Pentoxifylline is a methylxanthine derivative approved by the U.S. Food and Drug Administration for the treatment of intermittent claudication. It can inhibit tumor necrosis factor alpha production, reducing plasma levels of this cytokine, which is thought to be a mediator in cancer-associated anorexia and cachexia (Goldberg et al., 1995). Pentoxifylline was evaluated in anorexia.
Effectiveness Not Established
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.
Research Evidence Summaries
Goldberg, R.M., Loprinzi, C.L., Mailliard, J.A., O'Fallon, J.R., Krook, J.E., Ghosh, C., . . . Shanahan, T.G. (1995). Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology, 13, 2856–2859.
Intervention Characteristics/Basic Study Process:
Patients were randomized, in double-blind fashion, to pentoxifylline 400 mg by mouth three times daily or placebo three times daily. If patients lost 5% of their on-study weight, the bind was broken and patients could cross over to the pentoxifylline arm.
- N = 70 patients (randomized, 35 in each arm)
- ELIGIBILITY CRITERIA: Older than 18 years of age, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, life expectancy greater than three months, weight loss greater than five pounds over two months, estimated calorie intake of less than 20 kcal/kg/d
- EXCLUSION CRITERIA: Parenteral or tube feeding; edema or ascites; use of corticosteroids, androgens, progestational agents, or hydrazine sulfate within one month; mechanical gastrointestinal (GI) obstruction; more than five episodes of emesis per week; primary or metastatic brain tumors; hemoptysis, GI hemorrhage, or Sr. Cr more than two times normal
Patients were stratified by
- Primary tumor site
- Amount of weight loss
- Use of chemotherapy (CDDP versus non-CDDP)
- Sex, ECOG performance status, and MD estimate of survival.
Patients were randomized in a double-blind fashion.
- Objective evidence of weight change (excluded if patient had edema or ascites)
- Questionnaires to evaluate appetite and perceived food intake
No significant difference was seen between cohorts in weight gain (P = .43). According to the questionnaires, there was no evidence that pentoxifylline is more effective than placebo in enhancing appetite. Toxicity data were similar for both groups for nausea and vomiting, fluid retention, and abdominal pain. The study was closed after the planned interim analysis, and it was concluded that pentoxifylline is not an effective treatment for cancer anorexia and cachexia.
The 95% confidence interval for the difference in the percentage of weight gain for pentoxifylline minus placebo ranged from a loss of 3.3% to a gain of 1.9%; this confidence interval suggests that the percentage of weight gain for pentoxifylline-treated patients is about the same for patients receiving placebo.
- Heterogeneous group of patients with cancers arising from a variety of primary sites
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).