Should appetite stimulants be used in pediatric patients with cancer?

Background

Loss of appetite, or anorexia, in patients with cancer can be a significant cause of cancer-related malnutrition, when an excess or deficiency of nutrients, energy, or protein cause adverse effects on the body.1-3 Malnutrition is often defined as weight loss of more than 5 to 10% during a period of less than 6 months and a body mass index (BMI) of less than 18.5 to 20 kg/m2.4 Cancer-related malnutrition can affect up to 60% of the pediatric cancer population and can cause significant morbidity and mortality.3,5 Malnutrition has also been associated with increased rates of infections and mortality in patients with pediatric cancer compared to those who are well-nourished.6-8 Malnutrition is typically at its peak after oncologic treatment has begun, but can be highest at diagnosis as it varies by type of cancer.3,9 Children who are malnourished at the start of cancer therapy are also more likely to experience a relapse after therapy than those who have good nutritional status.10 Cachexia, a consequence of malnutrition, is a multifactorial metabolic syndrome characterized by decreased appetite, weight loss, inflammation, and loss of adipose and skeletal tissue, that is associated with lower quality of life and worse prognosis.4 As a result of increased metabolic demands from tumor burden, the risk of cachexia  increases as tumor burden and metastases grow.10 In adults, several criteria can be used to diagnose cachexia, but the main clinical feature is progressive weight loss due to loss of skeletal muscle mass.11 Unintended weight loss of more than 5% or BMI less than 20 kg/m2 plus any 3 of the following is considered diagnostic of cachexia: anorexia, fatigue, decreased muscle strength, loss of lean tissue, or abnormal laboratory values (high C-reactive protein, low hemoglobin, or low albumin). While it has been studied in adults, there is not a standardized definition of cachexia in adult or pediatric patients with cancer.

How to best improve the nutritional status of patients with pediatric cancer has been a dilemma for clinicians. Total parenteral nutrition (TPN) has been used to improve the nutritional status of these patients, however there is an increased risk of infection, specifically blood stream infections, in patients receiving long-term TPN.10 Enteral nutrition is the preferred method of nutritional support because of its ease of administration, more efficient use of nutrient substrates, beneficial effects on the gastrointestinal tract, decreased risk of infection, and cost effectiveness. However, in the pediatric population, there are issues with enteral nutrition, such as oral aversion secondary to nausea/vomiting, pain while eating from mucositis, and changes in taste from therapy.12 Enteral tube feeding can also lead to issues, such as nasopharyngeal irritation, need for reinsertion, and poor cosmetic appearance.6

Potential pharmacological treatment options

Appetite stimulants have been studied and used in adult and elderly patients with cancer, but there is no preferred pharmacologic option for this population. The current National Comprehensive Cancer Network (NCCN) guidelines for cachexia recommend treatment of reversible causes of weight loss and poor intake, and initiating pharmacologic treatment based on life expectancy.13 In adult patients with low or no appetite and a life expectancy of years (rather than months), the NCCN recommends megestrol acetate or olanzapine. If the patient has only weeks to months to live, the NCCN recommends megestrol acetate, olanzapine, dexamethasone, or a cannabinoid. The NCCN suggests initiating mirtazapine, regardless of life expectancy, if the cause of the anorexia is depression. The American Society of Clinical Oncology (ASCO) guidelines do not endorse any particular pharmacologic agent, citing insufficient evidence.14  A short-term trial of a progesterone analog, like megestrol, or a corticosteroid may be offered in patients with low appetite or weight loss, per the ASCO guidelines. There are few data to support the use of appetite stimulants in pediatric patients with cancer. Clinicians who treat pediatric patients are interested in novel ways to support their nutrition, especially because these patients desperately need calories for their development.

Megestrol acetate is a derivative of progesterone that has been used for weight gain and appetite stimulation in adults.15,16 Megestrol has been shown to increase appetite, food intake, and weight gain in adult patients with several types of cancer. There is no standard dosing of megestrol for appetite stimulation in adults, but doses of 160 to 1600 mg/day have been reported and dosing information is limited in pediatric patients.15,17

Cyproheptadine is a first generation antihistamine with serotonergic antagonism that has been shown to increase weight gain in adults with chronic diseases, like cancer and cystic fibrosis.1,18 It is also approved in children for allergic conditions, prevention of cyclic vomiting syndrome, and spasticity associated with spinal cord damage, in addition to appetite stimulation.19 The studied dosing regimen for appetite stimulation in pediatric patients with cystic fibrosis is 2 mg 4 times a day with an increase to 4 mg 4 times a day after 1 week.18

There is increasing interest in using cannabinoids and medical marijuana in patients with cancer as an antiemetic and appetite stimulant. A study evaluating delta-9-tetrahydrocannabinol (THC)  demonstrated improvement in appetite in patients with cancer-related cachexia.1 However, when compared with placebo in another study, neither cannabis extract nor THC were found to significantly improve appetite or quality of life in adult cancer patients with cachexia or weight loss.20 There are 2 approved synthetic forms of THC approved in the United States, dronabinol and nabilone, which are approved for chemotherapy-induced nausea and vomiting. Dronabinol has been approved for appetite stimulation in adult patients with acquired immunodeficiency syndrome (AIDS) at doses of 2.5 mg twice a day, to a maximum of 20 mg a day.19

There are several other appetite stimulants that have been studied in adults, such as growth hormone, corticosteroids, olanzapine, and mirtazapine.1 However, these agents have not been studied in pediatric patients. The purpose of this FAQ is to provide a summary of published literature evaluating the use of appetite stimulants in pediatric patients with cancer.

