heterogeneity: not applicable
Test for overall effect z=1.75 p=0.08
03 Other underlying pathology
Marchand 2000 6/6 0/6 3.0 13.00 [ 0.89, 189.39 ]
Subtotal (95% CI) 6 6 3.0 13.00 [ 0.89, 189.39 ]
Total events: 6 (Megestrol acetate), 0 (placebo)
Test for heterogeneity: not applicable
Test for overall effect z=1.88 p=0.06
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 I² =76.9%
Test for overall effect z=3.89 p=0.0001
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours MA
31Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 01.02. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 02 Weight gain
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT)
Outcome: 02 Weight gain
Study Megestrol acetate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 Cancer
Chen 1997 48 -1.71 (4.56) 40 -3.99 (5.52) 8.8 2.28 [ 0.14, 4.42 ]
De Conno 1998 21 1.06 (1.95) 21 -0.34 (1.01) 11.6 1.40 [ 0.46, 2.34 ]
Erkurt 2000 58 5.00 (6.00) 57 -5.90 (7.00) 8.3 10.90 [ 8.52, 13.28 ]
Fietkau 1996 32 -0.80 (3.60) 32 -3.20 (3.20) 10.0 2.40 [ 0.73, 4.07 ]
Loprinzi 1990b 67 1.36 (4.99) 66 -0.22 (3.01) 10.7 1.58 [ 0.18, 2.98 ]
McQuellon 2002 28 -1.22 (6.25) 29 -4.80 (4.80) 7.1 3.58 [ 0.68, 6.48 ]
Subtotal (95% CI) 254 245 56.5 3.56 [ 1.27, 5.85 ]
Test for heterogeneity chi-square=55.13 df=5 p=<0.0001 I² =90.9%
Test for overall effect z=3.05 p=0.002
02 AIDS
Von Roenn 1994 75 3.54 (4.29) 38 -0.72 (2.87) 10.8 4.26 [ 2.93, 5.59 ]
Subtotal (95% CI) 75 38 10.8 4.26 [ 2.93, 5.59 ]
Test for heterogeneity: not applicable
Test for overall effect z=6.27 p<0.00001
03 Other underlying pathology
Eubanks 2002 10 5.30 (3.60) 7 1.50 (1.60) 7.9 3.80 [ 1.27, 6.33 ]
Weisberg 2002 72 1.20 (1.40) 73 0.60 (1.10) 12.4 0.60 [ 0.19, 1.01 ]
Yeh 2000 36 1.05 (1.00) 33 0.91 (0.68) 12.4 0.14 [ -0.26, 0.54 ]
Subtotal (95% CI) 118 113 32.7 0.65 [ -0.14, 1.44 ]
Test for heterogeneity chi-square=9.48 df=2 p=0.009 I² =78.9%
Test for overall effect z=1.62 p=0.1
Total (95% CI) 447 396 100.0 2.78 [ 1.61, 3.95 ]
Test for heterogeneity chi-square=122.86 df=9 p=<0.0001 I² =92.7%
Test for overall effect z=4.66 p<0.00001
-10 -5 0 5 10
Favours Placebo Favours M A
32Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 01.03. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 03 Weight gain
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT)
Outcome: 03 Weight gain
Study Megestrol acetate placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Feliu 1992 21/76 5/74 7.7 4.09 [ 1.63, 10.27 ]
Lai 1994 6/20 3/19 4.9 1.90 [ 0.55, 6.54 ]
Loprinzi 1990b 11/67 1/66 2.0 10.84 [ 1.44, 81.58 ]
Rowland 1996 26/122 8/121 10.3 3.22 [ 1.52, 6.83 ]
Schmoll 1992 17/63 4/28 6.9 1.89 [ 0.70, 5.10 ]
Tchekmedyian 1992 27/49 16/40 17.4 1.38 [ 0.87, 2.17 ]
Vadell 1998 38/99 13/51 15.2 1.51 [ 0.89, 2.56 ]
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 I² =45.3%
Test for overall effect z=3.59 p=0.0003
02 AIDS
Von Roenn 1994 127/232 8/38 12.8 2.60 [ 1.39, 4.87 ]
Subtotal (95% CI) 232 38 12.8 2.60 [ 1.39, 4.87 ]
Total events: 127 (Megestrol acetate), 8 (placebo)
Test for heterogeneity: not applicable
Test for overall effect z=2.99 p=0.003
03 Other underlying pathology
Marchand 2000 6/6 4/6 14.3 1.50 [ 0.85, 2.64 ]
Yeh 2000 9/36 7/33 8.5 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 I² =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 ]
