Progestins are synthetic hormones that have activity that simulates progesterone, the female hormone that is elevated during pregnancy. Progestin is a type of steroid structure and is the main component of birth control medications. Progestins have been evaluated for their effect in patients with cancer for anorexia, chemotherapy-induced nausea and vomiting, hot flashes, and fatigue.
Recommended for Practice
Berenstein, E.G., & Ortiz, Z. (2005). Megestrol acetate for the treatment of anorexia-cachexia syndrome. Cochrane Database of Systematic Reviews, 2, CD004310.doi: 10.1002/14651858.CD004310.pub2
To evaluate the efficacy and safety of megestrol acetate (MA) in palliating anorexia-cachexia syndrome in patients with cancer, AIDS, or other underlying pathologies
Studies that met the following eligibility criteria were reviewed.
- Double-blind, single-blind, or unblended randomized controlled trials (RCTs)
- RCTs that assessed the use of MA compared to a placebo or other drug treatments in patients diagnosed with anorexia-cachexia related to cancer, AIDS, or other underlying pathologies
- Crossover studies that reported the results of the first phase of the study
Data extraction was conducted by two independent authors. Methodological quality was assessed using the Oxford scale (Jadad, 1996). Scores for methodological quality were generally high. Studies in which more that 50% of patients were lost to follow-up were excluded from the analysis.
- Thirty trials, which included a total of 4,123 participants, met the eligibility criteria.
- Mean participant age was 58 years in the treatment groups and 57 years in the control groups.
- The proportion of males to females in the treatment groups was 1,140/502 and 1,733/731 in the control groups.
- The doses of MA administered ranged from 100 mg to 1,600 mg per day.
- Twenty-one trials compared different doses of MA with a placebo; four compared different doses of MA with other drugs; three compared different doses of MA; and two compared MA with other drugs and a placebo.
Results for MA versus placebo: In patients with cancer, a statistically significant improvement in appetite was observed in the patients treated with MA. Weight gain also was observed in this group.
Results for MA versus other drugs: MA did not show benefits in terms of appetite improvement in comparison to other drugs. Significant differences in quality of life were not reported.
Results for different dose levels of MA: Using 400–800 mg as a cutoff and comparing high to low doses, significant differences in appetite outcomes could not be appreciated.
MA improves appetite and weight gain in patients with cancer. Due to study heterogeneity, no overall conclusion can be drawn about its impact on quality of life; a more systematic approach was suggested for the measurement of quality of life in the trials. The clinical effects of MA do not appear to be dose-related, and the mechanism by which MA increases weight gain is unknown.
MA cannot be recommended for use in patients with AIDS or anorexia-cachexia related to other pathologies. Edema, included in the adverse event profile of MA, is the only significant difference between the treatment and a placebo.
Brown, J.K. (2002). A systematic review of the evidence on symptom management of cancer-related anorexia and cachexia. Oncology Nursing Forum, 29, 517–532.doi: 10.1188/02.ONF.517-532
To review the studies regarding cancer-related anorexia and cachexia symptom management and to make recommendations for future directions
A literature search was conducted using the Cochrane Library, MEDLINE, CancerLit, CINAHL, Embase, CRISP, EBM Reviews: Best Evidence, and dissertation abstracts.
All studies focused on increasing food intake. Studies evaluated included:
- Seven nonpharmacologic randomized controlled trials (RCTs) that examined the effects of nutritional counseling and/or commercial oral liquid supplements. Sample sizes ranged from 26 to 180 patients. Clinical trials were included if the major focus was increasing food intake, decreasing energy usage, or minimizing weight loss.
- Four topical research reviews on pharmacologic and exercise interventions.
- Three overviews of the problem from 1998 to 2000.
- One meta-analysis on oncology nursing symptom-management interventions.
- Twenty-eight RCTs testing cancer symptom management interventions from published and unpublished studies from 1981 to 1990. Only one study focused on anorexia and cachexia.
Weight, appetite, and well-being were improved with progestational agents, with megestrol acetate having the most supporting evidence. All nonpharmacologic RCTs reported improved caloric intake resulting from nutritional counseling and oral liquid supplements. The meta-analysis concluded that insufficient evidence existed at the time to recommend any of the nursing interventions.