Literature Review

Megestrol

A case-control study of megestrol in pediatric patients with cancer (N=94) was performed by Azcona et al to evaluate if megestrol acetate was effective in treating anorexia and weight loss in children with malignant solid tumors.2 Children <18 years old with anorexia or weight loss at diagnosis or during treatment were started on megestrol 10 mg/kg/day for a maximum of 6 months in addition to nutritional support which included hypercaloric supplementation, psychologic support, and dietetic measures. Anorexia was defined as lack of natural appetite or a score of ≤ 3 out of 5 on the feel like eating scale. Weight gain, BMI, and degree of appetite were assessed monthly for the first 6 months and then at 9 and 12 months and compared to a control cohort. The control group consisted of 59 patients and the megestrol group consisted of 35 children. Mean age in the treatment group was 11.4 years (range 0.7 to 17.8 years). The mean dose of megestrol was 240 mg/day (range 40 to 560 mg/day). Weight significantly increased in the megestrol group at months 1 (p<0.001), 3 (p<0.05), 6 (p<0.01), and 12 (p<0.001) compared to the control. The percent increase in weight gain was 6.95 to 17.9% during the follow-up. Body mass index significantly increased after 1 month of megestrol and persisted through month 12 (p<0.001) when compared to the control group. Appetite and caloric intake both significantly increased in the megestrol group, p<0.001 for both measures. There were no significant side effects noted by the authors; one patient developed follicular acne which resolved after megestrol discontinuation. Morning cortisol levels decreased below the normal limit (p<0.001) by the second month of therapy, however the authors did not report any cases of adrenal crises. The authors concluded that megestrol is a powerful appetite stimulant that may reduce the need for more expensive nutritional supplementation. Limitations of the study included the small sample size, case-control study design, and lack of defined outcomes.

Orme and colleagues performed a retrospective chart review of pediatric patients with cancer (N=19) who had been started on megestrol acetate for at least 30 days for cancer-related anorexia or a decrease in weight z score (weight-for-age measurement expressed as the number of standard deviations above or below the standard average).21,22 Megestrol acetate was initiated only after other nutritional support interventions were given including psychologic support and high-calorie supplements. Megestrol was started at 10 mg/kg/day in a single or twice-daily dose; at the end of treatment, the dose was halved for a period of 2 weeks, then quartered for 1 week before cessation. Important outcomes were change in weight and weight z score during and at the end of therapy and morning cortisol levels throughout therapy. The median age was 7.2 years (range 1.7 to 17.8 years) The median dose of megestrol was 9.4 mg/kg (range 7.1 to 11.1 mg/kg) and median duration of therapy was 95 days (range 41 to 259 days). After 3 to 6 weeks of therapy, patients taking megestrol gained a median of 1.6 kg (range, -1 kg to 8.5 kg) and their z score increased by 0.46 (range -0.33 to 0.97). At the end of therapy, the median weight gain was 3.1 kg (range -1.6 kg to 10 kg) and median weight z score increase was 1.04 (range -0.64 to 2.88). When compared to paired observations, increases in both weight and weight z score were statistically significant, p=0.0008 and p=0.0007, respectively. Eleven patients had serial cortisol levels during therapy; all 11 exhibited significant decreases in the cortisol levels after a median of 42 days (range 22 to 203 days) on megestrol therapy (p=0.0033). One patient experienced a likely adrenal crisis in the setting of undetectable cortisol levels that subsequently resolved upon initiation of intravenous hydrocortisone. No other serious adverse events were noted in relation to the megestrol therapy. The authors concluded that megestrol has the ability to improve nutritional status, but the adrenal suppression is a serious adverse effect of its use. Limitations of the study include small sample size, short follow-up period, and retrospective nature.