Total events: 288 (Megestrol acetate), 69 (placebo)
Test for heterogeneity chi-square=14.28 df=9 p=0.11 I² =37.0%
Test for overall effect z=4.36 p=0.00001
0.1 0.2 0.5 1 2 5 10
Favours Placebo Favours M A
33Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 01.04. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 04 Quality of life
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT)
Outcome: 04 Quality of life
Study Megestrol acetate placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Feliu 1992 26/76 10/74 18.4 2.53 [ 1.31, 4.88 ]
Lai 1994 7/20 3/19 11.6 2.22 [ 0.67, 7.34 ]
Rowland 1996 87/122 91/121 24.2 0.95 [ 0.81, 1.10 ]
Vadell 1998 18/99 7/51 16.3 1.32 [ 0.59, 2.96 ]
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 I² =77.2%
Test for overall effect z=1.26 p=0.2
02 AIDS
Oster 1994 5/52 6/48 12.4 0.77 [ 0.25, 2.36 ]
Von Roenn 1994 91/232 6/38 17.1 2.48 [ 1.17, 5.27 ]
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 I² =66.0%
Test for overall effect z=0.68 p=0.5
03 Other underlying pathology
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (placebo)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 601 351 100.0 1.52 [ 0.87, 2.66 ]
Total events: 234 (Megestrol acetate), 123 (placebo)
Test for heterogeneity chi-square=21.46 df=5 p=0.0007 I² =76.7%
Test for overall effect z=1.47 p=0.1
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours M A
34Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 01.05. Comparison 01 Megestrol acetate vs placebo (ITT), Outcome 05 Side effects
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 01 Megestrol acetate vs placebo (ITT)
Outcome: 05 Side effects
Study Megestrol acetate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Edema
Beller 1997 4/161 0/79 1.1 4.44 [ 0.24, 81.54 ]
Bruera 1998 1/84 0/84 0.9 3.00 [ 0.12, 72.61 ]
Chen 1997 1/48 0/40 0.9 2.51 [ 0.11, 59.98 ]
Feliu 1992 7/76 3/74 5.2 2.27 [ 0.61, 8.45 ]
Loprinzi 1990b 18/67 8/66 15.6 2.22 [ 1.04, 4.74 ]
Rowland 1996 44/122 24/121 49.1 1.82 [ 1.18, 2.79 ]
Schmoll 1992 2/63 0/28 1.0 2.27 [ 0.11, 45.71 ]
Tchekmedyian 1992 8/49 6/40 9.6 1.09 [ 0.41, 2.88 ]
Vadell 1998 2/99 0/51 1.0 2.60 [ 0.13, 53.16 ]
Von Roenn 1994 14/232 4/38 8.1 0.57 [ 0.20, 1.65 ]
Weisberg 2002 11/72 4/73 7.5 2.79 [ 0.93, 8.35 ]
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 I² =0.0%
Test for overall effect z=3.60 p=0.0003
0.1 0.2 0.5 1 2 5 10
Favours M A Favours Placebo
35Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.01. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 01 Appetite improvement
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 02 Megestrol acetate vs other drugs (ITT)
Outcome: 01 Appetite improvement
Study Megestrol acetate Other drugs Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Lai 1994 11/20 6/19 20.3 1.74 [ 0.81, 3.77 ]
Loprinzi 1999a 26/79 64/159 41.5 0.82 [ 0.57, 1.18 ]
Loprinzi 1999b 26/79 39/158 38.2 1.33 [ 0.88, 2.02 ]
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 I² =57.1%
Test for overall effect z=0.64 p=0.5
02 AIDS
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
03 Other underlying pathology
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
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 I² =57.1%
Test for overall effect z=0.64 p=0.5