Patients with cancer should be screened at diagnosis and reevaluated at regular intervals for current and potential nutritional problems. If nutritional screening identifies an at-risk patient, a comprehensive nutritional assessment should be completed. A valid screening tool is needed.
Lesniak, W., Bala, M., Jaeschke, R., & Krzakowski, M. (2008). Effects of megestrol acetate in patients with cancer anorexia-cachexia syndrome—A systematic review and meta-analysis. Polskie Archiwum Medycyny Wewnetrznej, 118, 636–644.http://www.ncbi.nlm.nih.gov/pubmed/19140567
To assess the clinical effects of megestrol acetate (MA) on anorexia-cachexia syndrome (ACS) via systematic review and meta-analysis
The MEDLINE, Embase, and Central databases were used to find research from 2002–2007. The previous systematic review by Lopez et al. (2004) was used to identify additional references. Reference lists of the studies included were also reviewed.
The search keywords used were neoplasm, cancer, cachexia, anorexia, and megestrol acetate.
Inclusion criteria were:
- Studies of advanced-stage cancer (other than hormone-dependent cancer and ACS)
- An MA intervention compared to a placebo or other drugs
- Clinical studies of ACS or MA
- Study of outcomes such as survival, weight change, and performance status
- Study of quality-of-life parameters such as appetite, nausea, pain, fatigue, depression, well-being, or mood.
There were no language restrictions for the studies included. The review also included conference abstracts. No flowchart or additional description of initial study volume or eliminations was provided. The validity of eligible studies was assessed to ensure intent-to-treat analysis and completeness of follow-up.
Findings were presented for studies in 21 different categories. These categories were defined according to MA dose; outcomes evaluated; and whether MA was dispensed in varying doses, compared to a placebo, or compared to other drugs, with relative risk findings for effect size.
- The final number of included studies was 30. Five of these were abstracts.
- All studies included patients with advanced-stage cancer.
- In most studies, participants had a variety of cancers. In several studies, lung cancer was a criterion for inclusion; several more studies involved head and neck cancer.
Pooled analysis was completed and statistical significance of overall effects was calculated via the Z-test. Homogeneity of results between studies was analyzed with the chi-square test. Results were summarized by GRADE group categorization.
MA administration is associated with appetite improvement, increased probability of weight gain, and a higher probability of delay in deterioration of performance status. The conclusions regarding MA's influence on other symptoms, quality-of-life indices, and performance status were not clear.
There appears to be a dose-response relationship for achievement of weight gain. To obtain improved appetite, it appears that a low dose of MA (160 mg) is as effective as higher doses. At this low dose, there was a beneficial trend compared to the placebo, and a significant effect of a dose increase has not been demonstrated.
The effects of MA are not significantly different than those of glucocorticosteroids. In a previous review, lower-extremity edema in short-term follow-up and potential increased risk of embolic complications in long-term follow-up were identified as adverse effects of MA
Results suggest that MA has a beneficial effect on appetite.
- This review included only advanced cancer cases. The role of MA earlier in the course of disease was not addressed here.
- Studies reviewed were found to be of low quality. Due to this, additional randomized controlled trials with MA are suggested.
- It is suggested that further study of MA's role in ACS include determination of the relative value attributed by patients to individual symptoms affected by MA's use.
Lopez, A.P., i Figuls, M.R., Cuchi, G.U., Berenstein, E.G., Pasies, B.A., Alegre, M.B., & Herdman, M. (2004). Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. Journal of Pain and Symptom Management, 27, 360–369.http://www.ncbi.nlm.nih.gov/pubmed/15050664
To assess the efficacy and safety of megestrol acetate in improving appetite, weight gain, and health-related quality of life in patients with anorexia-cachexia syndrome who had advanced cancer, AIDS, or other underlying pathologies. Other aims were to evaluate the efficacy of different doses and the safety of megestrol acetate.
The following databases were searched: Cochrane Collaboration, Cochrane Controlled Trials Register, MEDLINE, and Embase. A hand search of reference lists was completed. The keywords used were randomized controlled clinical trial, double-blind, single-blind, megestrol acetate, terminally ill, terminal care, and wasting syndrome. Variants of megestrol acetate were also keywords. There was no language restriction. Data were extracted by two reviewers who used the Jadad scale to assess quality. A third reviewer participated if needed.
