A Systematic Review and Meta-Analysis of the Clinical Use of Megestrol Acetate for Cancer-Related Anorexia/Cachexia

Cancer-related anorexia/cachexia is known to be associated with worsened quality of life and survival; however, limited treatment options exist. Although megestrol acetate (MA) is often used off-label to stimulate appetite and improve anorexia/cachexia in patients with advanced cancers, the benefits are controversial. The present meta-analysis aimed to better elucidate the clinical benefits of MA in patients with cancer-related anorexia/cachexia. A systematic search of PubMed, EMBASE, OVID Medline, Clinicaltrials.gov, and Google Scholar databases found 23 clinical trials examining the use of MA in cancer-related anorexia. The available randomized, controlled trials were appraised using Version 2 of the Cochrane risk-of-bias tool (RoB 2) and they had moderate-to-high risk of bias. A total of eight studies provided sufficient data on weight change for meta-analysis. The studies were divided into high-dose treatment (>320 mg/day) and low-dose treatment (≤320 mg/day). The overall pooled mean change in weight among cancer patients treated with MA, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ2 = 9.35, I2 = 96%). Patients who received high-dose MA tended to have weight loss rather than weight gain. There were insufficient studies to perform a meta-analysis for the change in tricep skinfold, midarm circumference, or quality of life measures. MA was generally well-tolerated, except for a clear thromboembolic risk, especially with higher doses. On balance, MA did not appear to be effective in providing the symptomatic improvement of anorexia/cachexia in patients with advanced cancer.


Introduction
As a result of various central and peripheral causes including a greater inflammatory response, many patients with advanced cancers experience a marked loss of appetite, loss of weight, asthenia, and a poor prognosis [1][2][3]. This is collectively referred to as the cancer anorexia/cachexia syndrome, and it happens in more than half of all cancer patients [3]. Sustained loss of appetite and/or an aversion to food often compounds emotional distress in both patients and their caregivers [4] and are admittedly difficult aspects of cancer for patients' loved ones to comprehend [4,5].
Cancer-related anorexia/cachexia is also clinically significant as a patient's nutritional status affects their quality of life [6] and overall prognosis [7]. The weight loss of more than 5 percent of premorbid weight prior to the initiation of chemotherapy is associated with increased morbidity and early mortality [7]. 2 of 21 Providing dietary counseling, nutritional support and nutritional therapies are therefore important and endorsed by major clinical practice guidelines [8]. However, options may be limited as cancer-related cachexia is also often refractory to conventional nutritional support [9]. The management of cancer-related anorexia remains a substantial clinical challenge and numerous off-label, pharmacologic therapies have been tried, with variable tolerability and dissimilar efficacy on clinical outcomes and the quality of life measures [10][11][12]. One such example is megestrol acetate (MA), a synthetic progestin, which is often used to boost appetite and body weight in patients with cancer cachexia [12,13]. In clinical studies, MA has been found to decrease circulating inflammatory cytokines [13] and stimulate increases in body mass [14].
However, a 2013 Cochrane review [12] and 2018 systematic review [15] yielded inconclusive findings regarding the efficacy of MA for the treatment of anorexia/cachexia syndrome. Furthermore, the 2018 systematic review had marked heterogeneity and included patients with anorexia/cachexia related to any pathology (e.g., cancer, acquired immunodeficiency syndrome (AIDS), etc.). The optimal dosing strategy for MA also remains unknown. Given that newer randomized, controlled trials [16,17] have been published since, this updated systematic review and meta-analysis is thus timely and necessary.

Methods
This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42022320128.