0.1 0.2 0.5 1 2 5 10
Favours other drugs Favours treatment
36Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.02. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 02 Weight gain
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 02 Megestrol acetate vs other drugs (ITT)
Outcome: 02 Weight gain
Study Megestrol acetate Other drugs Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 Cancer
Chen 1997 48 -1.71 (4.56) 41 -5.41 (3.19) 20.6 3.70 [ 2.08, 5.32 ]
Loprinzi 1999a 79 2.50 (4.45) 159 2.01 (3.24) 21.0 0.49 [ -0.61, 1.59 ]
Loprinzi 1999b 79 2.50 (4.45) 158 1.77 (2.58) 21.1 0.73 [ -0.33, 1.79 ]
Subtotal (95% CI) 206 358 62.7 1.53 [ -0.18, 3.25 ]
Test for heterogeneity chi-square=11.51 df=2 p=0.003 I² =82.6%
Test for overall effect z=1.76 p=0.08
02 AIDS
Batterham 2001 4 10.20 (4.51) 6 4.01 (1.68) 16.2 6.19 [ 1.57, 10.81 ]
Timpone 1997 12 6.50 (1.10) 12 -2.00 (1.30) 21.1 8.50 [ 7.54, 9.46 ]
Subtotal (95% CI) 16 18 37.3 8.40 [ 7.46, 9.35 ]
Test for heterogeneity chi-square=0.92 df=1 p=0.34 I² =0.0%
Test for overall effect z=17.46 p<0.00001
03 Other underlying pathology
Subtotal (95% CI) 0 0 0.0 Not estimable
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 222 376 100.0 3.82 [ 0.06, 7.57 ]
Test for heterogeneity chi-square=159.12 df=4 p=<0.0001 I² =97.5%
Test for overall effect z=1.99 p=0.05
-10 -5 0 5 10
Favours other drugs Favours M A
37Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.03. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 03 Weight gain
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 02 Megestrol acetate vs other drugs (ITT)
Outcome: 03 Weight gain
Study Megestrol acetate Other drugs Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Lai 1994 6/20 4/19 8.1 1.43 [ 0.48, 4.27 ]
Loprinzi 1999a 6/79 8/159 9.3 1.51 [ 0.54, 4.20 ]
Loprinzi 1999b 5/79 5/158 6.6 2.00 [ 0.60, 6.71 ]
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 I² =0.0%
Test for overall effect z=1.45 p=0.1
02 AIDS
Batterham 2001 4/4 5/6 76.0 1.20 [ 0.84, 1.72 ]
Subtotal (95% CI) 4 6 76.0 1.20 [ 0.84, 1.72 ]
Total events: 4 (Megestrol acetate), 5 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect z=1.00 p=0.3
03 Other underlying pathology
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 182 342 100.0 1.29 [ 0.94, 1.76 ]
Total events: 21 (Megestrol acetate), 22 (Other drugs)
Test for heterogeneity chi-square=1.82 df=3 p=0.61 I² =0.0%
Test for overall effect z=1.58 p=0.1
0.1 0.2 0.5 1 2 5 10
Favours other drugs Favours M A
38Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 02.04. Comparison 02 Megestrol acetate vs other drugs (ITT), Outcome 04 Quality of life
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 02 Megestrol acetate vs other drugs (ITT)
Outcome: 04 Quality of life
Study Megestrol acetate Other drugs Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Cancer
Lai 1994 7/20 5/19 9.8 1.33 [ 0.51, 3.48 ]
Loprinzi 1999a 22/79 45/159 48.1 0.98 [ 0.64, 1.52 ]
Loprinzi 1999b 21/79 37/158 42.1 1.14 [ 0.71, 1.80 ]
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 I² =0.0%
Test for overall effect z=0.48 p=0.6
02 AIDS
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
03 Other underlying pathology
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (Megestrol acetate), 0 (Other drugs)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (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 I² =0.0%
