Ghrelin

Ghrelin

PEP Topic 
Anorexia
Description 

Ghrelin is a 28-amino acid peptide that is produced by cells lining the fundus of the stomach. It is a hormone that increases appetite through action on hypothalamic feeding centers. Ghrelin and ghrelin mimetics have been examined in treatment of cancer-related anorexia. Ghrelin has a short half-life (about 30 minutes) and is administered by injection.

Effectiveness Not Established

Research Evidence Summaries

Garcia, J.M., Friend, J., & Allen, S. (2012). Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: A multicenter, randomized, double-blind, crossover, pilot study. Supportive Care in Cancer, 21, 129–137.

doi: 10.1007/s00520-012-1500-1
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Study Purpose:

To evaluate the effects of anamorelin in patients with cancer-related cachexia

Intervention Characteristics/Basic Study Process:

Patients received anamorelin 50 mg/day or placebo for a three-day treatment period. This was followed by a seven-day washout period. After the washout, patients were switched to the opposite intervention. Assessments were done at baseline and at the end of each study period. Patients were stratified according to level of weight loss prior to random assignment to the treatment condition sequence.

Sample Characteristics:

  • The study reported on 16 patients.
  • Mean patient age was 62 years.
  • The sample was 75% male and 25% female.
  • Patients had various tumor types.
  • Most patients had an Eastern Cooperative Oncology Group performance status of 1.
  • All patients had experienced at least a 5% weight loss in the past six months.

Setting:

  • Multisite
  • Inpatient setting 
  • United States

Phase of Care and Clinical Applications:

  • Patients were undergoing palliative care.
  • The study has clinical applicability for late effects and survivorship.

Study Design:

The study was a double-blind, placebo-controlled, crossover, randomized controlled trial.

Measurement Instruments/Methods:

  • Body weight
  • Appetite scored on a 100 mm visual analog scale
  • Anderson Symptom Assessment Scale (ASAS)
  • Edmonton Symptom Assessment Scale
  • Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-F)
  • Bristol-Myers Anorexia/Cachexia Recovery Instrument
  • Caloric intake

Results:

There was no treatment effect on caloric intake. Growth hormone levels were significantly greater when patients received anamorelin compared to placebo (p = 0.005). ASAS total scores improved after three days of anamorelin (p < 0.002). Among individual symptom items, patients reported improved appetite (2.67 points with anamorelin and 0.5 points with placebo, p = 0.011). FACIT-F scores improved after anamorelin  compared to placebo (p = 0.018).

Conclusions:

Anamorelin was shown to have some positive effects on patients’ symptoms in this small pilot study. Further research is needed to evaluate efficacy.

Limitations:

The study had a small sample size, with less than 30 participants.

Nursing Implications:

This study was too small to enable any conclusions about the efficacy and safety of anamorelin. Further research with a larger sample is needed.

Hiura, Y., Takiguchi, S., Yamamoto, K., Takahashi, T., Kurokawa, Y., Yamasaki, M., . . . Doki, Y. (2012). Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients: A prospective, randomized, placebo-controlled phase 2 study. Cancer, 118, 4785–4794.

doi: 10.1002/cncr.27430
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Study Purpose:

To examine the effects of administration of synthetic ghrelin on appetite and oral intake in patients with advanced esophageal cancer during chemotherapy

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either ghrelin at 3 µg/kg over 30 minutes twice daily or placebo for seven consecutive days (days 1–7 of therapy) intravenously. All patients also received the same protocol of IV fluid of 3 L/day from days 1–3 and 2 L/day from days 4–7. Appetite was scored prior to each meal. A registered dietitian determined caloric intake by measuring the weight of each dish before and after every meal.

Sample Characteristics:

  • The study reported on a final sample of 40 patients.
  • Mean patient age was 63.4 years.
  • The sample was 87.5% male and 12.5% female.
  • All patients had stage II or higher esophageal disease. All were receiving cisplatin-based chemotherapy.

Setting:

  • Single site 
  • Inpatient setting
  • Japan

Phase of Care and Clinical Applications:

Patients were undergoing active antitumor treatment.

Study Design:

The study was a placebo-controlled randomized controlled trial.

Measurement Instruments/Methods:

  • Appetite visual analog scale (VAS)
  • Caloric intake
  • Rapid turnover protein levels: prealbumin, transferrin
  • Common Terminology Criteria for Adverse Events

Results:

Dietary intake declined after cisplatin administration to the lowest levels on days 5–7. It took another 4–7 days for oral intake to recover and enable discharge from the hospital. The decline in dietary intake was less in the ghrelin group (p = 0.0027). On day 7, intake with ghrelin was 26.7 kcal/kg/day compared to 23.1 kcal/kg/day for those receiving placebo. Prealbumin was higher in those on ghrelin (p = 0.042), and transferrin was higher with ghrelin (p = 0.037) compared to those levels in the placebo group. The severity grades of anorexia and nausea were lower with ghrelin (< 0.02).

Conclusions:

Findings suggest that administration of ghrelin during cisplatin-based chemotherapy was effective in reducing anorexia and maintaining caloric intake compared to placebo.

