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Multimodal approach appears promising for treatment of cancer cachexia
Cancer cachexia is a complex, multifactorial metabolic syndrome characterized by weight and muscle loss with or without loss of fat mass.
It occurs in 30% to 80% of patients with cancer, and it is identified as an independent predictor of shorter survival and increased risk for treatment failure and toxicity.
Although the pathogenesis behind cancer cachexia is still not completely known, it is thought that the hypermetabolic state that increases resting energy expenditure is most likely caused from the production of cytokines such as tumor necrosis factor (TNF) alpha, interleukin-6 (IL-6) and IL-1.
Breanne Peyton
Overall, management of this disease state is based on three factors: treating the cancer, nutritional support and pharmacologic treatment to reverse cachectic symptoms.
Many pharmacologic agents have been studied with the hope of finding a drug that will stimulate appetite, promote weight gain and increase lean body mass. The most commonly used agents are corticosteroids and progestogens.
Although corticosteroids stimulate appetite and promote a general well-being in patients, the overall effect is somewhat short-lived and, therefore, is recommended only for short-term use (less than 4 weeks).
Standard therapy
Currently, megestrol acetate is the standard of therapy for cancer cachexia. In clinical trials, it has been shown to stimulate appetite and promote weight gain compared with placebo. In terms of efficacy, megestrol acetate has been shown to be superior to fluoxymesterone and equivalent to dexamethasone. However, dexamethasone was associated with more adverse events. Disadvantages associated with megestrol acetate include cost and increased risk for thromboembolic events.
The use of anabolic steroids has been evaluated because these agents are associated with increasing lean body mass. In trials, fluoxymesterone was shown to be less effective than dexamethasone and megestrol acetate.
Oxandrolone 10 mg/day was shown to increase lean body mass slightly more than megestrol acetate. However, oxandrolone also was associated with a decrease in overall weight (–3.3 lb vs. +5.8 lb with megestrol). Anabolic steroids are controlled substances, and additional disadvantages include adverse effects such as increased lipid changes, hepatotoxicity, fluid retention, masculinization and drug interactions with anticoagulants.
Need for new agents
Due to the lack of selectivity of anabolic androgens, a need for more selective anabolic agents has emerged, resulting in the development of nonsteroidal selective androgen receptor modulators (SARMs). These agents have the potential to elicit beneficial anabolic effects while avoiding many of the side effects observed with steroidal agents.
The SARM furthest into clinical development is enobosarm (Ostarine, GTx). In a clinical trial, patients were randomly assigned to enobosarm 1 mg, enobosarm 3 mg or placebo. Both enobosarm groups showed significant increases in lean body mass compared with placebo.
Two phase 3 trials — POWER 1 and POWER 2 — designed to evaluate enobosarm in patients with non–small cell lung cancer have recently been completed. Although both trials showed increases in lean body mass compared with placebo, they failed to meet the prespecified criteria on lean body mass agreed upon by the FDA. Information regarding enobosarm’s effect on OS is still under investigation. There currently is no drug used for cachexia that has been able to show an OS benefit.
Thalidomide (Thalomid, Celgene) downregulates TNF-alpha and other pro-inflammatory cytokines, making it a rational treatment approach for cancer cachexia. In a small placebo-controlled trial, thalidomide 200 mg/day was found to be effective in slowing weight loss and improving arm muscle mass and physical function in patients with advanced pancreatic cancer.
The combination of thalidomide and megestrol acetate recently was evaluated. Patients assigned to the combination demonstrated significant changes from baseline in body weight, fatigue, quality of life and grip strength, suggesting the combination is more effective than megestrol alone.
Celecoxib (Celebrex, Pfizer), a selective Cox-2 inhibitor, has shown to have potent inhibitory and preventive effects on tumor growth in animal models. In theory, this antineoplastic activity may contribute to the drug’s ability to counteract cachexia.
In a small study conducted to compare celecoxib 200 mg twice daily with placebo, there were increases in body weight (+1 kg vs. –1.3 kg) and BMI (+0.31 kg/mg vs. –0.56 kg/mg) in the celecoxib group. A pilot study evaluated celecoxib 200 mg twice daily in combination with medroxyprogesterone, another progestogen, in 15 patients with cancer.
The addition of celecoxib to medroxyprogesterone stabilized or increased weight gain in 13 patients. Along with improvements in body-weight changes, this combination therapy also improved nausea, fatigue, appetite and performance status.
With evidence supporting cancer cachexia as a multifactorial process, a randomized, phase 3 study was conducted to establish the most effective and safest treatment to improve symptoms of cancer cachexia.
Patients were randomly assigned to one of five treatment arms: a progestogen (megestrol acetate or medroxyprogesterone), eicosapentaenoic acid (EPA), L-carnitine, thalidomide or a combination of the four drugs.
The most effective treatment in all primary endpoints (lean body mass, resting energy expenditure and fatigue) was the combination group. Patients in the combination group also showed improvements in appetite from baseline.
The inflammatory cytokine IL-6 decreased significantly in both the combination and thalidomide arms. Quality of life improved in the L-carnitine, thalidomide and combination groups. Toxicity was comparable between all treatment arms.
Conclusion
Cancer cachexia is a complex multifactorial process revealing to have a hypermetabolic state due to production of TNF-alpha, IL-6 and IL-1.
Megestrol acetate remains the standard of therapy in the treatment of cachexia, with corticosteroids as an option for short-term use. Along with the agents discussed in this article, many promising agents are currently being evaluated in clinical trials. They include mirtazapine, olanzapine, ghrelin mimetics, IL-6 antibodies and insulin. Much research also is being conducted with implementation of many investigational drugs, such as beta-adrenergic agonists, melanocortin antagonists and myostatin inhibitors.
Given the mechanism of cancer cachexia, a more multimodal therapy approach seems to have greater benefit than single-agent treatment. Combination regimens should be tailored to each patient with regard to underlying diseases and ability to comply with multiple drugs. Further studies are needed to determine which agents, both alone and in combination, are most beneficial for the treatment of cancer cachexia.
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For more information:
Breanne Peyton, PharmD, is a PGY-2 oncology resident at the University of Minnesota Medical Center, Fairview. She can be reached at University of Minnesota Medical Center, Fairview, 2450 Riverside Ave., Minneapolis, MN 55454.
Disclosure: Peyton reports no relevant financial disclosures.