Test for overall effect z=0.48 p=0.6
0.1 0.2 0.5 1 2 5 10
Favours other drugs Favours M A
39Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 03.01. Comparison 03 Sensitivity analysis, Outcome 01 Appetite improvement, treatment duration
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 01 Appetite improvement, treatment duration
Study Megestrol acetate placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 treatment duration more than 6 weeks
Erkurt 2000 55/58 7/57 24.6 7.72 [ 3.85, 15.49 ]
Feliu 1992 30/76 8/74 24.4 3.65 [ 1.79, 7.44 ]
Loprinzi 1990b 24/67 16/66 27.1 1.48 [ 0.87, 2.52 ]
Schmoll 1992 37/63 6/28 23.9 2.74 [ 1.31, 5.74 ]
Total (95% CI) 264 225 100.0 3.21 [ 1.54, 6.70 ]
Total events: 146 (Megestrol acetate), 37 (placebo)
Test for heterogeneity chi-square=14.76 df=3 p=0.002 I² =79.7%
Test for overall effect z=3.10 p=0.002
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours MA
Analysis 03.02. Comparison 03 Sensitivity analysis, Outcome 02 Weight gain, treatment duration
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 02 Weight gain, treatment duration
Study Treatment Control Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Treatment duration more than 6 weeks
Feliu 1992 21/76 5/74 10.9 4.09 [ 1.63, 10.27 ]
Loprinzi 1990b 16/67 11/66 16.5 1.43 [ 0.72, 2.85 ]
Rowland 1996 26/122 8/121 14.7 3.22 [ 1.52, 6.83 ]
Schmoll 1992 17/63 4/28 9.7 1.89 [ 0.70, 5.10 ]
Tchekmedyian 1992 27/49 16/40 25.9 1.38 [ 0.87, 2.17 ]
Vadell 1998 38/99 13/51 22.3 1.51 [ 0.89, 2.56 ]
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 I² =36.6%
Test for overall effect z=3.50 p=0.0005
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
40Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 03.03. Comparison 03 Sensitivity analysis, Outcome 03 Weight gain, treatment duration
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 03 Weight gain, treatment duration
Study Treatment Control Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 Treatment duration more than 6 weeks
Chen 1997 48 -1.71 (4.56) 40 -3.99 (5.52) 25.2 2.28 [ 0.14, 4.42 ]
Erkurt 2000 58 5.00 (6.00) 57 -5.90 (7.00) 24.8 10.90 [ 8.52, 13.28 ]
Loprinzi 1990b 67 1.36 (4.99) 66 -0.22 (3.01) 26.2 1.58 [ 0.18, 2.98 ]
McQuellon 2002 28 -1.22 (6.25) 29 -4.80 (4.80) 23.8 3.58 [ 0.68, 6.48 ]
Total (95% CI) 201 192 100.0 4.54 [ 0.43, 8.66 ]
Test for heterogeneity chi-square=45.47 df=3 p=<0.0001 I² =93.4%
Test for overall effect z=2.16 p=0.03
-10 -5 0 5 10
Favours Placebo Favours MA
Analysis 03.04. Comparison 03 Sensitivity analysis, Outcome 04 Appetite improvement, study quality
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 04 Appetite improvement, study quality
Study Megestrol acetate Control Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Study quality (Jadad score 3, 4 or 5)
Feliu 1992 30/76 8/74 17.0 3.65 [ 1.79, 7.44 ]
Loprinzi 1990b 24/67 16/66 19.9 1.48 [ 0.87, 2.52 ]
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 I² =75.6%
Test for overall effect z=1.77 p=0.08
02 Study quality (Jadad score 2 or low)
Erkurt 2000 55/58 7/57 17.2 7.72 [ 3.85, 15.49 ]
Lai 1994 11/20 4/19 13.3 2.61 [ 1.00, 6.80 ]
Schmoll 1992 37/63 6/28 16.5 2.74 [ 1.31, 5.74 ]