Limitations:

  • The study had a small sample size, with less than 100 participants.
  • Lack of blinding had an associated risk of bias.
  • Unintended interventions or applicable interventions were not described that would influence results.
  • The intervention was expensive, impractical, or required training.
  • The use of antiemetics during treatment was not described, so it is unclear whether there were differences between groups that could have affected outcomes.
  • Although findings were statistically significant, the actual difference in caloric intake appears to be fairly small.
  • The sample included only patients who had no previous chemotherapy, and physicians had discretion to exclude patients based on no particular criteria. It is unclear whether this could have produced sample bias. 
  • This protocol would only be feasible in an inpatient setting.

Nursing Implications:

Findings suggest that ghrelin as administered in this study may be beneficial to preserve appetite and nutritional intake during chemotherapy.  As done here, ghrelin and fluid administration would only be practical in an inpatient setting.

Neary, N.M., Small, C.J., Wren, A.M., Lee, J.L., Druce, M.R., Palmieri, C., . . . Bloom, S.R. (2004). Ghrelin increases energy intake in cancer patients with impaired appetite: Acute, randomized, placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism, 89, 2832–2836.

doi: 10.1210/jc.2003-031768
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Study Purpose:

To determine whether ghrelin stimulates appetite in patients with cancer who have anorexia. Ghrelin is an appetite-stimulating hormone.

Intervention Characteristics/Basic Study Process:

Patients received ghrelin (5 pmol/kg/min) or saline; four patients received ghrelin then saline (n = 4) or saline followed by ghrelin (n = 3).

Sample Characteristics:

  • The study reported on a sample of seven patients with metastatic cancer experiencing appetite loss and a mean weight loss of 13%.
  • Patients were assigned numbers in order of recruitment.
  • The sample was comprised of six females and one male, with an age range of 41–66 years.

Setting:

Patients were recruited from oncology clinics at Charing Cross Hospital (United Kingdom).

Study Design:

The study was a prospective, randomized, placebo-controlled, crossover clinical trial.

Measurement Instruments/Methods:

  • Edmonton Symptom Assessment Scale (for appetite as an individual item and all nine items as an overall measure of quality of life)
  • Energy intake from a buffet meal designed to be in excess
  • Meal appreciation assessed through visual analog scales (0–100 scale to the prompt “how pleasant was this meal?”)
  • 24-hour food intake completed after each infusion through the use of food diaries
  • Plasma ghrelin, insulin, glucose, triglyceride, and growth hormone levels

Results:

Energy intake from a buffet meal during saline or ghrelin infusion indicated there was a 31% increase in energy intake in patients during the ghrelin infusion, and greater meal appreciation (by 28 +/- 8%). No side effects of the ghrelin therapy were observed. No changes were reported in levels of insulin, glucose, or triglycerides. Patients recorded greater food consumption on the days they received the ghrelin.

Conclusions:

Further investigations are needed before conclusions can be drawn.

Limitations:

  • The study had a small sample size.
  • Ghrelin had been administered to only 100 patients worldwide at the time of this investigation.
  • The long-term effects of ghrelin have not yet been established.

Systematic Review/Meta-Analysis

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
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Search Strategy:

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.

Literature Evaluated:

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).

Sample Characteristics:

There were 55 studies reviewed that met the eligibility criteria.

Results:

Androgenic steroids
Androgenic steroids were studied in two studies involving 512 patients; no significant benefit was demonstrated.
 
Cannabinoids
Cannabinoids were studied in one RCT involving 469 patients; they did not confer an additional benefit.
 
Corticosteroids
Six studies investigated the use of corticosteroids in 647 patients. Some improvements in appetite were found; however, dosage and type of steroid varied such that optimal dose and duration of therapy could not be determined.
 
Cyproheptadine
Two studies investigated the use of cyproheptadine in 344 patients; these investigations had conflicting outcomes.
 
Eicosapentaenoic acid (EPA)
Three studies investigated the use of EPA in 689 patients; these reported conflicting results.
 
Erythropoietin (EPO)
EPO was investigated in two studies involving 417 patients. In one investigation, EPO was administered in combination with a COX-2 inhibitor with and without a specialized nutritional program. The intent-to-treat analysis was negative. No differences in food intake were noted.
 
Ghrelin
Ghrelin was investigated in one RCT involving seven patients; differences between groups were noted, but long-term safety data on the agent are not available.
 
Hydrazine sulfate
Five studies investigated the use of hydrazine sulfate in 796 patients. Multicenter RCTs in patients with lung and colon cancers did not demonstrate any benefit when compared to a placebo.
 
Interferon
Interferon was investigated in one study involving 57 patients; no differences were found.
 
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs were investigated in two trials involving 417 patients; these investigations failed to demonstrate a benefit in the NSAID arm.
 
Pentoxyfilline
One study investigated the use of pentoxyfilline in 70 patients and found no benefit. Melatonin was investigated in two studies involving 186 patients; these did not demonstrate any improvement in appetite or intake.
 
Progestins
Twenty-nine studies reviewed the safety and efficacy of progestins: 23 examined megesterol acetate (MA), and six investigated medroxyprogesterone acetate (MPA). Results favored progestins over placebo and found that side effects were tolerable. Ten studies assessed the influence of MA on quality of life; these demonstrated that the effect of MA on quality of life was minimal.
 
Prokinetics
Two studies investigated prokinetics for anorexia in a total of 55 patients. No improvement in caloric intake or appetite was noted.
 
Thalidomide
Thalidomide has not been investigated in prospective RCTs.

Conclusions:

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.

Nursing Implications:

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).


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