Of the 296 studies identified, 26 published between 1980 and 2002 met the inclusion criteria. Of these, 19 compared megestrol acetate to a placebo, 6 compared megestrol acetate to other drugs, and 6 studied the effectiveness of different dose levels. The quality of the studies was rated on the Jadad scale: 10 were high-quality, 7 were medium-quality, and 9 were low-quality.
- A total of 3,887 patients had cancer or AIDS and had a clinical diagnosis of anorexia-cachexia syndrome or indicative symptoms (e.g., loss of appetite, decrease in muscle mass).
- Of these patients, 86% (3,368) had cancer, 11% (427) had AIDS, and 2% (81) had other diagnoses.
- Of the patients with cancer, 40% had lung cancer, 23% had gastrointestinal cancer, 7% had head and neck cancer, 2% had pancreatic cancer, 2% had gynecologic cancer, and 26% had other cancers.
- Mean age in the megestrol acetate group was 57 years. Thirty-one percent were women.
- Mean age in the placebo group was 59 years. Thirty-two percent were women.
- There was no difference in sociodemographic characteristics between the megestrol acetate and placebo groups.
- Megestrol acetate doses ranged from 160 to 1,600 mg/day. The most frequently used dose was 480 mg/day.
- Ten of the 26 studies administered a dose of 800 mg/day.
A meta-analysis of the studies assessing appetite had homogeneous results, showing statistically significant improvement with megestrol acetate over the placebo (RR = 2.33, 95% CI 1.52–3.59)
For weight gain, results were homogeneous and in favor of megestrol acetate, but not statistically significant (RR = 1.88, 95% CI 1.43–2.47).
For quality of life, there was significant heterogeneity because of the variety of instruments used. When the results using only the Karnofsky Performance Status Scale were analyzed, heterogeneity was not observed, and the results were positive in favor of megestrol acetate (RR = 1.64, 95% CI 1.06–2.55). Subgroup analysis in patients with cancer showed positive results in favor of megestrol acetate over placebo on appetite (RR = 2.33, 95% CI 1.52–3.59), weight gain (RR = 2.16, 95% CI 1.45–3.21), and quality of life (RR = 1.81, 95% CI 1.13–2.89).
In comparing megestrol acetate to other drugs, it showed benefit in terms of weight gain. No difference was noted between megestrol acetate and other drugs in terms of quality of life. For appetite, megestrol acetate was superior to dronabinol, but showed no advantage to other drugs studied.
In comparing the efficacy of different megestrol acetate doses, the only statistically significant result was observed in patients with cancer, for whom higher doses were associated with greater weight gain (RR = 1.65, 95% CI 1.00–2.73). There were no statistically significant differences between treatment and placebo groups in terms of adverse events, excepting edema, which was greater in the megestrol acetate group (RR = 1.67, 95% CI 1.22–2.28).
When compared with a placebo, there were significant improvements in appetite and weight gain in patients with cancer who were treated with megestrol acetate. This meta-analysis confirms the results of earlier systematic reviews that demonstrated megestrol acetate's advantages over placebo in terms of weight gain and improved appetite. This review did not define the optimal dose of megestrol acete.
Given the adverse events profile, megestrol acetate is a safe treatment option.
Maltoni, M., Nanni, O., Scarpi, E., Rossi, D., Serra, P., & Amadori, D. (2001). High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: A systematic review of randomised clinical trials. Annals of Oncology, 12, 289–300.doi: 10.1023/A:1011156811739
To review the prospective randomized clinical trials (RCTs) that evaluate the use of progestins in cancer anorexia-cachexia syndrome compared with placebo in patients with hormone-independent tumors
Databases searched were MEDLINE, CANCERLIT, Embase, and CINAHL, in addition to hand searching of reference lists.
Of the 38 studies identified, 15 RCTs, published between July 1990 and June 1999, met inclusion criteria. The studies selected used various drug dosages, durations of treatment, eligibility criteria, population types, study designs, methods of assessment, methods of reporting results, and outcomes.
The review reported on 2,102 patients, compiled from six studies of 557 patients that received neither chemotherapy nor radiation, and nine studies of 1,545 patients that received some form of concomitant therapy.
Among the several outcomes analyzed, effect on body weight was assessed in all studies, and only two studies did not evaluate the effect on appetite. The most frequent method of assessing appetite was the visual analog scale.
There was a significant advantage for the use of high-dose progestins regarding improved appetite and body weight gain to support the safety and feasibility of treatment with oral progestins.
Most of the studies were short in duration, lasting from 1 to 12 weeks.
Important issues, such as dosage, duration of treatment, best time to start treatment, and eventual impact on overall improved quality of life, have yet to be defined.
Ruiz Garcia, V., Lopez-Briz, E., Carbonell Sanchis, R., Gonzalvez Perales, J.L., & Bort-Marti, S. (2013). Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database of Systematic Reviews, 3, CD004310.doi: 10.1002/14651858.CD004310.pub3
TYPE OF STUDY: Meta-analysis and systematic review
DATABASES USED: MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews
KEYWORDS: Extensive keyword and specific search term listing per database is provided.
INCLUSION CRITERIA: Studies were included if they were a randomized controlled trial; reported on patients with weight loss and anorexia-cachexia syndrome due to cancer, HIV, or other disease; and studied use of megestrol acetate (MA) compared to placebo, to active control, or at different doses.
TOTAL REFERENCES RETRIEVED: N = 950 articles
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Quality and risk of bias were evaluated according to the Cochrane handbook criteria.
FINAL NUMBER STUDIES INCLUDED: N (studies) = 35 studies: 23 trials in cancer, with 3,428 patients
KEY SAMPLE CHARACTERISTICS: Patients with lung, gastrointestinal, head and neck, and gynecologic cancer, as well as unspecified cancer types, were included in the studies.
Patients receiving MA had weight gain (RR = 1.55, 95% CI 1.06–2.66) among trials in patients with cancer. Appetite improved with MA in patients with cancer (RR = 2.57, 95% CI 1.48–4.49). In studies where MA was compared to another active drug, such as a steroid or an antidepressant, in patients with cancer, there was no significant advantage with MA in meta-analysis. There was no apparent impact of higher doses of MA on appetite. There were more adverse events with MA than with placebo, with the most common adverse events being edema and thromboembolism. The quality of evidence for findings related to appetite and weight gain were deemed to be very low, mainly due to high risk of bias.
Findings suggest that MA is effective in improving appetite and resulting in weight gain among patients with cancer; however, findings also show that the quality of evidence was very low. MA did not appear to be more effective than other medications such as steroids.
The quality of evidence was very low.
MA can be effective in improving appetite and weight gain in patients with cancer. Higher doses of MA do not appear to have any greater effect. Nurses should be aware of the possible adverse events associated with MA use, such as thromboembolism. Further research in comparison of risks and benefits of MA in comparison to other medications and strategies to improve appetite and weight gain would be useful.
Yavuzsen, T., Davis, M.P., Walsh, D., LeGrand, S., & Lagman, R. (2005). Systematic review of the treatment of cancer-associated anorexia and weight loss. Journal of Clinical Oncology, 23, 8500–8511.doi: 10.1200/JCO.2005.01.8010
Studies were included in the review if they reported on
- Adult patients older than 18 years of age
- Patients with nonhematologic malignancies
- Patients with anorexia or symptoms of anorexia, such as lack of appetite, weight loss, poor performance status, and decreased quality of life.
The review involved only prospective, randomized controlled trials (RCTs; double- and single-blind or unblended and phase III trials). The quality of studies was assessed using the validated scale published by Jadad et al. (1996).
There were 55 studies reviewed that met the eligibility criteria.
Multiple RCTs have been conducted to investigate the safety and efficacy of pharmacologic agents to stimulate appetite. Only two therapeutic interventions for cancer-related anorexia demonstrated enough evidence to support their use in patients with cancer: corticosteroids and progestins. Other studies had mixed outcomes, positive results in only a single randomized trial, or were not placebo-controlled.
There is strong evidence supporting the use of progestins in patients with cancer, of which the most commonly reported drugs were MA and MPA. There was increased weight with both progestins; there was also evidence of a dose-response, but higher doses did not confer any additional benefit with regard to appetite. Metaclopromide is effective for nausea and early satiety but has not been shown to directly stimulate appetite.