Zeca 1995 13/16 5/17 16.0 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 1 2 5 10
Favours Control Favours MA (Continued . . . )
41Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
(. . . Continued)
Study Megestrol acetate Control Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
Test for heterogeneity chi-square=6.25 df=3 p=0.10 I² =52.0%
Test for overall effect z=4.47 p<0.00001
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 I² =66.2%
Test for overall effect z=4.30 p=0.00002
0.1 0.2 0.5 1 2 5 10
Favours Control Favours MA
Analysis 03.05. Comparison 03 Sensitivity analysis, Outcome 05 Weight gain, study quality
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 05 Weight gain, study quality
Study Megestrol acetate Control Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 Study quality (Jadad score 3,4 or 5)
De Conno 1998 21 1.06 (1.95) 21 -0.34 (1.01) 18.5 1.40 [ 0.46, 2.34 ]
Fietkau 1996 32 -0.80 (0.20) 32 -3.20 (3.20) 18.3 2.40 [ 1.29, 3.51 ]
Loprinzi 1990b 67 1.36 (4.99) 66 -0.22 (3.01) 17.7 1.58 [ 0.18, 2.98 ]
McQuellon 2002 28 -1.22 (6.25) 29 -4.80 (4.80) 14.1 3.58 [ 0.68, 6.48 ]
Subtotal (95% CI) 148 148 68.6 1.87 [ 1.20, 2.54 ]
Test for heterogeneity chi-square=3.33 df=3 p=0.34 I² =10.0%
Test for overall effect z=5.45 p<0.00001
02 Study quality (Jadad score o or low)
Chen 1997 48 -1.71 (4.56) 40 -3.99 (5.52) 16.0 2.28 [ 0.14, 4.42 ]
Erkurt 2000 58 5.00 (6.00) 57 -5.90 (7.00) 15.4 10.90 [ 8.52, 13.28 ]
Subtotal (95% CI) 106 97 31.4 6.57 [ -1.87, 15.02 ]
Test for heterogeneity chi-square=27.77 df=1 p=<0.0001 I² =96.4%
Test for overall effect z=1.53 p=0.1
Total (95% CI) 254 245 100.0 3.53 [ 1.43, 5.62 ]
Test for heterogeneity chi-square=55.13 df=5 p=<0.0001 I² =90.9%
Test for overall effect z=3.30 p=0.001
-10 -5 0 5 10
Favours control Favours MA
42Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Analysis 03.06. Comparison 03 Sensitivity analysis, Outcome 06 Weight gain, study quality
Review: Megestrol acetate for treatment of anorexia-cachexia syndrome
Comparison: 03 Sensitivity analysis
Outcome: 06 Weight gain, study quality
Study Treatment Control Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 Study quality (Jadad score 3,4 or 5)
Feliu 1992 21/76 5/74 9.5 4.09 [ 1.63, 10.27 ]
Loprinzi 1990b 16/67 11/66 15.2 1.43 [ 0.72, 2.85 ]
Tchekmedyian 1992 27/49 16/40 26.2 1.38 [ 0.87, 2.17 ]
Vadell 1998 38/99 13/51 21.8 1.51 [ 0.89, 2.56 ]
Subtotal (95% CI) 291 231 72.7 1.66 [ 1.13, 2.44 ]
Total events: 102 (Treatment), 45 (Control)
Test for heterogeneity chi-square=4.75 df=3 p=0.19 I² =36.9%
Test for overall effect z=2.58 p=0.01
02 Study quality (Jadad score 2 or low)
Lai 1994 6/20 3/19 5.7 1.90 [ 0.55, 6.54 ]
Rowland 1996 26/122 8/121 13.3 3.22 [ 1.52, 6.83 ]
Schmoll 1992 17/63 4/28 8.4 1.89 [ 0.70, 5.10 ]
Subtotal (95% CI) 205 168 27.3 2.49 [ 1.45, 4.27 ]
Total events: 49 (Treatment), 15 (Control)
Test for heterogeneity chi-square=0.94 df=2 p=0.63 I² =0.0%
Test for overall effect z=3.32 p=0.0009
Total (95% CI) 496 399 100.0 1.83 [ 1.35, 2.50 ]
Total events: 151 (Treatment), 60 (Control)
Test for heterogeneity chi-square=7.89 df=6 p=0.25 I² =23.9%
Test for overall effect z=3.84 p=0.0001
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
43Megestrol acetate for treatment of anorexia-cachexia syndrome (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd