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Management of Cancer Cachexia Remains a Challenge
Though cancer cachexia has been researched extensively, it remains challenging to understand and treat.1-5
Cachexia is characterized by loss of appetite, weight, and skeletal muscle.1 Cancer patients with cachexia are more likely to experience fatigue, functional impairment, treatment-related toxicity, and poor survival and quality of life.
Generally, the main consensus diagnostic criterion for cancer cachexia is weight loss exceeding 5% in the previous 6 months.
However, this diagnostic approach should be used with caution in certain patients, according to Kyle Neale, DO, a palliative medicine physician in the department of hematology and medical oncology and medical director of outpatient palliative and supportive care at Cleveland Clinic in Ohio.
In countries with high rates of obesity or in patients with ascites, hypoalbuminemia, or lymphatic derangement, cachexia may be characterized by skeletal muscle loss in the absence of significant weight loss, Dr Neale said.
Underlying Mechanisms
"Cancer cachexia is a complex, multifactorial syndrome that results from a combination of metabolic alterations, systemic inflammation, and decreased appetite," explained Vijaya Surampudi, MD, an assistant professor of medicine in the division of human nutrition at the University of California, Los Angeles (UCLA) School of Medicine and assistant director of the UCLA Weight Management program.
The precise mechanisms involved in cancer cachexia remain unclear, but alterations in hypothalamic control of appetite and satiety cues can lead to cancer-associated weight loss via reductions in food intake.2 In addition, there appears to be a role for cytokine activation in the pathogenesis of cachexia.3
"Cytokine activation leads to an inflammatory response that concludes with anorexia, lipolysis, and skeletal muscle breakdown," Dr Neale said. "Additionally seen are metabolic derangements, including hyperglycemia, hypertriglyceridemia, and insulin resistance, as well as an increase in resting energy expenditure."
In a review published in April 2022, Paval et al examined links between numerous cytokines and cancer cachexia in 17 studies.3 The studies encompassed 1277 patients with incurable cancer and 155 healthy control participants. Cancers of the lung and pancreas were the most common.
The results suggested that levels of interleukin-6 (IL‐6), IL-8, and tumor necrosis factor-α (TNF-α) were higher in patients with cachexia than in healthy control participants. When researchers compared cachetic cancer patients with weight-stable cancer patients, those with cachexia had higher levels of IL-6 and IL-8 but not TNF-α.
There were no significant differences in leptin, interferon‐γ, IL‐1β, IL‐10, adiponectin, or ghrelin when comparing cachetic cancer patients, non-cachetic cancer patients, and healthy control individuals.
Noting the high degree of heterogeneity in the definitions of cachexia, weight-loss thresholds, and methodology used across studies, Paval et al wrote that future research should utilize consistent methodology and longitudinal designs.
Cachexia Management
The initial approach to care in cancer patients with cachexia "should include an assessment of potentially reversible contributors to anorexia, including nausea, pain, thrush, dysgeusia, constipation, dysphagia, and depression," Dr Neale said.
"Treatment of the underlying disease would be the best way to treat cancer cachexia, as it will likely be refractory to nutritional interventions," Dr Surampudi advised.
The 2020 American Society of Clinical Oncology (ASCO) guidelines for managing cancer cachexia discourage routine use of enteral or parenteral nutrition.1 The guidelines do suggest that a time-limited trial of parenteral nutrition may be appropriate for certain patients with other causes of malnutrition, such as reversible bowel obstruction or short bowel syndrome.
"Use of parenteral nutrition still carries risks, including fluid retention, worse mobility, and infection, and should be offered in the context of a patient's goals of care," Dr Neale said. He added that "artificial nutrition, orexigenic medications, and anabolic therapies have not been shown to improve survival or consistently improve quality of life."
Clinical studies investigating the use of orexigenic medications for cancer cachexia have demonstrated mixed results but no improvements in survival.4,5
"Megestrol acetate effectively boosts appetite but increases the risk of thromboembolism, and dexamethasone is similarly effective but also leads to many adverse effects with chronic use," Dr Neale noted.
He added that the management of cachexia "requires a multidisciplinary approach, including oncology, palliative care, nutrition, behavioral health, and social work, among others."
The ASCO guidelines recommend referral to a registered dietitian to provide counseling and support to patients and caregivers.1 Along with advising on safe feeding and nutritional needs, these consultations may help to prevent the use of unproven and potentially harmful approaches such as fad diets and dietary supplements that may increase the risk of adverse drug interactions and otherwise worsen the patient's condition.
Dr Neale recommends that clinicians clarify to patients and caregivers that the goal of therapy for cachexia is improved appetite rather than longevity. The emphasis should be on the significance of eating and sharing food when socializing or providing care to patients.
"Caregivers may feel inadequate if the patient shows impaired intake, or they may contribute to patient distress by haranguing the patient to eat more," Dr Neale said. "Clinicians should normalize the development of anorexia in advanced cancer and encourage eating for taste, socialization, and pleasure."
Disclosures: Dr Neale and Dr Surampudi have no relevant disclosures.
1. Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol. 2020;38(21):2438-2453. doi:10.1200/JCO.20.00611
2. Di Girolamo D, Tajbakhsh S. Pathological features of tissues and cell populations during cancer cachexia. Cell Regen. 2022;11(1):15. doi:10.1186/s13619-022-00108-9
3. Paval DR, Patton R, McDonald J, et al. A systematic review examining the relationship between cytokines and cachexia in incurable cancer. J Cachexia Sarcopenia Muscle. 2022;13(2):824-838. doi:10.1002/jcsm.12912
4. Marceca GP, Londhe P, Calore F. Management of cancer cachexia: Attempting to develop new pharmacological agents for new effective therapeutic options. Front Oncol. 2020;10:298. doi:10.3389/fonc.2020.00298
5. Currow DC, Glare P, Louw S, et al. A randomised, double blind, placebo-controlled trial of megestrol acetate or dexamethasone in treating symptomatic anorexia in people with advanced cancer. Sci Rep. 2021;11(1):2421. doi:10.1038/s41598-021-82120-8
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