The RCTs did not show sufficient evidence to justify the use of dronabinol, EPA, EPO, ghrelin, interferon, melatonin, nandrolone, NSAIDs, or pentoxyfilline in cancer-related anorexia. Cyproheptadine is a weak appetite stimulant, but side effects are limiting.
The optimal dose, start time, and duration of treatment for many appetite stimulants are still unknown. A more systematic approach to research methodology is needed. In addition, uniform outcome measures to better assess the value of various appetite stimulants are needed. These should include subjective ratings of appetite and associated symptoms (e.g., early satiety) and objective measures (e.g., food consumed, weight gain, weight loss).
Desport, J.C., Gory-Delabaere, G., Blanc-Vincent, M.P., Bachmann, P., Beal, J., Benamouzig, R., . . . Senesse, P. (2003). Standards, options and recommendations for the use of appetite stimulants in oncology (2000). British Journal of Cancer, 89(Suppl. 1), S98–S100.doi: 10.1038/sj.bjc.6601090
Purpose & Patient Population:
To review the literature on the use of appetite stimulants in oncology by a multidisciplinary group established by the French National Federation of Cancer Centers
Type of Resource/Evidence-Based Process:
The group conducted a literature search of four databases (MEDLINE, CancerLit, Embase, and the Cochrane Library) using search phrases: appetite stimulants, anorexia/drug therapy, cachexia/drug, or appetite associated with neoplasms. The search yielded 55 reports of randomized controlled trials (RCTs) published between 1990–1999 that evaluated the appetite-stimulating effect of corticosteroids, synthetic progestogens, or other drugs.
The group defined standards, options, and recommendations for the use of appetite stimulants.
- Standards: Clinical situations for which there exist strong indications or contraindications for a particular intervention.
- Options: Situations for which there are several alternatives without clear superiority of one choice over another.
- Recommendations: Additional information to enable the available options to be ranked using explicit criteria with an indication of the level of evidence.
They also defined the level of evidence.
- A: High-standard, meta-analysis, or several high-standard RCTs with consistent results.
- B: Good-quality evidence from randomized trials or prospective or retrospective studies with consistent results.
- C: Weak methodology of studies or inconsistent results.
- D: Lack of scientific data or case study reports only.
- Expert Agreement: Data do not exist for the method concerned, but the experts are unanimous in their judgment.
The primary outcome used in analysis of study results was anorexia. Secondary outcomes were improved quality of life, increase in body weight, increased food consumption, decrease in nausea and/or vomiting, and improvement in anthropometric and biologic parameters.
Guidelines & Recommendations:
Corticosteroids were found to be effective appetite stimulants. Their level of evidence was B1 (good-quality evidence from randomized trials), but optimal dose and scheduling information was lacking.
Megesterol acetate: Effective appetite stimulant (level B1) and beneficial effect on body weight (level B1). Minimum effective dose is 160 mg/day (level B1). Optimal dose is 480 mg/day (level C). No greater efficacy was seen with doses higher than 480 mg/day (level B1).*
Medroxyprogesterone acetate: Effective appetite stimulant (level B1). Effect on weight was not confirmed (level C). The group recommended more clinical trials to establish optimal dose and duration of therapy.
Cyproheptadine: May be an appetite stimulant, but adverse effects were reported (level C).
Dronabinol, metoclopramide, nandrolone, pentoxifylline: No appetite-stimulating effects were shown (level C). These should be used only in the setting of RCTs.
Hydrazine sulfate: Not an appetite stimulant (level A).
Corticosteroids and progestogens can be used in the treatment of anorexia in patients with cancer, especially in patients with advanced disease and with any type of cancer. Hydrazine sulfate should not be used.
* Data from trials completed after 1999 establish the safety and efficacy of higher doses of megesterol acetate.
National Comprehensive Cancer Network. (2012). NCCN Clinical Practice Guidelines in Oncology: Palliative Care [v.2.2012]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf
Purpose & Patient Population:
The objective of the guidelines is to provide palliative care practice guidelines for patients with cancer, facilitating the appropriate integration of palliative care into oncology practice.
Type of Resource/Evidence-Based Process:
These are consensus-based guidelines.
Phase of Care and Clinical Applications:
Included in the guidelines are multiple phases of care with palliative care applications.
Guidelines & Recommendations:
The NCCN made recommendations on the following symptoms.