Search Strategy
A systematic literature search was performed in accordance with the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. By using the following combinations of broad Major Exploded Subject Headings (MesH) terms or text words [megestrol] AND [anorexi* OR cachex* OR cachectic OR weight OR appetite], a comprehensive search of PubMed, EMBASE, OVID Medline, Clinicaltrials.gov, and Google Scholar databases yielded 2942 papers published in English between 1 January 1988 and 1 May 2021. Attempts were made to search the grey literature using the Google search engine. The titles and abstracts of records were downloaded and imported into EndNote bibliographic software and from there to the Covidence online tool (Vertitas Health Innovation Ltd, Melbourne, Australia. Available at www.covidence.org) to streamline our systematic review process. All duplicates were automatically removed once uploaded to Covidence. Titles and abstracts from the preliminary search were retrieved and reviewed for relevance independently by two study investigators (Q.X.N. and Y.L.L.). Full articles of relevant studies were then retrieved for further review and assessed by three study investigators (Q.X.N., Y.L.L., and M.X.H.) for inclusion based on the pre-defined criteria. All retrieved publications were manually reviewed and also checked for references of interest. Discrepancies were resolved by consensus amongst the three study investigators (Q.X.N., Y.L.L., and M.X.H.).

Inclusion and Exclusion Criteria
The inclusion criteria for this review were: (1) randomized, controlled trial (RCT); (2) study population involving oncological patients; (3) had cancer-related anorexia or cachexia as a primary endpoint; and (4) reported outcome measures on weight and/or quality of life. Any disagreement on inclusion was resolved by consensus. Exclusion criteria included cohort studies, single case reports or case series, conference abstracts, and proceedings, which were not accepted for this review.

Data Abstraction
Data were extracted using a standardized electronic form. Each article was doublecoded by either pair of researchers (C.Y.L.Y./S.E.T. or Y.M./D.J.L.), blinded within pairs. Disputes were resolved through consensus from the senior author (Q.X.N.). Data abstracted included the study characteristics (e.g., author name, year of publication, and country) and study population characteristics (e.g., sample size, country, study population, dosage of MA). The dosages of MA treatment were dichotomized into high dosage (>320 mg/day) and low dosage (≤320 mg/day). The primary outcomes collected were the change in weight (in kg), quality of life improvement, and side effects experienced for the duration that patients were treated with MA.
For continuous variables, the mean and standard deviation (SD) were abstracted. Where these data were unavailable, appropriate formulae were applied to transform the data from the median and range or interquartile range to the mean and SD. In the event where SD was unable to be derived from the aforementioned formulae, another formulae was used to derive the SD from other included studies.

Statistical Analysis
Data analyses were performed using R 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). A single-arm meta-analysis of means was conducted to pool the mean change in weight, tricep skinfold, and midarm circumference of patients who received megestrol acetate treatment. Individual studies were weighted by the inverse variance method. Heterogeneity was quantified using the τ 2 and I 2 statistics. I 2 value thresholds of 25%, 50%, and 75% signified low, moderate, and high heterogeneity, respectively. All models were random effects, regardless of the statistical heterogeneity. This was conducted as we expected clinical heterogeneity arising from different populations and time points. Two-tailed statistical significance was set at a p-value ≤ 0.05. Funnel plots, Egger regression test, and the Begg and Mazumdar rank correlation test were performed to evaluate the publication bias only when there were at least 10 data points.
For data that had fewer than three data points, meta-analysis was considered to be inappropriate and they were instead systematically reported. Quality of life improvement and the side effects experienced due to treatment with megestrol acetate treatment were also systematically reported.

Risk of Bias Assessment
The risk of bias assessment was conducted using Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [19]. The RoB2 tool assesses the quality on five domains: the randomization process, deviations from intended interventions, missing outcome data, outcome measurements, and reporting, graded based on the consensus of three study investigators (Q.X.N., Y.L.L., and M.X.H.). Figure 1 detailed the study selection and identification process. A total of 2942 records were found from the database search with 1842 records marked ineligible by automated filters and 368 records removed as duplicates. A total of 675 articles were further excluded after title and abstract screening, and subsequently, 34 articles were excluded after the full text review. Finally, a total of 23 studies were systematically reviewed, albeit only eight contained sufficient anthropometric data to perform a meta-analysis.

Retrieval of Studies
The 23 included studies represented a total of 3790 cancer patients treated with MA, and originated from seven countries, namely Australia, Canada, China, Italy, Taiwan, United Kingdom, and the United States of America. The study sample sizes ranged from six to 475 and the study duration was eight months maximum. The characteristics of the included studies are further described in Table 1. six to 475 and the study duration was eight months maximum. The characteristics of the included studies are further described in Table 1.   Side effects: 2 (2.5%) in the 160 mg/day group had pulmonary emboli; 4 (5%) in the 160 mg/day group had severe edema. Side effects: Generally well-tolerated. BMI-for-age z-scores were higher in the MA group. Patients in the MA group experienced an increase in mean BMI-Z of +1.58% (±1.37%), while patients in the placebo group experienced a decrease in mean BMI-Z of −0.29% (±0.50%).
Side effects: severe (15%, n = 2) and mild (15.4%, n = 2) adrenal suppression in the MA group. Clinical benefit: 44% of treatment group had Karnofsky score increased by ≥20 as compared to 20% of control group (p < 0.05). Showed no significant difference in tumor therapeutic response or survival rate.
Side Effects: Treatment group had higher reported rates of aversion to cold, fever, pantalgia, and stuffy nose compared to control group. showed that there was significant difference between baseline and maximum score compared to Dronabinol group (7.2 ± 10, p = 0.002), but no significant difference compared to combination group (9 ± 10, p = 0.30).
Side Effects: 18% of the male participants in MA group reported significant presence of impotence as compared to 4% with Dronabinol (p = 0.002). Other noted side effects that were not significant compared to other treatment arms included vomiting, fluid retention, muddled thinking, drowsiness, loss of coordination, and inappropriate behavior. Clinical benefit: Changes in total daily physical activity, 6 min walk test, and grip strength between arms were not significant.

Quality of life: No significant differences in both
individual arms from baseline, and no significant difference between both arms either.
Side effects: Generally well-tolerated. Side effects: Generally well tolerated, 1 case of DVT attributed to worsening disease rather than medication.

Meta-Analysis of Pooled Mean Change in Weight
A total of eight studies provided sufficient data on the weight change. The overall pooled mean change of weight among cancer patients treated with megestrol acetate, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ 2 = 9.35, I 2 = 96%) (Figure 2). For the purposes of the meta-analysis, the dosages of the MA treatment were dichotomized into high dosage (>320 mg/day) and low dosage (≤320 mg/day).

Meta-Analysis of Pooled Mean Change in Weight
A total of eight studies provided sufficient data on the weight change. The overall pooled mean change of weight among cancer patients treated with megestrol acetate, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ 2 = 9.35, I 2 = 96%) (Figure 2). For the purposes of the meta-analysis, the dosages of the MA treatment were dichotomized into high dosage (>320 mg/day) and low dosage (≤320 mg/day). The pooled mean change of weight among the cancer patients treated with high-dose megestrol acetate was −0.05 kg (95% CI = −2.71 to 2.60, τ 2 = 5.26, I 2 = 94%) ( Figure 2). The pooled mean change of weight among cancer patients treated with low-dose megestrol acetate was 2.24 kg (95% CI = −7.19 to 11.67, τ 2 = 9.35, I 2 = 96%) ( Figure 2). In all instances, the SMD did not achieve statistical significance.
There were insufficient studies (<3) to perform a meta-analysis for change in tricep skinfold and midarm circumference with megestrol treatment.

Risk of Bias Assessment
The included RCTs were appraised using the RoB2 and were classified to be of moderate-to-high risk of bias. The detailed risk of bias assessment results are available in Supplementary Table S1.

Publication Bias Assessment
There was no evidence of publication bias, based on a non-significant Egger regression test (p = 0.858) and Begg and Mazumdar rank correlation test (p = 0.621) and a visually symmetrical funnel plot ( Figure 3). The pooled mean change of weight among the cancer patients treated with high-dose megestrol acetate was −0.05 kg (95% CI = −2.71 to 2.60, τ 2 = 5.26, I 2 = 94%) ( Figure 2). The pooled mean change of weight among cancer patients treated with low-dose megestrol acetate was 2.24 kg (95% CI = −7.19 to 11.67, τ 2 = 9.35, I 2 = 96%) ( Figure 2). In all instances, the SMD did not achieve statistical significance.
There were insufficient studies (<3) to perform a meta-analysis for change in tricep skinfold and midarm circumference with megestrol treatment.

Risk of Bias Assessment
The included RCTs were appraised using the RoB2 and were classified to be of moderate-to-high risk of bias. The detailed risk of bias assessment results are available in Supplementary Table S1.

Publication Bias Assessment
There was no evidence of publication bias, based on a non-significant Egger regression test (p = 0.858) and Begg and Mazumdar rank correlation test (p = 0.621) and a visually symmetrical funnel plot (Figure 3).

Discussion
Despite the prevalence, the etiology of cancer-related anorexia/cachexia is incompletely understood but probably multifactorial in nature. Overall, MA did not appear to improve the weight gain amongst patients with cancer-related anorexia/cachexia. Notably, the high-dose MA also seemed to produce weight loss rather than weight gain when compared with the low-dose MA. However, this could be due to

Discussion
Despite the prevalence, the etiology of cancer-related anorexia/cachexia is incompletely understood but probably multifactorial in nature. Overall, MA did not appear to improve the weight gain amongst patients with cancer-related anorexia/cachexia. Notably, the high-dose MA also seemed to produce weight loss rather than weight gain when compared with the low-dose MA. However, this could be due to the fact that patients who received higher doses of MA may have had more refractory cachexia. In the study by [36], forty-six (63%) of the patients with advanced gastrointestinal cancer did not complete the trial as they had worsened disease, requiring further supportive care or pain control.
Based on a systematic review of available evidence, MA also did not appear to improve quality of life although limited studies examined this. In terms of the potential adverse events associated with its use, MA was generally well-tolerated, except for a clear thromboembolic risk, especially with higher doses.
In terms of the biological mechanisms of MA, it is a synthetic progesterone and may act to stimulate appetite and increase the body fat stores, but not lean body mass [42]. The metabolic effects are likely mediated via its anti-inflammatory actions. Studies have noted that after MA was discontinued, the effects were not sustained and weight loss reverted [43]. As with other progestins, common side effects would include headaches and nausea, and high doses sometimes cause thrombosis.
The findings of the present meta-analysis significantly extend those of earlier metaanalyses [12,15]. Compared to an earlier meta-analysis by Ruiz-Garcia et al. [15], which included patients with AIDS, anorexia nervosa, degenerative diseases, and other terminal illnesses, we focused specifically on patients with cancer-related anorexia/cachexia. We also included several studies [20,[22][23][24][25]27,29,31,[36][37][38][39][40][41] that were missed in the earlier 2018 review, and incorporated the findings of a recent randomized, double-blind, placebocontrolled RCT [17]. The 2018 review also did not provide any relevant changes in the MA effectiveness compared to the 2013 Cochrane review [12]. The present meta-analysis provides us with greater surety in recommending against the use of megestrol acetate for the symptomatic improvement of anorexia/cachexia in oncological patients with advanced cancer. The benefits of MA use were based on only low-quality evidence and MA did not produce a significant weight gain or notable improvements in the quality of life measures.

Limitations
Limitations of the present meta-analysis include that the literature in this field was generally dated, with the majority of the literature (13 of 23 included studies) on MA use in cancer-related anorexia/cachexia published more than 15 years ago. Moreover, there was considerable heterogeneity amongst the included studies, with patients with different malignancies and at different stages of the disease including those who were actively dying (i.e., refractory cachexia). Gastrointestinal cancers and metastases may also produce more profound anorexia/cachexia than those elsewhere because of the obstruction of the digestive tract. Second, the available trials were not designed with sufficient power to detect clinically meaningful differences in adverse events or survival. Third, there was also no information regarding the potential long-term benefits and harms associated with MA use given the limited study duration (up to 8 months).

Conclusions
MA did not produce significant weight gain in patients with advanced cancers. There was also no difference between patients who received high-dose (>320 mg/d) and low-dose (≤320 mg/d) MA. MA also did not appear to be associated with improvements in quality of life measures although limited studies were available for meta-analysis. On balance, the routine use of MA for cancer-related anorexia/cachexia should not be recommended, although there may be benefits in specific patient subpopulations, and this should be the focus of future research.