A randomized, double-blind, placebo controlled trial evaluated megestrol use in pediatric patients with cancer (N=26)  and weight loss.6 Children <18 years old with any type of cancer were included if they had at least 5% weight loss or a history of anorexia and a percent ideal body weight <90% (actual body weight divided by ideal body weight x 100%). There were 13 patients assigned to the megestrol group and 13 patients in the placebo group.  The megestrol dose used was 7.5 mg/kg/day for 90 days (maximum dose 800 mg/day) administered as a suspension. The primary outcome was the difference in mean percent weight change between arms. The median age in the megestrol group was 9.7 years (range 1.1 to 17.8 years) compared to 10.9 years (range 3.9 to 16.2 years) in the placebo arm. At follow-up, the megestrol group (n=13) had a percent weight gain of +19.7% (±15.3%) compared to -1.2% (±4.9%) in the placebo group (n=10), resulting in a mean percent weight change difference of +20.9% (95% CI +11.3 to 30.5%, p=0.003).  All 13 patients who received megestrol developed undetectable morning cortisol levels by the 4-week measurement and there were 2 reported cases of severe adrenal suppression. No other serious adverse effects were reported. The authors concluded that megestrol resulted in significant increases in mean percent weight change in patients, but cautioned widespread adoption of megestrol for appetite stimulation due to adrenal suppression. Limitations of the study include the lack of power and small sample size.

A phase 2 open-label trial performed by Couluris et al (see details of study below) evaluated  megestrol as an option for patients aged 2 to 20 years with cancer-related cachexia who continued to lose weight despite 4 weeks of cyproheptadine use.23 Megestrol acetate was started at 10 mg/kg/day for a 4-week duration. Seven patients were started on megestrol and 6 completed the 4 weeks of therapy. Of those, 5 were deemed responders to megestrol. The average weight gain was 2.5 kg (range 0.6 to 5.9 kg) after 4 weeks. No significant side effects with megestrol were noted.

Cyproheptadine

The study conducted by Couluris et al focused on the efficacy of cyproheptadine as an appetite stimulant in pediatric patients with cancer-related cachexia.23 Children (aged 2 to 20 years) were included if they had a history of weight loss of at least 5%, a drop in growth rate of 2 or more percentile ranks, or a weight for height less than the tenth percentile. Seventy patients were initially started on cyproheptadine at 0.25 mg/kg/day (maximum 20 mg/kg/day) in 2 divided doses for 4 weeks at which time response (defined as unchanged weight, weight loss < 1 percentile, or increased weight) to treatment was evaluated. The median age of the patients was 11.7 years (range 3.2 to 19.4 years). After 4 weeks, 76% (95% confidence interval [CI]: 64% to 85%) of 66 evaluable patients responded to cyproheptadine and the average weight gain was 2.6 kg (range -0.1 to 10 kg, 95% CI: 1.93 to 3.27). There was a significantly higher response rate to cyproheptadine for hematologic malignancies compared to non-hematologic malignancies (91.3% vs 67.4%, p=0.04), however there was not a significant change in weight based on type of malignancy. The most common side effects noted were drowsiness, headache, and dry mouth. Excessive somnolence required discontinuation in 3 patients. The authors concluded that cyproheptadine is safe and efficacious as an appetite stimulant in pediatric cancer patients. Limitations of the study include the short treatment duration, lack of a comparator arm, and lack of long-term follow-up.

Cannabinoids

There are very limited data on the use of cannabinoids in pediatric patients. Podda and colleagues conducted a survey to review cannabinoid use in pediatric patients with cancer.24 Of the 66 patients who responded to the survey, only 21 admitted to using cannabis or cannabinoids during their cancer treatment. Appetite improvement was seen in 48% of the 21 patients using cannabinoids. There are several limitations to this survey including lack of assessment of the type of cannabis used, the amount of cannabis consumed, or if the use was managed by a healthcare provider. Out of concerns for brain development, the American Academy of Pediatrics (AAP) has issued a policy statement against using cannabis in pediatric patients due to the lack of published literature in pediatrics, despite acknowledging that cannabis may be helpful in adults with cancer.25

Conclusion

Appetite stimulants in pediatric cancer patients have been of interest due to the poor outcomes associated with malnutrition and cachexia. The most recent literature suggests that appetite stimulants, like megestrol, cyproheptadine, and cannabinoids, may be efficacious for pediatric patients. However, the literature is very limited and has several weaknesses, such as small patient populations, lack of consistent outcomes, and varied definitions for cancer-related cachexia and malnutrition. There are also no data or guidelines to suggest which therapy is preferred and each of the studied medications carry the risk of side effects such as adrenal suppression with megestrol, excessive somnolence with cyproheptadine, and abnormal brain development with cannabinoids. Prior to the initiation of appetite stimulants, therapies for factors contributing to malnutrition, like constipation, nausea, and depression should be optimized.26 Supplementation of enteral nutrition with a percutaneous endoscopic gastronomy (PEG) tube or initiation of parenteral nutrition, although not ideal, can also be considered.10  Because the evidence is lacking, clinicians should evaluate each patient on a case-by-case basis and consider the potential risk and benefit of using an appetite stimulant.

References

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Prepared by:
Corinne Songer, PharmD
PGY2 Pediatric Pharmacy Resident
University of Illinois at Chicago College of Pharmacy

Edited by:
Rita Soni, PharmD, BCPS
Clinical Assistant Professor, Drug Information Pharmacist
University of Illinois At Chicago College of Pharmacy

January 2021

The information presented is current as of December 17, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.