Nutritional support, including enteral and parenteral feeding, should be considered. Appetite stimulants such as megestrol acetate and corticosteroids can be used when appetite is an important aspect of quality of life.
Chemotherapy-Induced Nausea and Vomiting (CINV)
Recommendations include prochlorperazine, haloperidol, metoclopramide, or benzodiazepines. Adding 5-HT3 receptor agonists, anticholinergics, antihistamines, corticosteroids, antipsychotics, and cannabinoids also can be considered. Palliative sedation can be considered as a last resort.
Increase fluid intake, dietary fiber, and physical activity. Opioid-induced constipation should be anticipated and treated prophylactically with laxatives.
Pharmacologic interventions include opioids or benzodiazapines. Scopolamine, atropine hyoscyamine, and glycopyrrolate are options to reduce excessive secretions.
Do not reduce opioid dose for symptoms such as decreased blood pressure or respiratory rate. Palliative sedation can be considered for refractory pain.
For refractory insomnia with no underlying physiologic cause, pharmacologic management includes diazepam, zolpidem, and sedating antidepressants. Cognitive behavioral therapy may be effective. If present, restless leg syndrome can be treated with ropinirole.
- Recommendations are predominantly consensus- rather than evidence-based.
- Recommendations are generally based on low-level evidence.
- Recommendations regarding CINV seem particularly out of date and are not in concert with current evidence.
Recommendations provide expert opinion/consensus-level suggestions for management of various symptoms. Many recommendations, such as those for CINV, do not agree with current evidence in these areas.
Research Evidence Summaries
Greig, C.A., Johns, N., Gray, C., MacDonald, A., Stephens, N.A., Skipworth, R.J., . . . Fearon, K.C. (2014). Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Supportive Care in Cancer, 22, 1269–1275.doi: 10.1007/s00520-013-2081-3
To test the safety, tolerance, and efficacy of an appetite stimulant and an anabolic beta 2 agonist in patients with cancer cachexia
Intervention Characteristics/Basic Study Process:
Patients were asked to take formoterol 40 mcg and megestrol 320 mg each morning and 40 mcg formoterol and 160 mg megestrol each evening for eight weeks. Self-reported intake and tablet counts were used to determine patient adherence. Patients were admitted to a clinical research facility on day 1 and discharged after the first dose of study drugs. Patients were contacted by phone after 24 hours for assessment. Additional assessments were done at weeks 2, 4, 6, 8, and 12.
- N = 9 (completed four weeks); 7 (completed eight weeks)
- MEDIAN AGE = 67 years
- MALES: Not provided, FEMALES: Not provided
- KEY DISEASE CHARACTERISTICS: All had advanced disease; specific types were not described.
- OTHER KEY SAMPLE CHARACTERISTICS: Mean weight loss was 11% body weight over the prior five to seven months.
- SITE: Single-site
- SETTING TYPE: Outpatient
- LOCATION: Scotland
Phase of Care and Clinical Applications:
- PHASE OF CARE: End-of-life care
- APPLICATIONS: Palliative care
Single arm observational
- National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI's CTCAE) version 3.0
- Body weight
- Maximum isometric knee extensor, lower limb extension, and maximum handgrip strength via dynamometry
- Muscle size measurement via MRI
- Physical activity measured via accelerometry as average daily step count
- European Organization for Research and Treatment of Cancer (EORTC) Quality of Life C30 questionnaire
Patients showed an increase in muscle strength and muscle size. Mean body weight increased by 2.6%. Physical activity increased in three of six patients who responded to treatment. Appetite improved (p = .005). Adverse events were tremor (n = 7), peripheral edema (n = 3), tachycardia (n = 2), and dyspepsia (n = 2).
The combination of megestrol and formoterol may have benefit for patients with cachexia. The sample size of this study was too small to draw conclusions.
- Small sample (< 30)
- Risk of bias (no control group)
- Risk of bias (no blinding)
- Risk of bias (no random assignment)
- Subject withdrawals ≥ 10%
- Other limitations/explanation: Four patients discontinued possibly due to study drug; 40% overall attrition
The combination of medications tested here may be associated with improved muscle function and appetite in patients with advanced cancer; however, due to the limitations of this study, efficacy and tolerance is not clear. Further well-designed research with these medications is needed to determine efficacy, safety, and tolerance.
Jatoi, A., Windschitl, H.E., Loprinzi, C.L., Sloan, J.A., Dakhil, S.R., Mailliard, J.A., . . . Christensen, B. (2002). Dronabinol versus megestrol acetate versus combination therapy for cancer associated anorexia: A North Central Cancer Treatment Group study. Journal of Clinical Oncology, 20, 567–573.doi: 10.1200/JCO.20.2.567
To evaluate the efficacy of megestrol acetate versus dronabinol, as well as a combination of these treatments
Intervention Characteristics/Basic Study Process:
This was a randomized, controlled, three-arm trial using a double-blind procedure. The first arm evaluated the efficacy of 800 mg/day of oral megestrol acetate plus a capsule placebo; the second arm evaluated the efficacy of 2.5 mg of oral dronabinol twice daily plus a liquid placebo; and the third arm combined both medications. Evaluations were taken at noted doses.
The final sample included 469 patients. The sample was stratified for confounding factors, including age, gender, cancer type, estimate of survival, performance status, severity of weight loss, concomitant radiation therapy, treatment center, and planned or ongoing treatment. Sample size calculations included a power analysis and accounted for attrition.
All participants shared the following characteristics:
- Adults with an incurable malignancy, with the exception of brain, breast, ovarian, and endometrial cancers
- An estimated life expectancy of more than three months, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2
- A self-reported weight loss of at least five pounds and/or physician-estimated caloric intake of less than 20 calories/kg of body weight/day.
North Central Cancer Treatment Group (NCCTG) trial involving 20 NCCTG institutions, including the Mayo Clinic
A double-blind, randomized controlled trial design was used.
- Weight was measured using home scales and office scales.
- Anorexia was assessed using validated NCCTG questionnaires.
- Quality of life was assessed using a single-item Uniscale and a 13-item, anorexia-specific Functional Assessment of Anorexia/Cachexia Cancer Therapy (FAACT) instrument. The validity and reliability of these instruments was previously reported.
No differences between groups at baseline were noted. A greater percentage of patients treated with megestrol acetate reported appetite improvement (75% versus 49%; p = 0.0001) and baseline weight gain (11% versus 3%, p = 0.02) for > 10%) compared with dronabinol-treated patients. Combination treatment conferred no additional benefit.
FAACT demonstrated improved quality of life among megestrol acetate–treated and combination-treated patients. Uniscale scores were similar for both groups. Toxicity among groups was comparable, with the exception of a greater incidence of impotence among men who received megestrol acetate.
- The study lacked a constitutive definition of anorexia.
- Eligibility criteria used self-reported weight loss and physician estimates of caloric intake.
- Outcome measures used weight measurement in the oncologist’s office; accuracy and precision of the scale used to assess weight were not explicated.
- Validity and reliability of instruments was not included.
- Recruitment sites were listed, but these settings were not described.
- Cost implications were not discussed.
Nelson, K.A., Walsh, D., & Hussein, M. (2002). A phase II study of low-dose megestrol acetate using twice-daily dosing for anorexia in nonhormonally dependent cancer. American Journal of Hospice and Palliative Care, 19, 206–210.doi: 10.1177/104990910201900313
To evaluate the efficacy of a low dose of megestrol acetate (MA) in debilitated patients with cancer experiencing cachexia
Intervention Characteristics/Basic Study Process:
Participants received 80 mg of MA twice daily after meals. After a two-week treatment period, participants were evaluated for efficacy, side effects, and satisfaction.
Consecutive patients (convenience sample)
Patients with advanced cancer and any degree of weight loss were eligible for the study. Of the 20 patients who were evaluable,
- 12 were female and 8 were male.
- The median age was 68.
- The most common malignancy was lung cancer.
- The median ECOG performance status was 2.
Excluded from the study were patients with
- A life expectancy of less than four weeks
- An ECOG performance status of less than 3
- Breast or prostate cancer who were currently receiving hormonal or cytotoxic therapy
- The presence of pleural effusion or ascites
- Uncontrolled hypertension, diabetes mellitus, or congestive heart failure
- A history of deep-vein thrombosis (DVT) or in treatment for DVT.
This single-site study took place in a large midwestern city at a large academic medical center with a cancer center.
The study was a phase II trial with a nonrandomized design and a descriptive, observational setup.
Outcomes included appetite, satisfaction, and side effects. Appetite and satisfaction were evaluated using a questionnaire that included one question for appetite (0 = absent, 4 = better than normal) and one yes/no question on satisfaction (Are you satisfied with the way the medication affected your appetite?). This empirical indicator appears to have been developed by the research team, although this is not clearly explicated. Side effects were measured using a “Side Effect Profile” (a list of MA side effects developed from a number of previous studies using varying doses of MA).
Fifteen out of 20 patients were deemed “responders.” Most responders had an appetite change of one degree in the categorical question, and 16 answered that they were “satisfied” with the way the medication affected their appetite. There were no significant differences in results based on gender, age, or performance status. The third outcome, side effects, was not specifically reported according to the Side Effect Profile. Researchers reported that five patients developed symptoms not present before the study; in three patients, these were considered drug-related.
The researchers concluded that a low dose of MA given twice daily was an effective appetite stimulant in patients with advanced cancer.
- The study lacked a constitutive definition of anorexia, appetite, satisfaction, and side effects.
- Participants were considered evaluable for side effects after two doses and for efficacy after four doses. This time period (1 to 2 days) does not allow time for the drug to take effect.
- Eligibility criteria lack specificity.
- The validity and reliability of the instrument used to measure appetite and satisfaction are absent.
- Researchers indicated that appetite improvement by one degree on the categorical scale was a response, but how or why one degree constituted a response was not specified.
- The recruitment sites were listed, but these settings were not described.
- The statistical discussion was weak, with no explanation of sample-size calculation, power, or effect size.
- There was limited discussion of the statistical methods used to assess outcomes.
- Cost implications were not discussed.
Tomiska, M., Tomiskova, M., Salajka, F., Adam, Z., & Vorlicek, J. (2003). Palliative treatment of cancer anorexia with oral suspension of megestrol acetate. Neoplasma, 50, 227–233.
To evaluate the effect of different doses of oral suspension of megestrol acetate (MA) on appetite, quality of life, body weight, and anthropometric measures in patients with advanced cancer
Intervention Characteristics/Basic Study Process:
Researchers evaluated a fixed dose of MA (480 mg) versus escalating doses of MA. Patients were evaluated at baseline, two, four, and eight weeks.
- The study included 22 patients with advanced, nonhormonally dependent cancer who were experiencing anorexia-related weight loss (at least 5% of usual body weight).
- Patients had a life expectancy of more than three months, and a World Health Organization performance status of two or less.
- Median patient age was 59 years.
- A total of 19 patients were evaluated (2 died, 1 withdrew): 15 men and 4 women.
- Patients were diagnosed with lung cancer (nine), gastrointestinal cancer (six), renal cancer (two), mesothelioma (one), and non-Hodgkin lymphoma (one).
- At eight weeks, 12 patients were evaluated (eight patients died, one withdrew from study, and one stopped because of side effects).
The study was a randomized, multicenter, blinded, two-arm trial.
- Visual analog scale using 0–100 mm to measure appetite (patient self-report)
- Body weight
- Anthropometric measures of mid-arm circumference and four skinfold thickness
- Hand grip strength
- Serum measure of albumin, prealbumin, c-reactive protein, and cortisol
- European Organization for Research and Treatment Cancer Core Quality of Life questionnaire (EORTC QLQ-C30, version 1.0)
Twelve patients were evaluated at eight weeks (eight patients died, one withdrew from study, and one stopped because of side effects). Therefore, the patients were evaluated as a single group regardless of whether they were receiving a fixed dose or an escalating dose of MA. There was statistically significant improvement in appetite over baseline in all patients at two weeks (p = 0.0001), four weeks (p = < 0.01), and eight weeks (p = 0.022). Overall quality of life improved in the majority of patients at two and eight weeks, but it was not statistically significant. There was no statistically significant improvement in body weight or other measures. In terms of side effects, 4 of 19 patients experienced clinically significant edema, resulting in 1 patient withdrawing from the study.
Original aims of the study could not be met because of the small sample size, so no conclusions can be drawn about the effectiveness of oral MA suspension or optimal or superior dose of MA.
- The study had a very small sample size, with significant attrition (36%).
- The study had no placebo group; all patients were assessed compared to their baseline measures.